Citations

Abstract Purpose: PI3K/AKT pathway activation is an important endocrine resistance mechanism in estrogen receptor–positive (ER+) breast cancer. After promising preclinical modeling of MK-2206, an allosteric pan-AKT inhibitor, with either estrogen deprivation or fulvestrant, we conducted a phase I trial in patients with metastatic ER+HER2− breast cancer to determine the recommended phase II treatment dose (RPTD) of MK-2206 when combined with either anastrozole, fulvestrant, or anastrozole/fulvestrant. Experimental Design: ER+ breast cancer cell lines were exposed in vitro to MK-2206 plus estrogen deprivation with or without fulvestrant and monitored for apoptosis. A standard 3+3 design was employed to first determine the maximum tolerated dose (MTD) of MK-2206 plus anastrozole based on cycle 1 toxicity. Each cycle was 28 days. The RPTD was determined on the basis of toxicities observed at MTD level during the first 3 cycles. Subsequent patients received MK-2206, at the RPTD determined above, plus fulvestrant or anastrozole/fulvestrant to define RPTD for these additional regimens. Results: MK-2206 induced apoptosis in parental ER+ but not in long-term estrogen-deprived cell lines, for which fulvestrant was required for apoptosis induction. Thirty-one patients enrolled. The RPTD was defined as MK-2206 150 mg orally weekly with prednisone prophylaxis for each combination. Grade 3 rash was dose limiting. 42% (95% CI, 23%–63%) patients derived clinical benefit without progression within 6 months. Response was not associated with tumor PIK3CA mutation. Conclusions: MK-2206 plus endocrine treatments were tolerable. MK-2206 in combination with anastrozole is being further evaluated in a phase II neoadjuvant trial for newly diagnosed ER+HER2− breast cancer. Clin Cancer Res; 22(11); 2650–8. ©2016 AACR. See related commentary by Jansen et al., p. 2599

Study Design Retrospective study. Objective This study reviews 1,768 consecutive cervical decompressions with or without instrumented fusion to identify patient-specific and procedural risk factors significantly correlated with the development of delayed cervical palsy (DCP). Methods Baseline demographic and procedural information was collected from the electronic medical record. Particular attention was devoted to reviewing each chart for recognized risk factors of postsurgical inflammatory neuropathy: autoimmune disease, blood transfusions, diabetes, and smoking. Results Of 1,669 patients, 56 (3.4%) developed a DCP. Although 71% of the palsies involved C5, 55% of palsies were multimyotomal and 18% were bilateral. Significant risk factors on univariate analysis included age ( p = 0.0061, odds ratio [OR] = 1.07, 95% confidence interval [CI] 1.008 to 1.050), posterior instrumented fusion ( p < 0.0001, OR = 3.30, 95% CI 1.920 to 5.653), prone versus semisitting/sitting position ( p = 0.0036, OR = 3.58, 95% CI 1.451 to 11.881), number of operative levels ( p < 0.0001, OR = 1.42, 95% CI 1.247 to 1.605), intraoperative transfusions ( p = 0.0231, OR = 2.57, 95% CI 1.152 to 5.132), and nonspecific autoimmune disease ( p = 0.0107, OR = 3.83, 95% CI 1.418 to 8.730). On multivariate analysis, number of operative levels ( p = 0.0053, OR = 1.27, 95% CI 1.075 to 1.496) and nonspecific autoimmune disease ( p = 0.0416, OR 2.95, 95% CI 1.047 to 7.092) remained significant. Conclusions Although this study partially supports a mechanical etiology in the pathogenesis of a DCP, we also describe a notable correlation with autoimmune risk factors. Bilateral and multimyotomal involvement provides additional support that some DCPs may result from an inflammatory response and thus an underlying multifactorial etiology for this complication.

OBJECT A chordoma is an indolent primary spinal tumor that has devastating effects on the patient's life. These lesions are chemoresistant, resistant to conventional radiotherapy, and moderately sensitive to proton therapy; however, en bloc resection remains the preferred treatment for optimizing patient outcomes. While multiple small and largely retrospective studies have investigated the outcomes following en bloc resection of chordomas in the sacrum, there have been few large-scale studies on patients with chordomas of the mobile spine. The goal of this study was to review the outcomes of surgically treated patients with mobile spine chordomas at multiple international centers with respect to local recurrence and survival. This multiinstitutional retrospective study collected data between 1988 and 2012 about prognosis-predicting factors, including various clinical characteristics and surgical techniques for mobile spine chordoma. Tumors were classified according to the Enneking principles and analyzed in 2 treatment cohorts: Enneking-appropriate (EA) and Enneking-inappropriate (EI) cohorts. Patients were categorized as EA when the final pathological assessment of the margin matched the Enneking recommendation; otherwise, they were categorized as EI. METHODS Descriptive statistics were used to summarize the data (Student t-test, chi-square, and Fisher exact tests). Recurrence and survival data were analyzed using Kaplan-Meier survival curves, log-rank tests, and multivariate Cox proportional hazard modeling. RESULTS A total of 166 patients (55 female and 111 male patients) with mobile spine chordoma were included. The median patient follow-up was 2.6 years (range 1 day to 22.5 years). Fifty-eight (41%) patients were EA and 84 (59%) patients were EI. The type of biopsy (p < 0.001), spinal location (p = 0.018), and if the patient received adjuvant therapy (p < 0.001) were significantly different between the 2 cohorts. Overall, 58 (35%) patients developed local recurrence and 57 (34%) patients died. Median survival was 7.0 years postoperative: 8.4 years postoperative for EA patients and 6.4 years postoperative for EI patients (p = 0.023). The multivariate analysis showed that the EI cohort was significantly associated with an increased risk of local recurrence in comparison with the EA cohort (HR 7.02; 95% CI 2.96–16.6; p < 0.001), although no significant difference in survival was observed. CONCLUSIONS EA resection plays a major role in decreasing the risk for local recurrence in patients with chordoma of the mobile spine.

OBJECT Endoscopic approaches to the anterior craniocervical junction are increasing in frequency. Choice of oral versus endoscopic endonasal approach to the odontoid often depends on the relationship of the C1–2 complex to the hard palate. However, it is not known how this relevant anatomy changes with age. We hypothesize that there is a dynamic relationship of C-2 and the hard palate, which changes with age, and potentially affects the choice of surgical approach. The aim of this study was to characterize the relationship of C-2 relative to the hard palate with respect to age and sex. METHODS Emergency department billing and trauma records from 2008 to 2014 were reviewed for patients of all ages who underwent cervical or maxillofacial CT as part of a trauma evaluation for closed head injury. Patients who had a CT scan that allowed adequate visualization of the hard palate, opisthion, and upper cervical spine (C-1 and C-2) were included. Patients who had cervical or displaced facial/skull base fractures, a history of rheumatoid arthritis, or craniofacial anomalies were excluded. The distance from McGregor's palatooccipital line to the midpoint of the inferior endplate of C-2 (McL–C2) was measured on midsagittal CT scans. Patients were grouped by decile of age and by sex. A 1-way ANOVA was performed with each respective grouping. RESULTS Ultimately, 483 patients (29% female) were included. The mean age was 46 ± 24 years. The majority of patients studied were in the 2nd through 8th decades of life (85%). Significant variation was found between McL–C2 and decile of age (p < 0.001) and sex (p < 0.001). The mean McL–C2 was 27 mm in the 1st decade of life compared with the population mean of 37 mm. The mean McL–C2 was also noted to be smaller in females (mean difference 4.8 mm, p < 0.0001). Both decile of age (p = 0.0009) and sex (p < 0.0001) were independently correlated with McL–C2 on multivariate analysis. CONCLUSIONS The relationship of C-2 and the hard palate significantly varies with respect to age and sex, descending relative to the hard palate a full centimeter on average in adulthood. These findings may have relevance in determining optimal surgical approaches for addressing pathology involving the anterior craniocervical junction.

Study Design Review of the literature. Objective Surgery and cement augmentation procedures are effective palliative treatment of symptomatic spinal metastases. Our objective is to systematically review the literature to describe the survival, prognostic factors, and clinical outcomes of surgery and cement augmentation procedures for breast cancer metastases to the spine. Methods We performed a literature review using PubMed to identify articles that reported outcomes and/or prognostic factors of the breast cancer patient population with spinal metastases treated with any surgical technique since 1990. Results The median postoperative survival for metastatic breast cancer was 21.7 months (8.2 to 36 months), the mean rate of any pain improvement was 92.9% (76 to 100%), the mean rate of neurologic improvement was 63.8% (53 to 100%), the mean rate of neurologic decline was 4.1% (0 to 8%), and the local tumor control rate was 92.6% (89 to 100%). Kyphoplasty studies reported a high rate of pain control in selected patients. Negative prognostic variables included hormonal (estrogen and progesterone) and human epidermal growth factor receptor 2 (HER2) receptor refractory tumor status, high degree of axillary lymph node involvement, and short disease-free interval (DFI). All other clinical or prognostic parameters were of low or insufficient strength. Conclusion With respect to clinical outcomes, surgery consistently yielded neurologic improvements in patients presenting with a deficit with a minimal risk of worsening; however, negative prognostic factors associated with shorter survival following surgery include estrogen receptor/progesterone receptor negativity, HER2 negativity, and a short DFI.