Since its initial characterization, pancreatic ductal adenocarcinoma has remained one of the most devastating and difficult cancers to treat. Pancreatic cancer is the fourth leading cause of death in ...the United States, resulting in an estimated 38460 deaths annually. With few screening tools available to detect this disease at an early stage, 94% of patients will die within five years of diagnosis. Despite decades of research that have led to a better understanding of the molecular and cellular signaling pathways in pancreatic cancer cells, few effective therapies have been developed to target these pathways. Other treatment options have included more sophisticated pancreatic cancer surgeries and combination therapies. While outcomes have improved modestly for these patients, more effective treatmentsare desperately needed. One of the greatest challenges in the future of treating this malignancy will be to develop therapies that target the tumor microenvironment and surrounding pancreatic cancer stem cells in addition to pancreatic cancer cells. Recent advances in targeting pancreatic stellate cells and the stroma have encouraged researchers to shift their focus to the role of desmoplasia in pancreatic cancer pathobiology in the hopes of developing newer-generation therapies. By combining novel agents with current cytotoxic chemotherapies and radiation therapy and personalizing them to each patient based on specific biomarkers, the goal of prolonging a patient’s life could be achieved. Here we review the most effective therapies that have been used for the treatment of pancreatic cancer and discuss the future potential of therapeutic options.
Schmorl's nodes were first described by the pathologist Christian Schmorl in 1927 as a herniation of the nucleus pulposus through the cartilaginous and bony endplate into the vertebral body. Although ...such lesions present most commonly as incidental findings in asymptomatic patients (or in patients with back or radicular pain due to other etiology), there have been several reports emphasizing the deleterious effects of the inflammatory response and endplate changes elicited by the herniation of for such reasons, Schmorl's nodes have been occasionally implicated in the etiology of chronic axial pain as well as in pathological osteoporotic fractures. In this article, a thorough literature review about the most relevant historical studies on Schmorl's nodes previously published is performed. Furthermore, the authors provide an overview about the recent advances in basic science research on the pathophysiology of such lesions, as well as on current diagnostic and therapeutic paradigms.
Glioblastoma is both the most common and most lethal primary CNS malignancy in adults, accounting for 45.6% of all malignant CNS tumors, with a 5-year survival rate of only 5.0%, despite the ...utilization of multimodal therapy including resection, chemotherapy, and radiation. Currently available treatment options for glioblastoma often remain limited, offering brief periods of improved survival, but with substantial side effects. As such, improvements in current treatment strategies or, more likely, the implementation of novel strategies altogether are warranted. In this topic review, the authors provide a comprehensive review on the potential of alternating electric fields (AEFs) in the treatment of glioblastoma. Alternating electric fields-also known as tumor-treating fields (TTFs)-represent an entirely original therapeutic modality with preliminary studies suggesting comparable, and at times improved, efficacy to standard chemotherapeutic agents in the treatment of recurrent glioblastoma. A recent multicenter, Phase III, randomized clinical trial comparing NovoTTF-100A monotherapy to physician's best choice chemotherapy in patients with recurrent glioblastoma revealed that AEFs have similar efficacy to standard chemotherapeutic agents with a more favorable side-effects profile and improved quality of life. In particular, AEFs were shown to have limited systemic adverse effects, with the most common side effect being contact dermatitis on the scalp at the sites of transducer placement. This study prompted FDA approval of the NovoTTF-100A system in April 2011 as a standalone therapy for treatment of recurrent glioblastoma refractory to surgical and radiation treatment. In addition to discussing the available clinical evidence regarding the utilization of AEFs in glioblastoma, this article provides essential information regarding the supposed therapeutic mechanism as well as modes of potential tumor resistance to such novel therapy, delineating future perspectives regarding basic science research on the issue.
Abstract
BACKGROUND
Atypical and anaplastic meningiomas have reduced progression-free/overall survival (PFS/OS) compared to benign meningiomas. Stereotactic radiosurgery (SRS) for atypical ...meningiomas (AMs) and anaplastic meningiomas (malignant meningiomas, MMs) has not been adequately described.
OBJECTIVE
To define clinical/radiographic outcomes for patients undergoing SRS for AM/MMs.
METHODS
An international, multicenter, retrospective cohort study was performed to define clinical/imaging outcomes for patients receiving SRS for AM/MMs. Tumor progression was assessed with response assessment in neuro-oncology (RANO) criteria. Factors associated with PFS/OS were assessed using Kaplan-Meier analysis and a Cox proportional hazards model.
RESULTS
A total of 271 patients received SRS for AMs (n = 233, 85.9%) or MMs (n = 38, 14.0%). Single-fraction SRS was most commonly employed (n = 264, 97.4%) with a mean target dose of 14.8 Gy. SRS was used as adjuvant treatment (n = 85, 31.4%), salvage therapy (n = 182, 67.2%), or primary therapy (1.5%). The 5-yr PFS/OS rate was 33.6% and 77.0%, respectively. Increasing age (hazard ratio (HR) = 1.01, P < .05) and a Ki-67 index > 15% (HR = 1.66, P < .03) negatively correlated with PFS. MMs (HR = 3.21, P < .05), increased age (HR = 1.04, P = .04), and reduced KPS (HR = 0.95, P = .04) were associated with shortened OS. Adjuvant versus salvage SRS did not impact PFS/OS. A shortened interval between surgery and SRS improved PFS for AMs (HR = 0.99, P = .02) on subgroup analysis. Radiation necrosis occurred in 34 (12.5%) patients. Five-year rates of repeat surgery/radiation were 33.8% and 60.4%, respectively.
CONCLUSION
AM/MMs remain challenging tumors to treat. Elevated proliferative indices are associated with tumor recurrence, while MMs have worse survival. SRS can control AM/MMs in the short term, but the 5-yr PFS rates are low, underscoring the need for improved treatment options for these patients.
Graphical Abstract
Graphical Abstract
Abstract Background context Although giant cell tumors (GCTs) are histologically benign, they may become locally aggressive bone tumors. As these lesions tend to respond poorly to radio- and ...chemotherapy, currently the standard surgical paradigm for the treatment of spinal GCTs involves en bloc surgical resection. Denosumab is a newly developed monoclonal antibody designed to inhibit the receptor activator of nuclear factor kappa-B ligand (RANKL) which has already been demonstrated to induce marked radiographic responses on GCTs of the appendicular skeleton. Nevertheless, the role of denosumab in the treatment algorithm of GCTs of the spine has not yet been defined. Purpose To describe the first case of sustained long-term complete clinical and radiographic regression of a GCT of the spine after treatment with the new RANKL antibody denosumab. Study design Case report and literature review. Methods The authors describe the case of 22-year-old female patient, harboring a GCT involving the C2 vertebral body and odontoid process, who was treated in monotherapy with denosumab, resulting in complete long-term clinical and radiographic tumor remission. Results There were no major side effects associated with the long-term pharmacological treatment with denosumab. From the clinical standpoint, the patient demonstrated complete remission of the disease while under treatment. The 16-month radiographic follow-up demonstrated complete disappearance of the osteolytic process and intense new cortical bone formation with restoration of the bone integrity of the C2 vertebral body. Conclusions This is the first report of sustained long-term complete clinical and radiographic regression of a GCT of the spine after treatment with the new RANKL antibody denosumab. Although future long-term follow-up studies are still necessary to establish important key points regarding the best therapeutic protocol with such a new drug (such as the optimal time frame to keep the patient under treatment), denosumab promises to bring major changes to the current therapeutic paradigm for GCTs of the spine, which, up to now, has strongly relied on en bloc surgical resection.
Graphene, a monolayer atomic-scale honeycomb lattice of carbon atoms, has been considered the greatest revolution in metamaterials research in the past 5 years. Its developers were awarded the Nobel ...Prize in Physics in 2010, and massive funding has been directed to graphene-based experimental research in the last years. For instance, an international scientific collaboration has recently received a 1 billion grant from the European Flagship Initiative, the largest amount of financial resources ever granted for a single research project in the history of modern science. Because of grapheneʼs unique optical, thermal, mechanical, electronic, and quantum properties, the incorporation of graphene-based metamaterials to biomedical applications is expected to lead to major technological breakthroughs in the next few decades. Current frontline research in graphene technology includes the development of high-performance, lightweight, and malleable electronic devices, new optical modulators, ultracapacitors, molecular biodevices, organic photovoltaic cells, lithium-ion microbatteries, frequency multipliers, quantum dots, and integrated circuits, just to mention a few. With such advances, graphene technology is expected to significantly impact several areas of neurosurgery, including neuro-oncology, neurointensive care, neuroregeneration research, peripheral nerve surgery, functional neurosurgery, and spine surgery. In this topic review, the authors provide a basic introduction to the main electrophysical properties of graphene. Additionally, future perspectives of ongoing frontline investigations on this new metamaterial are discussed, with special emphasis on those research fields that are expected to most substantially impact experimental and clinical neurosurgery in the near future.
ABBREVIATIONS:BCI, brain-computer interfaceCNS, central nervous systemFRET, fluorescence resonance energy transferGO, graphene oxideMEMS, microelectromechanical systemNEMS, nanoelectromechanical systemNIR, near-infrared region; rGO, reduced graphene oxide
Vestibular schwannomas (VSs) related to neurofibromatosis type 2 (NF2) are challenging tumors. The increasing use of stereotactic radiosurgery (SRS) necessitates further investigations of its role ...and safety.
To evaluate tumor control, freedom from additional treatment (FFAT), serviceable hearing preservation, and radiation-related risks of patients with NF2 after SRS for VS.
We performed a retrospective study of 267 patients with NF2 (328 VSs) who underwent single-session SRS at 12 centers participating in the International Radiosurgery Research Foundation. The median patient age was 31 years (IQR, 21-45 years), and 52% were male.
A total of 328 tumors underwent SRS during a median follow-up time of 59 months (IQR, 23-112 months). At 10 and 15 years, the tumor control rates were 77% (95% CI: 69%-84%) and 52% (95% CI: 40%-64%), respectively, and the FFAT rate were 85% (95% CI: 79%-90%) and 75% (95% CI: 65%-86%), respectively. At 5 and 10 years, the serviceable hearing preservation rates were 64% (95% CI: 55%-75%) and 35% (95% CI: 25%-54%), respectively. In the multivariate analysis, age (hazards ratio: 1.03 95% CI: 1.01-1.05; P = .02) and bilateral VSs (hazards ratio: 4.56 95% CI: 1.05-19.78; P = .04) were predictors for serviceable hearing loss. Neither radiation-induced tumors nor malignant transformation were encountered in this cohort.
Although the absolute volumetric tumor progression rate was 48% at 15 years, the rate of FFAT related to VS was 75% at 15 years after SRS. None of the patients with NF2-related VS developed a new radiation-related neoplasm or malignant transformation after SRS.
Purpose
No standard strategy exists for the management of cervical kyphotic deformity in patients with severe osteoporosis. In fact, in such subpopulation, standard algorithms commonly used in ...patients with normal bone mineral density may not be applicable. In this Grand Rounds, the authors present a challenging case of a patient with Hajdu–Cheney syndrome, a rare disorder of bone metabolism induced by a Notch-2 mutation, who presented with cervical kyphotic deformity and severe osteoporosis.
Methods
A 65-year-old female patient with a previous diagnosis of Hajdu–Cheney syndrome presented with cervical myelopathy and cervical kyphotic deformity. The initial MRi demonstrated multilevel cervical canal stenosis. The CT-scan also revealed marked spondylolisthesis of C6 over C7 as well as numerous laminar and pedicle fractures, resulting in a cervical kyphosis of approximately 50 degrees.
Results
The patient was submitted to 360-degree decompression and fusion of the cervical spine consisting of a staged C6 anterior corpectomy and multilevel microdiscectomies with wide opening of the posterior longitudinal ligament in order to provide a satisfactory release of anterior spinal structures, followed by 24 h of cervical halo-traction, a second anterior approach for bone graft implantation in the site of the corpectomy as well as insertion of allografts and completion of the ACDF C2–T1 and plating, and, finally, a posterior C2–T3 pedicle screw instrumentation using intra-operative CT-scan (O-arm) navigation guidance.
Conclusions
This case illustrates some intra-operative nuances as well as specific surgical recommendations for cervical deformity surgery in patients with severe osteoporosis, such as avoidance of Caspar pins for interbody distraction, use of intra-operative fluoroscopy for achievement of bicortical purchase of anterior cervical screws and placement of pedicle screws during posterior instrumentation. Moreover, such illustrative case demonstrates that, in the subpopulation of patients with severe osteoporosis, it may be possible to successfully apply cervical distraction after an isolated anterior approach with a satisfactory improvement in the cervical alignment, possibly avoiding more laborious 540-degree approaches such as the previously described back–front–back or front–back–front surgical algorithms.
Previous studies have described the association of spinal epidural lipomatosis with several conditions including chronic steroid therapy, Cushing's syndrome, obesity, Paget disease, and ...hypothyroidism. We present a report of rapid development of spinal epidural lipomatosis after treatment with second-generation anti-androgen therapy, a new strategy for treatment of metastatic castration-resistant prostate cancer that has been increasingly employed in the past few years. A comprehensive discussion of the underlying molecular networks involving androgen receptor blockage and adipocyte differentiation, as well as the clinical implications of such a phenomenon, are provided.
We describe the clinical and radiological evolution of a 58-year-old male patient with metastatic prostate cancer, who developed new onset of rapidly progressing lumbosacral epidural lipomatosis with significant compression of the nerve roots of the cauda equina a few months after initiation of treatment with second-generation androgen receptor antagonists.
The underlying pathophysiology of adipose tissue growth following the administration of anti-androgen therapy is discussed, with emphasis on both the canonical Wnt/β-catenin pathway as well as in the Wnt-independent pathway involving direct activation of downstream transcription factors from the T-cell factor family by the androgen receptor. As second-generation androgen receptor antagonists have been increasingly used for treatment of castration-resistant stage metastatic prostate cancer, new onset of symptomatic epidural lipomatosis should be considered as a possible differential diagnosis, especially because the urinary symptoms of cauda equina compression may be improperly attributed to the primary prostate neoplasm.
The recent characterization of glioma stem cells (GSCs) prompts a necessary examination of the signaling pathways that facilitate invasiveness. Molecular crosstalk between expression mechanisms has ...been identified in a range of cancers, including glioblastoma multiforme. However, hardly any literature exists that addresses whether cancer stem cells utilize these same interconnected pathways. Protein factors commonly implicated in malignant tumors include extracellular signal-regulated kinase (ERK), N-cadherin, and integrin α6. Although studies have reported the molecular crosstalk involved among these proteins, the present study illustrates the importance of the ERK transduction pathway in N-cadherin and integrin α6 regulated invasion in GSCs. Conversely, the data also suggests that GSCs rely on N-cadherin and integrin α6 interaction to regulate ERK signaling. Moreover, confocal visualization revealed the co-localization of N-cadherin and integrin α6 in GSCs and clinical surgical biopsies extracted from glioma patients. Interestingly, ERK knockdown reduced this co-localization. Upon co-culturing GSCs with human umbilical cord blood stem cells (hUCBSCs), we observed a subsequent decrease in pERK, N-cadherin and integrin α6 expression. In addition, co-culturing hUCBSCs with GSCs decreased co-localization of N-cadherin and integrin α6 in GSCs. Our results demonstrate the dynamic interplay among ERK, N-cadherin and integrin α6 in GSC invasion and also reveal the therapeutic potential of hUCBSCs in treating the molecular crosstalk observed in GSC-regulated invasion.
► GSCs use N-cadherin and integrin α6 interactions to regulate ERK mediated invasion. ► GSC and surgical biopsies reveal the co-localization of N-cadherin and integrin α6. ► ERK knockdown reduces N-cadherin and integrin α6 co-localization in GSC. ► hUCBSC co-culture decreases N-cadherin, integrin α6 and pERK associations in GSC.
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