Clemens Reinshagen

A novel translaminar crossover approach for pathologies in the lumbar hidden zone.

We report eight patients with disc herniations who underwent sequestrectomy via a crossover translaminar technique. The lateral lumbar spinal canal can be divided into several regions: the subarticular, foraminal and extraforaminal zone. Due to its difficult surgical exposure, some authors refer to part of the subarticular and foraminal region as the hidden zone. Conventional approaches involve partial or total facet joint resection, introducing risk of postoperative instability. Under fluoroscopic guidance, a high speed drill was used to create a small, angled fenestration at the base of the spinous process aimed at the contralateral hidden zone. The nerve root was visualized and disc fragments were removed without facet joint violation. Patients were registered in the International Spine Registry, Spine Tango. Numeric rating scale (NRS), Oswestry disability index (ODI) and core outcome measures index (COMI) were used to evaluate outcome after 6 weeks and 3 months. Outcome was further statistically matched with the Spine Tango pool of patients who underwent sequestrectomy via conventional techniques. Postoperative CT scans showed the translaminar crossover approach with the preserved facet joints. There was significant postoperative improvement of NRS scores and ODI at all follow-up intervals. COMI achieved significant improvement at 3 months. Statistical comparison with Spine Tango data confirmed that the translaminar crossover approach matches the clinical results of the conventional techniques. This series is a proof of principle for a successful translaminar crossover approach to the lumbar hidden zone. The outcome is not inferior to conventional inter- and translaminar routes and the technique potentially offers risk reduction for postoperative instability by preserving facet joint function, especially in the case of recurrent disease.

A novel minimally invasive technique for lumbar decompression, realignment, and navigated interbody fusion

We present a novel, minimally invasive, navigation-guided approach for surgical treatment of degenerative spondylolisthesis (DS) that is a hybrid of the two most common techniques, posterior interbody fusion (PLIF) and transforaminal interbody fusion (TLIF). DS is an acquired condition with intersegmental instability of one or more lumbar motion segments. Seven patients with single level lumbar DS underwent lumbar arthrodesis utilizing the hybrid technique (HLIF) in our center. Using a standard unilateral midline approach a decompression and partial facetectomy on one side was performed, allowing for implantation of a specially designed interbody cage. Pedicle screws were placed using neuronavigation in a vertical vector on the side of the partial facetectomy and dorsolaterally (percutaneous) on the contralateral side. Patient and operative data, numeric rating scale (NRS) pain scores, core outcome measures index (COMI) and Oswestry disability index (ODI) were recorded preoperatively as well as 6 weeks, 3 months, 6 months and 1 year after surgery. All patients completed the 1 year follow-up. There was significant postoperative improvement of NRS, COMI and ODI scores at all postoperative follow-up time points (p<0.05). The radiological assessments of realignment showed a reduction of listhesis from an average of 21.04% (standard deviation [SD] 5.1) preoperatively to 9.14% (SD 4.0) postoperatively (p<0.001). The average blood loss was 492 ml. Post-procedure CT scans demonstrated correct implant placement in all but one patient who required a revision of a single pedicle screw. HLIF allows thorough decompression as well as realignment and interbody fusion for patients with DS and may help reduce tissue trauma in comparison to other minimally invasive lumbar fusion techniques.

Bi-specific molecule against EGFR and death receptors simultaneously targets proliferation and death pathways in tumors

Developing therapeutics that target multiple receptor signaling pathways in tumors is critical as therapies targeting single specific biomarker/pathway have shown limited efficacy in patients with cancer. In this study, we extensively characterized a bi-functional molecule comprising of epidermal growth factor receptor (EGFR) targeted nanobody (ENb) and death receptor (DR) targeted ligand TRAIL (ENb-TRAIL). We show that ENb-TRAIL has therapeutic efficacy in tumor cells from different cancer types which do not respond to either EGFR antagonist or DR agonist monotherapies. Utilizing pharmacological inhibition, genetic loss of function and FRET studies, we show that ENb-TRAIL blocks EGFR signalling via the binding of ENb to EGFR which in turn induces DR5 clustering at the plasma membrane and thereby primes tumor cells to caspase-mediated apoptosis. In vivo, using a clinically relevant orthotopic resection model of primary glioblastoma and engineered stem cells (SC) expressing ENb-TRAIL, we show that the treatment with synthetic extracellular matrix (sECM) encapsulated SC-ENb-TRAIL alleviates tumor burden and significantly increases survival. This study is the first to report novel mechanistic insights into simultaneous targeting of receptor-mediated proliferation and cell death signaling pathways in different tumor types and presents a promising approach for translation into the clinical setting.

Predictive modeling and in vivo assessment of cerebral blood flow in the management of complex cerebral aneurysms

Cerebral aneurysms are weakened blood vessel dilatations that can result in spontaneous, devastating hemorrhage events. Aneurysm treatment aims to reduce hemorrhage events, and strategies for complex aneurysms often require surgical bypass or endovascular stenting for blood flow diversion. Interventions that divert blood flow from their normal circulation patterns have the potential to result in unintentional ischemia. Recent developments in computational modeling and in vivo assessment of hemodynamics for cerebral aneurysm treatment have entered into clinical practice. Herein, we review how these techniques are currently utilized to improve risk stratification and treatment planning.

Intracranial dural based chondroma

Intracranial chondromas are benign, slow-growing, cartilaginous tumors, which comprise only about 0.2% of all intracranial tumors. The majority of these lesions occur at the base of the skull, where they are thought to arise from residual embryonic chondrogenic cells along the basal synchondrosis. Very rarely, they may also originate from the convexity dura, falx cerebri, or the brain parenchyma. We present a patient with a dural based chondroma to highlight the technical considerations of surgical resection. The recent literature on intracranial chondromas regarding incidence, pathophysiologic origin, clinical symptoms, imaging, histopathology and prognosis is reviewed.

Surgical Approaches to the Lumbar Hidden Zone: Current Strategies and Future Directions

The lateral lumbar spinal canal may be subdivided into the subarticular (lateral recess), the foraminal (pedicle) and the extraforaminal (far lateral) zone. Within these regions lies the “hidden zone”, an area known for its difficult surgical exposure (Fig. 1A) (Macnab, 1971). Common pathologies of this region include foraminal osseous stenosis (narrowing of the foramen through which the nerve root exits the spinal canal) as well as disc herniations. It has been estimated that roughly 10–20% of all disc herniations migrate in a craniolateral direction and may hence be located in the preforaminal and foraminal regions of the “hidden zone”. Due to the local anatomy, these lesions may affect both the traversing (level below) as well as the exiting (same level) nerve root. Patients typically present with neurological symptoms of (poly-)radiculopathy, including pain, weakness and numbness. Commonly, and in contrast to the above-mentioned zones, all types of disc herniations that affect the exiting nerve root at the same level are referred to as “far- or extreme-lateral”, including pre-, intra- and extra-foraminal herniations. Whilst a variety of effective techniques for approaching extraforaminal and purely intraforaminal lesions have been developed, there continues to be disagreement with regard to the optimal approach to lesions located in the pre- and intra-foraminal regions of the hidden zone. Fig. 1 Lumbar anatomy and surgical approaches to the hidden zone. A) Overview of applied neurosurgical anatomy of the lumbar spine, depicting a representative craniolateral disc herniation affecting both the exiting L2 and the passing L3 nerve root. Besides ... In order to understand this discord, it is crucial to comprehend the difficulties and patient-specific concerns associated with the surgical exposure of this region. Anatomically, the medial hidden zone is an area bordered laterally by the pedicle, ventrally by the dorsal part of the vertebral body and covered dorsally by the pars interarticularis of the hemilamina (Fig. 1A). Open surgical exploration of this region via the traditional interlaminar route (Fig. 1B) is therefore only possible after at least partial removal of the ipsilateral hemilamina (extended laminotomy or even hemilaminectomy) and may additionally require partial or complete facetectomy (removal of the facet joint) (Schulz et al., 2014). Extended laminotomy as a means to approach the hidden zone has therefore lost popularity, since the associated removal of biomechanically important bony structures has been suggested to increase the risk of secondary segmental instability (Abumi et al., 1990) and may subsequently necessitate fusion surgery. Other, more lateral approaches have been suggested; however, these require specific anatomical knowledge, and offer inferior access to more medial spinal pathologies of the hidden zone. In 1998, Di Lorenzo et al. (1998) proposed a less invasive direct procedure by utilizing a translaminar approach (TLA) through a fenestration of the pars interarticularis, thus circumventing facetectomy or hemilaminectomy in many cases (Fig. 1C). The increasing availability of high-definition imaging modalities (MRI, CT) has contributed to the growing popularity of the TLA, since identifying the exact location and extent of the spinal lesion is crucial for surgical planning to limit unnecessary biomechanical damage and prevent intraoperative conversion to conventional approaches. In recent years, several studies have demonstrated the feasibility, safety and efficacy of this technique to successfully treat disc herniations affecting the foraminal and preforaminal regions. Endoscopic approaches to the hidden zone have been suggested, including endoscopic transforaminal (Fig. 1D) or translaminar techniques (Schulz et al., 2014; Dezawa et al., 2012). However, whilst the endoscopic TLA might offer an incremental improvement with regard to trauma, transforaminal endoscopic procedures are not recommended for the more medial foraminal lesions of the hidden zone due to imposed spatial restrictions, especially in the lower lumbar levels. Consequently, endoscopic transforaminal approaches to these pathologies have been associated with increased operating times as well as higher complication and revision rates (Schulz et al., 2014; Lee et al., 2007). Nevertheless, even though the TLA seems to be the method of choice to approach craniolateral disc herniations, some authors have argued that this technique also has its limitations. Due to segment-dependent changes of vertebral anatomy, Di Lorenzos approach must be located very laterally in the more upper lumbar levels in order to reach the medial hidden zone. Disruption of the lateral hemilamina (pars interarticularis), however, has been linked to an increased risk of stress fracture and instability (Ivanov et al., 2007). This becomes more relevant as the relative risk of cranial disc sequestration increases significantly in higher lumbar levels and cranial sequestration is strongly correlated with increased age (Daghighi et al., 2014). Since older patients are also more likely to suffer from osteoporosis and degenerative spinal disorders such as facet joint hypertrophy, which may manifest segmental instability, less invasive medial approaches to the hidden zone are warranted. Recently, Reinshagen et al. (2015) suggested approaching craniolateral disc herniations via a crossover translaminar approach (cTLA), which utilizes a fenestration of the contralateral hemilamina at the base of the spinous process to reach the hidden zone (Fig. 1E). Besides avoiding disruption of the lateral half of the hemilamina, this facet-sparing technique might additionally offer advantages when treating recurrent patients who previously underwent extended laminotomy, as approaching the recurrent pathology from the contralateral side avoids additional ipsilateral bone resection. A minimally invasive technique, similar to that reported by Reinshagen et al., has been proposed by Alimi et al. (2014)). Although not a translaminar approach, Alimis technique also features a crossover route to the foraminal region and demonstrated good results for treating foraminal stenosis in a series of 32 patients. The main limitation of both TLA and cTLA techniques is their restricted access to the intervertebral disc space, especially at lower lumbar levels. Although cranial disc herniations mostly appear as completely sequestered fragments, preoperative imaging and meticulous surgery planning is crucial in order to minimize reversion to conventional approaches. In the future, combining the TLA or cTLA with preoperative simulation software as well as intraoperative neuronavigation might prove helpful in further minimizing surgical tissue trauma when treating these challenging pathologies. In conclusion, access to the hidden zone remains surgically challenging. However, with an increasing number of reliable techniques the surgeon can now decide which procedure is the most appropriate for a patients individual pathology. Furthermore, even though common sense implies that less bone disruption increases spinal stability, data on TLA and cTLA approaches still need to be supported by a large prospective randomized trial to assess the preservation of spinal stability and patient outcomes compared to conventional approaches.

Impurity of stem cell graft by murine embryonic fibroblasts - implications for cell-based therapy of the central nervous system

Stem cells have been demonstrated to possess a therapeutic potential in experimental models of various central nervous system disorders, including stroke. The types of implanted cells appear to play a crucial role. Previously, groups of the stem cell network NRW implemented a feeder-based cell line within the scope of their projects, examining the implantation of stem cells after ischemic stroke and traumatic brain injury. Retrospective evaluation indicated the presence of spindle-shaped cells in several grafts implanted in injured animals, which indicated potential contamination by co-cultured feeder cells (murine embryonic fibroblasts – MEFs). Because feeder-based cell lines have been previously exposed to a justified criticism with regard to contamination by animal glycans, we aimed to evaluate the effects of stem cell/MEF co-transplantation. MEFs accounted for 5.3 ± 2.8% of all cells in the primary FACS-evaluated co-culture. Depending on the culture conditions and subsequent purification procedure, the MEF-fraction ranged from 0.9 to 9.9% of the cell suspensions in vitro. MEF survival and related formation of extracellular substances in vivo were observed after implantation into the uninjured rat brain. Impurity of the stem cell graft by MEFs interferes with translational strategies, which represents a threat to the potential recipient and may affect the graft microenvironment. The implications of these findings are critically discussed.

CRISPR-enhanced engineering of therapy-sensitive cancer cells for self-targeting of primary and metastatic tumors.

CRISPR-engineered receptor-specific self-targeted tumor cells demonstrate antitumor efficacy in vitro and in vivo. Cellular double agents Tumor cells exhibit a “self-homing” behavior, whereby cells released into the circulation can home back to the main tumor site. To take advantage of this behavior and use the cells as vehicles to deliver therapies to the main tumor site, Reinshagen et al. engineered self-targeting tumor cells. These cells were designed to secrete death receptor–targeting ligands to which they were resistant to kill the main tumor but not destroy themselves. Conversely, they could be eliminated on demand using a drug-triggered cellular suicide system to prevent them from repopulating the tumor site. The authors then tested the efficacy and safety of this method in mouse models of primary, recurrent, and metastatic tumors. Tumor cells engineered to express therapeutic agents have shown promise to treat cancer. However, their potential to target cell surface receptors specific to the tumor site and their posttreatment fate have not been explored. We created therapeutic tumor cells expressing ligands specific to primary and recurrent tumor sites (receptor self-targeted tumor cells) and extensively characterized two different approaches using (i) therapy-resistant cancer cells, engineered with secretable death receptor–targeting ligands for “off-the-shelf” therapy in primary tumor settings, and (ii) therapy-sensitive cancer cells, which were CRISPR-engineered to knock out therapy-specific cell surface receptors before engineering with receptor self-targeted ligands and reapplied in autologous models of recurrent or metastatic disease. We show that both approaches allow high expression of targeted ligands that induce tumor cell killing and translate into marked survival benefits in mouse models of multiple cancer types. Safe elimination of therapeutic cancer cells after treatment was achieved by co-engineering with a prodrug-converting suicide system, which also allowed for real-time in vivo positron emission tomography imaging of therapeutic tumor cell fate. This study demonstrates self-tumor tropism of engineered cancer cells and their therapeutic potential when engineered with receptor self-targeted molecules, and it establishes a roadmap toward a safe clinical translation for different cancer types in primary, recurrent, and metastatic settings.

Tumor Resection Recruits Effector T Cells and Boosts Therapeutic Efficacy of Encapsulated Stem Cells Expressing IFNβ in Glioblastomas

Purpose: Despite tumor resection being the first-line clinical care for glioblastoma (GBM) patients, nearly all preclinical immune therapy models intend to treat established GBM. Characterizing cytoreductive surgery-induced immune response combined with the administration of immune cytokines has the potential of offering a new treatment paradigm of immune therapy for GBMs. Experimental Design: We developed syngeneic orthotopic mouse GBM models of tumor resection and characterized the immune response of intact and resected tumors. We also created a highly secretable variant of immune cytokine IFNβ to enhance its release from engineered mouse mesenchymal stem cells (MSC-IFNβ) and assessed whether surgical resection of intracranial GBM tumor significantly enhanced the antitumor efficacy of targeted on-site delivery of encapsulated MSC-IFNβ. Results: We show that tumor debulking results in substantial reduction of myeloid-derived suppressor cells (MDSC) and simultaneous recruitment of CD4/CD8 T cells. This immune response significantly enhanced the antitumor efficacy of locally delivered encapsulated MSC-IFNβ via enhanced selective postsurgical infiltration of CD8 T cells and directly induced cell-cycle arrest in tumor cells, resulting in increased survival of mice. Utilizing encapsulated human MSC-IFNβ in resected orthotopic tumor xenografts of patient-derived GBM, we further show that IFNβ induces cell-cycle arrest followed by apoptosis, resulting in increased survival in immunocompromised mice despite their absence of an intact immune system. Conclusions: This study demonstrates the importance of syngeneic tumor resection models in developing cancer immunotherapies and emphasizes the translational potential of local delivery of immunotherapeutic agents in treating cancer. Clin Cancer Res; 23(22); 7047–58. ©2017 AACR.