Metastatic Meningioma Research Articles

Evolution of a Meningothelial Meningioma: From WHO Grade 1 to Anaplastic Grade 3 with Extracranial Metastasis Including Extensive Liver Metastasis.

A 61-year-old patient was diagnosed with a left-sided falx meningioma. Histopathological analysis following extirpation showed a meningothelial meningioma ZNS WHO grade 1 with sparse mitoses. Over the course of 12 years, the patient received irradiation (54.0 Gy), peptide radio-receptor therapy (177Lu-DOMITATE) and targeted therapy (mTOR inhibitor). Follow-up imaging revealed an increased size of the residual tumor. Due to increased liver function parameters, imaging of the liver was performed, showing widespread space-occupying lesions with atypical appearance. Biopsy revealed metastasis of the meningioma, now with 2.7 mitoses/mm2, necrosis and homozygous CDKN2A/B deletion, corresponding to an anaplastic CNS meningioma WHO grade 3. A second small meningioma on the left petroclival side has been consistent in size over 12 years. Metastatic meningiomas pose a pertinent clinical challenge due to poor prognosis. The lung, bone, liver and cervical lymph nodes are the most common sites of extracranial metastasis. According to the World Health Organization criteria, the most important predictive factor for recurrence and metastasis is the tumor grade.

A blinded study using laser induced endogenous fluorescence spectroscopy to differentiate ex vivo spine tumor, healthy muscle, and healthy bone

Ten patients undergoing surgical resection for spinal tumors were selected. Samples of tumor, muscle, and bone were resected, de-identified by the treating surgeon, and then scanned with the TumorID technology ex vivo. This study investigates whether TumorID technology is able to differentiate three different human clinical fresh tissue specimens: spine tumor, normal muscle, and normal bone. The TumorID technology utilizes a 405 nm excitation laser to target endogenous fluorophores, thereby allowing for the detection of tissue based on emission spectra. Metabolic profiles of tumor and healthy tissue vary, namely NADH (bound and free emission peak, respectively: 487 nm, 501 nm) and FAD (emission peak: 544) are endogenous fluorophores with distinct concentrations in tumor and healthy tissue. Emission spectra analyzed consisted of 74 scans of spine tumor, 150 scans of healthy normal bone, and 111 scans of healthy normal muscle. An excitation wavelength of 405 nm was used to obtain emission spectra from tissue as previously described. Emission spectra consisted of approximately 1400 wavelength intensity pairs between 450 and 750 nm. Kruskal–Wallis tests were conducted comparing AUC distributions for each treatment group, α = 0.05. Spectral signatures varied amongst the three different tissue types. All pairwise comparisons among tissues for Free NADH were statistically significant (Tumor vs. Muscle: p = 0.0006, Tumor vs. Bone: p < 0.0001, Bone vs. Muscle: p = 0.0357). The overall comparison of tissues for FAD (506.5–581.5 nm) was also statistically significant (p < 0.0001), with two pairwise comparisons being statistically significant (Tumor vs. Muscle: p < 0.0001, Tumor vs. Bone: p = 0.0045, Bone vs. Muscle: p = 0.249). These statistically significant differences were maintained when stratifying tumor into metastatic carcinoma (N = 57) and meningioma (N = 17). TumorID differentiates tumor tissue from normal bone and normal muscle providing further clinical evidence of its efficacy as a tissue identification tool. Future studies should evaluate TumorID’s ability to serve as an adjunctive tool for intraoperative assessment of surgical margins and surgical decision-making.

Transformation From Atypical to Anaplastic Metastatic Meningioma: Evolutionary Turning Point Marked by Strong 18 F-FDG Avidity and Uptake Collapse From 68 GA-DOTATOC.

World Health Organization (WHO) grade III anaplastic meningioma is scarce. In this way, most studies compared WHO grade I and II. Otherwise, some authors are uncertain about using 18 F-FDG as a diagnostic tool to estimate the WHO grade, especially high. We report the case from a man with a grading tumor evolution from WHO grade II atypical to grade III anaplastic metastatic meningioma. This turning point was imaged using 68 Ga-DOTATOC and 18 F-FDG. Diagnostic was confirmed by histology. The case underlines the unparalleled power of molecular imaging characterized by high sensitivity staging and spectacular avidity changing relationship with grading tumor evolution.

Case of Metastatic Atypical Meningioma to Lung: Utility of Cytological Preparations for Intraoperative Diagnosis

Abstract Introduction/Objective Meningiomas are the most common primary intracranial and intraspinal tumors. They are typically benign with an indolent behavior but can metastasize extracranially to the skin, bone, lymph node and liver. Lung metastasis is exceptionally rare, and the diagnosis can be challenging, especially during intraoperative diagnosis without ancillary studies. We describe a metastatic atypical meningioma to the lung for which intraoperative cytology facilitated the diagnosis and guided management. Methods/Case Report A 53-year-old woman with a history of left frontal atypical meningioma and multiple surgical resections for recurrences at outside hospitals, presented with an incidental left lung nodule. A lung wedge resection was performed and submitted for intraoperative diagnosis. Gross examination revealed a well-circumscribed, tan- white, and rubbery subpleural nodule. Cytological preparations— Diff-Quik and H&amp;E stains—and frozen section were prepared. Cytologically, the nodule displayed cohesive distinctive papillary whorls of uniform eosinophilic cells with indistinct cell membranes, round to oval nuclei with central nucleoli and intranuclear pseudoinclusions. The frozen section exhibited similar cytological features, few identifiable whorls and predominantly solid sheets of tumor cells typical of non-small cell carcinoma. Based primarily on the cytological findings, the intraoperative diagnosis was a neoplasm with papillary growth pattern, and a metastasis was favored based on the whorled pattern and clinical history; no further resection was performed. Permanent sections displayed mitoses and no necrosis. Immunohistochemical analysis revealed positivity for somatostatin receptor 2a, progesterone receptor, and EMA (focal); no staining was seen with pancytokeratin, TTF-1, or p40. A diagnosis of atypical meningioma, WHO grade 2, was rendered. Subsequently, an atypical cranial and temporalis muscle meningioma at the site of the prior craniotomy bone flap was resected and had an identical molecular profile (1p36 deletion) to that in the lung, further supporting metastasis to the lung. Results (if a Case Study enter NA) NA Conclusion This case illustrates a rare presentation of metastatic atypical meningioma and highlights the distinctive intraoperative utility of cytology preparations—architectural and cytological details—for diagnosis and appropriate management. Cytology preparations can be a valuable tool and complement frozen sections, in which certain morphological features may be less obvious or confounded by freezing artifact.

Complete loss of E-cadherin expression in a rare case of metastatic malignant meningioma: a case report

BackgroundHematogenous tumor spread of malignant meningiomas occurs very rarely but is associated with very poor prognosis.Case presentationWe report an unusual case of a patient with a malignant meningioma who developed multiple metastases in bones, lungs and liver after initial complete resection of the primary tumor. After partial hepatic resection, specimens were histologically analyzed, and a complete loss of E-cadherin adhesion molecules was found. No oncogenic target mutations were found. The patient received a combination of conventional radiotherapy and peptide receptor radionuclide therapy (PRRT). Due to aggressive tumor behavior and rapid spread of metastases, the patient deceased after initiation of treatment.ConclusionsE-cadherin downregulation is associated with a higher probability of tumor invasion and distant metastasis formation in malignant meningioma. Up to now, the efficacy of systemic therapy, including PRRT, is very limited in malignant meningioma patients.

Metastatic meningioma: a case series and systematic review.

Meningiomas are the most common primary intracranial tumor. While the majority of meningiomas are benign, rarely they can metastasize extracranially. There is a need for a more comprehensive review of these patients to improve our understanding of this rare phenomenon and its prevalence globally. Here we describe our institution's experience of patients presenting with metastatic meningiomas. We further perform a systematic review of the existing literature to explore common features of this rare manifestation of meningioma and review the efficacy of current treatments. We performed a retrospective clinical review of all adult patients with metastatic meningioma managed at our institution over the past 20years, identifying 6 patients. We then performed a systematic review of cases of metastatic meningioma in the literature ranging from the years 1886 to 2022. A descriptive analysis was then conducted on the available data from 1979 onward, focusing on the grade and location of the primary tumor as well as the latency period to, and location of, the metastasis. In total, we analyzed 155 cases. Fifty-four percent of patients initially presented with a primary meningioma located in the convexity. The most common site of metastasis was the lung. Risk factors associated with a shorter time to metastasis were male sex and a high initial grade of the tumor. Regarding treatment, the addition of chemotherapy was the most common adjunct to the standard management of surgery and radiotherapy. Despite an exhaustive review we were unable to identify effective treatments. The majority of published cases came from centers situated in high-income countries (84%) while only 16% came from lower- and middle-income countries. Metastatic meningiomas pose a pertinent, and likely underestimated, clinical challenge within modern neurosurgery. To optimize management, timely identification of these patients is important. More research is needed to explore the mechanisms underlying these tumors to better guide the development of effective screening and management protocols. However, screening of each meningioma patient is not feasible, and at the heart of this challenge is the inability to control the primary disease. Ultimately, a consensus is needed as to how to correctly screen for and manage these patients; genomic and epigenomic approaches could hold the answer to finding druggable targets.

Recurrent Anaplastic Meningioma with Metastasis

Meningioma is the commonest primary intracranial tumor in adults, with the majority being benign. Malignant meningioma is exceedingly rare and carries a poor prognosis because of its tendency for local recurrence and distant metastasis. We present the case of a 53 years old male with anaplastic malignant meningioma, which recurred after excision and radiotherapy and later metastasised to pleura, bones and brain. Keywords: Metastatic meningioma, Anaplastic meningioma, Pleural metastasis, Intracranial tumor, Extracranial metastasis

Diffuse Pulmonary Meningotheliomatosis: Clinic-Pathologic Entity or Indolent Metastasis from Meningioma (or Both)?

Pulmonary minute meningothelial-like nodules (MMNs) are common incidental findings in surgical specimens, consisting of tiny proliferation (usually no larger than 5-6 mm) of bland-looking meningothelial cells showing a perivenular and interstitial distribution, sharing morphologic, ultrastructural, and immunohistochemical profiles with meningiomas. The identification of multiple bilateral MMNs leading to an interstitial lung disease characterized by diffuse and micronodular/miliariform patterns radiologically allows the diagnosis of diffuse pulmonary meningotheliomatosis (DPM). Nevertheless, the lung is the most common site of metastatic primary intracranial meningioma, and differential diagnosis with DPM may be impossible without clinic-radiologic integration. Herein, we report four cases (three females; mean age, 57.5 years) fitting the criteria of DPM, all incidentally discovered and histologically evidenced on transbronchial biopsy (2) and surgical resection (2). All cases showed immunohistochemical expression of epithelial membrane antigen (EMA), progesterone receptor, and CD56. Notably, three of these patients had a proven or radiologically suspected intracranial meningioma; in two cases, it was discovered before, and in one case, after the diagnosis of DPM. An extensive literature review (44 patients with DPM) revealed similar cases with imaging studies excluding intracranial meningioma in only 9% (4 of 44 cases studied). The diagnosis of DPM requires close correlation with the clinic-radiologic data since a subset of cases coexist with or follow a previously diagnosed intracranial meningioma and, thus, may represent incidental and indolent metastatic deposits of meningioma.

Recurrent grade III anaplastic meningioma metastasising to the humerus: a case report

Meningiomas are usually slow growing neoplasms that follow a benign clinical course. However, atypical and anaplastic meningiomas can show more aggressive behaviour and have the potential to metastasise. The most common sites for metastases are lung, spine, soft tissue, liver and bone. Bone metastases are exceedingly rare. We report a case of a 70-year-old man with a previous history of recurrent anaplastic meningioma (WHO grade III) with a pathological fracture of the left humerus. Histopathology aided by immunohistochemistry revealed metastatic meningioma.

Metastatic high-grade meningioma: A case report and review of risk factors for metastasis.

Abstract Meningiomas are the most common primary tumor of the CNS, and although they usually have a good prognosis, meningiomas can metastasize to extracranial sites, greatly worsening the prognosis. Due to its infrequency, the clinical and molecular risk factors associated with this event are poorly characterized in the literature. A 69-year-old man was found to have a meningioma in the left parieto-occipital parafalcine region. Over the subsequent decade, the patient experienced multiple local tumor recurrences, including with invasion through the scalp and superior sagittal sinus. The tumor was WHO grade 2-3 and next-generation sequencing was notable for TERT promoter mutation, homozygous deletion of CDKN2A, and high variant allele frequency of NF2. The tumor metastasized to the axial and appendicular skeleton, liver, kidney, and lung, and the patient ultimately succumbed to disease. In summary, this is the first report of multiple simultaneous and anatomically-distinct extracranial metastases from a primary intracranial meningioma.

NCCN Guidelines® Insights: Central Nervous System Cancers, Version 2.2022

The NCCN Guidelines for Central Nervous System (CNS) Cancers focus on management of the following adult CNS cancers: glioma (WHO grade 1, WHO grade 2-3 oligodendroglioma [1p19q codeleted, IDH-mutant], WHO grade 2-4 IDH-mutant astrocytoma, WHO grade 4 glioblastoma), intracranial and spinal ependymomas, medulloblastoma, limited and extensive brain metastases, leptomeningeal metastases, non-AIDS-related primary CNS lymphomas, metastatic spine tumors, meningiomas, and primary spinal cord tumors. The information contained in the algorithms and principles of management sections in the NCCN Guidelines for CNS Cancers are designed to help clinicians navigate through the complex management of patients with CNS tumors. Several important principles guide surgical management and treatment with radiotherapy and systemic therapy for adults with brain tumors. The NCCN CNS Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel's most recent recommendations regarding molecular profiling of gliomas.

NCMP-11. METASTATIC MENINGIOMA: AN UNUSUAL COURSE OF A COMMON DISEASE

Abstract BACKGROUND The most common central nervous system (CNS) tumor in adult patients is meningioma, accounting for 30% of all intracranial tumors. Despite this, extracranial meningioma metastases are exceedingly rare, accounting for 0.1% of cases, with common locations for metastases localized to the lungs, liver, lymph nodes, and bone. RESULTS We present a 55-year-old female with a past medical history of tobacco use, hypertension and depression, who initially presented due to a generalized tonic-clonic seizure. MRI brain revealed an intracranial lesion in the left occipital lobe with mass effect, requiring craniotomy and resection. Pathology was consistent with WHO grade I meningioma and post-operatively a small area of residual tumor remained. PET/CT found a left lung nodule, which was thought to be due to her smoking history and was followed with annual scans. Four years later, she had an increase in the size of the meningioma on surveillance MRI scans. The patient then required repeat craniotomy which redemonstrated pathology of WHO grade I meningioma, then treated with stereotactic radiation 14 Gy. The subsequent annual surveillance pulmonary scan showed a growth of left pulmonary nodule. She underwent a left lingual wedge resection and was found to have low grade spindle cell tumor, consistent with metastatic meningioma. CONCLUSION Although rare, metastatic meningioma should be included in the differential diagnosis of patients with concomitant extracranial lesions. Our case highlights the importance of annual, surveillance scans of extracranial lesions in meningioma patients.

A rare case report of recurrent atypical meningioma with multiple metastases treated with anti-PD-1 and anti-VEGF therapy

BackgroundMeningioma is the most common type of primary intracranial tumor with 0.1–1% of all primary meningiomas have been reported to develop into metastases. However, there is no proven therapeutic strategy for multiple metastases of meningiomas.Case presentationA 60-year-old female accepted total tumor resection of a right frontal lobe meningioma in September 2018, In October 2021, the patient was admitted to hospital because of cough and shortness of breath and diagnosed with metastatic meningiomas. The computed tomography (CT) scan revealed the presence of large masses in the right thoracic and abdominal cavity. After two cycles of anti-PD-1 and anti-VEGF treatment, the symptoms were relieved and the tumor was necrotic. Follow up to June 21, 2022, the patient has been given eleven cycles of the treatment every 3 weeks without tumor progression.ConclusionsThis case showed combined anti-PD-1 and anti-VEGF treatment stimulates peripheral blood immune cells to kill metastatic meningioma cells. Whether combined immunotherapy is more effective for metastatic meningioma needs further exploration.

Metastasis of Malignant Intracranial Meningioma to the Lung: Report of a Case and Review of the Relevant Literature

Background and Importance: Distant extracranial metastasis of meningioma is rare, and the pathophysiology of metastasis in meningioma remains a topic of debate. This study aimed to describe a patient who suffered from multiple pulmonary metastases of meningioma. Case Presentation: This report introduced a rare case of a 47-year-old female who presented with right hemiparesis. Cranial Computed Tomography (CT) demonstrated a homogeneously enhanced tumor in the left temporal lobe. The patient underwent tumor resection; the pathological result was found to be World Health Organization (WHO) grade I meningothelial meningioma. Recurrence of the tumor transpired after two years and a second operation was performed. WHO grade II atypical meningioma was diagnosed. Subsequently, the patient developed a chronic cough and her chest x-ray showed multiple lung masses. CT-guided biopsy of the right lung mass was performed. Finally, pulmonary metastatic meningioma was diagnosed. Conclusion: Distant extracranial metastasis and malignant transformation of meningioma involve the genetic alteration of a tumor, which should be studied further.

517 Metastasis in High-Grade Meningioma: A Systematic Review of Incidence and Risk Factors

INTRODUCTION: Meningioma is the most common primary tumor of the central nervous system and has relatively good outcomes. Rarely, meningiomas metastasize and greatly reduce the likelihood of survival. Due to its infrequency, there is little information available to inform physicians whether a meningioma patient is at-risk for experiencing metastasis. METHODS: We searched PubMed, Scopus, Embase, and Ovid for studies with intracranial meningiomas metastasizing to non-CNS locations. Case reports and studies with metastasis to the spinal cord were excluded. Primary tumors were characterized based on location, recurrence, histological grade, patient sex, and overall survival. RESULTS: Our database search yielded 1,002 unique articles, of which 5 were included in the final review. The studies yielded a total of 480 patients with high-grade meningioma. Overall, there were 21 patients from this cohort that suffered metastasis of their primary tumor (4.38%). The majority of metastatic patients were female (61.1%), and 18 of the 21 patients experienced recurrence of their primary tumor, along with metastasis (85.7%). Multiple risk factors were individually analyzed by studies, including skull base location, sinus invasion, and molecular characteristics. CONCLUSION: Metastatic meningioma is a rare occurrence but greatly reduces the survival of meningioma patients. Due to its infrequent incidence, there is a paucity of literature comparing risk factors for metastasis to guide clinical decision-making. Our study summarizes the current literature available on the overall incidence of metastasis in high-grade meningiomas and highlights multiple risk factors that future studies should characterize to provide a more comprehensive understanding of this rare pathology.

Solitary pulmonary metastasis after meningioma surgery of the head: a case report

BackgroundMeningioma is the most common type of benign primary brain tumor that is rarely associated with distant metastasis. No established treatment strategy for metastatic meningiomas exists to date. Herein, we report a case of solitary pulmonary metastasis of meningioma detected 2 years after neurosurgical resection of the primary tumor.Case presentationA 75-year-old male patient underwent neurosurgical resection of a convexity meningioma (World Health Organization grade II atypical meningioma), followed by postoperative radiotherapy for the residual tumor. Two postoperative years later, a solitary 10-mm pulmonary nodule in the left lower lung lobe was detected on chest computed tomography. The patient underwent video-assisted thoracoscopic left lower lobectomy for suspected pulmonary metastasis of meningioma. The pathological diagnosis was solitary pulmonary metastasis of meningioma. No sign of further recurrence was noted at 8 months postoperatively.ConclusionsWe present a rare and unique surgical case of solitary pulmonary metastasis of meningioma. Further investigation is necessary to establish the standardized treatment strategy for metastatic meningiomas.

The Myth of Prometheus in metastatic meningioma to the liver: from craniotomy to hepatectomy.

Metastases from intracranial meningiomas are rare, and among them, meningiomas with hepatic dissemination are extremely rare. Therefore, there are currently no guidelines for staging and treatment of metastatic disease in meningioma, a disease that is a challenge for both the clinician and the pathologist. Our literature review revealed 24 cases of liver metastases originating from intracranial meningiomas. We used them to analyze the pathological patterns of dissemination and to assess the different management strategies available, the most efficient and beneficial being surgery and chemotherapy, especially in the case of meningiomas with hepatic and/or systemic dissemination.

Genetic analysis of a malignant meningioma and associated metastases.

To identify genes altered in a highly aggressive metastatic meningioma primary as well as its metastases. Exome sequencing of a primary anaplastic meningioma and metastatic lesions in which DNA could be extracted and compared to germline DNA. Genetic analysis of the metastatic sites found 31 common mutations among the primary tumor and two metastatic sites. Additionally, genetic mutations were identified which were either infrequently (MUC3A, ALDH1A3, HOXA1) or not at all previously described in meningiomas (CASS4, CMKLR1). Exome sequencing of a metastatic meningioma and its distant metastases outside the CNS identified mutations that were not previously well described.

INNV-23. CASE REPORT OF CISPLATIN + ETOPOSIDE FOR THE TREATMENT OF METASTATIC MALIGNANT MENINGIOMA

Abstract INTRODUCTION Meningioma have an annual incidence of 5 per 100,000 and is the most frequent primary tumor of the central nervous system. Risk factors include radiotherapy and hormone intake. Most meningioma are grade I benign tumors, but up to 15% are atypical and 2% anaplastic according to the WHO 2016 histological criteria. Extra-CNS metastasis is exceedingly rare but carry a poor prognosis. Surgical resection and radiation therapy are the only approved therapies for the treatment of high grade or recurrent meningioma. Chemotherapy options have been limited and none have shown significant response rates. METHODS We report a case of a 33 year old male with an anaplastic meningioma (WHO Grade III) with metastasis to the lungs and rapid progression despite repeat resection. The subject was previously treated with resection and radiation therapy to a skull base/sinonasal lesion. Progression occurred at anterior cranial fossa, which required repeat resection. Within a month, the meningioma showed substantial progression with invasion into the orbit and nasopharynx as well as metastasis to the lung. The subject experienced significant clinical decline which included bilateral vision loss. The subject was treated with Cisplatin and Etoposide for 4 cycles. RESULTS The patient had immediate clinical improvement after the first cycle. Repeat MRI imaging of the brain showed partial response with approximately 40% tumor reduction, and CT of the chest showed complete response. The subject’s performance status also improved significantly with treatment including recovery of eyesight bilaterally. CONCLUSION This case showed that the use of Cisplatin + Etoposide for metastatic malignant meningioma can have significant objective and clinical response. The use of this regimen warrants further investigation. A clinical trial is currently being developed.

CTIM-32. IMMUNE CHECKPOINT INHIBITOR NIVOLUMAB IN PEOPLE WITH RECURRENT SELECT RARE CNS CANCERS: RESULTS OF INTERIM ANALYSIS IN A HEAVILY PRETREATED COHORT

Abstract INTRODUCTION Standard and experimental therapies for patients with rare CNS tumors are scarce. Nivolumab (PD-1 inhibitor) is approved for several non-CNS cancers. This ongoing Phase II trial (NCT03173950) will determine the efficacy of nivolumab in adults with recurrence/progression of one of 11 selected rare primary CNS tumors. Efficacy is measured by Disease Control Rate (DCR; confirmed CR/PR or durable SD for ≥ 6 months) in 2 cohorts: heavily and non-heavily pretreated patients (heavily pretreated: ≥ 3 prior therapies; non-heavily pretreated: ≤ 2). We report efficacy and safety results of a preplanned interim analysis in the heavily pretreated cohort. METHODS Eligibility includes recurrence/progression of an eligible tumor; age ≥ 18 years; tumor tissue available for histopathology, molecular and immune profiling; KPS ≥ 70; and no steroids at study entry. A total of 150 evaluable patients will be enrolled (75 to each cohort). Prior therapies include radiation and/or standard or investigational drugs. Nivolumab treatment is 240 mg IV every 2 weeks (4 doses); then 480 mg every 4 weeks (14 additional doses). Interim analysis was planned when sample size reached 32 in each cohort. RESULTS As of March 10, 2021, DCR exceeded the minimum required for interim analysis in the heavily pretreated cohort. Among 30 patients, 4 achieved SD &amp;gt; 6 months (medulloblastoma, anaplastic ependymoma, myxopapillary ependymoma, metastatic atypical meningioma). Safety profile (related AEs): grade 3 = 7; grade 4 = 1. Most frequent grade 3-5 AEs regardless of attribution: tumor progression (6); anemia, hydrocephalus, lymphopenia (3 each); cerebral edema, headache (2 each). CONCLUSION DCR exceeded the “go” boundary (i.e., &amp;gt; 2) in the heavily pretreated cohort. Nivolumab showed safety profile consistent with other studies. This cohort will continue to stage 2 and complete total accrual of 75 patients. The trial is currently being expanded to 10 additional sites across the BTTC/NCI-CONNECT consortium.