Autologous cell immunotherapy (IGV-001) with IGF-1R antisense oligonucleotide in newly diagnosed glioblastoma patients.

Standard-of-care first-line therapy for patients with newly diagnosed glioblastoma (ndGBM) is maximal safe surgical resection, then concurrent radiotherapy and temozolomide, followed by maintenance temozolomide. IGV-001, the first product of the Goldspire™ platform, is a first-in-class autologous immunotherapeutic product that combines personalized whole tumor-derived cells with an antisense oligonucleotide (IMV-001) in implantable biodiffusion chambers, with the intent to induce a tumor-specific immune response in patients with ndGBM. Here, we describe the design and rationale of a randomized, double-blind, phase IIb trial evaluating IGV-001 compared with placebo, both followed by standard-of-care treatment in patients with ndGBM. The primary end point is progression-free survival, and key secondary end points include overall survival and safety.

Glioblastoma (GBM) is a fast-growing brain tumor that happens in about half of all gliomas. Surgery is the first treatment for patients with newly diagnosed GBM, followed by the usual radiation and chemotherapy pills named temozolomide. Temozolomide pills are then given as a long-term treatment. The outcome for the patient with newly diagnosed GBM remains poor. IGV-001 is specially made for each patient. The tumor cells are removed during surgery and mixed in the laboratory with a small DNA, IMV-001. This mix is the IGV-001 therapy that is designed to give antitumor immunity against GBM. IGV-001 is put into small biodiffusion chambers that are irradiated to stop the growth of any tumor cells in the chambers. In the phase IIb study, patients with newly diagnosed GBM are chosen and assigned to either the IGV-001 or the placebo group. A placebo does not contain any active ingredients. The small biodiffusion chambers containing either IGV-001 or placebo are surgically placed into the belly for 48 to 52 h and then removed. Patients then receive the usual radiation and chemotherapy treatment. Patients must be adults aged between 18 and 70 years. Patients also should be able to care for themselves overall, but may be unable to work or have lower ability to function. Patients with tumors on both sides of the brain are not eligible. The main point of this study is to see if IGV-001 helps patients live longer without making the illness worse compared with placebo. Clinical Trial Registration: NCT04485949 (ClinicalTrials.gov).

Postmortem study of organ-specific toxicity in glioblastoma patients treated with a combination of temozolomide, irinotecan and bevacizumab.

PURPOSE: Systemic chemotherapy including monotherapy with temozolomide (TMZ) or bevacizumab (BEV); two-drug combinations, such as irinotecan (IRI) and BEV, TMZ and BEV and a three-drug combination with TMZ, IRI and BEV (TIB) have been used in treating patients with progressive high-grade gliomas including glioblastoma (GBM). Most patients tolerated these regimens well with known side effects of hypertension, proteinuria, and reversible clinical myelosuppression (CM). However, organ- or system- specific toxicities from chemotherapy agents have never been examined by postmortem study. This is the largest cohort used to address this issue in glioma patients. METHODS: Postmortem tissues (from all major systems and organs) were prospectively collected and examined by standard institution autopsy and neuropathological procedures from 76 subjects, including gliomas (N = 68, 44/M, and 24/F) and brain metastases (N = 8, 5/M, and 3/F) between 2009 and 2019. Standard hematoxylin and eosin (H&E) were performed on all major organs including brain specimens. Electronic microscopic (EM) study was carried out on 14 selected subject's kidney samples per standard EM protocol. Medical records were reviewed with adverse events (AEs) analyzed and graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4.03. A swimmer plot was utilized to visualize the timelines of patient history by treatment group. The binary logistic regression models were performed to explore any associations between treatment strategies and incident myelosuppression. RESULTS: Twenty-four glioma subjects were treated with TIB [median: 5.5 (range: 1-25) cycles] at tumor recurrence. Exposure to IRI significantly increased the frequency of CM (p = 0.05). No unexpected adverse events clinically, or permanent end-organ damage during postmortem examination was identified in glioma subjects who had received standard or prolonged duration of BEV, TMZ or TIB regimen-based chemotherapies except rare events of bone marrow suppression. The most common causes of death (COD) were tumor progression (63.2%, N = 43) followed by aspiration pneumonia (48.5%, N = 33) in glioma subjects. No COD was attributed to acute toxicity from TIB. The study also demonstrated that postmortem kidney specimen is unsuitable for studying renal ultrastructural pathological changes due to autolysis. CONCLUSION: There is no organ or system toxicity by postmortem examinations among glioma subjects who received BEV, TMZ or TIB regimen-based chemotherapies regardless of durations except for occasional bone marrow suppression and reversible myelosuppression clinically. IRI, but not the extended use of TMZ, significantly increased CM in recurrent glioma patients. COD most commonly resulted from glioma tumor progression with infiltration to brain stem and aspiration pneumonia.

Correction to: First results on survival from a large Phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma.

Following publication of the original article [1], the authors reported an error in the spelling of one of the author names. In this Correction the incorrect and correct author names are indicated and the author name has been updated in the original publication. The authors also reported an error in the Methods section of the original article. In this Correction the incorrect and correct versions of the affected sentence are indicated. The original article has not been updated with regards to the error in the Methods section.

First results on survival from a large Phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma.

BACKGROUND: Standard therapy for glioblastoma includes surgery, radiotherapy, and temozolomide. This Phase 3 trial evaluates the addition of an autologous tumor lysate-pulsed dendritic cell vaccine (DCVax®-L) to standard therapy for newly diagnosed glioblastoma. METHODS: After surgery and chemoradiotherapy, patients were randomized (2:1) to receive temozolomide plus DCVax-L (n = 232) or temozolomide and placebo (n = 99). Following recurrence, all patients were allowed to receive DCVax-L, without unblinding. The primary endpoint was progression free survival (PFS); the secondary endpoint was overall survival (OS). RESULTS: For the intent-to-treat (ITT) population (n = 331), median OS (mOS) was 23.1 months from surgery. Because of the cross-over trial design, nearly 90% of the ITT population received DCVax-L. For patients with methylated MGMT (n = 131), mOS was 34.7 months from surgery, with a 3-year survival of 46.4%. As of this analysis, 223 patients are ≥ 30 months past their surgery date; 67 of these (30.0%) have lived ≥ 30 months and have a Kaplan-Meier (KM)-derived mOS of 46.5 months. 182 patients are ≥ 36 months past surgery; 44 of these (24.2%) have lived ≥ 36 months and have a KM-derived mOS of 88.2 months. A population of extended survivors (n = 100) with mOS of 40.5 months, not explained by known prognostic factors, will be analyzed further. Only 2.1% of ITT patients (n = 7) had a grade 3 or 4 adverse event that was deemed at least possibly related to the vaccine. Overall adverse events with DCVax were comparable to standard therapy alone. CONCLUSIONS: Addition of DCVax-L to standard therapy is feasible and safe in glioblastoma patients, and may extend survival. Trial registration Funded by Northwest Biotherapeutics; Clinicaltrials.gov number: NCT00045968; https://clinicaltrials.gov/ct2/show/NCT00045968?term=NCT00045968&rank=1 ; initially registered 19 September 2002.

Intramuscular myxoma of the cervical paraspinal musculature: case report and review of the literature.

CASE: A 57year old female patient presented with a painful right-sided neck mass that on MRI was shown to be adherent to the posterior aspect of the sternocleidomastoid muscle. The mass was surgically resected en bloc without complications. Histopathologic analysis revealed the mass to be a myxoma. REVIEW: To date, there have been several case reports of myxomas, although very few involving the head or neck. The majority of the literature available concurs that myxomas are benign neoplasms that exhibit characteristic qualities on MRI imaging. The definitive treatment by consensus is surgical excision. CONCLUSIONS: Although the incidence of head and neck myxomas is low, it is important to include in the differential of a neck mass with certain radiographic findings.

Extracranial arteriovenous malformation mimicking a peripheral nerve tumor: illustrative case.

BACKGROUND: Arteriovenous malformations (AVMs) are vascular malformations that are more commonly found intracranially, followed by the head, neck, limbs, and trunk. Extracranially, AVMs can mimic peripheral nerve tumors, leading to misdiagnosis. OBSERVATIONS: A 19-year-old female, who presented with left lateral lower leg pain, was preoperatively thought to have a peripheral nerve tumor; at surgery, however, she was found to have an extracranial AVM. The distinct margins of the tumor on preoperative magnetic resonance imaging suggested that the patient might have a peripheral nerve tumor; however, the clinical symptoms of focal pain at rest and the absence of Tinel's sign should have raised questions about this diagnosis. LESSONS: This case highlights the difficulty in differentiating a peripheral nerve tumor from an extracranial AVM in certain clinical scenarios. It is important to use a multifaceted diagnostic approach to get a correct preoperative diagnosis and plan treatment appropriately.

Postoperative Hyponatremia after Endoscopic Endonasal Resection of Pituitary Adenomas: Historical Complication Rates and Risk Factors.

BACKGROUND: Hyponatremia is a common complication following endoscopic endonasal resection (EER) of pituitary adenomas. We report a single center, multi-surgeon study detailing baseline clinical data, outcomes, and factors associated with postoperative hyponatremia. METHODS: A retrospective cohort study of patients undergoing EER for pituitary adenoma at Tufts Medical Center was conducted. Most procedures were performed by the senior author (CBH). Cases were included if at least one postoperative sodium value was available and pathology confirmed pituitary adenoma. Hyponatremia was considered postoperative sodium <135 mEq/L. RESULTS: 272 patients underwent 310 EER procedures that met study criteria. Mean age was 53.3 years and mean tumor size was 18.8 mm. Postoperative hyponatremia occurred in 12.6% of cases, with 3.6% developing hyponatremia prior to discharge. Lower pre-operative sodium was associated with increased risk of developing any postoperative hyponatremia. Older age, prolactinoma pathology, and SSRI use were associated with moderate-severe hyponatremia (≤129 mEq/L), while lower preoperative sodium was associated with mild hyponatremia (130-134 mEq/L). Hyponatremia-related readmissions within 30 days occurred in 3.9% of patients. African-American race and postoperative hyponatremia were both associated with an increased risk of 30-day readmission. Mean nadir sodium for hyponatremic patients was 129.9 mEq/L. Growth hormone secreting pathology was associated with lower postoperative nadir sodium, while higher preoperative sodium was associated with higher postoperative nadir sodium. CONCLUSIONS: Hyponatremia is a common postoperative complication of EER for pituitary lesions that can cause significant morbidity, increase readmissions, and lead to increased healthcare costs.

Survival and Radiation Dose Differences Between Single Versus Multi-Session Gamma Knife Stereotactic Radiosurgery in Patients Treated for Multiple (≥10) Brain Metastases.

OBJECTIVE:  To explore whether treatment with multiple Gamma Knife sessions (mGK) resulted in different survival outcomes or cumulative radiation doses compared to single session Gamma Knife (sGK) in patients who have been treated for ≥10 brain metastases (BMs). METHODS:  Thirty-five patients with ≥10 BMs treated with Gamma Knife stereotactic radiosurgery (GK SRS) were identified and separated into sGK vs. mGK cohorts. Survival outcomes and dosimetry data were compared between the two groups. Recursive partitioning analysis (RPA) classes were used to further stratify patients. RESULTS:  mGK patients survived longer from the first GK treatment (p<0.009). By RPA class, patients with class 1 had a prolonged survival from BM diagnosis than those in classes 2 and 3 (p=0.004). However, survival was not significantly different between the classes from the first GK treatment (p=0.089). Stratified by mGK vs. sGK and RPA classes, sGK patients in RPA class 1 had the longest survival from BM diagnosis but the worst survival from GK treatment. mGK patients in any RPA class had the best survival from the first GK treatment. For patients with RPA class 2+3, mGK was associated with longer survival from both BM diagnosis and first treatment. Statistical but not clinical differences between the mGK vs. sGK groups were observed in the max dose to the targets and cochlea, and the V40Gy whole brain dose. CONCLUSIONS:  mGK may be beneficial if GK is initiated early at first BM diagnosis vs. sGK initiated late. Future research is required to confirm these findings and explore additional areas of interest, such as quality-of-life and economic considerations.

Primary Spinal Cord Astrocytomas: Two-Center Clinical Experience of Low- and High-Grade Lesions.

OBJECTIVE: Primary spinal cord astrocytomas are rare, fatal, and poorly studied. METHODS: This study included a 2-center, retrospective analysis of primary spinal cord astrocytoma patients from 1997 to 2020. Patients with drop metastases or without at least one follow-up were excluded. RESULTS: Seven World Health Organization grade I, 6 grade II, 7 grade III, and 4 grade IV astrocytoma patients were included. Older patients had higher grades (median 20 years in grade I vs. 36.5 in grade IV). The median follow-up was 15 months. Thirteen patients were discharged to rehabilitation. Eight patients demonstrated radiographic progression. Adjuvant therapy was utilized more in higher grades (5 of 13 grades III vs. all 11 grades IIIIV). Six patients died (1 death in grades III vs. 5 in grades IIIIV). Ten patients had worsened symptoms at the last follow-up. The median progression-free survival in grade I, II, III, and IV tumors was 116, 36, 8, and 8.5 months, respectively. The median overall survival in grade I, II, III, and IV tumors was 142, 69, 19, and 12 months, respectively. Thrombotic complications occurred in 2 patients, one with isocitrate dehydrogenasewild type glioblastoma. CONCLUSIONS: Outcomes worsen with higher grades and lead to difficult postoperative periods. Clinicians should be vigilant for thromboembolic complications. Further research is needed to understand these rare tumors.

Tufts Medical Center Experience With Long-Term Follow-Up of Vestibular Schwannoma Treated With Gamma Knife Stereotactic Radiosurgery: Novel Finding of Delayed Pseudoprogression.

PURPOSE: Our purpose was to evaluate the long-term outcomes of patients with vestibular schwannoma (VS) treated with Gamma Knife stereotactic radiosurgery (GKSRS) with modern techniques, with attention to posttreatment tumor growth dynamics, dosimetric predictors, and late toxicities. METHODS AND MATERIALS: One hundred twelve patients with VS were treated with GKSRS with a median dose of 12.5 Gy to the 50% isodose line treated between 2004 and 2015, with patients followed up to 15 years. Target and organ-at-risk doses were recorded, and tumor diameter/volume, audiologic decline, and trigeminal/facial nerve preservation were tracked from treatment onward. RESULTS: GKSRS yielded local control of 5, 10, and 15 years at 96.9%, 90.0%, and 87.1% respectively. Pseudoprogression was found in 45%, with a novel pattern detected with peak swelling at 31 months. Pseudoprogression was associated with smaller tumor diameter at treatment and fewer treatment isocenters, but not with the development of any toxicity, nor was it predicted by any dosimetric factor. Median time to hearing loss was 3.4 years with actuarial hearing preservation at 2, 5, and 10 years of 66.5%, 43.1%, and 37.6%, with rate of hearing loss correlating with maximum cochlea and modiolus doses. Trigeminal and facial nerve preservation rates were 92.7% and 97.6%, respectively. Increasing maximum tumor dose was associated with facial paresthesia. CONCLUSIONS: Modern GKSRS is a safe and effective treatment for VS on long-term follow-up, with high levels of facial and trigeminal nerve preservation. A novel pattern of pseudoprogression has been identified suggesting longer imaging follow-up may be needed before initiating salvage in those without symptomatic progression. Several tumor and dosimetric predictors have been suggested for the development of different toxicities, requiring further evaluation.

Primary meningeal melanoma masquerading as neurofibromatosis type 2: illustrative case.

BACKGROUND: Primary meningeal melanocytic neoplasms are exceedingly rare tumors, representing only 0.06% to 0.1% of all primary brain tumors and ranging in spectrum from benign localized tumors to highly aggressive malignant lesions. The diagnosis of these tumors is often challenging from clinical, radiological, and pathologic standpoints. Equally challenging is the distinction between primary meningeal melanocytic neoplasm and metastatic melanoma. OBSERVATIONS: The authors reported the case of a 41-year-old man with imaging findings diagnostic of neurofibromatosis type 2: bilateral internal auditory canal lesions (most consistent with bilateral vestibular schwannomas), two dura-based lesions presumed to be meningiomas, multiple spinal lesions consistent with peripheral nerve sheath tumors, and one intramedullary spinal lesion consistent with an ependymoma. Biopsy of these lesions revealed melanocytic neoplasms with mild to moderate atypia and a mildly elevated proliferation index, which made the distinction between benign and malignant challenging. In addition, the disseminated nature of these tumors made it difficult to determinate whether they arose from the meninges or represented metastases from an occult primary melanoma. LESSONS: This case illustrated the challenges presented by the diagnosis of meningeal melanocytic neoplasms and highlighted the importance of integrating the clinical and radiographic findings with histologic appearance and molecular studies.

STAT3 is required for proliferation and maintenance of multipotency in glioblastoma stem cells.

Signal transducer and activator of transcription 3 (STAT3) regulates diverse cellular processes, including cell growth, differentiation, and apoptosis, and is frequently activated during tumorigenesis. Recently, putative glioblastoma stem cells (GBM-SCs) were isolated and characterized. These cells can self-renew indefinitely in culture, are highly tumorigenic, and retain the ability to differentiate in culture. We have found that treatment of GBM-SCs with two chemically distinct small molecule inhibitors of STAT3 DNA-binding inhibits cell proliferation and the formation of new neurospheres from single cells. Genetic knockdown of STAT3 using a short hairpin RNA also inhibits GBM-SC proliferation and neurosphere formation, confirming that these effects are specific to STAT3. Although STAT3 inhibition can induce apoptosis in serum-derived GBM cell lines, this effect was not observed in GBM-SCs grown in stem cell medium. Markers of neural stem cell multipotency also decrease upon STAT3 inhibition, suggesting that STAT3 is required for maintenance of the stem-like characteristics of these cells. Strikingly, even a transient inhibition of STAT3 leads to irreversible growth arrest and inhibition of neurosphere formation. These data suggest that STAT3 regulates the growth and self-renewal of GBM-SCs and is thus a potential target for cancer stem cell-directed therapy of glioblastoma multiforme.

Adjuvant Gamma Knife radiosurgery following surgical resection of brain metastases: a 9-year retrospective cohort study.

Given the potential morbidity of whole brain radiation therapy (WBRT), there has been an increasing trend to defer WBRT and deliver Gamma Knife stereotactic radiosurgery (GKS) to cerebral metastatic lesions. We analyzed our experience delivering GKS to the tumor cavity following surgical resection of brain metastases and compared our results to patients receiving WBRT after surgical resection of a metastatic lesion. We performed a retrospective review of patients undergoing surgical resection of at least one brain metastasis between December 1999 and December 2008. Both univariate and multivariate Cox proportional hazards regression were utilized to analyze the influence of various prognostic factors on survival. Twenty-five patients had a metastatic lesion resected followed by adjuvant GKS to the resection cavity while another 18 had surgical resection followed by WBRT. Aside from a disparity in gender distribution (72% of GKS patients were female while women only constituted 28% of the WBRT group), no significant differences existed between groups. The median survival for patients receiving GKS was 15.00 months as compared to 6.81 months among those receiving WBRT (P = 0.08). Univariate Cox regression analysis identified the number of metastases (HR 1.65, 95% CI 1.07-2.54, P = 0.02) and regional recurrence (RR 5.23, 95% CI 1.78-15.38, P = 0.003) as poor prognostic factors. Multivariate regression analysis showed that regional recurrence (HR 5.17, 95% CI 1.69-15.78, P = 0.004) was again strongly associated with worse survival. Although limited by the retrospective nature of our study and lack of some clinical measures, patients undergoing GKS to the resection cavity had a trend towards longer median survival.

Facial nerve outcomes following gamma knife radiosurgery for subtotally resected vestibular schwannomas: Early versus delayed timing of therapy.

OBJECTIVES: Initially treating vestibular schwannomas (VSs) with subtotal resection (STR) followed by Gamma Knife radiosurgery (GKRS) for progression of tumor residual is a strategy that balances maximal tumor resection with preservation of neurological function. The effect of timing of GKRS for residual and recurrent VSs remains poorly defined. We developed a simple and practical treatment algorithm for the timing of GKRS after STR of VSs and reviewed our follow-up results to determine outcomes between patients treated with early vs. late GKRS. PATIENTS AND METHODS: Patients that underwent STR between 1999 and 2017 for a VS at Tufts Medical Center were identified and included in the study cohort. Patients who received GKRS ≤ 12 months after STR were included in the early intervention group. Patients who received GKRS > 12 months after STR or did not have tumor progression on follow-up thus not requiring GKRS were included in the observation/delayed intervention group. RESULTS: STR of VSs was performed on 23 patients. Mean patient age at the time of STR was 53.0 years (range: 20-86.2). The mean follow-up was 4.2 years (range: 1 month-15.5 years). Patients most frequently presented with hearing loss. There were 5 patients (21.7 %) in the early intervention group and 18 (78.3 %) patients in the observation/delayed intervention group. Ten of 23 patients (43.5 %) required GKRS. Thirteen (56.5 %) did not receive GKRS. None of the patients in the early intervention group or the observation/delayed intervention group had changes in House-Brackmann (HB) Grade either after GKRS or at the end of the study period. CONCLUSIONS: GKRS of residual or recurrent tumor is safe following STR of VS and appears to carry a low risk of worsening facial nerve function when performed for progressive tumor growth.

Retreatment of trigeminal neuralgia with Gamma Knife radiosurgery: is there an appropriate cumulative dose? Clinical article.

OBJECT: Trigeminal neuralgia (TN) is a disorder of the trigeminal nerve that results in intense episodic pain. Primary treatment with Gamma Knife surgery (GKS) is well established; however, a significant number of patients experience recurrence of TN over time. Repeat GKS can be performed, but the retreatment dose has not been well established. In this study, the authors present their institutional retreatment results and compare them with other series. METHODS: Between December 2003 and January 2006, 28 patients were treated at Tufts Medical Center with repeat GKS for recurrence of TN. All patients had been initially treated with GKS at this institution, and only those with significant pain improvement were offered retreatment. The maximum dose was prescribed using a single isocenter; the 4-mm collimator was used. The initial median GKS dose was 80 Gy, the median retreatment dose was 45 Gy, and the median cumulative dose was 125 Gy. The median time between GKS procedures was 18.1 months. Facial pain outcomes were defined using the Marseille scale. Excellent outcome was defined as no pain (with or without medications), and good outcome was defined as > 50% pain relief. Toxicity was categorized as none, mild, or bothersome. The median clinical follow-up after the second GKS was 19.7 months. Our clinical outcomes were compared with 8 previously reported retreatment series (including 1 abstract), both for rate of pain control and for rate of complications. RESULTS: Outcomes after the second GKS were excellent in 29% (8 patients), good in 32% (9), and poor in 39% (11). Four patients (14%) experienced no improvement after repeat GKS. Eight patients (29%) experienced new trigeminal nerve dysfunction, including numbness (11%), paresthesia (14%), dysesthesia (4%), taste alteration (11%), and bite weakness (4%). None of these were bothersome. No patient developed corneal numbness. Univariate analysis failed to reveal any significant predictors of pain control or complications. Seven published peer-reviewed retreatment series and the authors' data (total 215 patients) were analyzed. There was a cumulative dose-response relationship for both pain control (p = 0.04) and new trigeminal dysfunction (p = 0.08). Successful pain control was strongly correlated with development of new dysfunction (p = 0.02). A cumulative dose > 130 Gy was more likely to result in successful (> 50%) pain control, but was also more likely (> 20%) to result in development of new dysfunction. CONCLUSIONS: Successful retreatment of patients in whom the initial GKS treatment fails is feasible. Patients who respond initially may be at a higher risk of retreatment-related complications. There appears to be a dose-response relationship for both pain control and development of new side effects. It is important to counsel and treat patients individually based on this dose-response relationship.

Convexity dural cavernous malformation with intradural and extradural extension mimicking a meningioma: a case report.

BACKGROUND: Dural-based cavernous malformations are rare and have been more commonly described in the middle fossa. Fewer than 20 cases outside of the middle fossa have been reported and they often mimic more commonly found lesions such as meningiomas or hemangiopericytomas. CASE DESCRIPTION: We describe the unusual case of a right frontal convexity dural cavernous malformation with intradural and extradural components as well as erosion through the calvarium. The patient underwent a right frontal craniotomy and en-bloc resection of the mass. Final pathologic interpretation confirmed a cavernous malformation that had eroded through the calvarium. CONCLUSION: Dural-based cavernous malformations are a rare entity, but should be considered in the differential diagnosis of atypical appearing dural-based lesions and soft subgaleal masses. If atypical features are present, further radiographic investigations should be undertaken. To our knowledge, this is the only reported case of a dural-based cavernous malformation eroding through the calvarium and presenting initially as a soft scalp mass.

A Rare Occurrence of Isolated Brain Metastases from Gastric Cancer.

BACKGROUND: Gastric cancer is the fourth most common cancer worldwide and the second most common cause of cancer-related death. The majority of newly diagnosed gastric cancer cases present either as locally advanced tumor growth or with distant metastases. CASE REPORT: Here, we describe a case of isolated brain metastases in a male patient with gastric cancer. Initially, our patient presented with dysphagia and was diagnosed with gastric cancer after a thorough evaluation. One year after chemotherapy and surgical resection of his gastric cancer, he presented with headaches, nausea, dizziness, and photophobia. Further evaluation of these symptoms led to the discovery of three metastatic brain lesions without evidence of extracranial metastases. CONCLUSIONS: Our review of the literature has found that such cases are rare. Additionally, our review of the literature demonstrates the poor outcomes associated with metastatic brain lesions from gastric cancer and highlights the importance of surgical resection in increasing overall survival time.

Case Report: Metastasis of a Trigeminal Malignant Peripheral Nerve Sheath Tumor to the Corpus Callosum.

BACKGROUND AND IMPORTANCE: Malignant peripheral nerve sheath tumors (MPNST) are relatively rare tumors of peripheral nerves that are notable for their locally aggressive nature, ability to metastasize, poor prognosis, and association with Neurofibromatosis type I. We present the case of a patient with a trigeminal nerve MPNST who developed an unusual metastasis to the corpus callosum, in the absence of any other central nervous system or systemic metastatic disease. We review the pathology and presentation of MPNST. CLINICAL PRESENTATION: A 53-yr-old woman presented with a 1-yr history of paroxysmal facial pain and dysesthesias in the right V1 and V2 distributions of the trigeminal nerve. She was initially diagnosed with trigeminal neuralgia although further imaging showed a cavernous sinus mass extending along the trigeminal nerve. She later developed an isolated lesion in the corpus callosum that was biopsied and consistent with MPNST. CONCLUSION: This case reviews the pathology and aggressive nature of MPNST and demonstrates an unusual site of metastasis. Clinicians should remain aware that MPNST can metastasize to sites in the central nervous system as well as systemically. Furthermore, clinicians should have a high index of suspicion for secondary causes of trigeminal neuralgia in cases with atypical features.

High p16 Expression Is Associated with Malignancy and Shorter Disease-Free Survival Time in Solitary Fibrous Tumor/Hemangiopericytoma.

Objective Solitary fibrous tumors (SFT) and hemangiopericytomas (HPC) are now classified along a single spectrum of fibroblastic mesenchymal tumors with NAB2-STAT6 fusion. This fusion acts as a driver mutation that constitutively activates EGR1, which is known to be involved in the p16 pathway. Overexpression of p16 is associated with malignancy and worse prognosis in multiple mesenchymal tumors. The authors sought to investigate p16 immunoexpression in association with malignancy and prognosis of SFT/HPC tumors. Design Twenty-three SFT/HPC tumors (central nervous system [CNS]: 12, non CNS: 11) diagnosed at our institution from 2002 to 2016 were assigned into 3 grades. Data from microarray immunohistochemistry for STAT6, synaptophysin, CD56, chromogranin, SST2A, EGR1, Ki67, and p16, grade and survival were analyzed. Results CNS SFT/HPCs tend to be malignant (grade 3; 67 vs. 18%, p = 0.036) and more likely to express synaptophysin (33 vs. 0%, p = 0.035) than non CNS tumors. Overexpression of p16 (immunopositivity ≥ 50% tumor cells) was associated with malignant (grade 3) tumors, and has a sensitivity of 70% (7/10), and a specificity of 77% (10/13), as a predictive marker for malignancy. SFT/HPC patients with low p16 expression demonstrated significantly longer disease-free survival time (median survival > 113 months) than those with high p16 expression (median survival = 30 months, p = 0.045). Conclusions SFT/HPCs in the CNS are more likely to be malignant than the tumors in other sites. High p16 expression is also associated with malignancy and shorter disease-free survival time in SFT/HPC tumors in our study cohort. Clinically, p16 overexpression can be used as predictive marker for malignancy and prognosis and a possible therapeutic target.

3D extracellular matrix microenvironment in bioengineered tissue models of primary pediatric and adult brain tumors.

Dynamic alterations in the unique brain extracellular matrix (ECM) are involved in malignant brain tumors. Yet studies of brain ECM roles in tumor cell behavior have been difficult due to lack of access to the human brain. We present a tunable 3D bioengineered brain tissue platform by integrating microenvironmental cues of native brain-derived ECMs and live imaging to systematically evaluate patient-derived brain tumor responses. Using pediatric ependymoma and adult glioblastoma as examples, the 3D brain ECM-containing microenvironment with a balance of cell-cell and cell-matrix interactions supports distinctive phenotypes associated with tumor type-specific and ECM-dependent patterns in the tumor cells' transcriptomic and release profiles. Label-free metabolic imaging of the composite model structure identifies metabolically distinct sub-populations within a tumor type and captures extracellular lipid-containing droplets with potential implications in drug response. The versatile bioengineered 3D tumor tissue system sets the stage for mechanistic studies deciphering microenvironmental role in brain tumor progression.