PI3 kinase inhibitors in the clinic: an update

The phosphoinositide-3 kinase/protein kinase-B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway has been identified as a key signaling pathway for important cellular functions such as growth control, metabolism and translation initiation. Several proteins within this pathway are valuable anticancer drug targets, among which several inhibitors of mTOR are now administered in routine practice. A better understanding of the structure and functions of PI3K has led to the development of novel inhibitors that have a more favorable toxicity profile as compared to the first generation of anti-PI3K drugs. In this article, we review the basics of PI3K biology and focus on its inhibitors, currently under investigation in clinical trials. The perspective for future directions in the setting of PI3K inhibition and novel trials is also discussed.     

Whole-body (18)F-FDG PET and conventional imaging for predicting outcome in previously treated breast cancer patients.

This study was conducted to determine the ability of (18)F-FDG PET and conventional imaging (CI) to predict the outcomes in breast cancer patients who have previously undergone primary treatment. METHODS: The study population consisted of 61 female patients (median age, 54 y; range, 32--91 y) who were reevaluated with (18)F-FDG PET and CI after treatment. The median interval between the last treatment and PET was 0.4 y (range, 0--16 y). PET was performed within 3 mo of CI (median interval, 25 d; range, 2--84 d). To determine the independent impact of PET on outcome, PET images were reinterpreted in a blind fashion. Availability of clinical information after PET scanning (21 plus minus 12 mo) was required for study inclusion. Study endpoints were clinical evidence of progression of disease or death. RESULTS: Of 61 patients, 19 (31.1%) had no clinical evidence and 38 (62.3%) had evidence of residual or recurrent disease by the end of follow-up. Four patients (6.6%) had died. The positive and negative predictive values (PPV and NPV, respectively) of PET were 93% and 84%, respectively. CI yielded a PPV of 85% and an NPV of 59%. The prognostic accuracy of single whole-body PET was superior to that of multiple procedures with CI (90% vs. 75%; P < 0.05). Kaplan--Meier estimates of disease-free survival in patients with negative PET findings compared with those with positive PET findings revealed a significant difference between the 2 curves (log-rank test = 0.001). Kaplan--Meier estimates of disease-free survival stratified by CI results showed a marginally significant difference between CI-positive and CI-negative patients (log-rank test = 0.04). CONCLUSION: FDG PET can be used to improve prediction of the clinical outcome of previously treated breast cancer patients relative to what is achievable through CI alone.     

Effect of (18)F-FDG PET/CT imaging in patients with clinical Stage II and III breast cancer

PURPOSE: To investigate the potential effect of using (18)F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) in the initial assessment of patients with clinical Stage II or III breast cancer. METHODS AND MATERIALS: During 14 consecutive months, 39 patients (40 tumors) who presented with Stage II or III breast cancer on the basis of a routine extension assessment were prospectively included in this study. PET/CT was performed in addition to the initial assessment. RESULTS: In 3 cases, PET/CT showed extra-axillary lymph node involvement that had not been demonstrated with conventional techniques. Two of these patients had hypermetabolic lymph nodes in the subpectoral and infraclavicular regions, and the third had a hypermetabolic internal mammary node. PET/CT showed distant uptake in 4 women. Of these 4 women, 1 had pleural involvement and 3 had bone metastasis. Overall, of the 39 women, the PET/CT results modified the initial stage in 7 (18%). The modified staging altered the treatment plan for 5 patients (13%). It led to radiotherapy in 4 patients (bone metastasis, pleural lesion, subpectoral lymph nodes, and internal mammary nodes) and excision of, and radiotherapy to, the infraclavicular lymph nodes in 1 patient. CONCLUSIONS: PET/CT can provide information on extra-axillary lymph node involvement and can uncover occult distant metastases in a significant percentage of patients. Therefore, initial PET/CT could enable better treatment planning for patients with Stage II and III breast cancer.     

Spinal anesthesia-induced hypotension: a risk comparison between patients with severe preeclampsia and healthy women undergoing preterm cesarean delivery

We previously showed that, in comparison with term healthy parturients, patients with severe preeclampsia had a less frequent incidence of spinal hypotension, which was less severe and required less ephedrine. In the present study, we hypothesized that these findings were attributable to preeclampsia-associated factors rather than to a smaller uterine mass. The incidence and severity of hypotension were compared between severe preeclamptics (n = 65) and parturients with preterm pregnancies (n = 71), undergoing spinal anesthesia for cesarean delivery (0.5% bupivacaine, sufentanil, morphine). Hypotension was defined as the need for ephedrine (systolic blood pressure <100 mm Hg in parturients with preterm fetuses or 30% decrease in mean blood pressure in both groups). Apgar scores and umbilical arterial blood pH were also studied. Neonatal and placental weights were similar between the groups. Hypotension was less frequent in preeclamptic patients than in women with preterm pregnancies (24.6% versus 40.8%, respectively, P = 0.044). Although the magnitude of the decrease in systolic, diastolic, and mean arterial blood pressure was similar between groups, preeclamptic patients required less ephedrine than women in the preterm group to restore blood pressure to baseline levels (9.8 +/- 4.6 mg versus 15.8 +/- 6.2 mg, respectively, P = 0.031). The risk of hypotension in the preeclamptic group was almost 2 times less than that in the preterm group (relative risk = 0.603; 95% confidence interval, 0.362-1.003; P = 0.044). The impact of Apgar scores was minor, and umbilical arterial blood pH was not affected. We conclude that preeclampsia-associated factors, rather than a smaller uterine mass, account for the infrequent incidence of spinal hypotension in preeclamptic patients.     

Diffuse primary angiosarcoma of the pleura: a case report and review of the literature

Primary pleural angiosarcoma is an extremely rare tumor. We report the case of a patient who presented with recurrentmassive bilateral hemothoraxes. Although thoracoscopy was performed, biopsy samples of the pleura were inconclusive.The delayed onset of skin metastases led to the diagnosis of angiosarcoma, however the patient died from pleuropulmonaryprogression before treatment could be started. We review the literature of primary pleuropulmonary angiosarcoma anddiscuss its treatment modalities.     

Patients with severe preeclampsia experience less hypotension during spinal anesthesia for elective cesarean delivery than healthy parturients: a prospective cohort comparison

In this prospective cohort study, we compared the incidence and severity of spinal anesthesia (SA)-associated hypotension in severely preeclamptic (n = 30) versus healthy (n = 30) parturients undergoing cesarean delivery. After the administration of IV fluids, SA was performed with hyperbaric 0.5% bupivacaine, sufentanil, and morphine. Blood pressure (BP) was recorded before and at 2-min intervals for 30 min after SA. Clinically significant hypotension was defined as the need for ephedrine (systolic BP decrease to <100 mm Hg in healthy parturients or 30% decrease in mean BP in both groups). Despite receiving a smaller fluid volume (1653 +/- 331 mL versus 1895 +/- 150 mL; P = 0.005) and a larger bupivacaine dose (10.5 +/- 0.9 mg versus 10.0 +/- 0.7 mg; P = 0.019), the severely preeclamptic patients had a less frequent incidence of clinically significant hypotension (16.6% versus 53.3%; P = 0.006), which was less severe and required less ephedrine. The risk of hypotension was almost six times less in severely preeclamptic patients (odds ratio, 0.17; 95% confidence interval, 0.05-0.58; P = 0.006) than that in healthy patients.