Intracranial Infiltration Research Articles

Performance of 68Ga-Labeled Fibroblast Activation Protein Inhibitor PET/CT in Evaluation of Erdheim-Chester Disease: A Comparison with 18F-FDG PET/CT.

Erdheim-Chester disease (ECD) involves multiple organs and tissues and has diverse manifestations, which makes it difficult to distinguish lesions caused by ECD from those caused by other diseases. Variable degrees of fibrosis are present in ECD. Therefore, we conducted a prospective cohort study to explore the ability of 68Ga fibroblast activation protein inhibitor (68Ga-FAPI) PET/CT to detect lesions in ECD patients. Methods: Fourteen patients diagnosed with ECD, as confirmed by histology, were included in this study. For every patient, 68Ga-FAPI PET/CT and 18F-FDG PET/CT were conducted within 1 wk. The positive rate and SUVmax of the lesions in the involved organs were compared between the examinations. Results: The most commonly involved organs were bone (100%), heart (57.1%), lung (57.1%), kidney (42.9%), and peritoneum or omentum (35.7%); other common manifestations were intracranial infiltration (50%) and cutaneous infiltration (35.7%). 68Ga-FAPI PET/CT detected 64 of 67 lesions in 14 patients, whereas 18F-FDG PET/CT detected 51 of 67 lesions (P = 0.004). The SUVmax for 68Ga-FAPI PET/CT was significantly higher than the SUVmax for 18F-FDG PET/CT of the heart (4.9 ± 2.4 vs. 2.8 ± 1.2, respectively; P = 0.050), lung or pleura (6.8 ± 4.9 vs. 3.1 ± 1.3, respectively; P = 0.025), peritoneum or omentum (5.7 ± 3.6 vs. 2.8 ± 1.7, respectively; P = 0.032), and kidney or perinephric infiltration (4.9 ± 1.2 vs. 2.9 ± 1.1, respectively; P = 0.009). Conclusion: The detectivity of 68Ga-FAPI PET/CT is superior to that of 18F-FDG PET/CT. Moreover, 68Ga-FAPI PET/CT has a better image contrast and higher SUVmax for lesions in multiple organs including the heart, lungs, peritoneum, and kidneys. 68Ga-FAPI PET/CT is a promising tool to assess pathologic features and disease extent in ECD patients.

Intravascular large B-cell lymphoma appearance on dual-energy computed tomography: a case report

BackgroundIntravascular large B-cell lymphoma (IVLBCL) is the proliferation of neoplastic B lymphocytes in the vascular space. Since conventional computed tomography (CT) shows nonspecific findings, differentiation between IVLBCL and other lung diseases, such as diffuse interstitial lung disease, is difficult.Case presentationA 73-year-old man presented with dyspnea and hypoxemia. Laboratory findings showed an increased lactate dehydrogenase level of 1690 U/L (normal: 130–235 U/L) and soluble interleukin-2 receptor level of 1140 U/mL (normal: 157–474U/mL). Dual-energy CT iodine mapping showed a significant symmetrical decrease in iodine distribution in the upper lungs, suggesting an unusual distribution of pulmonary hypoperfusion. Therefore, IVLBCL was suspected. A random skin biopsy confirmed the diagnosis of IVLBCL. Due to the severity of the disease, lung biopsy was averted. After admission to the hospital, high-dose methotrexate was administered for central nervous system involvement, due to findings of suspected intracranial infiltration on a brain magnetic resonance imaging and elevated cell counts on lumbar puncture. Subsequently, oxygen demand improved, and rituximab along with cyclophosphamide, doxorubicin, vincristine, and prednisone was added to the patient’s regime. Eventually, oxygen administration was terminated, the patient’s general condition improved, and the patient was discharged after 47 days of hospitalization.ConclusionsSince the diagnosis of IVLBCL depends on whether it is possible to suspect IVLBCL, the finding of decreased iodine perfusion demonstrated on dual-energy CT is considered important information for diagnosis. An immediate diagnosis of IVLBCL is needed to avoid rapid disease progression and introduce early treatment for a favorable prognosis. In this case, unique pulmonary hypoperfusion demonstrated by dual-energy CT promoted early diagnosis of IVLBCL.

Study of frontal and ethmoid sinus of sinonasal complex along with olfactory fossa: anatomical considerations for endoscopic sinus surgery.

The Functional endoscopic sinus surgery through transnasal approach is a common modality of treatment for disorders of the nasal cavity, paranasal air sinuses as well as cranial cavity. The olfactory fossa (OF) is located along the superior aspect of cribriform plate which varies in shape and depth. This variable measurement of the depth of OF is mostly responsible for greater risk of intracranial infiltration during endoscopic procedures in and around the nasal cavity. The morphology of frontal and ethmoid sinus (ES) vary from simple to complex. This cadaveric study is planned to improve the ability of the otolaryngologist, radiologist to understand the possible morphological variations and plan steps of less invasive "precision surgery" to have a safe and complication free procedures. A total of 37 human head regions were included in the study. For classification of OF, Modified Kero's classification was used. The size, shape and cells of frontal and ES were noted. We found, type II (60.8%) OF was more common followed by type I (29.7%) than type III (9.5%). The shape of frontal sinus was comma shaped (55.4%) followed by oval (18.9%) than irregular (16.2%). Most common two cells type of ES was seen in 50.0% of both anterior and posterior ES. Out of 74 ES, 8.1% of Onodi cells and 14.9% of agger nasi cells were seen.

11C-Methionine PET/CT and 18F-FDG PET/CT in the Evaluation of Adult Alveolar Rhabdomyosarcoma.

A 70-year-old man with a tumor in the nasal and paranasal space, was pathologically diagnosed with an alveolar rhabdomyosarcoma, with right cervical lymph node metastasis. Magnetic resonance imaging revealed a primary tumor in the nasal and paranasal sinuses, with associated intracranial infiltration. 11C-methionine positron emission tomography/computed tomography (PET/CT) revealed increased uptake in the primary tumor and right cervical lymph node metastasis. 18F-fluorodeoxyglucose PET/CT also revealed increased uptake in the primary tumor and right cervical lymph node. However, the physiological brain uptake overlapped with the primary tumor uptake. Our case suggests the usefulness of 11C-methionine PET/CT for accurately assessing the extent of alveolar rhabdomyosarcoma, especially in cases with intracranial infiltration or those approximating the brain.

Inoperable or incompletely resected craniofacial osteosarcoma treated by particle radiotherapy.

BackgroundTo report survival of craniofacial osteosarcoma patients treated by particle radiotherapy.MethodsBetween January 2010 and December 2021, 51 patients with primary (N = 35) or recurrent (N = 16) inoperable or incompletely resected craniofacial osteosarcoma were treated. In most cases, intracranial infiltration (59%) and macroscopic tumor on MRI/CT (75%) were present. Thirteen had a secondary osteosarcoma (25%). Treatment concepts included combined ion beam radiotherapy (CIBRT, N = 18), protons only (N = 3), carbon ions only (N = 12), IMRT with a carbon ion boost (N = 5), and carbon ion re-irradiation (N = 13). Eighty percent (N = 41) received additionally chemotherapy, most frequently EURAMOS-1 (47%) or EURO-B.O.S.S. (18%).ResultsThe median age was 38, and all patients finished treatment predominantly as outpatients (N = 44). Information on overall survival was available for N = 49 patients. The median follow-up of the survivors was 55 months. For the whole cohort 1-, 2-, 3-, and 5-year overall survival (OS) was 82.8%, 60.4%, 55.2%, and 51.7%, respectively. Those treated by CIBRT (N = 17) demonstrated a superior OS with 92.9% after 1 and 2 years and 83.6% after 3 and 5 years. The median clinical target volume (CTV) was 192.7 and 95.2 cc for the primary and boost plan, respectively. CIBRT, primary diagnosis, age ≤40a, and no macroscopic residual tumor were associated with improved survival in univariate analysis (p = 0.006, p = 0.004, p = 0.002, p = 0.026, respectively), while any foregoing resection compared to biopsy was not identified as a prognostic factor. CIBRT and no macroscopic residual tumor were confirmed as independent predictors of OS on multivariate analysis (HR = 0.107, 95% CI = [0.014, 0.797], p = 0.029 and HR = 0.130, 95% CI = [0.023, 0.724], p = 0.020, respectively). No acute toxicity > grade III was observed.ConclusionCIBRT shows promising results for patients with inoperable or incompletely resected craniofacial osteosarcoma.

Multi Bacterial Infection in Immunocompromised Patient

Infection is a major cause of morbidity and mortality in immunocompromised cancer patients due to chemotherapy, radiotherapy, or anti-inflammatory therapy. Approximately 0.9%-39% of cancer patients with febrile non neutropenia has bacteremia and about 7.3% of cancer patients hospitalized have positive bacterial blood cultures. Multi-bacterial infection with Multi Drug Resistant (MDR) in immunocompromised cancer patients complicates therapy and is often fatal. A 6 years old boy diagnosed with left orbital tumor intracranial infiltration. Physical examination: lump in the left eye ± 8 x 10 cm, solid, reddish in color, there was a wound on the left eye ± 12 x 10 cm; Temperature 390C. Hematology examination Hb 10.3 g / dL; PLT 156 x103 / uL; WBC 28.92 x103 / uL. Blood culture results: Methicillin Resistant Staphylococcus aureus (MRSA) resistant to Gentamicin, Amoxicillin Clavulanic Acid, Ampicillin, Penicillin G, Oxacillin and Enterococcus faecium resistant to Gentamicin, Ampicillin, Cotrimoxazole, Trimetoprim, Erythromycin, and Clindamycin. Results of pus culture from the left eye wound was Staphylococcus intermedius resistant to Gentamicin, Amoxicillin Clavulanic Acid, Ampicillin, Penicillin G, Oxacillin, Chloramphenicol, Ciprofloxacin. Based on the results of blood and pus culture, all bacterial isolates included multidrug-resistant organisms (MDRO). Multidrug resistant organisms are microorganisms, especially bacteria that are resistant to at least 1 antibiotic of three or more categories. Cancer patients are susceptible to infection with multi-drug resistant bacteria because of their decreased immune system, especially after undergoing chemotherapy. Appropriate antibiotic treatment determines patient morbidity and mortality. Infection due to multi-bacteria accompanied by multi-drug resistance in immunocompromised patients is a condition that has to be treated immediately since the onset of the disease to reduce morbidity and mortality.

Giant Temporal Bone Angiosarcoma: Case Report and Literature Review

The authors describe a very rare case of an angiosarcoma originating from the petrous portion of the temporal bone that evolved as an indolent lesion until it became a giant retroauricular mass. A biopsy demonstrated that it was an angiosarcoma. A presurgical embolization from the left occipital and left parietal branches of the left middle meningeal artery was performed, followed by a total resection of the tumor. The patient developed a transient dysphasia during early follow-up, from which, subsequently, she fully recovered. There were no signs of recurrence in the current 3 years of follow-up. Free margins can be achieved even in some giant tumors and remain the most important prognostic factor for soft tissue malignant tumors with intracranial infiltration.

Clinically relevant orthotopic xenograft models of patient-derived glioblastoma in zebrafish.

ABSTRACTAn accurate prediction of the intracranial infiltration tendency and drug response of individual glioblastoma (GBM) cells is essential for personalized prognosis and treatment for this disease. However, the clinical utility of mouse patient-derived orthotopic xenograft (PDOX) models remains limited given current technical constraints, including difficulty in generating sufficient sample numbers from small tissue samples and a long latency period for results. To overcome these issues, we established zebrafish GBM xenografts of diverse origin, which can tolerate intracranial engraftment and maintain their unique histological features. Subsequent single-cell RNA-sequencing (scRNA-seq) analysis confirmed significant transcriptional identity to that of invading GBM microtumors observed in the proportionally larger brains of model animals and humans. Endothelial scRNA-seq confirmed that the zebrafish blood–brain barrier is homologous to the mammalian blood–brain barrier. Finally, we established a rapid and efficient zebrafish PDOX (zPDOX) model, which can predict long-term outcomes of GBM patients within 20 days. The zPDOX model provides a novel avenue for precision medicine of GBM, especially for the evaluation of intracranial infiltration tendency and prediction of individual drug sensitivity.

γδ T cells aggravate blood–brain-barrier injury via IL-17A in experimental ischemic stroke

Backgroundγδ T cells were reported to play a key role in ischemic stroke. The integrity of the blood–brain barrier (BBB) directly affects the prognosis of ischemic stroke. This study aimed to determine whether γδ T cells aggravate BBB injury and determine the outcome of ischemic stroke. MethodsOxygen-glucosedeprivation (OGD) and middle cerebral artery occlusion (MCAO) were used as ischemic stroke models in vitro and in vivo. Flow cytometry was used to evaluate the intracranial infiltration of γδ T cells. RT–qPCR was used to evaluatethe mRNA levels of cytokines and γδ T cell markers. ELISA was used to test the levels of cytokines. Immunofluorescence, TEER and western blotting were used to measure BBB injury. ResultsIn this study, we found that a large number of γδ T cells infiltrated the ischemic penumbra 24 h after MCAO. Knockout of γδ T cells improved the motor function injury induced by MCAO and significantly reduced the volume of cerebral infarction and blood–brain barrier injury. IL-17A neutralization could rescue the BBB injury induced by γδ T cells both in vitro and in vivo. ConclusionsPeripheral γδ T cells immediately infiltrated into the lesion site after ischemic stroke and aggravated BBB injury by releasing IL-17A, which might be a potential therapeutic target for ischemic stroke.

Difficulty in Management of Advanced Pediatric Orbital Tumor

Introduction: Tertiary care centers often manage pediatric orbital tumors, especially in advanced lesions and complex management. We report a case of a young boy with a malignant orbital tumor involving intracranial infiltration. Case presentation: A four-year-old boy had proptosis on the left eye for two months accompanied with blurred vision, pain, and oftenly bleeds with ipsilateral nasal congestion. There was no history of trauma, eye disorders, systemic diseases, or growth disorders. The physical examination showed stable vital signs, however a weak general condition and no enlarged regional lymph nodes. Visual acuity of the left eye was no light perception. There was a mass with protrusion of the left eye, swelling of the eyelid with an irregular surface, and a tendency to bleeds. The cornea was hazy with partly scarring, so we could not evaluate the posterior segment. MRI of the head presented a malignant soft tissue mass of the left orbital region with intracranial infiltration. The patient was given adjuvant chemotherapy; however, he could not survive due to systemic complications. Conclusions: The definitive diagnosis for the orbital tumor is obtained by histopathological examination. The investigation with CT scan or MRI imaging could be considered if not possible. However, since the definitive diagnosis still not assessed, the management can be affected. It is essential to have a definitive diagnosis to provide adequate treatment for the patients. Delayed and inadequate management can make malignant orbital tumors potentially life-threatening.

An Oncolytic Virus Expressing IL15/IL15Rα Combined with Off-the-Shelf EGFR-CAR NK Cells Targets Glioblastoma.

IL15 is a pleiotropic cytokine with multiple roles that improve immune responses to tumor cells. Oncolytic viruses (OV) specifically lyse tumors and activate immune responses. Systemic administration of IL15 or its complex with the IL15Rα and chimeric antigen receptor (CAR) natural killer (NK) cells are currently being tested in the clinic. Here, we generated a herpes simplex 1-based OV-expressing human IL15/IL15Rα sushi domain fusion protein (named OV-IL15C), as well as off-the-shelf EGFR-CAR NK cells, and studied their monotherapy and combination efficacy in vitro and in multiple glioblastoma (GBM) mouse models. In vitro, soluble IL15/IL15Rα complex was secreted from OV-IL15C-infected GBM cells, which promoted GBM cytotoxicity and improved survival of NK and CD8+ T cells. Frozen, readily available off-the-shelf EGFR-CAR NK cells showed enhanced killing of tumor cells compared with empty vector-transduced NK cells. In vivo, OV-IL15C significantly inhibited tumor growth and prolonged survival of GBM-bearing mice in the presence of CD8+ T cells compared with parental OV. OV-IL15C plus EGFR-CAR NK cells synergistically suppressed tumor growth and significantly improved survival compared with either monotherapy, correlating with increased intracranial infiltration and activation of NK and CD8+ T cells and elevated persistence of CAR NK cells in an immunocompetent model. Collectively, OV-IL15C and off-the-shelf EGFR-CAR NK cells represent promising therapeutic strategies for GBM treatment to improve the clinical management of this devastating disease. SIGNIFICANCE: The combination of an oncolytic virus expressing the IL15/IL15Rα complex and frozen, ready-to-use EGFR-CAR NK cells elicits strong antitumor responses in glioblastoma.

Schwannoma in Hemophilic Patient: Surgical Considerations

Introduction: Schwannoma is a benign, encapsulated, tumor that arises from Schwann cells of myelinated nerves. In this report, we present a case of schwannoma in a hemophilic patient and its surgical considerations related to bleeding complications. Case Presentation: We present a case of a 27-year-old male coming to our center with a chief complaint of a painless, non-progressive growing mass on the back of his head since a year prior to admission. Physical examination showed that the mass was mobile, firm, and had a welldefined margin beneath the scalp. His radiograph showed a soft tissue mass beneath the scalp. MRI demonstrated a dense-multilobulated mass without intracranial infiltration. The patient had hemophilia A from the age of 5. We performed marginal excision of the mass with regiments of factor VIII (FVIII) concentrates preoperatively, intraoperatively, and postoperatively. Pathology was consistent with schwannoma.Conclusions: Schwannoma management in hemophilic patients needs several considerations. Perioperative planning plays a major part in the management of patients with tumors and hemophilia to prevent bleeding complications.

Extracranial metastases in secondary glioblastoma multiforme: a case report

BackgroundGlioblastoma (GBM) is known for its devastating intracranial infiltration and its unfavorable prognosis, while extracranial involvement is a very rare event, more commonly attributed to IDH wild-type (primary) GBM evolution.Case presentationWe present a case of a young woman with a World Health Organization (WHO) grade II Astrocytoma evolved to WHO grade IV IDH mutant glioblastoma, with subsequent development of lymphatic and bone metastases, despite the favorable biomolecular pattern and the stability of the primary brain lesion.ConclusionsOur case highlights that grade II Astrocytoma may evolve to a GBM and rarely lead to a secondary metastatic diffusion, which can progress quite rapidly; any symptoms referable to a possible systemic involvement should be carefully investigated.

The diagnostic and prognostic value of MRI in central nervous system involvement of acute myeloid leukemia: a retrospective cohort of 84 patients

ABSTRACT Objective: To assess the diagnostic and prognostic value of magnetic resonance imaging (MRI) in Acute Myeloid Leukemia (AML) complicated with central nervous system leukemia (CNSL). Methods: A total of 84 patients with AML and confirmed of CNSL from January 2010 to September 2019 were selected and underwent MRI scan. We retrospectively analyzed their MRI findings, summarized the imaging features of AML central infiltration, and assessed the guiding significance of MRI on diagnosis and prognosis of this disease. Results: A total of 52 patients (61.90%, 52/84) had abnormal MRI findings, of which 31 cases clearly indicated intracranial infiltration of leukemia. Among the 31 patients, the most common site of infiltration is parenchyma (19/31). Most MRI of these patients showed multiple lesions with low T1 signal and high T2 signal, which were more obvious on enhanced scan. Sensitivity of MRI in diagnosing AML central infiltration was 36.90%. Despite of its low sensitivity, it still had superior diagnostic value on some patients with false-negative CSF. The median disease-free survival (DFS) and overall survival (OS) time of patients with MRI clearly indicated central invasion were 4 and 9 months, respectively. But there was no significant difference in survival analysis compared with MRI negative patients (including abnormal but non-invasive). Conclusion: MRI manifestation of central infiltration in AML patients has certain characteristic findings, which is helpful to improve the diagnostic efficiency. Prognosis of MRI positive patients is relatively worse than that of MRI negative patients however there is no siginificant difference.

Scalp Reconstruction after Malignant Tumor Resection: An Analysis and Algorithm.

Background An oncologic tumor resection of the scalp can result in complex wounds that result in challenging scalp reconstructions. This study aimed to evaluate the outcomes of microvascular-based scalp reconstructions (MSR) in oncologic patients and to propose an algorithmic treatment approach. Methods Within a 5-year period, 38 patients having undergone 41 MSR (15 anterolateral thigh (ALT), 15 gracilis muscle (GM), and 11 latissimus dorsi muscle (LDM) flaps) after extensive scalp tumor resections fulfilled inclusion criteria for this study. Results Malignant skin disease included superficial and/or deep infiltration of the calvarium in 26 and combined intracranial infiltration in 12 patients. In case of bone replacement (24 patients), MSR was done concomitant, otherwise MSR was performed after pathological confirmation of tumor-free margins. LDM flaps were used in cases with defect sizes of 400 to 1250cm 2 , whereas ALT- and GM flaps were chosen for defects ranging from 40 to 350cm 2 . The average length of the pedicle was comparable in ALT- and LDM flaps and longer than in GM flaps. Total flap loss with need for revision surgery and minor donor site morbidity occurred in four and three patients, respectively. Conclusion Microsurgical reconstruction of moderate-to-extensive scalp defects remains a reliable method with overall low risks and satisfactory aesthetic results, while, according to our experience, muscle flaps show the best functional and aesthetic results. However, in cases of central scalp defects and in situations when a long vascular pedicle of the flap is important, the ALT flap seems to be the best solution.

Komplikasi Neurologis pada Karsinoma Nasofaring

Nasopharyngeal Carcinoma (NPC) frequently cause neurological complication such as local ivasion, intracranial infiltration, radicular pain, metastatic spread to brain and spine, And stroke like syndrome due to hypercoagulation. This study was conducted to describe neurological complication in NPC and the factors that may influence. This was a cross sectional study used the data from medical records of patients were referred to neurology department for further assestement on neurological complication and stagging purpose from January until December 2014. Statistical analysis was done with SPSS for windows version 20.0. From 86 samples, mean of age was 49.23 + 11.28 years old, majority of men (73.3%), tumor size of T3 and T4 (68.6 %), and histopathologically non-keratinized (96.5%, Type II and III of WHO). Clinical onset of NPC were found in 11.89 months, and clinical onset of neurological complication were found in 14.32 months. Local invasion of NPC was noted in all samples (100%) with fifth cranial nerve involvement (26.1 %) of samples. The only factor that significantly influence neurological complication due to local invasion and intracranial infiltration was the size of tumor (p=0.032 ; p=0.02). It was concluded that the main neurological complications were cranial nerve lesions due to local invasion. There is a relationship between tumor size and local invasion and intracranial infiltration.

TGFβ Treatment Enhances Glioblastoma Virotherapy by Inhibiting the Innate Immune Response.

Oncolytic viruses, including oncolytic herpes simplex virus (oHSV), have produced provocative therapeutic responses in patients with glioblastoma, the most aggressive brain tumor. Paradoxically, innate immune responses mediated by natural killer (NK) cells and macrophages/microglia appear to limit oHSV efficacy. Therefore, we investigated whether pretreatment with an immunosuppressive cytokine, TGFβ, might reverse these effects and thereby potentiate oHSV efficacy. TGFβ treatment of NK cells rendered them less cytolytic against oHSV-infected glioblastoma cells and stem-like cells in vitro. Furthermore, TGFβ treatment of NK cells, macrophages, or microglia increased viral titers of oHSV in cocultures with glioblastoma cells. In a syngeneic mouse model of glioblastoma, administering TGFβ prior to oHSV injection inhibited intracranial infiltration and activation of NK cells and macrophages. Notably, a single administration of TGFβ prior to oHSV therapy was sufficient to phenocopy NK-cell depletion and suppress tumor growth and prolong survival in both xenograft and syngeneic models of glioblastoma. Collectively, our findings show how administering a single dose of TGFβ prior to oncolytic virus treatment of glioblastoma can transiently inhibit innate immune cells that limit efficacy, thereby improving therapeutic responses and survival outcomes.

Modulation of Natural Killer Cell Activity in the Setting of Oncolytic Virotherapy and with a Chimeric Antigen Receptor

Natural killer (NK) cells are innate lymphocytes that can rapidly eradicate tumor cells, especially those lacking MHC Class I molecules. NK cells can also rapidly eradicate herpes virus-infected cells. We designed an oncolytic herpes virus (oHSV) to selectively infect, replicate within, and lyse glioblastoma (GBM), a devastating brain tumor with a median survival of only 15 months following diagnosis. We have shown that the rapid influx of NK cells limits oHSV efficacy in GBM as they impede oHSV replication and spread [Alvarez-Breckenridge et al., Nat Med, 2012, 18(12):1827-34]. In the current study, we developed NK cell-based novel GBM therapies by decreasing the brain influx of NK cells to enhance the efficacy of oHSV, while arming NK cells in the brain with a chimeric antigen receptor (CAR) that targets both the wild-type EGFR and its mutant form EGFRvIII, two GBM tumor-associated antigens. We then investigated the synergistic effects between EGFR-CAR NK cells and oHSV.Transforming growth factor (TGF)-β is a potent immunosuppressive cytokine of NK cells [Yu et al, Immunity, 2006, 24(5):575-90]. We first determined if oHSV efficacy for treatment of GBM would be augmented by inhibiting anti-oHSV activity of NK cells with TGF-β pre-treatment. In vitro, NK cells pre-treated with TGF-β displayed less cytolytic capacity against oHSV-infected GBM cell lines and patient-derived GBM stem-like cells. In viral replication assays, co-culturing oHSV-infected GBM cells with NK cells pre-treated with TGF-β significantly increased virus titers. In an immunocompetent syngeneic GBM mouse model,administration of TGF-β to GBM-bearing mice prior to oHSV injection significantly inhibited intracranial infiltration and activation of NK cells (P < 0.05). In orthotopic human GBM xenograft mouse models and in syngeneic GBM mouse models, TGF-β treatment in vivo prior to oHSV therapy resulted in inhibition of NK cell infiltration, suppression of tumor growth and significantly prolonged survival of GBM-bearing mice (P < 0.05). Furthermore, depletion of NK cells incompletely blocked the positive effects of in vivo treatment of GBM with TGF-β on survival, suggesting that TGF-β may also directly act on other innate immune cells such as macrophages/microglia. These data demonstrate a single dose of TGF-β prior to oHSV administration enhances anti-tumor efficacy for GBM at least in part through the transient inhibition of the innate immune responses to oHSV infection.We next investigated whether NK cell activity could be enhanced to more directly target brain tumors while sparing eradication of oHSV. We therefore infected both human NK-92 cells and primary human NK cells to express the second generation CAR targeting both EGFR and EGFRvIII that we designed. Further, we asked if the treatment with EGFR-CAR NK cells plus oHSV could create a therapeutic synergy for the treatment to brain tumors. In vitro, compared with mock-transduced CAR-NK-cells, EGFR-CAR NK cells exhibited significantly higher cytotoxicity and IFN-γ production when co-cultured with tumor cells, for both NK-92 and primary NK cells (P < 0.01). Further, significantly higher cytolytic activity against tumor cells was obtained when CAR NK cells were combined with oHSV-1 infection of tumor cells, compared to either of the monotherapies alone (P < 0.05). In mice, to avoid oHSV clearance by the EGFR-CAR NK cells following the inoculation of the mouse with tumor cells, we administered these two agents sequentially; administering EGFR-CAR NK cells directly into the tumor first as a single injection of 2 × 106 cells, followed by intracranial infection with 2 × 105 plaque-forming units oHSV five days later, presumably after EGFR-CAR NK survival has diminished. Compared to vehicle controls, intracranial administration of either EGFR-CAR NK cells or oHSV blunted tumor growth. However, the combination of EGFR-CAR NK cells followed by oHSV infection resulted in significantly more efficient killing of tumor cells (P < 0.05) and significantly longer survival for tumor-bearing mice when compared to either monotherapy alone.Collectively, our studies demonstrate that in animal tumor models, we can combine novel NK cell and oHSV therapies to significantly improve survival. DisclosuresNo relevant conflicts of interest to declare.

Multiple myeloma with intracranial extension and bilateral renal infiltration: A case report and review of the literature

Multiple myeloma (MM) is a rare hematological malignancy, characterized by uncontrolled proliferation of plasma cells in the bone marrow. MM is usually confined to the bone marrow, however, it may occasionally infiltrate other tissues, which is known as extramedullary plasmacytoma (EMP). The majority of EMPs involve the head and neck region, although different anatomical sites, including the gastrointestinal tract, central nervous system, thyroid gland and breast may also be affected. The simultaneous presentation of EMP in the kidney and head is rare, presenting diagnostic challenges due to its unusual location and non-specific or absent symptoms. To the best of our knowledge, no case of extramedullary plasmacytoma presenting with simultaneous renal and intracranial infiltration has been reported in the literature thus far. However, the present study reports a case of primary renal and intracranial extramedullary plasmacytoma in a 76-year-old male patient. The patient presented with a swelling over the right side of the forehead, which had slowly increased in size prior to hospital admission. The swelling was associated with dizziness and weakness, without bone pain. Contrast magnetic resonance imaging suggested an osteolytic skull lesion with intracranial extension. Abdominal enhanced computed tomography scanning revealed a large tumor mass extending around and into the kidneys. Immunohistochemical examination of the renal tumor biopsy, and blood and serum samples, as well as immunoelectrophoresis of serum proteins, resulted in a diagnosis of EMP being proposed. Therefore, the patient was administered with two cycles of cyclophosphamide and thalidomide in combination with dexamethasone. Follow-up imaging performed 4 months later revealed almost complete disappearance of the intracranial tumor mass and renal infiltration. The current study also presented a review of the literature. This study revealed that EMPs may co-exist with MM or present as the main symptom of MM. The diagnosis of an EMP is complex and requires radiological, hematological, biochemical and histological investigation. At present, no guidelines for EMP treatment have been established and thus, treatment options include surgery, chemotherapy and radiotherapy, either alone or in combination. We hypothesize that combined treatment may provide the best patient outcome.

712. Conditionally Replicating Adenovirus Influences Intracranial Infiltration of Regulatory T Cells in Experimental Mouse Model of Brain Tumor

712. Conditionally Replicating Adenovirus Influences Intracranial Infiltration of Regulatory T Cells in Experimental Mouse Model of Brain Tumor