Minimally invasive resection of brain metastases

Minimally invasive resection of brain metastases aims to maximize resection while minimizing brain trauma. Patients with one or more metastases resection following neuro-oncology multidisciplinary meeting discussion from Sep 2014 to Oct 2018 with pre- and post-operative MRI were included. All patients including posterior fossa metastases or multiple metastases were positioned supine. Hair was not shaved. Volumetric post-contrast T1 MRI was used for incision planning and neuronavigation. The craniotomy site was tailored to tumor depth according to keyhole principles and ranged between 2 to 3cm. Intraoperative monitoring and awake mapping were carried out in selected cases. Out of 320 consecutive patients with brain metastases, 44 patients were identified as suitable for minimally invasive resection. 9 had no post-operative imaging and were excluded. There were 39 metastases in 35 patients. There were 18 cerebellar metastases, 9 frontal, 5 parietal, 3 occipital, 2 temporal, 1 intraventricular and 1 basal ganglia. Median length of stay was days (range: 1 – 24). Average tumor volume was 54.7cm3 (range: 10 – 240cm3). Endoscopic assistance was used in 4 patients. Median performance status improved from 2 to 1(range: pre-operative: 0 – 4; post-operative: 0 – 2). Median survival was 14.7 months. Minimally invasive resection of brain metastasis is safe and effective and in selected cases confers advantages compared to standard techniques.

Expression of Ki-67 and P16 INK4a in chemically-induced perioral squamous cell carcinomas in mice.

ABSTRACT Objective: to evaluate the influence of Ki-67 and P16INK4a proteins immunohistochemical expressions on the clinical and morphological parameters of perioral squamous cell carcinoma induced with 9,10-dimethyl-1,2-benzanthracene (DMBA) in mice. Methods: we topically induced the lesions in the oral commissure of ten Swiss mice for 20 weeks, determining the time to tumors onset and the average tumor volume up to 26 weeks. In histopathological analysis, the variables studied were histological malignancy grade and the immunohistochemical expression of Ki-67 and P16INK4a proteins. The correlation between variables was determined by application of the Spearman correlation test. Results: the mean time to onset of perioral lesions was 21.1 ± 2.13 weeks; mean tumor volume was 555.91 ± 205.52 mm3. Of the induced tumors, 80% were classified as low score and 20% high score. There was diffuse positivity for Ki-67 in 100% of lesions - Proliferation Index (PI) of 50.1 ± 18.0. There was a strong direct correlation between Ki-67 immunoreactivity and tumor volume (R = 0.702) and a low correlation with the malignancy score (R = 0.486). The P16INK4a protein expression was heterogeneous, showing a weak correlation with tumor volume (R = 0.334). There was no correlation between the immunohistochemical expression of the two proteins studied. Conclusion: in an experimental model of DMBA-induced perioral carcinogenesis, tumor progression was associated with the tumor proliferative fraction (Ki-67 positive cells) and with tumor histological grading, but not with P16INK4a expression.

Synergic Effect ofα-Mangostin on the Cytotoxicity of Cisplatin in a Cervical Cancer Model

Cervical cancer is the second leading cause of death among Mexican women. The treatment with cis-diamminedichloroplatinum (II) (CDDP) has some serious side effects.Alpha-mangostin (α-M), has a protective effect against CDDP-induced nephrotoxicity, as well as antioxidant, antitumor, and anti-inflammatory properties. Hence, we explored the in vitro and in vivo effect ofα-M on human cervical cancer cell proliferation when combined with CDDP. In vitro, The cytotoxic effect ofα-M and/or CDDP was measured by the 3-(3,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium assay. Meanwhile, apoptosis, reactive oxygen species (ROS) production, and the cell cycle were determined with flow cytometry. Forα-M+CDDP treatment, both a coincubation and preincubation scheme were employed. In vivo, xenotransplantation was performed in female athymic BALB/c (nu/nu) mice, and then tumor volume and body weight were measured weekly, whereasα-M interfered with the antiproliferative activity of CDDP in the coincubation scheme, with preincubation withα-M+CDDP showing significantly greater cytotoxicity than CDDP orα-M alone, significantly inhibiting average tumor volume and preventing nephrotoxicity. This effect was accompanied by increased apoptosis and ROS production by HeLa cervical cancer cells, as well as an arrest in the cell cycle. These results suggest thatα-M may be useful as a neoadjuvant agent in cervical cancer therapy.

The Subtemporal Approach to Retroinfundibular Craniopharyngiomas: A New Look at an Old Approach

BACKGROUND Retrochiasmatic, retroinfundibular craniopharyngiomas are surgically challenging tumors. Anterolateral, posterolateral, and endoscopic endonasal approaches represent the most commonly used techniques to access these tumors, but all require an extensive exposure time, and each has its own risks and limitations. The subtemporal approach is a well-known neurosurgical approach that is rarely described for craniopharyngiomas. OBJECTIVE To assess the feasibility, advantages, and disadvantages of a subtemporal approach for craniopharyngiomas. METHODS Five patients with retrochiasmatic craniopharyngiomas where the majority of the tumor extended behind the dorsal clival line underwent a subtemporal approach for resection. Extent of resection, degree of temporal lobe injury, visual and endocrine outcomes, and time to recurrence were analyzed. RESULTS Average tumor volume was 6.4 cm3. Near-total resection was achieved in 80% (4/5) and subtotal in 20% (1/5). All patients had stable or improved vision. There was 1 new permanent endocrine deficiency. Minimal temporal lobe edema was observed in 80% (4/5) of patients. Three patients required postoperative radiation. CONCLUSION The subtemporal approach represents a feasible approach for retrochiasmatic, retroinfundibular craniopharyngiomas when gross total resection is not mandatory. It provides rapid access to the tumor and a caudal-to-cranial visualization that promotes minimal manipulation of critical neurovascular structures, particularly the optic apparatus.

MUC1 As a Potential Therapeutic Target in Cutaneous T-Cell Lymphoma

Introduction: MUC1 is an oncoprotein that is aberrantly expressed in many epithelial tumors and hematologic malignancies, conferring cell growth and survival. Expression and functional significance of MUC1 in cutaneous T-cell lymphoma (CTCL) has not been previously characterized. In the present study, we evaluated the potential role that MUC1 mediated signaling plays in the pathogenesis of Mycosis Fungoides (MF) and Sezary Syndrome cells (SS), the 2 common subtypes of CTCL. Methods and results: MUC1 was strongly expressed on the SS cell lines HuT-78 (60%), H9 (77%) and SeAx (59%) and the MF cell lines, Myla (94%) and HuT-102 (87%) when incubated with anti-MUC1 antibody and analyzed by flow cytometry (FCM) . In contrast, B-cell lymphoma (BCL) cell lines (Val, K422, Toledo, SU-DHL-2, OCI-Ly7, OCI-Ly8, SU-DHL-5, SU-DHL-8, OCI-Ly3, RCK8, Ramos, Daudi, JVM-2) expressed minimal levels of MUC1 (0-7%), as did circulating T-cell populations isolated from healthy controls (0-3%). The finding of high MUC1 expression on CTCL and minimal expression on BCL and normal circulating T cells was confirmed byimmunoblotting (IB) with another antibody directed against MUC1-C, the oncogenic subunit. The expression profile of MUC1-C was found to be similar at the mRNA level by RT-PCR analysis. We subsequently examined MUC1 as a therapeutic target in CTCL. We have developed an inhibitor of the MUC1-C receptor subunit, designated GO-203, which blocks MUC1-C dimerization necessary for nuclear translocation and downstream signaling. Growth inhibition was determined using CellTiter-Glo that measures ATP produced by live and proliferating cells and demonstrated that the concentration required to inhibit growth by 50% (IC50) following 72-hour exposure ranged from 3 uM to 3.5 uM in most cell lines (HuT-78, H9 and Myla). Culture of HuT-78, H9 and Myla cells in the presence of 5 uM GO-203 concentration for 72-hours resulted in 70, 80 and 90% cell death respectively as determined by Annexin V and propidium iodide staining by FCM. Cell proliferation, as assessed by incorporation of tritiated thymidine, was inhibited by 70% and 80% in 2 cell lines (HuT-78 and Myla respectively) when treated with GO-203 at concentration of 5 uM for 72-hours. To determine mechanism of action of GO-203 induced apoptosis in vitro, level of hydrogen peroxide (H2O2), a reactive oxygen species (ROS) was measured using FCM based conversion of carboxy-2′7′ dichlorodihydrofluorescein diacetate to 2′7′-dichlorodihydrofluorescein. Cell lysates were analyzed for expression of the protein TIGAR, a fructose-2-6-bisphosphatase p53-inducible regulator of glycolysis and apoptosis by IB. Exposure of Hut-78, Myla and H9 cells to GO-203 for 72-hours was associated with an increase in ROS and down regulation of TIGAR expression. To confirm ROS mediated apoptosis by GO-203, in vitro treatment with the antioxidant N-acetylcysteine (NAC) was performed and levels of H2O2 were measured including IB with anti-TIGAR antibody. Treatment with NAC blocked the decreases in TIGAR levels, supporting the hypothesis that this response was mediated by increases in ROS. The ability of GO-203 to eradicate disease was evaluated in vivo across a spectrum of tumor volumes in 2 xenograft mouse models. Five million HuT-78 and 2.5 million Myla cells were injected subcutaneously (SC) into NOD-SCID IL2Rgammanull (NSG) mice. Treatment with GO-203 was administered daily at the dose of 14mg/kg SC for 3 weeks. Tumor volumetric analysis by three-dimensional ultrasound (3D-US) in HuT-78 and Myla xenograft NSG mouse models demonstrated a statistically significant decrease in tumor volume in mice treated with GO-203 compared to control (In the HuT-78 xenograft, average tumor volume was 707 mm3 in the GO-203 treated arm versus 1171 mm3 in the control arm rendering a p-value of 0.0029; whereas in the Myla xenograft average tumor volume was 184 mm3 in the GO-203 treated arm versus 1080 mm3 in the control arm rendering a p-value of 0.0001). Conclusion: The data demonstratesthat MUC1-C is highly expressed in CTCL cell lines, and that blockade of the oncogenic MUC1-C subunit with the peptide inhibitor GO-203 induces apoptosis in vitro and in vivo. Targeting MUC1-C in in vitro is associated with down-regulation of TIGAR and increases in ROS, indicating that MUC1-C functions in maintaining redox balance. Our results highlight the potential of MUC1-C to be an exciting new therapeutic target in CTCL. Disclosures Kufe: Genus Oncology: Consultancy, Equity Ownership.

Prolactinoma-associated headache and dopamine agonist treatment

Aim The aim of this article is to investigate the phenotype and etiology of prolactinoma-associated headache as well as present and discuss the plausible pain-relieving effect of dopamine agonist treatment. Methods In this case-based audit we included 11 patients with prolactinomas and one patient with idiopathic hyperprolactinemia presenting with headache that subsequently improved or resolved after dopamine agonist treatment. Results A significant ipsilateral location of tumor mass and reported headache symptoms was observed ( p = 0.018). After dopamine agonist treatment seven out of 12 patients became pain free within 2.5 months; after one year of treatment 11 out of 12 reported headache improvement or resolution. Average tumor volume reduction after treatment was 47 ± 22% during 9.5 ± 8.4 months of follow-up. There was no significant association between headache relief and tumor shrinkage ( p = 0.43) or normalization of serum prolactin ( p = 1.00), respectively. Conclusions 1) The significant association between lateralization of tumor and headache suggests a mechanical origin of the headache, 2) headache responded to dopamine agonist treatment in most patients, and 3) our observations encourage future prospective controlled trials to investigate the role of hyperprolactinemia in the pathogenesis of headache as well as the therapeutic effects of dopamine agonists.

Stereotactic Radiosurgery Yields Long-term Control for Benign Intradural, Extramedullary Spinal Tumors

BACKGROUND: The role of stereotactic radiosurgery in the treatment of benign intracranial lesions is well established. Although a growing body of evidence supports its role in the treatment of malignant spinal lesions, a much less extensive dataset exists for treatment of benign spinal tumors. OBJECTIVE: To examine the safety and efficacy of stereotactic radiosurgery for treatment of benign, intradural extramedullary spinal tumors. METHODS: From 1999 to 2008, 87 patients with 103 benign intradural extramedullary spinal tumors (32 meningiomas, 24 neurofibromas, and 47 schwannomas) were treated with stereotactic radiosurgery at Stanford University Medical Center. Forty-three males and 44 females had a median age of 53 years (range, 12–86). Twenty-five patients had neurofibromatosis. Treatment was delivered in 1 to 5 sessions (median, 2) with a mean prescription dose of 19.4 Gy (range, 14-30 Gy) to an average tumor volume of 5.24 cm3 (range, 0.049-54.52 cm3). RESULTS: After a mean radiographic follow-up period of 33 months (range, 6–87), including 21 lesions followed for ≥ 48 months, 59% were stable, 40% decreased in size, and a single tumor (1%) increased in size. Clinically, 91%, 67%, and 86% of meningiomas, neurofibromas, and schwannomas, respectively, were symptomatically stable to improved at last follow-up. One patient with a meningioma developed a new, transient myelopathy at 9 months, although the tumor was smaller at last follow-up. CONCLUSION: As a viable alternative to microsurgical resection, stereotactic radiosurgery provides safe and efficacious long-term control of benign intradural, extramedullary spinal tumors with a low rate of complication.

A murine model of xenotransplantation of human glioblastoma with imunosupression by orogastric cyclosporin

Several animal experimental models have been used in the study of malignant gliomas. The objective of the study was to test the efficacy of a simple, reproducible and low cost animal model, using human cells of glioblastoma multiforme (GBM) xenotransplantated in subcutaneous tissue of Wistar rats, immunosuppressed with cyclosporin given by orogastric administration, controlled by nonimunosuppressed rats. The animals were sacrificed at weekly intervals and we have observed gradual growth of tumor in the immunosuppressed group. The average tumor volume throughout the experiment was 4.38 cm³ in the immunosuppressed group, and 0.27 cm³ in the control one (p<0.001). Tumors showed histopathological hallmarks of GBM and retained its glial identity verified by GFAP and vimentin immunoreaction. Immunosuppression of rats with cyclosporin was efficient in allowing the development of human glioblastoma cells in subcutaneous tissues. The model has demonstrated the maintenance of most of the histopathological characteristics of human glioblastoma in an heterotopic site and might by considered in research of molecular and proliferative pathways of malignant gliomas.

MiR-15a and Mir-16-1 Affects the Angiogenesis of Multiple Myeloma by Targeting VEGF-A

Abstract 4039 MicroRNAs (miRNAs) are non-coding small RNAs that negatively modulate protein expression at a post-transcriptional level and are deeply involved in the pathogenesis of a variety of cancers. Two miRNAs, miR-15a and miR-16, which act as putative tumor suppressor by targeting the oncogene BCL2, have been implicated in cell cycle, apoptosis and proliferation. Here we investigated the possible role of miR-15a/miR-16 in the angiogenesis of multiple myeloma (MM). Using stem-loop quantitative reverse transcription-PCR analysis, we showed that miR-15a/miR-16 are significantly underexpressed in primary MM cells as well as MM cell lines (RPMI 8226, ARH-77, OPM-2, KM3, U266 and NIH929). The aberrant expression of miR-15a/miR-16 were detected especially in advanced stage multiple myeloma. The expression of miR-15a and miR-16-1 were remarkably lower in stage III MM patients (n=23), whereas it were significantly higher in healthy individuals (n=18) and stage 2, II MM patients (n=14) (P<0.01 and P<0.001, respectively). In human MM cell lines and normal plasma cell, expression of miR-15a/miR-16 inversely correlated with the expression of vascular endothelial growth factor (VEGF). Consistently with the proposed role of miRNAs as key regulators of angiogenesis, here we identified VEGF-A as a target for miR-15a and -16. Enforced miR-15a or miR-16 expression reduced VEGF-A protein level and the luciferase reporter assays demonstrated that miR-15a and -16 specifically suppress expression of VEGF-A by directly interacting with its 3′-untranslated region. Moreover, Ectopic overexpression of miR-15a and -16 led to decreased pro-angiogenic activity of MM cells. Conditioned medium of pri-miR-15a- and pri-miR-16- transfected RPMI 8226 cells inhibited human bone marrow microvascular endothelial cell (BMEC-1) proliferation, chemotactic motility and capillary formation in vitro as compared with conditioned medium of scramble probe-transfected RPMI 8226 cells (P<0.05). Finally, miR-15a/miR-16 was shown to greatly inhibit the process of tumor formation in an animal model. Infection of lentivirus-miR-15a or lentivirus-miR-16 can significantly inhibit the xenograft tumor growth in nude mice. The average tumor volume after 4 weeks for GFP-transfected cells was 372.5 mm3. While the average tumor volume for miR-15a-transfected cells was 47 mm3 (P<0.05) and for miR-16-transfected cells was 93.6 mm3 (P<0.05). Of interest, neoangiogenesis analysis by immunohistochemistry staining of anti-CD31 showed that there were significant reductions in microvessel density present in the miR-15a group and miR-16 group as compared to control (P<0.05). Take together, our findings suggested that miR-15a and miR-16 could play a role in the tumorigenesis of MM at least in part by modulation of angiogenesis through targeting VEGF-A. These findings have therapeutic implications and may be exploited for future treatment of MM. Disclosures: No relevant conflicts of interest to declare.

Radiosurgery for large-volume (> 10 cm3) benign meningiomas

Object Stereotactic radiosurgery (SRS) has proven to be a safe and effective treatment for many patients with intracranial meningiomas. Nevertheless, the morbidity associated with radiosurgery of larger meningiomas is poorly understood. Methods The authors performed a retrospective review of 116 patients who underwent SRS for meningiomas (WHO Grade I) > 10 cm3 between 1990 and 2007, with a minimum follow-up of 12 months. Patients with atypical or malignant meningiomas and those who received prior radiotherapy were excluded. The average tumor volume was 17.5 cm3 (range 10.1–48.6 cm3); the average tumor margin dose was 15.1 Gy (range 12–18 Gy); and the mean follow-up duration was 70.1 months (range 12–199 months). Results Tumor control was 99% at 3 years and 92% at 7 years after radiosurgery. Thirty complications after radiosurgery were noted in 27 patients (23%), including 7 cases of seizures, 6 cases of hemiparesis, 5 cases of trigeminal injury, 4 cases of headaches, 3 cases of diplopia, 2 cases each of cerebral infarction and ataxia, and 1 case of hearing loss. Patients with supratentorial tumors experienced a higher complication rate compared with patients with skull base tumors (44% compared with 18%) (hazard ratio 2.9, 95% CI 1.3–6.7, p = 0.01). Conclusions The morbidity associated with SRS for patients with benign meningiomas > 10 cm3 is greater for supratentorial tumors compared with skull base tumors. Whereas radiosurgery is relatively safe for patients with large-volume skull base meningiomas, resection should remain the primary disease management for the majority of patients with large-volume supratentorial meningiomas.