Analiz Rodriguez

The role of laser interstitial thermal therapy in enhancing progression‐free survival of difficult‐to‐access high‐grade gliomas: a multicenter study

Surgical extent‐of‐resection has been shown to have an impact on high‐grade glioma (HGG) outcomes; however, complete resection is rarely achievable in difficult‐to‐access (DTA) tumors. Controlled thermal damage to the tumor may have the same impact in DTA‐HGGs. We report our multicenter results of laser interstitial thermal therapy (LITT) in DTA‐HGGs. We retrospectively reviewed 34 consecutive DTA‐HGG patients (24 glioblastoma, 10 anaplastic) who underwent LITT at Cleveland Clinic, Washington University, and Wake Forest University (May 2011–December 2012) using the NeuroBlate® System. The extent of thermal damage was determined using thermal damage threshold (TDT) lines: yellow TDT line (43°C for 2 min) and blue TDT line (43°C for 10 min). Volumetric analysis was performed to determine the extent‐of‐coverage of tumor volume by TDT lines. Patient outcomes were evaluated statistically. LITT was delivered as upfront in 19 and delivered as salvage in 16 cases. After 7.2 months of follow‐up, 71% of cases demonstrated progression and 34% died. The median overall survival (OS) for the cohort was not reached; however, the 1‐year estimate of OS was 68 ± 9%. Median progression‐free survival (PFS) was 5.1 months. Thirteen cases who met the following two criteria—(1) <0.05 cm3 tumor volume not covered by the yellow TDT line and (2) <1.5 cm3 additional tumor volume not covered by the blue TDT line—had better PFS than the other 21 cases (9.7 vs. 4.6 months; P = 0.02). LITT can be used effectively for treatment of DTA‐HGGs. More complete coverage of tumor by TDT lines improves PFS which can be translated as the extent of resection concept for surgery.

Quantitative in vivo cytokine analysis at synthetic biomaterial implant sites

To further elucidate the foreign body reaction, investigation of cytokines at biomaterial implant sites was carried out using a multiplex immunoassay and ELISA. Macrophage activation cytokines (IL-1beta, IL-6, and TNFalpha), cytokines important for macrophage fusion (IL-4 and IL-13), antiinflammatory cytokines (IL-10 and TGFbeta), chemokines (GRO/KC, MCP-1), and the T-cell activation cytokine IL-2 were quantified at biomaterial implant sites. Empty cages (controls) or cages containing synthetic biomedical polymer (Elasthane 80A (PEU), silicone rubber (SR), or polyethylene terephthalate (PET)) were implanted subcutaneously in Sprague-Dawley rats for 4, 7, or 14 days, and cytokines in exudate supernatants and macrophage surface adhesion and fusion were quantified. The presence of a polymer implant did not affect the levels of IL-1beta, TGFbeta, and MCP-1 in comparison to the control group. IL-2 was not virtually detected in any of the samples. Although the levels of IL-4, IL-13, IL-10, and GRO/KC were affected by polymer implantation, but not dependent on a specific polymer, IL-6 and TNFalpha were significantly greater in those animals implanted with PEU and SR, materials that do not promote fusion. The results indicate that differential material-dependent cytokine profiles are produced by surface adherent macrophages and foreign body giant cells in vivo.

The foreign body reaction in T‐cell‐deficient mice

The role(s) of T lymphocytes in the foreign body response has not been thoroughly elucidated. Lymphocytes are known to augment macrophage adhesion and fusion in vitro. Furthermore, T lymphocytes are a possible source of the cytokines, IL-4 and IL-13, which induce macrophage fusion. In this study, we used BALB/c mice and BALB/c (nu/nu) nude mice to investigate foreign body giant cell (FBGC) formation in a T-cell-deficient setting. Mice were implanted with Elasthane 80A (PEU), silicone rubber (SR), or poly(ethylene terephthalate) (PET) for 7, 14, or 21 days using the cage implant system. Exudate cells and IL-4 and IL-13 levels in exudate supernatants were analyzed by flow cytometry and a multiplex immunoassay, respectively, at Days 7, 14, and 21. Macrophage adhesion and fusion on material surfaces were analyzed using optical microscopy. T-cell-deficient mice had lower total leukocyte concentrations at the biomaterial implant site at all time points. Adherent cell density was comparable between normal and T-cell-deficient mice except in the PEU group at Day 21. However, percent fusion, average nuclei per FBGC, and FBGC morphology were comparable between normal and T-cell-deficient mice. IL-4 was not detected in any sample, but IL-13 levels were also comparable between normal and T-cell-deficient mice indicating Th2-polarized T-cells are not the sole source of this cytokine. We have shown that there are pathways that do not require thymus-matured T lymphocytes, which lead to a normal foreign body response to biomaterials in a murine model.

Novel placement of cortical bone trajectory screws in previously instrumented pedicles for adjacent-segment lumbar disease using CT image-guided navigation

OBJECT Symptomatic adjacent-segment lumbar disease (ASLD) after lumbar fusion often requires subsequent surgical intervention. The authors report utilizing cortical bone trajectory (CBT) pedicle screw fixation with intraoperative CT (O-arm) image-guided navigation to stabilize spinal levels in patients with symptomatic ASLD. This unique technique results in the placement of 2 screws in the same pedicle (1 traditional pedicle trajectory and 1 CBT) and obviates the need to remove preexisting instrumentation. METHODS The records of 5 consecutive patients who underwent lumbar spinal fusion with CBT and posterior interbody grafting for ASLD were retrospectively reviewed. All patients underwent screw trajectory planning with the O-arm in conjunction with the StealthStation navigation system. Basic demographics, operative details, and radiographic and clinical outcomes were obtained. RESULTS The average patient age was 69.4 years (range 58-82 years). Four of the 5 surgeries were performed with the Minimal Access Spinal Technologies (MAST) Midline Lumbar Fusion (MIDLF) system. The average operative duration was 218 minutes (range 175-315 minutes). In the entire cohort, 5.5-mm cortical screws were placed in previously instrumented pedicles. The average hospital stay was 2.8 days (range 2-3 days) and there were no surgical complications. All patients had more than 6 months of radiographic and clinical follow-up (range 10-15 months). At last follow-up, all patients reported improved symptoms from their preoperative state. Radiographic follow-up showed Lenke fusion grades of A or B. CONCLUSIONS The authors present a novel fusion technique that uses CBT pedicle screw fixation in a previously instrumented pedicle with intraoperative O-arm guided navigation. This method obviates the need for hardware removal. This cohort of patients experienced good clinical results. Computed tomography navigation was critical for accurate CBT screw placement at levels where previous traditional pedicle screws were already placed for symptomatic ASLD.

Neurosurgical Techniques for Disruption of the Blood–Brain Barrier for Glioblastoma Treatment

The blood–brain barrier remains a main hurdle to drug delivery to the brain. The prognosis of glioblastoma remains grim despite current multimodal medical management. We review neurosurgical technologies that disrupt the blood–brain barrier (BBB). We will review superselective intra-arterial mannitol infusion, focused ultrasound, laser interstitial thermotherapy, and non-thermal irreversible electroporation (NTIRE). These technologies can lead to transient BBB and blood–brain tumor barrier disruption and allow for the potential of more effective local drug delivery. Animal studies and preliminary clinical trials show promise for achieving this goal.

Evaluation of clinical biomaterial surface effects on T lymphocyte activation

Previous in vitro studies in our laboratory have shown that lymphocytes can influence macrophage adhesion and fusion on biomaterial surfaces. However, few studies have evaluated how material adherent macrophages can influence lymphocyte behavior, specifically T cells. In this study, we cultured human peripheral blood mononuclear cells from healthy donors on three synthetic nonbiodegradable biomedical polymers: elasthane 80A (PEU), silicone rubber (SR), or polyethylene terephthalate (PET) and tissue culture polystyrene (TCPS). Upregulation of T cell surface activation markers (CD69 and CD25), lymphocyte proliferation, and interleukin-2 (IL-2) and interferon-gamma (IFNgamma) concentrations were evaluated by flow cytometry, carboxy-fluorescein diacetate, succinimydyl ester (CFSE) incorporation, and multiplex cytokine immunoassay, respectively, to assess T cell activation. Following 3 and 7 days of culture, CD4+ helper T cells from cultures of any of the material groups did not express the activation markers CD69 and CD25 and lymphocyte proliferation was not present. IL-2 and IFNgamma levels were produced, but dependent on donor. These data indicate that T cells are not activated in response to clinically relevant synthetic biomaterials. The data also suggest that lymphocyte subsets exclusive of T cells are the source of the lymphokines, IL-2 and IFN-gamma, in certain donors.

Chimeric Antigen Receptors T Cell Therapy in Solid Tumor: Challenges and Clinical Applications

Adoptive cellular immunotherapy (ACT) employing engineered T lymphocytes expressing chimeric antigen receptors (CARs) has demonstrated promising antitumor effects in advanced hematologic cancers, such as relapsed or refractory acute lymphoblastic leukemia, chronic lymphocytic leukemia, and non-Hodgkin lymphoma, supporting the translation of ACT to non-hematological malignancies. Although CAR T cell therapy has made remarkable strides in the treatment of patients with certain hematological cancers, in solid tumors success has been limited likely due to heterogeneous antigen expression, immunosuppressive networks in the tumor microenvironment limiting CAR T cell function and persistence, and suboptimal trafficking to solid tumors. Here, we outline specific approaches to overcome barriers to CAR T cell effectiveness in the context of the tumor microenvironment and offer our perspective on how expanding the use of CAR T cells in solid tumors may require modifications in CAR T cell design. We anticipate these modifications will further expand CAR T cell therapy in clinical practice.

Tracking Career Paths of Women in Neurosurgery

BACKGROUND Women represent a growing cohort of US neurosurgeons. OBJECTIVE To describe postresidency fellowship, practice environment, and updated academic rank among female neurosurgeons. METHODS Databases from the American Association of Neurological Surgeons (AANS) and the American Board of Neurological Surgery (ABNS) from 1964 to 2013 were reviewed for female neurosurgery residency graduates. Data on postresidency fellowships, practice environment (private vs academic), academic rank, board certification, and AANS/CNS (Congress of Neurological Surgeons) Joint Section on Women in Neurosurgery (WINS) membership were collected in 2016. Academic rank was verified from program websites and electronic correspondence. Faculty members were asked to report directorships and tenure. The AANS/CNS Joint Section on Women in Neurosurgery verified WINS membership. RESULTS A total of 379 female neurosurgery residency graduates were identified in this 50-yr span. Of these, 70% became ABNS certified, and 2.1% left neurosurgery. Twenty-seven percent of women (n = 103) pursued fellowships, with pediatric neurosurgery (33%) the most common. Regarding practice environment, 26% entered academic medicine (n = 91), with 42 at the rank of assistant professor, 33 at the rank of associate professor, and 16 reaching the rank of full professor. CONCLUSION Upon completion of training, 27% of women pursue fellowships. The distribution of women in private vs academic practice environments is proportionate to male neurosurgeons; however, the number women in academic leadership positions remains exceedingly low, with disproportionate representation in higher academic ranks. Women in national organized neurosurgery are increasing. Tracking the career paths of women in neurosurgery is a necessary step to identifying current achievements and opportunities for future progress.

Chimeric antigen receptor T-cell therapy for glioblastoma

Chimeric antigen receptor (CAR) T-cell therapy has shown great promise in the treatment of hematological disease, and its utility for treatment of solid tumors is beginning to unfold. Glioblastoma continues to portend a grim prognosis and immunotherapeutic approaches are being explored as a potential treatment strategy. Identification of appropriate glioma-associated antigens, barriers to cell delivery, and presence of an immunosuppressive microenvironment are factors that make CAR T-cell therapy for glioblastoma particularly challenging. However, insights gained from preclinical studies and ongoing clinical trials indicate that CAR T-cell therapy will continue to evolve and likely become integrated with current therapeutic strategies for malignant glioma.

Anatomical Variations of the Transverse-Sigmoid Sinus Junction: Implications for Endovascular Treatment of Idiopathic Intracranial Hypertension.

Venous sinus pathology can result in multiple pathological diseases, including idiopathic intracranial hypertension (IIH). There remains a paucity of information on anatomical luminal variations of the major venous sinuses which may contribute to the etiology of certain disease states. Thirty‐six transverse and sigmoid sinuses were removed following dissection of 19 unfixed cadaveric heads. Sinuses were opened longitudinally to study luminal variations. A semiquantitative classification system was developed to assess septations and blind pouches. Seventy‐nine percent of cadavers had a luminal anatomical variation. Forty‐four percent and 42% of sinuses dissected had occurrence of a septations or blind pouches, respectively. Thirty percent of septations and 25% of pouches were classified as large. Incidence of anatomical variations was not statistically significant between cadaver gender or sinus laterality. Luminal variations are present in the transverse and sigmoid sinuses at rates higher than expected. This study is the first to report the presence of blind pouches in the luminal wall of transverse and sigmoid sinuses. These variations can have clinical importance to the endovascular surgeon and may also contribute to the pathophysiological etiology of venous sinus diseases. Anat Rec, 299:1037–1042, 2016.