Mike Y. Chen

Clinical Efficacy of Stem Cell Mediated Osteogenesis and Bioceramics for Bone Tissue Engineering

Lower back pain is a common disorder that often requires bony spinal fusion for long-term relief. Current arthrodesis procedures use bone grafts from autogenous bone, allogenic backed bone or synthetic materials. Autogenous bone grafts can result in donor site morbidity and pain at the donor site, while allogenic backed bone and synthetic materials have variable effectiveness. Given these limitations, researchers have focused on new treatments that will allow for safe and successful bone repair and regeneration. Mesenchymal stem cells (MSCs) have received attention for their ability to differentiate into osteoblasts, cells that synthesize the extracellular matrix and regulate matrix mineralization. Successful bone regeneration requires three elements: MSCs that serve as osteoblastic progenitors, osteoinductive growth factors and their pathways that promote development and differentiation of the cells as well as an osteoconductive scaffold that allows for the formation of a vascular network. Future treatments should strive to combine mesenchymal stem cells, cell-seeded scaffolds and gene therapy to optimize the efficiency and safety of tissue repair and bone regeneration.

Axial spondylectomy and circumferential reconstruction via a posterior approach.

BACKGROUND Spinal metastases of the second cervical vertebra are a subset of tumors that are particularly difficult to address surgically. Previously described techniques require highly morbid circumferential dissection posterior to the pharynx for resection and reconstruction. OBJECTIVE To perform a biomechanical analysis of instrumented reconstruction configurations used after axial spondylectomy and to demonstrate safe use of a novel construct in a patient case report. METHODS Several different published and novel reconstruction configurations were inserted into 7 occipitocervical spines that underwent axial spondylectomy. A biomechanical analysis of the stiffness of the constructs in flexion and extension, lateral bending, and rotation was performed. A patient then underwent a posterior-only approach for axial spondylectomy and circumferential reconstruction. RESULTS Biomechanical analysis of different constructs demonstrated that anterior column reconstruction with bilateral cages spanning the C1 lateral mass to the C3 facet in combination with occipitocervical instrumentation was superior in flexion-extension and equivalent in lateral bending and rotation to currently used constructs. The patient in whom this construct was placed via a posterior-only approach for axial spondylectomy and instrumentation remained at neurological baseline and demonstrated no recurrence of local disease or failure of instrumentation to date. CONCLUSION When C1 lateral mass to C3 facet bilateral cage plus occipitocervical instrumentation is compared with existing anterior and posterior constructs, this novel reconstruction is biomechanically equivalent if not superior in performance. In a patient, the posterior-only approach for C2 spondylectomy with the novel reconstruction was safe and durable and avoided the morbidity of the anterior approach.

Modified lateral extracavitary approach for vertebral column resection and expandable cage reconstruction of thoracic spinal metastases

Background: Spinal metastasis is common and can be associated with considerable morbidity. Vertebral resection and reconstruction have been shown to preserve neurological function and decrease pain. Most commonly, two-stage, combined anterior/posterior approaches are performed to surgically address significant vertebral metastasis. Recently, single-stage posterior approaches for vertebrectomies have been performed more often as a result of advances in instrumentation and anesthesia. The objective is to describe a series of patients with metastatic thoracic spine tumors who were treated using a modified, lateral extracavitary approach for a posterior-only vertebral column resection and expandable cage reconstruction. Methods: A retrospective analysis of 21 cases and 20 patients was performed. Results: The average estimated blood loss and length of surgery were 1700 ml (range, 200–7600 ml) and 6.8 h (range, 4–9 h), respectively. The mean follow-up was 14 months (range, 4–30 months). One patient had a permanent neurological deficit as a result of a postoperative hematoma. Of the five patients who were unable to walk prior to surgery, two regained the ability to ambulate. The total complication rate was 43% with majority being minor. A total of 94% of patients had durable preservation of the neurological function. Conclusion: The posterior approach for vertebral column resection and reconstruction is a viable alternative to the standard combined approach. We demonstrate the feasibility of performing the lateral extracavitary approach through a midline incision from T1 to T12. This less invasive approach continues to evolve as instrumentation becomes more advanced and possesses significant advantages in the oncologic setting.

Astrocyte-induced Reelin expression drives proliferation of Her2(+) breast cancer metastases.

Breast cancer metastasis to the brain develops after a clinical latency of years to even decades, suggesting that colonization of the brain is the most challenging step of the metastatic cascade. However, the underlying mechanisms used by breast cancer cells to successfully colonize the brain’s microenvironment remain elusive. Reelin is an archetypal extracellular glycoprotein that regulates migration, proliferation, and lamination of neurons. It is epigenetically silenced in various cancers, and its expression in multiple myelomas is linked to poor patient survival. We found that Reelin expression was low in primary breast cancer tissue. However, its expression was significantly higher in Her2+ breast cancers metastasizing to the brain. In particular, Reelin was highly expressed in the tumor periphery adjacent to surrounding astrocytes. This augmented Reelin expression was seen in Her2+ metastases, but not in triple negative (TN) primary tumors or in TN breast to brain metastasis cells co-cultured with astrocytes. Furthermore, the elevated expression was sustained in Her2+ cells grown in the presence of the DNA methyltransferase inhibitor 5-azacytidine, indicating epigenetic regulation of Reelin expression. The relative growth and rate of spheroids formation derived from Her2+ primary and BBM cells co-cultured with astrocytes were higher than those of TN primary and BBM cells, and knockdown of both Reelin and Her2 suppressed the astrocyte-induced growth and spheroid forming ability of Her2+ cells. Collectively, our results indicate that within the neural niche, astrocytes epigenetically regulate Reelin expression and its interaction with Her2 leading to increased proliferation and survival fitness.

Prevalence of hepatitis B and C in patients with meningiomas and glioblastoma multiforme

The prevalence of hepatitis B and C in patients with glioblastoma multiforme or meningiomas has not been described. These infections are known to modulate the activity of the immune system, which potentially influences the development and course of cancer. We hypothesized that chronic hepatitis infection, which activates the immune system, decreases the risk of brain tumors, particularly those that are highly malignant. We performed a retrospective study to examine the prevalence of hepatitis B and C in patients with meningiomas and glioblastomas. The combined prevalence of hepatitis B and C in the USA from 1999–2008 was 5.7%. The prevalence of hepatitis B and C in patients with meningiomas was 2.4%; while among glioblastoma patients, the prevalence of hepatitis B and C was 1.38%. The odds ratio of having hepatitis B or C with glioblastoma versus meningiomas was 0.56, with a confidence interval of 0.19–1.6 and a P-value of 0.29. Compared with historical controls, the prevalence of hepatitis B and C in meningioma and glioblastoma patients was decreased. However, this difference may be attributed to the retrospective nature of our data and the natural history of hepatitis B and C infections. The prevalence of these viral infections was not statistically different in patients with meningiomas and glioblastomas. This suggests that hepatitis B and C primarily influence slow-growing, benign tumors and more aggressive cancers equally, if at all. To definitively test our hypothesis, future studies in which data are prospectively gathered are likely to be required.

Surface topography can be used to instruct stem cell fate.

nificantly longer PFS from vaccination and histologic diagnosis than patients with methylated MGMT who did not receive the vaccine. A major limitation of the study is that overall survival may not be significantly different from recent studies using different forms of immunotherapy. In addition, considering that only one third of patients with GBM express EGFRvIII (10, 30), the overall target population is restricted. Recently, Jun et al, developed a genetically engineered mouse model of EGFR associated gliomagenesis based on activation of EGFR in coalition with deletions in the Ink4a/Arf and PTEN genes. They found chronic activation of wild-type EGFR with a ligand is necessary. These tumors are resistant to EGFR tyrosine kinase inhibition. EGFR inhibition causes an alteration in gene expression of GBM tumor cells including activation of the MET tyrosine kinase. This MET activity causes activation of downstream signaling pathways resulting in survival of GBM cells, supporting the importance of transcriptional activation of the MET receptor tyrosine kinase. Most importantly, targeted pharmacological inhibition of MET reversed this function and overcame the resistance to EGFR inhibition in these cells. These results elucidate mechanisms of resistance to EGFR inhibition and provide further evidence that multi-targeted therapy will likely be necessary in the treatment of GBM. Despite advances, further knowledge of GBM subtypes and gene expression, along with their methods of resistance, will be essential.

Cancer stem cells can arise from differentiated neoplastic cells.

Project. Patient recruitment was a combination of invited patients from the MD Anderson registry, as well as unsolicited participants from the Collaborative Ependymoma Research Network website. In total, 59 of 136 invited patients (43%) participated from the local registry, and 59 of 105 (56%) unsolicited patients who visited the website participated from remote sites. 44% of patients harbored brain tumors, 51% harbored spine tumors, and 5% had tumors in both locations. All grades of ependymoma were included, though the majority was reported as grade 2 tumors (59%). Median time from diagnosis was 50 months for brain tumors and 74 months for spine tumors. The vast majority of patients had previously undergone either total or subtotal resection, and 54% had received no adjuvant therapy at the time of the survey. Complication rates as reported by these patients were significant. Overall, 38% of patients reported postoperative weakness, 20% reported paralysis, and 32% reported that their physical condition was worse than it had been preoperatively (Table). Recurrence was reasonably common, reported in 31% of brain patients and 27% of spine patients. Finally, patients were being primarily managed by a wide variety of physicians, ranging from neurosurgeons (44%) and neuro-oncologists (30%) to family physicians (18%). Most were not being treated at major academic centers. The authors are to be commended for compiling this data from such a large group of patients. Like any research based on patient surveys, this study is subject to multiple sources of bias. However, the conclusions of the study regarding patient outcomes and lack of standardization of care for ependymomas underscores the need for more centralized management of these patients. In addition, this study joins many others from multiple disciplines in advocating the value of patient-reported outcome assessment in clinical research.