Dual inhibition of the TrkA and JAK2 pathways using entrectinib and pacritinib suppresses the growth and metastasis of HER2-positive and triple-negative breast cancers.

HER2-positive and triple-negative breast cancers (TNBC) are difficult to treat and associated with poor prognosis. Despite showing initial response, HER2-positive breast cancers often acquire resistance to HER2-targeted therapies, and TNBC lack effective therapies. To overcome these clinical challenges, we evaluated the therapeutic utility of co-targeting TrkA and JAK2/STAT3 pathways in these breast cancer subtypes. Here, we report the novel combination of FDA-approved TrkA inhibitors (Entrectinib or Larotrectinib) and JAK2 inhibitors (Pacritinib or Ruxolitinib) synergistically inhibited in vitro growth of HER2-positive breast cancer cells and TNBC cells. The Entrectinib-Pacritinib combination inhibited the breast cancer stem cell subpopulation, reduced expression of stemness genes, SOX2 and MYC, and induced apoptosis. The Entrectinib-Pacritinib combination suppressed orthotopic growth of HER2-positive Trastuzumab-refractory breast cancer xenografts and basal patient-derived xenograft (PDXs), reduced tumoral SOX2 and MYC, and induced apoptosis in both mouse models. The Entrectinib-Pacritinib combination inhibited overall metastatic burden, and brain and bone metastases of intracardially inoculated TNBC cells without toxicity. Together, our results demonstrate for the first time that co-inhibition of TrkA and JAK2 synergistically suppresses breast cancer growth and metastasis, thereby providing preclinical evidence that supports future clinical evaluations.

Cerebrovascular Complications Associated With Iatrogenic Fungal Meningitis Following Surgical Procedures in Mexico.

BACKGROUND: The current fungal meningitis outbreak caused by contaminated epidural anesthesia with Fusarium solani among patients who underwent surgical procedures in Matamoros, Mexico remains a cause of concern. Its association with an increased susceptibility for cerebrovascular complications (CVC) has not been reported. This single-center study describes 3 patients with a unique pattern of CVC attributed to fungal meningitis. METHODS: A retrospective case series of patients diagnosed with fungal meningitis following surgical procedures under contaminated epidural anesthesia who developed a unique pattern of CVC during their hospitalization. RESULTS: Three female patients (mean age, 35 years) with CVC due to iatrogenic fungal meningitis were included. Positive Fungitell ß-D-glucan assay in cerebrospinal fluid was documented in all cases, and F. solani was confirmed by polymerase chain reaction in case 3. All cases were complicated by severe vertebrobasilar circulation vasculopathy and arterial dissections with resultant subarachnoid hemorrhage and intraventricular hemorrhage, ultimately leading to patients' death. CONCLUSIONS: The death toll from the ongoing fungal meningitis outbreak keeps rising, underscoring the need for early recognition and aggressive treatment. We highlight the risk for vertebrobasilar circulation CVC among these patients. The angioinvasive nature of F. solani is yet to be clarified; however, a clear pattern has been observed. Public health awareness should be raised and a strong response should be pursued.

Noninstrumented Free Fibula Flap for Cervical Osteomyelitis.

BACKGROUND AND IMPORTANCE: Severe cases of cervical vertebral osteomyelitis can pose a challenge regarding reconstruction, stability/alignment, and infection eradication. Here we describe the application of vascularized free fibula (FF) flaps to reconstruct the cervical spine without instrumentation in the setting of severe osteomyelitis. CLINICAL PRESENTATION: Two patients presented with symptomatic multilevel cervical osteomyelitis. Both patients were treated with corpectomy and FF flap without instrumentation using a novel wedging and distraction technique to secure the flap into position. Clinical outcomes were based on neurological recovery and infection management. Computed tomography (CT) and CT angiography with 3-dimensional reconstruction were used to measure fusion status and patency of the anastomoses. CT of the cervical spine completed 8 weeks postoperatively demonstrated robust fusion of the fibula flaps to adjacent cervical vertebrae. In both patients, CT angiography demonstrated patency of the arterial anastomoses. Both flaps maintained persistent deformity correction. Both patients made full neurological recovery. DISCUSSION: This reconstructive approach represents a salvage technique that offers advantages in cases of prior hardware failure or unfavorable host factors with rapid fusion and definitive treatment with a single surgery. CONCLUSION: The use of FF flap without instrumentation seems to be a safe and effective option for cervical spine reconstruction in the setting of severe osteomyelitis.

Factors Associated With Pregnancy and Perinatal Outcomes in Female Neurosurgeons: A Cross-Sectional Study.

Neurosurgery is male dominated with women representing only 12% of residents and 5% of practicing neurosurgeons. The conflicting demands of training versus pregnancy and motherhood are significant deterrents to women entering the field. We examined pregnancy incidence and timing, perinatal complications, and the perceived career impact of motherhood on female neurosurgeons using an anonymous survey of 643 training, practicing, and retired female neurosurgeons from the United States. Among 260 respondents, 50.8% (132/260) reported pregnancies, with an average age at first pregnancy that was significantly higher than the national average (32.1 vs 26.3 yr). In all, 40.1% (53/132) of respondents reported perinatal complications in at least one of their pregnancies. Only 25% (33/132) of respondents noted designated program maternity allowances. The most significant challenges associated with being a mother and neurosurgeon reported were issues relating to work/life balance, "mommy guilt," and sleep deprivation. A majority of respondents, 70.1% (82/116), reported fear of backlash from co-residents, partners, and staff, as well as hindered career advancement related to childbearing. Female neurosurgeons face challenges surrounding family planning different from those faced by male practitioners. Higher perinatal and fetal complications, backlash from colleagues, and demanding workload are significant issues. Progress requires institutional support and mentorship for women to create a more diverse field of practitioners.

Predictors of survival in metastatic melanoma patients with leptomeningeal disease (LMD).

PURPOSE: Although the survival of most melanoma patients diagnosed with leptomeningeal disease (LMD) is short, some patients can have better outcomes and prolonged survival. A large retrospective cohort of patients was analyzed to identify features associated with survival with LMD from melanoma. METHODS: Clinical characteristics, treatments and survival were collected for melanoma patients diagnosed with LMD from 1999 to 2015. The Kaplan-Meier method was used to estimate overall survival (OS) and Cox proportional hazards regression was used to test statistical significance of associations with survival. Multivariate analysis was performed using Cox proportional regression modeling. RESULTS: 178 melanoma patients with LMD were identified. Median age at LMD diagnosis was 51 years. Most (n = 153) patients received at least one treatment for LMD, including radiation (n = 98), chemotherapy (n = 89), targeted therapy (n = 60), immunotherapy (n = 12), or intrathecal (IT) therapy (n = 64). Median OS from LMD diagnosis was 3.5 months. One-, two-, and five-year OS rates were 22%, 14%, and 9%, respectively. Factors significantly associated with OS on multivariate analysis included Eastern Cooperative Oncology Group [ECOG] performance status > 0 (HR 2.1, P < 0.0001); neurological symptoms (HR 1.6, P < 0.0001); absent systemic disease (HR 0.4, P < 0.0001); and LMD treatment (HR 0.4, P = 0.0024), targeted therapy (HR 0.6, P = 0.0060), or IT therapy (HR 0.5, P = 0.0019). CONCLUSION: Despite their overall poor prognosis a subset of melanoma patients with LMD achieve longer survival. The factors associated with outcomes may be used to guide patient management and to inform the design of future clinical trials for this population.

Noninstrumented Lumbar Fusion with Bone Morphogenetic Proteins for Spinal Stenosis with Spondylolisthesis in the Elderly.

OBJECTIVE: This study examined the use of noninstrumented posterolateral lumbar fusion with bone morphogenetic protein (BMP) and compared its effectiveness with that of instrumented fusion for the treatment of lumbar spinal stenosis (LSS) with spondylolisthesis in elderly patients. METHODS: This study was a retrospective review of 93 patients treated in a single-surgeon neurosurgical private practice over a 15-year period. Fifty-nine patients over the age of 65 who underwent noninstrumented posterolateral fusion with rhBMP-2 (Infuse) for LSS with spondylolisthesis were compared with 34 patients who underwent instrumented fusion without rhBMP-2. Outcomes in terms of reoperation rate, pain improvement, Oswestry Disability Index (ODI) score, and number of extra follow-up visits due to persistent problems were characterized by the use of t tests and χ2 tests. RESULTS: The reoperation rate in the noninstrumented rhBMP-2 fusion group was significantly lower than in the instrumented fusion group (17.6% vs. 3.4%, P = 0.048). The mean pain improvement was significantly higher in the noninstrumented rhBMP-2 group at 3 months (8.1 vs. 6.0, P < 0.001, 95% confidence interval [CI] 1.2 to 3.0) and at 1 year (7.25 vs. 5.6, P = 0.030, 95% CI 0.3 to 3.1). The ODI score improvement was significantly higher in the noninstrumented rhBMP-2 group (51 vs. 42.8, P < 0.001, 95% CI 4.7 to 11.6). The mean number of additional follow-up visits per patient was significantly lower in the noninstrumented rhBMP-2 group (0.068 vs. 1.23, P < 0.001, 95% CI 0.59 to 1.75). CONCLUSION: Noninstrumented posterolateral lumbar fusion with rhBMP-2 in elderly patients with LSS and spondylolisthesis is a viable alternative to instrumented fusion based on clinical outcomes measured in this study.

Hypoglossal schwannomas: A systematic review of the literature.

BACKGROUND: Schwannomas of the hypoglossal nerve are rare and account for a very small percentage of non-vestibular schwannomas. OBJECTIVES: In this systematic review of the literature, we examined the epidemiology, symptomatology, management, and outcomes of patients with hypoglossal schwannomas. METHODS: The electronic database Pubmed was searched for all reports of hypoglossal schwannomas with descriptions of symptoms, management, and outcome characteristics. Data was extracted from each study and compiled in a spreadsheet. Continuous variables were reported as means and medians. Categorical variables were reported as proportions. Additional analysis was not done due to inconsistent reporting of outcomes and small sample sizes. RESULTS: A total of 59 studies (94 total individual cases) were included. 64% of patients were female with mean age of 44.6 years. The majority were intracranial/extracranial (50%). The most common symptoms were tongue deviation or speech disturbance (38%) and headaches (33%). Hypoglossal nerve dysfunction was present in 80% of patients. Surgical excision was performed in 93%, with a 15% complication rate. Evidence of residual mass after surgery was noted in 29%. Permanent hypoglossal nerve deficits occurred in 67%. Recurrence of tumor burden was reported in 6 studies, with median time to recurrence of 16.5 months. CONCLUSION: Current evidence suggests overall favorable outcomes with surgical resection of hypoglossal schwannomas, with a large percentage of patients experiencing mild and usually well-tolerated neurologic deficit. Limitations of this study include the use of retrospective data taken from case reports/series with highly selected patients, selective reporting, and absence of control groups.

Neoadjuvant Stereotactic Radiosurgery Before Surgical Resection of Cerebral Metastases.

OBJECTIVE: Stereotactic radiosurgery (SRS) has redefined the treatment paradigm for cerebral metastases. The benefits of SRS after surgical resection of a metastatic brain tumor have been well-defined. However, it is unclear whether preoperative SRS can improve the outcomes in select patients. The present study examined the safety and efficacy of preoperative neoadjuvant SRS (NaSRS) for the treatment of cerebral metastases. METHODS: We performed a retrospective review of 12 patients treated at The University of Texas Southwestern Medical Center. All patients underwent NaSRS, followed by surgical resection of a cerebral metastasis, from 2011 to 2015. Recurrence and overall survival were characterized using Kaplan-Meier and log-rank analyses. RESULTS: The mean age was 57.5 years (range, 39-69). The median follow-up period was 13 months (range, 1-22.6). The median maximum tumor diameter was 3.66 cm (range, 2.19-4.85). The 6- and 12-month local control rates were 81.8% and 49.1%, respectively. The distant disease control rates were 72.7% and 14.5% at 6 and 12 months, respectively. Overall survival was 83.3% and 74.1% at 6 and 12 months, respectively. Two patients developed leptomeningeal disease at a mean of 11.3 months. A trend toward increased local failure was seen with larger tumor volumes and diameters (P = 0.06). CONCLUSIONS: NaSRS is a promising new approach for the treatment of select cerebral metastases that require surgical intervention. The approach is safe and effective at achieving local control. Further randomized studies with larger patient cohorts are necessary to determine whether the long-term outcomes are improved.

Hypoglossal Schwannoma of Neck: Case Report and Review of Literature.

BACKGROUND: Schwannomas are benign, slow-growing neoplasms of the myelin-producing Schwann cells of peripheral nervous system that most commonly affect sensory nerves. Hypoglossal schwannomas, tumors of purely motor nerves, comprise <5% of all head and neck schwannomas. Since the first description of a hypoglossal schwannoma in 1933, there have been few case reports of extracranial origins. The most common location of an extracranial hypoglossal schwannoma is in the parapharyngeal space and can mimic paragangliomas. We describe the case of a woman presenting with an enlarging neck mass originally thought to be a paraganglioma but ultimately discovered to be a hypoglossal schwannoma at surgery. CASE DESCRIPTION: A 63-year-old woman had a well-circumscribed, mobile, nontender, 3-cm firm mass at the mandibular angle. On computed tomography, the mass was at the level of the carotid bifurcation, splaying the branching vessels. It was further evaluated with magnetic resonance imaging, which revealed a homogeneous, T2-hyperintense, T1-isointense mass with homogeneous contrast enhancement and scant flow voids. Biopsy revealed a spindle cell mass with positive S-100 staining. She underwent resection with the mass originating from the hypoglossal nerve. CONCLUSIONS: Hypoglossal schwannomas are rare lesions with a variable location along the course of the nerve. An extracranial lesion was described here, which was initially mistaken for a paraganglioma. Surgical resection is the consensus recommendation and is often well tolerated with low risk of long-term recurrence.