Name: surgical treatment of an endolymphatic sac tumor
Uploaded: 2023-05-26T13:10:00
Description: Watch this Scientific Journal Video about Surgical Treatment of an Endolymphatic Sac Tumor at JoVE.com

The local ethical committee approved the publication of this clinical case. A written informed consent form was collected from the patient.
1. Clinical and audiological evaluation
<ol>
	<li>Collect personal or familiar history of VHL disease or compatible symptoms from the patient.</li>
	<li>Perform a neurological examination to investigate central causes. Ensure that there is no pathological cause to be underlined and the facial nerve function is normal.</li>
	<li>Assess ex...

<ol>
	<li>Heffner, D. K. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Low-grade+adenocarcinoma+of+probable+endolymphatic+sac+origin+A+clinicopathologic+study+of+20+cases.">Low-grade adenocarcinoma of probable endolymphatic sac origin A clinicopathologic study of 20 cases.</a> Cancer. 64 (11), 2292-2302 (1989).</li><li>Lonser, R. R., Baggenstos, M., Kim, H. J., Butman, J. A., Vortmeyer, A. O. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+vestibular+aqueduct:+site+of+origin+of+endolymphatic+sac+tumors.">The vestibular aqueduct: site of origin of endolymphatic sac tumors.</a> J Neurosurg. 108 (4), 751-756 (2008).</li><li>Megerian, C. A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Endolymphatic+sac+tumors:+histopathologic+confirmation,+clinical+characterization,+and+implication+in+von+Hippel-Lindau+disease.">Endolymphatic sac tumors: histopathologic confirmation, clinical characterization, and implication in von Hippel-Lindau disease.</a> Laryngoscope. 105, 801-808 (1995).</li><li>Zanoletti, E., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Endolymphatic+sac+tumour+in+von+Hippel-Lindau+disease:+management+strategies.">Endolymphatic sac tumour in von Hippel-Lindau disease: management strategies.</a> Acta Otorhinolaryngol Ital. 37 (5), 423-429 (2017).</li><li>Mendenhall, W. M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Current+Treatment+of+Endolymphatic+Sac+Tumor+of+the+Temporal+Bone.">Current Treatment of Endolymphatic Sac Tumor of the Temporal Bone.</a> Adv Ther. 35 (7), 887-898 (2018).</li><li>Wu, N., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Surgical+management+of+endolymphatic+sac+tumor:+classification,+outcomes+and+strategy.+A+single+institution's+experience.">Surgical management of endolymphatic sac tumor: classification, outcomes and strategy. A single institution's experience.</a> Eur Arch Otorhinolaryngol. , (2022).</li><li>Bausch, B., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Characterization+of+endolymphatic+sac+tumors+and+von+Hippel-Lindau+disease+in+the+International+Endolymphatic+Sac+Tumor+Registry.">Characterization of endolymphatic sac tumors and von Hippel-Lindau disease in the International Endolymphatic Sac Tumor Registry.</a> Head Neck. 38, E673-E679 (2016).</li><li>Tang, J. D., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Systematic+Review+of+Endolymphatic+Sac+Tumor+Treatment+and+Outcomes.">Systematic Review of Endolymphatic Sac Tumor Treatment and Outcomes.</a> Otolaryngol Head Neck Surg. , (2022).</li><li>Balasubramaniam, S., Deshpande, R. B., Misra, B. K. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Gamma+knife+radiosurgery+in+jugular+foramen+endolymphatic+sac+adenocarcinoma.">Gamma knife radiosurgery in jugular foramen endolymphatic sac adenocarcinoma.</a> J Clin Neurosci. 16 (5), 710-711 (2009).</li><li>Poletti, A. M., Dubey, S. P., Colombo, G., Cugini, G., Mazzoni, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Treatment+of+endolymphatic+sac+tumour+(Papillary+adenocarcinoma)+of+the+temporal+bone.">Treatment of endolymphatic sac tumour (Papillary adenocarcinoma) of the temporal bone.</a> Rep Pract Oncol Radiother. 21 (4), 391-394 (2016).</li><li>Bambakidis, N. C., Megerian, C. A., Ratcheson, R. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Differential+grading+of+endolymphatic+sac+tumor+extension+by+virtue+of+von+Hippel-Lindau+disease+status.">Differential grading of endolymphatic sac tumor extension by virtue of von Hippel-Lindau disease status.</a> Otol Neurotol. 25 (5), 773-781 (2004).</li><li>Schipper, J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Endolymphatic+sac+tumours:+surgical+management.">Endolymphatic sac tumours: surgical management.</a> J Otolaryngol. 35 (6), 387-394 (2006).</li><li>Li, F., Zhang, Y. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Grading+system+and+surgical+approaches+for+endolymphatic+sac+tumors.">Grading system and surgical approaches for endolymphatic sac tumors.</a> Arch Otorhinolaryngol. 278 (5), 1345-1353 (2021).</li><li>Chittiboina, P., Lonser, R. R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Von+Hippel-Lindau+disease.">Von Hippel-Lindau disease.</a> Handb Clin Neurol. 132, 139-156 (2015).</li><li>Sykopetrites, V., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+endolymphatic+sac+tumor:+challenges+in+the+eradication+of+a+localized+disease.">The endolymphatic sac tumor: challenges in the eradication of a localized disease.</a> Eur Arch Otorhinolaryngol. 278 (7), 2297-2304 (2021).</li><li>Devaney, K. O., Ferlito, A., Rinaldo, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Endolymphatic+sac+tumor+(low-grade+papillary+adenocarcinoma)+of+the+temporal+bone.">Endolymphatic sac tumor (low-grade papillary adenocarcinoma) of the temporal bone.</a> Acta Otolaryngol. 123 (9), 1022-1026 (2003).</li></ol>

ELST are rare and locally aggressive neoplasms that arise on the posteromedial surface of the temporal bone. Due to their slow growth rate, and the initial paucity of the symptoms, the diagnosis is often delayed, resulting in an advanced tumor stage. Since the surgery morbidity as well as the oncologic outcomes are strongly correlated with the tumor dimensions and extension6,8,13,15, an early d...

Endolymphatic sac tumors (ELST) are neoplasms originating from the endolymphatic sac, a neuroectoderm-derived organ located in the posteromedial surface of the temporal bone. Histologically, ELST are characterizable as low-grade papillary adenocarcinoma1. Usually, ELST are slow-growing, with local aggressiveness and a low risk of distant metastases2,3,4. ELST can be sporadic, but they are also frequently associated with von Hippel Lindau disease (VHL)4.
Given the slow growing rate, the paucity of the clinical signs, and the late onset of the symptoms, they are difficult to diagnose in the early stages, especially when not associated with VHL5,6. The typical symptomatology at diagnosis of ELST includes hearing loss (79.8%), tinnitus (52.6%), and disequilibrium (45.5%), due to endolymphatic hydrops or intralabyrinthine hemorrhages4,7,8. Further and less frequent symptoms are facial palsy (25.6%), headache (13.8%), otalgia (5.1%), and trigeminal symptoms (3.2%)8.
The current treatment of ELST is primarily surgical resection. The tumor&#39;s residuals can be treated with stereotactic radiosurgery, which can be considered if the patient cannot tolerate the operation9,10. The surgical approach and the prognosis are mostly related to the tumor extension6. Even if there is no official staging system for ELST11,12, a recent grading system proposed by Li and colleagues13, based on imaging data and intraoperative findings, defined four main grades, according to the tumor extension. This and other previously proposed staging systems are reported in Table 1.
<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr>
			<td>Article</td>
			<td colspan="4">ELST Staging / Grading</td>
		</tr>
		<tr>
			<td>Bambakidis et al.11</td>
			<td colspan="4">Stage I: confiled to the temporal bone and middle ear</td>
		</tr>
		<tr>
			<td></td>
			<td colspan="4">Stage II: extended to the posterior fossa</td>
		</tr>
		<tr>
			<td></td>
			<td colspan="4">Stage III: extended to the middle cranial fossa</td>
		</tr>
		<tr>
			<td></td>
			<td colspan="4">Stage IV: extended to the clivus and/or sphenoid wing</td>
		</tr>
		<tr>
			<td>Schipper et al.12</td>
			<td colspan="4">Type A: limited to the dura of the posterior cranial fossa</td>
		</tr>
		<tr>
			<td></td>
			<td colspan="4">Type B: infiltration of lateral semicircular canal and/or cochlea</td>
		</tr>
		<tr>
			<td></td>
			<td colspan="4">Type C: infiltration of sigmoid sinus and/or jugular bulb</td>
		</tr>
		<tr>
			<td>Li et al.13</td>
			<td colspan="4">Grade I: confined to the posterior petrous bone between posterior semicircular canal and posterior fossa, may involve facial nerve, no inner ear and jugular foramen invasion</td>
		</tr>
		<tr>
			<td></td>
			<td colspan="4">Grade II: extended anteriorly with invasion of semicircular canals, cochlea, IAC, middle ear, without cerebellopotine angle and jugular foramen involvement</td>
		</tr>
		<tr>
			<td></td>
			<td colspan="4">Grade IIIa: involvement of jugular foramen or internal carotid artery or clivus</td>
		</tr>
		<tr>
			<td></td>
			<td colspan="4">Grade IIIb: extensive intracranial invasion or involvement of cavernous sinus or jugular foramen</td>
		</tr>
		<tr>
			<td>Wu et al.6</td>
			<td colspan="4">Type I: confined to the endolymphatic sac region</td>
		</tr>
		<tr>
			<td></td>
			<td colspan="4">Type II: extended to at least another one anatomic structure</td>
		</tr>
	</tbody>
</table>
Table 1: Previously published tumor staging systems. An overview of previously published grading/staging systems.
To date, only ~300 cases were reported, mostly as single clinical cases or small case series5,6. Recurrence rates and survival estimates have not been clearly defined yet8. In the present paper, we report the clinical and surgical management of a single case of sporadic ELST, as well as the follow-up results, providing clinicians our experience of the handling of such a challenging otologic skull base surgery and rare disease. Here, we describe ELST in a 55-year-old woman who accessed our otologic tertiary level referral center from a peripheric hospital. The patient had been hospitalized 3 days before for a sudden worsening of the left hearing loss, which began 3 months earlier, accompanied by an episode of acute vertigo with nausea and vomiting. The anamnesis was positive for hypertension and hypercholesterolemia, both under treatment, and smoking (3 pack-years). No personal or familiar history of VHL disease or compatible symptoms were reported by the patient.

<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr>
			<td>AC40</td>
			<td>Interacoustic</td>
			<td></td>
			<td>Clinical audiometer</td>
		</tr>
		<tr>
			<td>AT235</td>
			<td>Interacoustic</td>
			<td></td>
			<td>Clinical tympanometry</td>
		</tr>
		<tr>
			<td>Innova 3131</td>
			<td>GE Healthcare</td>
			<td></td>
			<td>Biplane angiograph</td>
		</tr>
		<tr>
			<td>LightSpeed VCT</td>
			<td>GE Healthcare</td>
			<td></td>
			<td>64 Slice CT system</td>
		</tr>
		<tr>
			<td>S2 &#960;Drive</td>
			<td>Striker</td>
			<td></td>
			<td>Drilling system for Otosurgery</td>
		</tr>
		<tr>
			<td>Signa HDX</td>
			<td>GE Healthcare</td>
			<td></td>
			<td>1.5 T MRI system</td>
		</tr>
		<tr>
			<td>SYNAPSYS VNG</td>
			<td>Inventis</td>
			<td></td>
			<td>Video nystagmograph</td>
		</tr>
	</tbody>
</table>

surgical treatment of an endolymphatic sac tumor

Endolymphatic sac tumors (ELST) are low-grade papillary adenocarcinoma originating from the endolymphatic sac. Usually slow-growing, with local aggressiveness and a low risk of distant metastases, ELST can be sporadic but also frequently associated with von Hippel Lindau disease. The current treatment of ELST is primarily surgical resection. A 55-year-old woman accessed our otologic tertiary level referral center for a sudden worsening of hearing loss in her left ear and vertigo. A magnetic resonance (MRI) and computer tomography scan study subsequently showed a mass in the petrous bone; hence, the presence of an ELST was hypothesized. After embolization of the mass, the patient underwent surgical removal of the lesion. The resection of the mass was done through a translabirinthine approach, with an uneventful procedure. No residual disease remained after surgery. After 24 months of radiologic follow up with MRI, there are no signs of recurrence disease. This paper reports the management of this sporadic ELST, as well as the follow up results, providing clinicians this protocol for the handling of such a challenging otologic skull base surgery and rare disease.

From the audiologic assessment, it was possible to identify a moderately severe left sensorineural hearing loss (Figure 1), with a reduction of word discrimination. The tympanometry was bilaterally normal, and the stapedial reflexes were evocable with ipsilateral and contralateral stimulus. At the videonystagmography , it was possible to assess a grade II horizontal spontaneous nystagmus beating on the right side, which grew in intensity after head shaking. From the clinical and audiological...

Watch this Scientific Journal Video about Surgical Treatment of an Endolymphatic Sac Tumor at JoVE.com

Surgical Treatment of an Endolymphatic Sac Tumor

Here, we discuss clinical and radiological features of endolymphatic sac tumors and report the methodology and results of a surgical removal in a case in care at our otologic referral center.

Endolymphatic sac tumors (ELST) are low-grade papillary adenocarcinoma originating from the endolymphatic sac. Usually slow-growing, with local ...

This protocol is significant as it shows how to treat an endolymphatic sac tumor effectively. A prompt diagnosis based on the clinical picture and imaging assessment could lead to a manageable surgery for tumor removal. To begin, perform MRI examination using axial fluid-attenuated inversion recovery and axial fast spin echo T2-weighted sequences.Target steady-state free precession images with a fast imaging employing steady-state acquisition, or FIESTA, sequence on the inner ear. If a mass appears in the context of the petrous bone, perform a high-resolution computer tomography with at least 64-slice scan to confirm the diagnosis. Once the ELST is suspected, define the grading of the tumor and plan the surgical approach for the mass resection.After performing a coil embolization and resection of the mass, make a C-shaped retroauricular incision, and raise the flap of the temporalis muscle. Perform ample mastoidectomy with a Stryker S2 PiDrive drilling system, and cut the round precision fluted tips and the coarse and fine diamond round tips from the drilled structures. Expose the sigmoid sinus posteriorly and the dura of the middle cranial fossa superiorly.Complete an ample antrotomy with complete exposure of the small process of the incus. Then prepare a posterior tympanotomy by drilling out all the retrofacial mastoid cells up to the mastoid tip until the jugular bulb is identified. Complete the posterior labyrinthectomy by dissecting the semicircular canals.Dissect the posterior bony labyrinth until identification of the internal auditory canal. Next, cut the dura and remove it on block with the tumor to identify the neoplasm and completely remove the tumor. Conduct an intraoperative extemporaneous histological examination.Seal the posterior tympanotomy and the antrotomy with surgical wax, and fill the ample mastoid cavity with autologous abdominal fat and fibrin glue. From the audiologic assessment, it was possible to identify moderately severe left sensory neural hearing loss with reduced word discrimination. The left mastoid cells were occupied by high-intensity mucous material, causing a swollen appearance of the cortex bone and the posterior side of the petrous part with obliteration of the ipsilateral pontocerebellar cistern and minimal imprint on the left cerebellar gyri, consistent with the presence of an ELST.The high-resolution computer tomography of the petrous bone with a 64-slice scan confirmed the presence of an isodense mass on the posterior wall of the petrous bone with erosion in an infiltrative moth-eaten pattern. According to the Lee grading system, a grade 2 ELST was suspected. The diagnostic digital subtraction angiogram showed a vascular tumor with tumor blush due to blood supply from the left external carotid artery's ascending pharyngeal, posterior auricular, and occipital branches.The post-embolization angiogram showed complete obliteration of the tumor blush without any complications during and after the procedure. After a prompt diagnosis, a full resection of an endolymphatic sac tumor is doable, even if demanding. During the surgery, the most important point is to perform a very ample mastoidectomy, providing a full exposure of the posterior labyrinth and a good access to the endolymphatic sac region.

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Method for Novel Anti-Cancer Drug Development using Tumor Explants of Surgical Specimens

The current therapies for malignant glioma have only palliative effect. For therapeutic development, one hurdle is the discrepancy of efficacy determined by current drug efficacy tests and the efficacy on patients. Thus, novel and reliable methods for evaluating drug efficacy are warranted in pre-clinical phase. In vitro culture of tumor tissues, including cell lines, has substantial phenotypic, genetic, and epigenetic alterations of cancer cells caused by artificial environment of cell culture, which may not reflect the biology of original tumors in situ. Xenograft models with the immunodeficient mice also have limitations, i.e., the lack of immune system and interspecies genetic and epigenetic discrepancies in microenvironment. Here, we demonstrate a novel method using the surgical specimens of malignant glioma as undissociated tumor blocks to evaluate treatment effects. To validate this method, data with the current first-line chemotherapeutic agent, temozolomide (TMZ), are described.


We used the freshly-removed surgical specimen of malignant glioma for our experiments. We performed intratumoral injection of TMZ or other drug candidates, followed by incubation and analysis on surgical specimens. Here, we sought to establish a tumor tissue explant method as a platform to determine the efficacy of novel anti-cancer therapies so that we may be able to overcome, at least, some of the current limitations and fill the existing gap between the current experimental data and the efficacy on an actual patient's tumor. This method may have the potential to accelerate identifying novel chemotherapeutic agents for solid cancer treatment.

Here, we established a method for drug efficacy testing with surgical specimens of brain tumors, termed &#x201C;tumor explant method&#x201D;. With this method, we can evaluate drug efficacy without breaking the microenvironment of solid tumors. To validate reliability of this method, we describe representative data with our glioma specimen treated with the current first-line chemotherapeutic agent, temozolomide.


The current therapies for malignant glioma have only palliative effect. For therapeutic development, one hurdle is the discrepancy of efficacy determined ...

An Orthotopic Bladder Tumor Model and the Evaluation of Intravesical saRNA Treatment

We present a novel method for treating bladder cancer with intravesically delivered small activating RNA (saRNA) in an orthotopic xenograft mouse bladder tumor model. The mouse model is established by urethral catheterization under inhaled general anesthetic. Chemical burn is then introduced to the bladder mucosa using intravesical silver nitrate solution to disrupt the bladder glycosaminoglycan layer and allows cells to attach. Following several washes with sterile water, human bladder cancer KU-7-luc2-GFP cells are instilled through the catheter into the bladder to dwell for 2 hours. Subsequent growth of bladder tumors is confirmed and monitored by in vivo bladder ultrasound and bioluminescent imaging. The tumors are then treated intravesically with saRNA formulated in lipid nanoparticles (LNPs). Tumor growth is monitored with ultrasound and bioluminescence. All steps of this procedure are demonstrated in the accompanying video.

Establishing an orthotopic bladder tumor model to evaluate antitumor effects of intravesically delivered saRNA and monitoring tumor growth by ultrasound and bioluminescent imaging.

We present a novel method for treating bladder cancer with intravesically delivered small activating RNA (saRNA) in an orthotopic xenograft mouse bladder ...

Molecular Profiling of the Invasive Tumor Microenvironment in a 3-Dimensional Model of Colorectal Cancer Cells and Ex vivo Fibroblasts

Invading colorectal cancer (CRC) cells have acquired the capacity to break free from their sister cells, infiltrate the stroma, and remodel the extracellular matrix (ECM). Characterizing the biology of this phenotypically distinct group of cells could substantially improve our understanding of early events during the metastatic cascade.

Tumor invasion is a dynamic process facilitated by bidirectional interactions between malignant epithelium and the cancer associated stroma. In order to examine cell-specific responses at the tumor stroma-interface we have combined organotypic co-culture and laser micro-dissection techniques.
Organotypic models, in which key stromal constituents such as fibroblasts are 3-dimentioanally co-cultured with cancer epithelial cells, are highly manipulatable experimental tools which enable invasion and cancer-stroma interactions to be studied in near-physiological conditions.

Laser microdissection (LMD) is a technique which entails the surgical dissection and extraction of the various strata within tumor tissue, with micron level precision.
By combining these techniques with genomic, transcriptomic and epigenetic profiling we aim to develop a deeper understanding of the molecular characteristics of invading tumor cells and surrounding stromal tissue, and in doing so potentially reveal novel biomarkers and opportunities for drug development in CRC.&#160;&#160;&#160;

Molecular Profiling of the Invasive Tumor Microenvironment in a 3-Dimensional Model of Colorectal Cancer Cells and Ex vivo Fibroblasts

Molecular profiling of laser microdissected cells and stroma from synthetic, tissue-engineered colorectal cancer models represents a novel and manipulatable approach to characterize and dissect the distinctive biology at the interface between tumor cells at the invasive front and cancer associated stromal cells. &#160;

Invading colorectal cancer (CRC) cells have acquired the capacity to break free from their sister cells, infiltrate the stroma, and remodel the ...

Tumor Treating Field Therapy in Combination with Bevacizumab for the Treatment of Recurrent Glioblastoma

A novel device that employs TTF therapy has recently been developed and is currently in use for the treatment of recurrent glioblastoma (rGBM). It was FDA approved in April 2011 for the treatment of patients 22 years or older with rGBM. The device delivers alternating electric fields and is programmed to ensure maximal tumor cell kill1.
Glioblastoma is the most common type of glioma and has an estimated incidence of approximately 10,000 new cases per year in the United States alone2. This tumor is particularly resistant to treatment and is uniformly fatal especially in the recurrent setting3-5. Prior to the approval of the TTF System, the only FDA approved treatment for rGBM was bevacizumab6. Bevacizumab is a humanized monoclonal antibody targeted against the vascular endothelial growth factor (VEGF) protein that drives tumor angiogenesis7. By blocking the VEGF pathway, bevacizumab can result in a significant radiographic response (pseudoresponse), improve progression free survival and reduce corticosteroid requirements in rGBM patients8,9. Bevacizumab however failed to prolong overall survival in a recent phase III trial26. A pivotal phase III trial (EF-11) demonstrated comparable overall survival between physicians&#8217; choice chemotherapy and TTF Therapy but better quality of life were observed in the TTF arm10.
There is currently an unmet need to develop novel approaches designed to prolong overall survival and/or improve quality of life in this unfortunate patient population. One appealing approach would be to combine the two currently approved treatment modalities namely bevacizumab and TTF Therapy. These two treatments are currently approved as monotherapy11,12, but their combination has never been evaluated in a clinical trial. We have developed an approach for combining those two treatment modalities and treated 2 rGBM patients. Here we describe a detailed methodology outlining this novel treatment protocol and present representative data from one of the treated patients.

A novel methodology that is employed for the treatment of recurrent glioblastomas is described. This treatment approach employs the application of alternating electric tumor treating fields (TTFields), known as TTF Therapy in combination with bevacizumab, a targeted agent that is currently FDA approved as monotherapy.

A novel device that employs TTF therapy has recently been developed and is currently in use for the treatment of recurrent glioblastoma (rGBM). It was FDA ...

Bioluminescence-Based Tumor Quantification Method for Monitoring Tumor Progression and Treatment Effects in Mouse Lymphoma Models

Although bioluminescence imaging (BLI) shows promise for monitoring tumor burden in animal models of cancer, these analyses remain mostly qualitative. Here we describe a method for bioluminescence imaging to obtain a semi-quantitative analysis of tumor burden and treatment response. This method is based on the calculation of a luminoscore, a value that allows comparisons of two animals from the same or different experiments. Current BLI instruments enable the calculation of this luminoscore, which relies mainly on the acquisition conditions (back and front acquisitions) and the drawing of the region of interest (manual markup around the mouse). Using two previously described mouse lymphoma models based on cell engraftment, we show that the luminoscore method can serve as a noninvasive way to verify successful tumor cell inoculation, monitor tumor burden, and evaluate the effects of in situ cancer treatment (CpG-DNA). Finally, we show that this method suits different experimental designs. We suggest that this method be used for early estimates of treatment response in preclinical small-animal studies.

Bioluminescence imaging is a well-known tool for localizing tumors and metastases, but quantification of these images often requires complex calculations and particular instruments. We describe the easy-to-use luminoscore method, based on precise acquisition conditions, requiring no calculations, and enabling tumor burden and treatment response to be monitored in mouse models.

Although bioluminescence imaging (BLI) shows promise for monitoring tumor burden in animal models of cancer, these analyses remain mostly qualitative. ...

Intravital Microscopy of Tumor-associated Vasculature Using Advanced Dorsal Skinfold Window Chambers on Transgenic Fluorescent Mice

Tumor and tumor vessel development, as well as tumor response to therapeutics, are highly dynamic biological processes. Histology provides static information and is often not sufficient for a correct interpretation. Intravital evaluation, in which a process is followed in time, provides extra and often unexpected information. With the creation of transgenic animals expressing cell-specific markers and live cell tracers, improvements to imaging equipment, and the development of several imaging chambers, intravital microscopy has become an important tool to better understand biological processes. This paper describes an experimental design for the investigation of tumor vessel development and of therapeutic effects in a spatial and temporal manner. Using this setup, the stage of vessel development, tip cell and lumen formation, blood flow, extravasation, an established vascular bed, and vascular destruction can be visualized and followed. Furthermore, therapeutic effects, intratumoral fate, and the localization of chemotherapeutic compounds can also be followed.

This protocol describes the intravital imaging of transgenic mice expressing cell-specific fluorescent markers. Intravital imaging provides a non-invasive method for high-resolution observations in living animals using implantable windows through which the microscopic visualization of processes is possible. This method is especially useful to study longitudinal processes.

Tumor and tumor vessel development, as well as tumor response to therapeutics, are highly dynamic biological processes. Histology provides static ...

Surgical Treatment for Benign Prostatic Hyperplasia: Holmium Laser Enucleation of the Prostate (HoLEP).

Benign prostatic hyperplasia (BPH) commonly occurs among elderly males. The condition causes symptoms in the lower urinary tract, thereby reducing the quality of life. BPH includes 2 major treatments: medication and surgery. Surgical treatment is often the most effective and final intervention. Holmium laser enucleation of the prostate (HoLEP), one of the most efficient surgical procedures for BPH, is conducted transurethrally. During surgery, the most important and most difficult part is to locate the surgical capsule of the prostate, which is consistent to the idea of anatomic surgery. Different skills may be needed in treating different parts of the prostate. HoLEP tends to be efficient and safe with good hemostatic properties, and able to treat bladder calculus, which may be the complications of BPH. The technique is particularly suitable for prostate of varying volumes and sizes. Indeed, HoLEP also presents certain disadvantages, such as a long learning curve and costly equipment. Regardless, this method may be the "new standard" and the excellent method for the surgical treatment of BPH.

Surgical Treatment for Benign Prostatic Hyperplasia: Holmium Laser Enucleation of the Prostate HoLEP.

Here we present a safe and efficient protocol, holmium laser enucleation of the prostate, to treat benign prostatic hyperplasia.

Benign prostatic hyperplasia (BPH) commonly occurs among elderly males. The condition causes symptoms in the lower urinary tract, thereby reducing the ...

An Ex Vivo Tissue Culture Model for Fibrovascular Complications in Proliferative Diabetic Retinopathy

Diabetic retinopathy (DR) is the most common microvascular complication of diabetes and one of the leading causes of blindness in working-age adults. No current animal models of diabetes and oxygen-induced retinopathy develop the full-range progressive changes manifested in human proliferative diabetic retinopathy (PDR). Therefore, understanding of the disease pathogenesis and pathophysiology has relied largely on the use of histological sections and vitreous samples in approaches that only provide steady-state information on the involved pathogenic factors. Increasing evidence indicates that dynamic cell-cell and cell-extracellular matrix (ECM) interactions in the context of three-dimensional (3D) microenvironments are essential for the mechanistic and functional studies towards the development of new treatment strategies. Therefore, we hypothesized that the pathological fibrovascular tissue surgically excised from eyes with PDR could be utilized to reliably unravel the cellular and molecular mechanisms of this devastating disease and to test the potential for novel clinical interventions. Towards this end, we developed a novel method for 3D ex vivo culture of surgically-excised patient-derived fibrovascular tissue (FT), which will serve as a relevant model of human PDR pathophysiology. The FTs are dissected into explants and embedded in fibrin matrix for ex vivo culture and 3D characterization. Whole-mount immunofluorescence of the native FTs and end-point cultures allows thorough investigation of tissue composition and multicellular processes, highlighting the importance of 3D tissue-level characterization for uncovering relevant features of PDR pathophysiology. This model will allow the simultaneous assessment of molecular mechanisms, cellular/tissue processes and treatment responses in the complex context of dynamic biochemical and physical interactions within the PDR tissue architecture and microenvironment. Since this model recapitulates PDR pathophysiology, it will also be amenable for testing or developing new treatments.

Here, we present a protocol to study the pathophysiology of proliferative diabetic retinopathy by using patient-derived, surgically-excised, fibrovascular tissues for three-dimensional native tissue characterization and ex vivo culture. This ex vivo culture model is also amenable for testing or developing new treatments.

Diabetic retinopathy (DR) is the most common microvascular complication of diabetes and one of the leading causes of blindness in working-age adults. No ...

Diagnosis and Surgical Treatment of Human Brucellar Spondylodiscitis

Brucellar spondylodiscitis (BS) is the most prevalent and significant osteoarticular presentation of human Brucellosis, which is commonly manifested in pastoral communities. It is difficult to differentially diagnose and usually leads to irreversible neurologic deficits and spinal deformities. The initial diagnosis of BS is based on clinical findings and radiographic assessments, and the confirmed diagnosis should be established by the isolation of Brucella species from the blood and/or the standard tube agglutination test. Differential diagnosis of multifocal BS from either degenerative disc diseases or tuberculosis is especially highlighted. The surgical approach, either endoscopic or open, is demonstrated in detail, accompanied by radiographic evidence of structural compression or severe instability. Further, the crucial surgical steps, including single-stage transforaminal decompression, debridement, interbody fusion, and internal fixation, are explained. Moreover, perioperative care and postoperative rehabilitation are also addressed. Taken together, this clinical algorithm presents a practical guide that has yielded substantially satisfactory outcomes in the past decades, which can also be introduced for large-scale application to manage human BS, especially in endemic regions.

We describe a clinical algorithm, based on decades of front-line experience of diagnosis and surgical treatment of human Brucellar spondylodiscitis in the largest medical center of the China's Xinjiang Pastoral Area.

Brucellar spondylodiscitis (BS) is the most prevalent and significant osteoarticular presentation of human Brucellosis, which is commonly manifested in ...

Endolymphatic Duct Blockage as a Surgical Treatment Option for M&#233;ni&#232;re's Disease

Endolymphatic duct blockage is a relatively new treatment option for M&#233;ni&#232;re's disease, aiming to reduce vertigo attacks while sparing hearing and equilibrium. After a regular mastoidectomy, the posterior semicircular canal is identified, and Donaldson's line is determined. This is a line through the horizontal semicircular canal, crossing the posterior semicircular canal. The endolymphatic sac is usually found at this site under the posterior semicircular canal. The bone of the endolymphatic sac and the dura are thinned until the sac is skeletonized, after which the endolymphatic duct is identified. The duct is then blocked with a titanium clip. Using a computerized tomography (CT) scan, the position is confirmed. Follow-up visits take place 1 week, 6 weeks and 1 year after surgery. To this day, only one prospective trial assessing this method has been conducted, comparing this new method to endolymphatic sac decompression. Results of the duct blockage are promising, with 96.5% of the patients free of vertigo after 2 years. However, further research is required.

Endolymphatic Duct Blockage as a Surgical Treatment Option for M&amp;#233;ni&amp;#232;re&#039;s Disease

Endolymphatic duct blockage is a relatively new surgical method for patients suffering from M&#233;ni&#232;re's disease. Following a regular mastoidectomy, the endolymphatic duct is identified and ligated using a regular titanium hemoclip. The effectiveness of this procedure is currently being assessed in a randomized trial.

Endolymphatic duct blockage is a relatively new treatment option for M&#233;ni&#232;re's disease, aiming to reduce vertigo attacks while sparing hearing ...