Spinal Metastases from Colorectal Cancer at Mass General Brigham: A Twenty-Year Case Series With Literature Review.

OBJECTIVE: We present an institutional case series of patients treated for colorectal carcinoma (CRC) spinal metastases to investigate the outcomes between no treatment, radiation, surgery, and surgery/radiation. METHODS: A retrospective cohort of patients with CRC spinal metastases presenting to affiliated institutions between 2001 and 2021 wereidentified. Information related to patient demographics, treatment modality, treatment outcomes, symptom improvement, and survival was collected by chart review. Overall survival (OS) was compared between treatments by log-rank significance testing. A literature review was conducted to identify other cases series of CRC patients with spinal metastases. RESULTS: Eighty-nine patients (mean age 58.5) with CRC spinal metastases across a mean of 3.3 levels met inclusion criteria: 14 (15.7%) received no treatment, 11 (12.4%) received surgery alone, 37 (41.6%) received radiation alone, and 27 (30.3%) received both radiation and surgery. Patients treated with combination therapy had the longest median OS of 24.7 months (range 0.6-85.9), which did not significantly differ from the median OS of 8.9 months (range 0.2-42.6) observed in patients who received no treatment (P = 0.075). Combination therapy provided objectively longer survival time in comparison to other treatment modalities but failed to reach statistical significance. The majority of patients that received treatment (n = 51/75, 68.0%) experienced some degree of symptomatic or functional improvement. CONCLUSIONS: Therapeutic intervention has the potential to improve the quality of life in patients with CRC spinal metastases. We demonstrate that surgery and radiation are useful options for these patients, despite their lack of objective improvement in OS.

Surgical considerations for spinal epidural hematoma evacuation in the setting of blue rubber bleb nevus syndrome in a child.

Blue rubber bleb nevus syndrome (BRBNS) is a rare condition that presents with venous malformation blebs throughout the body, most commonly on the skin and gastrointestinal tract. There have only been a limited number of reports of benign BRBNS lesions involving the spine in children, which were detected after chronic symptomatology. We herein present a unique case of a ruptured BRBNS venous malformation into the epidural space of the lumbar spine in a child presenting with acute neurologic deficit and discuss the relevant surgical considerations for operating in the setting of BRBNS.

Immunotherapy approaches for the treatment of diffuse midline gliomas.

Diffuse midline gliomas (DMG) are a highly aggressive and universally fatal subgroup of pediatric tumors responsible for the majority of childhood brain tumor deaths. Median overall survival is less than 12 months with a 90% mortality rate at 2 years from diagnosis. Research into the underlying tumor biology and numerous clinical trials have done little to change the invariably poor prognosis. Continued development of novel, efficacious therapeutic options for DMGs remains a critically important area of active investigation. Given that DMGs are not amenable to surgical resection, have only limited response to radiation, and are refractory to traditional chemotherapy, immunotherapy has emerged as a promising alternative treatment modality. This review summarizes the various immunotherapy-based treatments for DMG as well as their specific limitations. We explore the use of cell-based therapies, oncolytic virotherapy or immunovirotherapy, immune checkpoint inhibition, and immunomodulatory vaccination strategies, and highlight the recent clinical success of anti-GD2 CAR-T therapy in diffuse intrinsic pontine glioma (DIPG) patients. Finally, we address the challenges faced in translating preclinical and early phase clinical trial data into effective standardized treatment for DMG patients.

Spinal osteomyelitis and epidural abscess caused by ureterovertebral fistula: A case report.

Background: Ureteral fistulas are abnormal connections between the ureters and other organs. Maintaining a high index of suspicion is important because they can precipitate dangerous complications such as sepsis and renal failure. Connections to a vertebral body have only been documented in the setting of trauma. Here, we present a 67-year-old female with a ureterovertebral fistula extending into the L3 vertebral body. Case Description: A 67-year-old female with a history of endometrial adenocarcinoma underwent surgery and radiation therapy complicated by a right ureteral obstruction requiring stent placement. Five months later, she developed back pain and MR-documented L2-L4 level osteomyelitis/discitis with a psoas phlegmon/abscess, which required drainage. A fistula was later identified between the right ureter and the psoas phlegmon. Despite percutaneous nephrostomy placement and aggressive IV antibiotic treatment, she was readmitted for persistent signs of infection over the next few months during which time she was repeatedly and unsuccessfully treated with multiple antibiotics. Sixteen months following her original stent placement, she developed right leg weakness and urinary incontinence attributed to the MR-documented ureteropsoas fistula extending into the L3 vertebral body. Following a nephrectomy with ureteral ligation, an L3 anterior corpectomy with interbody fusion for discitis at both L2-L3 and L3-L4, and an L1-L5 posterolateral fusion, she was discharged to a rehabilitation center. Conclusion: In patients with recurrent sepsis, osteomyelitis/discitis, or psoas abscess of unknown origin or who have a significant history (e.g., pelvic malignancy, radiation, and instrumentation), it is important to consider urodynamic testing to look for a ureteral leak or fistula.

Standard clinical approaches and emerging modalities for glioblastoma imaging.

Glioblastoma (GBM) is the most common primary adult intracranial malignancy and carries a dismal prognosis despite an aggressive multimodal treatment regimen that consists of surgical resection, radiation, and adjuvant chemotherapy. Radiographic evaluation, largely informed by magnetic resonance imaging (MRI), is a critical component of initial diagnosis, surgical planning, and post-treatment monitoring. However, conventional MRI does not provide information regarding tumor microvasculature, necrosis, or neoangiogenesis. In addition, traditional MRI imaging can be further confounded by treatment-related effects such as pseudoprogression, radiation necrosis, and/or pseudoresponse(s) that preclude clinicians from making fully informed decisions when structuring a therapeutic approach. A myriad of novel imaging modalities have been developed to address these deficits. Herein, we provide a clinically oriented review of standard techniques for imaging GBM and highlight emerging technologies utilized in disease characterization and therapeutic development.

Targeting oncometabolism to maximize immunotherapy in malignant brain tumors.

Brain tumors result in significant morbidity and mortality in both children and adults. Recent data indicate that immunotherapies may offer a survival benefit after standard of care has failed for malignant brain tumors. Modest results from several late phase clinical trials, however, underscore the need for more refined, comprehensive strategies that incorporate new mechanistic and pharmacologic knowledge. Recently, oncometabolism has emerged as an adjunct modality for combinatorial treatment approaches necessitated by the aggressive, refractory nature of high-grade glioma and other progressive malignant brain tumors. Manipulation of metabolic processes in cancer and immune cells that comprise the tumor microenvironment through controlled targeting of oncogenic pathways may be utilized to maximize the efficacy of immunotherapy and improve patient outcomes. Herein, we summarize preclinical and early phase clinical trial research of oncometabolism-based therapeutics that may augment immunotherapy by exploiting the biochemical and genetic underpinnings of brain tumors. We also examine metabolic pathways related to immune cells that target tumor cells, termed "tumor immunometabolism". Specifically, we focus on glycolysis and altered glucose metabolism, including glucose transporters, hexokinase, pyruvate dehydrogenase, and lactate dehydrogenase, glutamine, and we discuss targeting arginase, adenosine, and indoleamine 2,3-dioxygenase, and toll-like receptors. Lastly, we summarize future directions targeting metabolism in combination with emerging therapies such as oncolytic virotherapy, vaccines, and chimeric antigen receptor T cells.

Tumor-Associated Macrophages/Microglia in Glioblastoma Oncolytic Virotherapy: A Double-Edged Sword.

Oncolytic virotherapy is a rapidly progressing field that uses oncolytic viruses (OVs) to selectively infect malignant cells and cause an antitumor response through direct oncolysis and stimulation of the immune system. Despite demonstrated pre-clinical efficacy of OVs in many cancer types and some favorable clinical results in glioblastoma (GBM) trials, durable increases in overall survival have remained elusive. Recent evidence has emerged that tumor-associated macrophage/microglia (TAM) involvement is likely an important factor contributing to OV treatment failure. It is prudent to note that the relationship between TAMs and OV therapy failures is complex. Canonically activated TAMs (i.e., M1) drive an antitumor response while also inhibiting OV replication and spread. Meanwhile, M2 activated TAMs facilitate an immunosuppressive microenvironment thereby indirectly promoting tumor growth. In this focused review, we discuss the complicated interplay between TAMs and OV therapies in GBM. We review past studies that aimed to maximize effectiveness through immune system modulation-both immunostimulatory and immunosuppressant-and suggest future directions to maximize OV efficacy.

Three-dimensional Navigation-guided, Prone, Single-position, Lateral Lumbar Interbody Fusion Technique.

Lateral interbody fusion provides a significant biomechanical advantage over the traditional transforaminal lumbar interbody fusion due to the large implant size and optimal implant position. However, current methods for lateral interbody cage placement require either a two-staged procedure or a single lateral decubitus position that precludes surgeons from having either full access to the posterior spine for direct decompression or comfortable pedicle screw placement. Herein is one institution's experience with 10 cases of a prone single-position approach for simultaneous access to the anterior and posterior lumbar spine. This allows both lateral lumbar interbody cage placement, direct posterior decompression, and pedicle screw placement, all in one position. Three-dimensional (3D) navigation is utilized for increased precision in both approaching the lateral spine and interbody cage placement. The traditional blind psoas muscle tubular dilation was also modified. Tubular retractors and lateral vertebral body retractor pins were used to minimize the risks to the lumbar plexus.

Atypical representation of sensorimotor cortex in a patient with autism and epilepsy confirmed by direct electrocortical stimulation.

Prior studies have used functional neuroimaging to demonstrate that the organization of the autistic brain is different from that of the non-autistic brain. Similarly, patients with epilepsy have also shown cortical reorganization. We present a case study that provides direct confirmation of disorganized sensorimotor distribution in a patient with autism spectrum disorder and epilepsy. To our knowledge, this is the first time cortical mapping directly showing abnormal cortical organization in a patient with autism spectrum disorder and epilepsy has been reported in the literature.

The Neural Sulcus of the Cervical Vertebrae: A Review of Its Anatomy and Surgical Perspectives.

The neural sulcus is a bony channel that spans the transverse process in the subaxial cervical spine. It is located between the anterior and posterior tubercles on either side of the transverse foramen, housing the spinal nerve as it passes through the intervertebral foramina. Although numerous studies have evaluated the anatomy of the cervical spine, very little data on detailed anatomy of the neural sulcus and its implication in cervical spine surgery exist. Here, we review the anatomy of the neural sulcus and surgical considerations. The neural sulcus has important surgical implications, and knowledge of its anatomy is important in considering and planning posterior cervical segmented instrumentation. This increases the ability of the neurosurgeon to choose the best suitable surgical approach to the subaxial cervical spine, allowing good outcomes for the patient.

Reattachment of the Multifidus Tendon in Lumbar Surgery to Decrease Postoperative Back Pain: A Technical Note.

The posterior midline approach to the lumbar spine requires significant manipulation of the paraspinal muscles. Muscle detachment and retraction results in iatrogenic damage such as crush injury, devascularization, and denervation, all of which have been associated with postoperative pain. The muscle most directly affected by the posterior approach is the lumbar multifidus (LM), the largest and most medial of the deep lumbar paraspinal muscles. The effects of the posterior approach on the integrity of the LM is concerning, as multiple studies have demonstrated that intraoperative injuries sustained by the LM lead to postoperative muscle atrophy and potentially worsening low back pain. Given the inevitability of intraoperative paraspinal muscle manipulation when using the posterior approach, this technical note describes methods by which surgeons may minimize LM tissue disruption and restore the anatomical position of the LM to ultimately expedite recovery, minimize postoperative pain, and improve patient satisfaction.

Delayed Cerebral Ischemia of the Corpus Callosum: A Case Report.

Ischemic infarction of the corpus callosum is a rare condition due to its rich vascular supply and therefore has been infrequently reported. Here, we present a case of a patient who developed a delayed infarct of the corpus callosum in the body. The condition was characterized by bilateral lower extremity weakness and visual disturbances following intraventricular hemorrhage managed with ventriculostomy. Understanding the anatomy and function of the corpus callosum is crucial to understanding the etiology of infarctions as well as their clinical significance. It is also essential to distinguish between relatively common post-shunting changes and true infarction and to recognize the limited consequences of corpus callosum infarction. Increased awareness of this rare infarct would help to prevent unnecessary interventions and increase the ability of the physician to provide optimal care for the patient.

Multimodal imaging-defined subregions in newly diagnosed glioblastoma: impact on overall survival.

BACKGROUND: Although glioblastomas are heterogeneous brain-infiltrating tumors, their treatment is mostly focused on the contrast-enhancing tumor mass. In this study, we combined conventional MRI, diffusion-weighted imaging (DWI), and amino acid PET to explore imaging-defined glioblastoma subregions and evaluate their potential prognostic value. METHODS: Contrast-enhanced T1, T2/fluid attenuated inversion recovery (FLAIR) MR images, apparent diffusion coefficient (ADC) maps from DWI, and alpha-[11C]-methyl-L-tryptophan (AMT)-PET images were analyzed in 30 patients with newly diagnosed glioblastoma. Five tumor subregions were identified based on a combination of MRI contrast enhancement, T2/FLAIR signal abnormalities, and AMT uptake on PET. ADC and AMT uptake tumor/contralateral normal cortex (T/N) ratios in these tumor subregions were correlated, and their prognostic value was determined. RESULTS: A total of 115 MRI/PET-defined subregions were analyzed. Most tumors showed not only a high-AMT uptake (T/N ratio > 1.65, N = 27) but also a low-uptake subregion (N = 21) within the contrast-enhancing tumor mass. High AMT uptake extending beyond contrast enhancement was also common (N = 25) and was associated with low ADC (r = -0.40, P = 0.05). Higher AMT uptake in the contrast-enhancing tumor subregions was strongly prognostic for overall survival (hazard ratio: 7.83; 95% CI: 1.98-31.02, P = 0.003), independent of clinical and molecular genetic prognostic variables. Nonresected high-AMT uptake subregions predicted the sites of tumor progression on posttreatment PET performed in 10 patients. CONCLUSIONS: Glioblastomas show heterogeneous amino acid uptake with high-uptake regions often extending into non-enhancing brain with high cellularity; nonresection of these predict the site of posttreatment progression. High tryptophan uptake values in MRI contrast-enhancing tumor subregions are a strong, independent imaging marker for longer overall survival.

Candida parapsilosis Infection of Ventriculoperitoneal Shunt in Adult: Case Report and Literature Review.

BACKGROUND: Candida parapsilosis is an incredibly rare cause of ventriculoperitoneal (VP) shunt infections, with only 1 adult case reported in the literature to date. CASE DESCRIPTION: We describe the case of a 45-year-old man admitted for a traumatic fall and subsequently treated with VP shunt placement for obstructive hydrocephalus secondary to a cerebellar contusion and intraventricular hemorrhage. Eight months following VP shunt placement, the patient presented with a 2-month history of clear fluid leakage through a dehiscent surgical abdominal wound overlying the distal VP shunt. Cerebrospinal fluid cultures were obtained and grew C. parapsilosis. The patient subsequently underwent VP shunt externalization and began antifungal treatment with intravenous liposomal amphotericin B. Cerebrospinal fluid studies continued to redemonstrate C. parapsilosis infection, for which VP shunt removal and external ventricular drain placement was performed. Three days into treatment with amphotericin B, he endured significant nephrotoxicity necessitating a switch to oral fluconazole. Following 3 weeks of oral fluconazole treatment with negative serial cerebrospinal fluid cultures, the patient underwent external ventricular drain removal and VP shunt insertion. Following the procedure and 22 total days of oral fluconazole treatment, our patient recovered well and was discharged to a rehabilitation facility in stable condition. CONCLUSIONS: In our report, we describe the clinical course of our patient and offer a review and analysis of the most up-to-date literature concerning C. parapsilosis shunt infections, as well as treatment guidelines for central nervous system candidiasis.

Deep brain stimulation for seizure control in drug-resistant epilepsy.

Antiepileptic drugs prevent morbidity and death in a large number of patients suffering from epilepsy. However, it is estimated that approximately 30% of epileptic patients will not have adequate seizure control with medication alone. Resection of epileptogenic cortex may be indicated in medically refractory cases with a discrete seizure focus in noneloquent cortex. For patients in whom resection is not an option, deep brain stimulation (DBS) may be an effective means of seizure control. Deep brain stimulation targets for treating seizures primarily include the thalamic nuclei, hippocampus, subthalamic nucleus, and cerebellum. A variety of stimulation parameters have been studied, and more recent advances in electrical stimulation to treat epilepsy include responsive neurostimulation. Data suggest that DBS is effective for treating drug-resistant epilepsy.

Investigation of the aryl hydrocarbon receptor and the intrinsic tumoral component of the kynurenine pathway of tryptophan metabolism in primary brain tumors.

INTRODUCTION: There is mounting evidence supporting the role of tryptophan metabolism via the kynurenine pathway (KP) in the pathogenesis of primary brain tumors. Under normal physiological conditions, the KP is the major catabolic pathway for the essential amino acid tryptophan. However, in cancer cells, the KP becomes dysregulated, depletes local tryptophan, and contributes to an immunosuppressive tumor microenvironment. METHODS: We examined the protein expression levels (in 73 gliomas and 48 meningiomas) of the KP rate-limiting enzymes indoleamine 2,3-dioxygenase (IDO) 1, IDO2, and tryptophan 2,3-dioxygenase (TDO2), as well as, the aryl hydrocarbon receptor (AhR), a carcinogenic transcription factor activated by KP metabolites. In addition, we utilized commercially available small-molecules to pharmacologically modulate IDO1, IDO2, TDO2, and AhR in patient-derived glioma and meningioma cell lines (n = 9 each). RESULTS: We observed a positive trend between the grade of the tumor and the average immunohistochemical staining score for IDO1, IDO2, and TDO2, with TDO2 displaying the strongest immunostaining. AhR immunostaining was present in all grades of gliomas and meningiomas, with the greatest staining intensity noted in glioblastomas. Immunocytochemical staining showed a positive trend between nuclear localization of AhR and histologic grade in both gliomas and meningiomas, suggesting increased AhR activation with higher tumor grade. Unlike enzyme inhibition, AhR antagonism markedly diminished patient-derived tumor cell viability, regardless of tumor type or grade, following in vitro drug treatments. CONCLUSIONS: Collectively, these results suggest that AhR may offer a novel and robust therapeutic target for a patient population with highly limited treatment options.

Alternating electric tumor treating fields for treatment of glioblastoma: rationale, preclinical, and clinical studies.

OBJECTIVE Treatment for glioblastoma (GBM) remains largely unsuccessful, even with aggressive combined treatment via surgery, radiotherapy, and chemotherapy. Tumor treating fields (TTFs) are low-intensity, intermediate-frequency, alternating electric fields that have antiproliferative properties in vitro and in vivo. The authors provide an up-to-date review of the mechanism of action as well as preclinical and clinical data on TTFs. METHODS A systematic review of the literature was performed using the terms "tumor treating fields," "alternating electric fields," "glioblastoma," "Optune," "NovoTTF-100A," and "Novocure." RESULTS Preclinical and clinical data have demonstrated the potential efficacy of TTFs for treatment of GBM, leading to several pilot studies, clinical trials, and, in 2011, FDA approval for its use as salvage therapy for recurrent GBM and, in 2015, approval for newly diagnosed GBM. CONCLUSIONS Current evidence supports the use of TTFs as an efficacious, antimitotic treatment with minimal toxicity in patients with newly diagnosed and recurrent GBM. Additional studies are needed to further optimize patient selection, determine cost-effectiveness, and assess the full impact on quality of life.

Management of brain tumor-related epilepsy.

Seizures are common in both primary and metastatic brain tumors, although the rate of seizures differ significantly between the different types of neoplasms. Patients with brain tumor-associated seizures need treatment with antiepileptic drugs (AEDs) to prevent recurrence, whereas strong clinical data exists to discourage routine prophylaxis in patients who have not had seizures. The newer AEDs, such as levetiracetam, lamotrigine, lacosamide, topiramate, or pregabalin, are preferable for various reasons, primarily related to the side-effect profile and limited interactions with other drugs. If seizures persist despite initiation of an appropriate monotherapy (in up to 30-40% of cases), additional anticonvulsants may be necessary. Early surgical intervention improves seizure outcomes in individuals with medically refractory epilepsy, especially in patients with a single lesion that is epileptogenic. Data for this review article were compiled by searching for scholarly articles using the following keywords: brain tumor, epilepsy, seizure, tumor-related epilepsy, central nervous system, epidemiology, review, clinical trial, and surgery. Articles were screened for relevance by title and abstract, and selected for review and inclusion based on significant contribution to the topics discussed.

Prognostic Molecular and Imaging Biomarkers in Primary Glioblastoma.

PURPOSE: Several molecular glioma markers (including isocitrate dehydrogenase 1 [IDH1] mutation, amplification of the epidermal growth factor receptor [EGFR], and methylation of the O6-methylguanine-DNA methyltransferase [MGMT] promoter) have been associated with glioblastoma survival. In this study, we examined the association between tumoral amino acid uptake, molecular markers, and overall survival in patients with IDH1 wild-type (primary) glioblastoma. PATIENTS AND METHODS: Twenty-one patients with newly diagnosed IDH1 wild-type glioblastomas underwent presurgical MRI and PET scanning with alpha[C-11]-L-methyl-tryptophan (AMT). MRI characteristics (T2- and T1-contrast volume), tumoral tryptophan uptake, PET-based metabolic tumor volume, and kinetic variables were correlated with prognostic molecular markers (EGFR and MGMT) and overall survival. RESULTS: EGFR amplification was associated with lower T1-contrast volume (P = 0.04) as well as lower T1-contrast/T2 volume (P = 0.04) and T1-contrast/PET volume ratios (P = 0.02). Tumors with MGMT promoter methylation showed lower metabolic volume (P = 0.045) and lower tumor/cortex AMT unidirectional uptake ratios than those with unmethylated MGMT promoter (P = 0.009). While neither EGFR amplification nor MGMT promoter methylation was significantly associated with survival, high AMT tumor/cortex uptake ratios on PET were strongly prognostic for longer survival (hazards ratio, 30; P = 0.002). Estimated mean overall survival was 26 months in patients with high versus 8 months in those with low tumoral AMT uptake ratios. CONCLUSIONS: The results demonstrate specific MRI and amino acid PET imaging characteristics associated with EGFR amplification and MGMT promoter methylation in patients with primary glioblastoma. High tryptophan uptake on PET may identify a subgroup with prolonged survival.