Pre-surgical trial of the AKT inhibitor MK-2206 in patients with operable invasive breast cancer: a New York Cancer Consortium trial

Introduction: The PI3K/AKT/mTOR pathway is an oncogenic driver in breast cancer (BC). In this multi-center, pre-surgical study, we evaluated the tissue effects of the AKT inhibitor MK-2206 in women with stage I-III BC. Materials and methods: Two doses of weekly oral MK2206 were administered at days − 9 and − 2 before surgery. The primary endpoint was reduction of pAktSer473 in breast tumor tissue from diagnostic biopsy to surgery. Secondary endpoints included changes in PI3K/AKT pathway tumor markers, tumor proliferation (ki-67), insulin growth factor pathway blood markers, pharmacokinetics (PK), genomics, and MK-2206 tolerability. Paired t tests were used to compare biomarker changes in pre- and post-MK-2206, and two-sample t tests to compare with prospectively accrued untreated controls. Results: Despite dose reductions, the trial was discontinued after 12 patients due to grade III rash, mucositis, and pruritus. While there was a trend to reduction in pAKT after MK-2206 (p = 0.06), there was no significant change compared to controls (n = 5, p = 0.65). After MK-2206, no significant changes in ki-67, pS6, PTEN, or stathmin were observed. There was no significant association between dose level and PK (p = 0.11). Compared to controls, MK-2206 significantly increased serum glucose (p = 0.02), insulin (p < 0.01), C-peptide (p < 0.01), and a trend in IGFBP-3 (p = 0.06). Conclusion: While a trend to pAKT reduction after MK-2206 was observed, there was no significant change compared to controls. However, the accrued population was limited, due to toxicity being greater than expected. Pre-surgical trials can identify in vivo activity in the early drug development, but side effects must be considered in this healthy population

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Pre-surgical trial of the AKT inhibitor MK-2206 in patients with operable invasive breast cancer: a New York Cancer Consortium trial.

INTRODUCTION: The PI3K/AKT/mTOR pathway is an oncogenic driver in breast cancer (BC). In this multi-center, pre-surgical study, we evaluated the tissue effects of the AKT inhibitor MK-2206 in women with stage I-III BC. MATERIALS AND METHODS: Two doses of weekly oral MK2206 were administered at days - 9 and - 2 before surgery. The primary endpoint was reduction of pAktSer473 in breast tumor tissue from diagnostic biopsy to surgery. Secondary endpoints included changes in PI3K/AKT pathway tumor markers, tumor proliferation (ki-67), insulin growth factor pathway blood markers, pharmacokinetics (PK), genomics, and MK-2206 tolerability. Paired t tests were used to compare biomarker changes in pre- and post-MK-2206, and two-sample t tests to compare with prospectively accrued untreated controls. RESULTS: Despite dose reductions, the trial was discontinued after 12 patients due to grade III rash, mucositis, and pruritus. While there was a trend to reduction in pAKT after MK-2206 (p = 0.06), there was no significant change compared to controls (n = 5, p = 0.65). After MK-2206, no significant changes in ki-67, pS6, PTEN, or stathmin were observed. There was no significant association between dose level and PK (p = 0.11). Compared to controls, MK-2206 significantly increased serum glucose (p = 0.02), insulin (p < 0.01), C-peptide (p < 0.01), and a trend in IGFBP-3 (p = 0.06). CONCLUSION: While a trend to pAKT reduction after MK-2206 was observed, there was no significant change compared to controls. However, the accrued population was limited, due to toxicity being greater than expected. Pre-surgical trials can identify in vivo activity in the early drug development, but side effects must be considered in this healthy population.

Treatment of early breast cancer.

Surgical intervention for breast cancer has continually evolved. The current review reports on updates from the pivotal trials, examines areas of controversy, and explores possible future directions.

[Computer-assisted occlusal finishing]. / Les finitions occlusales assistées par ordinateur.

The finishing of a fixed appliance case is one of the greatest challenges in our specialty and is playing an ever-increasing role in treatment considerations as patients become more demanding. The quality of the finishing is, in fact, often seen as an indicator of the orthodontist's skills. The finishing of a lingual case is subject to exceptionally exacting requirements. This often leads not only to longer chair times towards the end of the treatment but to longer treatment times overall. The procedure described in this article permits high-quality finishing with no greater clinical resource input than with conventional labial appliances. Five essential factors are presented and discussed.

Brain hemodynamic changes in preterm infants after maintenance dose caffeine and aminophylline treatment.

OBJECTIVE: To investigate the acute effects of low-dose caffeine and aminophylline on cerebral blood flow in preterm infants, using both near-infrared spectroscopy (NIRS) and cerebral Doppler ultrasonography. METHODS: Preterm infants with a gestational age of <32 weeks and birth weight of <1,500 g were randomized to receive either caffeine or aminophylline treatment for apnea of prematurity. The study period went from 30 min before to 60 min after the administration of the maintenance dose of pure caffeine (2.5 mg/kg once a day) or aminophylline (1.25 mg/kg twice a day). NIRS was used to measure changes in oxygenated hemoglobin (O(2)Hb), deoxygenated hemoglobin (HHb), oxidized-reduced cytochrome aa3 (CtOx), and mean cerebral oxygen saturation (SmO(2) = O(2)Hb/total Hb). Changes in cerebral blood volume (DeltaCBV) after caffeine or aminophylline administration were calculated. Cerebral blood flow velocity (CBV) in the pericallosal artery was evaluated by cerebral Doppler ultrasounds. RESULTS: Data collected by NIRS and cerebral Doppler ultrasounds did not show significant differences before and after caffeine treatment. We observed a significant increase in O(2)Hb and HHb concentration and in CBV at 30 min after the infusion of aminophylline, which tended to return to baseline at the end of the study period. CONCLUSION: Caffeine does not significantly affect brain hemodynamics, while aminophylline induces a significant transient increase in O(2)Hb and HHb concentration and CBV.

Changes in mesenteric blood flow response to feeding: conventional versus fiber-optic phototherapy.

OBJECTIVE: To evaluate whether fiberoptic phototherapy influences the postprandial increase in mesenteric blood flow velocity similarly to conventional phototherapy in preterm infants. PATIENTS AND METHODS: With the use of Doppler color ultrasonography, blood flow velocity in the superior mesenteric artery was measured both preprandially and postprandially in 19 preterm infants during and after conventional phototherapy, and in 20 preterm infants during and after fiber-optic phototherapy. The mean arterial blood pressure/mean flow velocity ratio was calculated as an estimate of relative vascular resistance of the superior mesenteric artery. RESULTS: The study shows that conventional phototherapy blunts the postprandial mesenteric blood flow response to feeding in preterm infants. Furthermore, it shows that the postprandial increase in intestinal blood flow is not attenuated when fiber-optic phototherapy is administered, and that such postprandial increase of blood flow is significantly greater than in infants receiving conventional phototherapy. During and after fiber-optic phototherapy, a significant reduction in postprandial relative vascular resistance was found; such reduction was significantly greater than during conventional phototherapy. CONCLUSIONS: Fiber-optic phototherapy is preferable to conventional phototherapy for the treatment of hyperbilirubinemia in preterm infants because it does not affect the physiologic postprandial redistribution of blood flow from the periphery to the gastrointestinal system as does conventional phototherapy.

Risk factors for the development of respiratory distress syndrome and transient tachypnoea in newborn infants. Italian Group of Neonatal Pneumology.

Respiratory distress syndrome (RDS) and transient tachypnoea (TT) are the most frequent acute respiratory diseases in the newborn. This study investigated the risk factors for RDS and TT in newborn infants. A population of 63,537 newborns was enrolled in a 12-month survey in Italy, 734 (1.15%) affected by RDS and 594 (0.93%) affected by TT. Multivariate regression analysis of maternal and perinatal data and the calculation of odds ratios (with 95% confidence intervals) were performed. It was demonstrated that gestational age, birthweight, maternal age, elective and emergency caesarean section (CS), and male sex were risk factors for RDS, while gestational age, maternal diseases, twinning, birthweight, operative vaginal delivery, elective and emergency CS, and male sex were risk factors for TT. The data confirm previous reports and demonstrate that advanced maternal age is a risk factor for RDS, while ruling out maternal diseases as independent risk factors for RDS.

Acute neonatal respiratory distress in Italy: a one-year prospective study. Italian Group of Neonatal Pneumology.

A prospective multicentre 12-month survey of neonatal respiratory disorders in 63 537 Italian infants was performed to evaluate the incidence of acute neonatal respiratory disorders and of the main related complications. A total of 1427 developed respiratory disorders (2.2%), 208 of whom died (14.6%). The incidence of respiratory distress syndrome was 1.16%, with a case fatality rate (CFR) of 24%; that of transient tachypnoea was 0.93%, with a CFR of 1.3%. The rates of meconium aspiration syndrome, persistent pulmonary hypertension and pneumonia were 0.06%, 0.02% and 0.07%, with CFRs of 10.3%, 38.5% and 21.7%, respectively. The occurrences of the main complications in affected newborns were: bronchopulmonary dysplasia 5.6%, necrotizing enterocolitis 1.7%, patent ductus arteriosus 9.8%, 3 degrees and 4 degrees grade intraventricular haemorrhage 6.8% and air leak 4.9%. It was concluded that the incidence of acute neonatal respiratory disorders and the main related complications was lower than that reported two decades ago and that the CFR of acute neonatal respiratory disorders had increased. These results may be the consequences of (i) progress in the management of high-risk pregnancies, (ii) an increased number of viable infants with extremely low birth weight and (iii) diffusion of antenatal treatment with corticosteroids which, in this series, seemed to reduce the morbidity but not the mortality in the high-risk infants.