bluuebunny/crossref_metadata_2025 huggingface dataset:
Unsupervised Analysis Uncovers Changes in Histopathologic Diagnosis in Supervised Genomic Studies
Authors: Nykter Matti , Hunt Kelly K. , Pollock Raphael E. , El-Naggar Adel K. , Taylor Ellen , Shmulevich Ilya , Yli-Harja Olli , Zhang Wei
Published: October 2014

Human gastrointestinal stromal tumors (GIST) have recently emerged as a distinct mesenchymal tumor type that has a unique phenotype characterized by a gain of function mutations in c-kit. In contrast, leiomyosarcomas (LMS) of the gastrointestinal tract or retroperitoneum, which were previously classified together with GISTs as gastrointestinal sarcomas, have much less frequent mutations of c-kit. We performed microarray analyses to gain a comprehensive understanding of the difference between the two types of soft-tissue sarcomas at the level of gene expression. Microarray experiments were performed on 30 GISTs and 30 LMSs that were collected at the time of surgical resection. These tumors were categorized based on the histopathologic diagnosis recorded in our institutional database. Prior to our search for genes that are differentially expressed between these two types of cancers, we first carried out an unsupervised analysis using multidimensional scaling (MDS) to determine whether the two groups have marked overall differences in gene expression. Initially, the MDS did not reveal a good separation between the two groups. We then re-reviewed the histopathology of these tumors and realized that some of the cases included in our study were acquired 10 years ago when the diagnosis of gastrointestinal sarcoma was made according to histopathologic criteria alone without immunohistochemistry for c-kit. An experienced pathologist reviewed all of the specimens and this revealed that a number of the GIST cases were classified as LMS in the clinical database. Correction of the histopathologic diagnosis and relabeling of the samples resulted in a much more pronounced separation of GIST and LMS in the MDS analysis. This study underscores the need to re-review histopathology as reclassification occurs. While updating the clinical database may be desired, this is usually impractical. For molecular studies that use archival samples, it is critical to have the archival samples re-reviewed by a pathologist. Further, unsupervised analysis often proves to be a critical quality control step in identifying structural problems that may exist. Finally, MDS analysis further supports that GIST is a distinct type of sarcoma.
Convection-Enhanced and Local Delivery of Targeted Cytotoxins in the Treatment of Malignant Gliomas
Authors: Muro Kenji , Das Sunit , Raizer Jeffrey J.
Published: October 2014

Despite advances in our knowledge about the genesis, molecular biology, and natural history of malignant gliomas and the use of a multi-disciplinary approach to their treatment, patients harboring this diagnosis continue to face a grim prognosis. At the time of diagnosis, patients typically undergo surgery for the establishment of a histologic diagnosis, the reduction of tumor burden, and the relief of mass effect, with the maintenance of the patient's neurological function in mind. This is followed by the administration of adjuvant therapeutics, including radiation therapy and chemotherapy.

Many investigational agents with laboratory evidence of efficacy against malignant gliomas have not met their promise in the clinical setting, largely due to the barriers that they must overcome to reach the tumor at a therapeutically meaningful concentration for a durable period of time. The relevant aspects of the blood-brain barrier, blood-tumor barrier, and blood-cerebrospinal fluid barrier, as they pertain to the delivery of agents to the tumor, will be discussed along with the strategies devised to circumvent them. This discussion will be followed by a description of agents currently in preclinical and clinical development, many of which are the result of intense ongoing research into the molecular biology of gliomas.
Neuro-Oncological Applications of Optical Spectroscopy
Authors: Toms Steven A , Konrad Peter E. , Lin Wei-Chiang , Weil Robert J.
Published: October 2014

Advances in optics and molecular imaging have occurred rapidly in the past decade. One technique poised to take advantage of these developments is optical spectroscopy (OS). All optical spectroscopic techniques have in common tissue interrogation with light sources ranging from the ultraviolet (UV) to the infrared (IR) ranges of the spectrum, and collection of information on light reflected (reflectance spectroscopy) or light interactions with tissue and emergence at different wavelengths (fluorescence and Raman spectroscopy). OS can provide information regarding intrinsic tissue optical properties such as tissue structure, nuclear density, and the presence or absence of endogenous or exogenous fluorophores. Among other applications, this information has been used to distinguish tumor from normal brain tissues, to detect tumor margins in intrinsic, infiltrating gliomas, to identify radiation damage to tissues, and to assess tissue viability and predict the onset of apoptosis in vitro and in vivo. Potential applications of OS include detection of specific central nervous system (CNS) structures, such as brain nuclei, identification of cell types by the presence of specific neurotransmitters, and the detection of optically labeled cells or drugs during therapeutic interventions. All have potential utility in neuro-oncology, have been investigated in our laboratories, and will be the subject of this review.
Convection-enhanced Delivery of Interleukin-13 Receptor-directed Cytotoxin for Malignant Glioma Therapy*
Authors: Kioi Mitomu , Husain Syed R. , Croteau David , Kunwar Sandeep , Puri Raj K.
Published: October 2014

The treatment of patients with malignant brain tumors, in particular glioblastoma multiforme (GBM) is very challenging because of their diffuse infiltrative nature and the cytological heterogeneity. The median survival of patients with newly diagnosed GBM is only 12–15 months, and only 8–12% of them survive for two years. Novel approaches for brain tumor therapy are needed. Recently, targeted therapies have emerged as promising modality for cancer targeting. We have discovered that high affinity plasma membrane receptor for interleukin-13 (IL-13), an immune regulatory cytokine, is over-expressed in 60–80% of malignant brain tumors. To target these IL-13R, we generated a chimeric fusion protein, composed of human IL-13 and mutated Pseudomonas exotoxin (PE), termed IL-13 cytotoxin (IL 13-PE), and tested its cytotoxicity to IL-13R-expressing GBM cells. IL-13 cytotoxin was highly potent and selective in killing IL-13R-expressing GBM cells. In contrast, normal cells including brain, immune, and endothelial cells were generally not affected by this cytotoxin due to no or low expression of IL-13R. In vivo pre-clinical studies for safety and toxicity were also performed in mice, rats, and monkeys, and IL-13 cytotoxin was found to be well tolerated by both systemic and intracerebral administrations. IL-13 cytotoxin was found to mediate remarkable efficacy in animal models of human brain tumors. Encouraged by these pre-clinical studies, four Phase 1/2 clinical trials in adult patients with recurrent malignant glioma have been completed. These clinical trials involved convection-enhanced delivery (CED) of IL-13 cytotoxin either intratumoral or intraparenchymal after resection of tumor. CED is a novel loco-regional drug delivery method for intracranial tumors that relies on a continuous pressure gradient to distribute drug into interstitial space. This route of IL-13 cytotoxin administration appears to be very well tolerated and have a good risk-benefit profile. Most recently, a randomized controlled Phase 3 clinical trial (PRECISE) with intraparenchymal IL-13 cytotoxin administration was completed and subjects are being monitored for safety and survival.
Locoregional Proton Radiotherapy of a Primary Cavernous Sinus Non-Hodgkin's Lymphoma: Case Report
Authors: Ronson Brian , Rossi Carl , Johnson Stéphane , Berdeja Antonio , Slater James M. , Slater Jerry D.
Published: October 2014

Primary B cell lymphomas of the skull base are uncommon and lack well-defined treatment guidelines. We report a case of diffuse, large B-cell lymphoma of the cavernous sinus with sphenoid sinus and clival extension, treated with partial resection, chemotherapy, and proton beam irradiation. To our knowledge, this is the first report of a skull-base lymphoma treated with protons. A 53-year-old female presented with a two-month history of diplopia, persistent headaches, and paresthesia over the left side of her mouth. A skull MRI revealed an enhancing mass in the right cavernous sinus and right sphenoid sinus. Transsphenoidal subtotal resection of the mass confirmed the presence of a diffuse, large B-cell lymphoma.

Treatment consisted of CHOP-R chemotherapy and locoregional radiation with protons. Locoregional radiation of the lesion required moderate doses, below the radiation tolerance of adjacent normal structures. Conformal protons were utilized to minimize the volume of normal brain receiving radiation. Conformal proton beam radiotherapy to a moderate dose proved valuable in this case because it minimized the volume of normal brain receiving low to moderate doses of radiation.
Multi-detector CT in the Evaluation of Patients with Recurrence of Rectal Cancer
Authors: Stueckle Christoph A. , Adams Stefan , Stueckle Kerstin F. , Szpakowski Michael , Schneider Oliver , Friedrich Christoph , Thiem Ulrich , Pientka Ludger , Liermann Dieter
Published: October 2014

The advantages of multiplanar reconstruction in rectal cancer recurrence diagnostics using medium resolution multi-detector CT are evaluated.

We included 40 patients after a rectal cancer operation in this study. During follow-up ten patients developed a recurrence. All patients received a minimum of two CT-examinations in their follow-up program. A total of 131 CT-scans were evaluated. Each examination was reviewed by two experienced radiologists in respect to recurrence. Each examination was presented in axial reconstruction with a slice thickness of 8mm with an increment of 7mm and a slice thickness of 3mm with an increment of 2mm. The thin slices were used for the multi-planar reconstruction.

Multi-planar reconstructions showed better results for the detection of recurrence than axial reconstruction. A reduced slice thickness did not lead to better results in axial reconstruction. Multi-planar reconstruction showed a sensitivity of 0.88, a specificity of 1.0 and an accuracy of 0.97. Our axial reconstruction results were: 0.86, 0.96, and 0.93, respectively. Sensitivity and accuracy showed a significant increase after the first and second examinations. Multi-planar reconstructions allow for better detection of rectal cancer recurrence when compared to axial reconstructions. Thinner axial slice thickness shows no diagnostic advantage.
Identification of Primary Tumors of Brain Metastases by Infrared Spectroscopic Imaging and Linear Discriminant Analysis
Authors: Krafft Christoph , Shapoval Larysa , Sobottka Stephan B. , Schackert Gabriele , Salzer Reiner
Published: October 2014

This study applies infrared (IR) spectroscopy to distinguish normal brain tissue from brain metastases and to determine the primary tumor of four frequent brain metastases such as lung cancer, colorectal cancer, breast cancer, and renal cell carcinoma. Standard methods sometimes fail to identify the origin of brain metastases. As metastatic cells contain the molecular information of the primary tissue cells and IR spectroscopy probes the molecular fingerprint of cells, IR spectroscopy based methods constitute a new approach to determine the primary tumor of a brain metastasis. IR spectroscopic images were recorded by a FTIR spectrometer equipped with a macro sample chamber and coupled to a focal plane array detector. Unsupervised cluster analysis of IR images revealed variances within each sample and between samples of the same tissue type. Cluster averaged IR spectra of tissue classes with known diagnoses were selected to develop a metric with eight variables. These data trained a supervised classification model based on linear discriminant analysis that was used to identify the origin of 20 cryosections including one brain metastasis with an unknown primary tumor.
Resolution Improvement in Positron Emission Tomography Using Anatomical Magnetic Resonance Imaging
Authors: Chu Yong , Su Min-Ying , Mandelkern Mark , Nalcioglu Orhan
Published: October 2014

An ideal imaging system should provide information with high-sensitivity, high spatial, and temporal resolution. Unfortunately, it is not possible to satisfy all of these desired features in a single modality. In this paper, we discuss methods to improve the spatial resolution in positron emission imaging (PET) using a priori information from Magnetic Resonance Imaging (MRI). Our approach uses an image restoration algorithm based on the maximization of mutual information (MMI), which has found significant success for optimizing multimodal image registration. The MMI criterion is used to estimate the parameters in the Sharpness-Constrained Wiener filter. The generated filter is then applied to restore PET images of a realistic digital brain phantom. The resulting restored images show improved resolution and better signal-to-noise ratio compared to the interpolated PET images. We conclude that a Sharpness-Constrained Wiener filter having parameters optimized from a MMI criterion may be useful for restoring spatial resolution in PET based on a priori information from correlated MRI.
Rationale for the Combination of Nuclear Medicine with Magnetic Resonance for Pre-clinical Imaging
Authors: Wagenaar Douglas J. , Kapusta Maciej , Li Junqiang , Patt Bradley E.
Published: October 2014

Multi-modality combinations of SPECT/CT and PET/CT have proven to be highly successful in the clinic and small animal SPECT/CT and PET/CT are becoming the norm in the research and drug development setting. However, the use of ionizing radiation from a high-resolution CT scanner is undesirable in any setting and particularly in small animal imaging (SAI), in laboratory experiments where it can result in radiation doses of sufficient magnitude that the experimental results can be influenced by the organism's response to radiation. The alternative use of magnetic resonance (MR) would offer a high-resolution, non-ionizing method for anatomical imaging of laboratory animals. MR brings considerably more than its 3D anatomical capability, especially regarding the imaging of laboratory animals. Dynamic MR imaging techniques can facilitate studies of perfusion, oxygenation, and diffusion amongst others. Further, MR spectroscopy can provide images that can be related to the concentration of endogenous molecules in vivo. MR imaging of injected contrast agents extends MR into the domain of molecular imaging. In combination with nuclear medicine (NM) SPECT and PET modalities in small animal imaging, MR would facilitate studies of dynamic processes such as biodistribution, pharmacokinetics, and pharmacodynamics. However, the detectors for nearly all PET and SPECT systems are still based on vacuum tube technology, namely: photomultiplier tubes (PMT's) in which the signal is generated by transporting electrons over a substantial distance within an evacuated glass tube, making them inoperable in even small magnetic fields. Thus the combination of SPECT or PET with MR has not been practical until the recent availability of semiconductor detectors such as silicon avalanche photodiodes (APD's) for PET and CdZnTe (CZT) detectors for SPECT coupled with the availability of high-density low noise ASIC electronics to read out the semiconductor detectors. The strong advantage of these technologies over PMT's is their insensitivity to magnetic fields which makes their use in co-axial multi-modality nuclear medicine/magnetic resonance instrumentation possible.
Optimal Probing of Optical Contrast of Breast Lesions of Different Size Located at Different Depths by US Localization
Authors: Zhu Quing , Xu Chen , Guo Puyun , Aguirre Andres , Yuan Baohong , Huang Fei , Castilo Diego , Gamelin John , Tannenbaum Susan , Kane Mark , Hegde Poornima , Kurtzman Scott
Published: October 2014

We report a frequency domain optical tomography system utilizing three RF modulation frequencies, which are optimized for probing breast lesions of different size located at different depths. A real-time co-registered ultrasound scanner is used to provide on-site estimation of lesion size and location. Based on the lesion information, an optimal light modulation frequency can be selected, which may yield more accurate estimates of lesion angiogenesis and hypoxia. Phantom experiments have demonstrated that a high modulation frequency, such as 350Mhz, is preferable for probing small lesions closer to the surface while a low modulation frequency, such as 50Mhz, is desirable for imaging deeper and larger lesions. A clinical example of a large invasive carcinoma is presented to demonstrate the application of this novel technique.
Image-Guided Radiosurgical Ablation of Intra- and Extra-Cranial Lesions
Authors: Romanelli Pantaleo , Schaal David W. , Adler John R.
Published: October 2014

For decades since its introduction, stereotactic radiosurgery (SRS) was used only to treat intracranial lesions because intracranial targets could be immobilized and located relative to a rigid metal frame affixed to the patient's head. Lesions outside the head were generally not treated with SRS because it is difficult to immobilize extracranial lesions and to attach stereotactic frames elsewhere on the body. Advances in computerized image guidance and robotics allowed the development of systems, such as the CyberKnife SRS System (Accuray, Inc, Sunnyvale, CA), that could target intracranial lesions without the stereotactic frame. Enhancements have resulted in a radiation delivery system that can accurately deliver high-dose, focal radiation to lesions in the spine, chest, and abdomen, even if they move during respiration. In this review we will describe the technical features of frameless SRS systems and briefly review their application to treating intracranial and extracranial lesions, focusing in particular on spinal lesions.
Intensity Modulated Radiation Therapy: A Review of Current Practice and Future Directions
Authors: Sanghani Mona , Mignano John
Published: October 2014

The use of intensity modulated radiation therapy (IMRT) has been rapidly growing in the United States. This technology is now being used in a multitude of academic and community centers throughout the country and is being incorporated into the treatment of cancers in almost every anatomical site, most commonly head and neck cancer, central nervous system tumors, and prostate cancer. In addition, current protocols are investigating the use of IMRT for the treatment of breast cancer, lung cancer, abdominal/retroperitoneal malignancies, and gynecological diseases. This article presents a brief technical review of IMRT and addresses specific clinical concerns and caveats that radiation oncologists should be aware of when utilizing this technology.
Independent Evaluations of IMRT through the Use of an Anthropomorphic Phantom
Authors: Ibbott Geoffrey S. , Molineu Andrea , Followill David S.
Published: October 2014

Intensity-modulated radiation therapy (IMRT) has gained rapid and wide-spread acceptance in the radiation oncology community for its ability to create dose distributions that conform to the convoluted shapes of many tumors. It is a complicated treatment technique, for which quality assurance procedures are correspondingly complicated and labor intensive. Several of the cooperative cancer study groups that conduct clinical trials under the auspices of the National Cancer Institute have required participating institutions to seek credentialing before enrolling patients in trials involving IMRT. The Radiological Physics Center has conducted such credentialing programs through the use of anthropomorphic phantoms that evaluate the planning and delivery of IMRT. The experience obtained through the irradiation of the phantoms by a number of institutions demonstrates that institutions vary significantly in their ability to deliver doses and dose distributions that agree with their own treatment plans.
Frameless Stereotactic Radiosurgery for Recurrent Head and Neck Carcinoma
Authors: Voynov George , Heron Dwight E. , Burton Steven , Grandis Jennifer , Quinn Annette , Ferris Robert , Ozhasoglu Cihat , Vogel William , Johnson Jonas
Published: October 2014

The aim of this study was to assess the feasibility and toxicity of stereotactic radiosurgery (CK-SRS) using the CyberKnife® Frameless Radiosurgery System (Accuray Inc., Sunnyvale, CA) in the management of recurrent squamous cell carcinoma of the head and neck region (SCCHN). Between November 2001 and February 2004, 22 patients with recurrent, previously irradiated SCCHN were treated with CK-SRS. The following endpoints were assessed post-CK-SRS: local control (LC), cause-specific survival (CSS), overall survival (OS), symptom relief, and acute and late toxicity. Kaplan-Meier survival analyses were used to estimate the LC, CSS, and OS rates. Clinical symptoms were graded as “improved,” “stable,” or “progressed” after CK-SRS. Acute and late toxicity were graded according to the National Cancer Institute Common Toxicity Criteria (CTC) scale, version 2.0. Seventeen patients were followed until their death. The median follow-up in the remaining five patients was 19 months (range 11–40 months). The median survival time for the entire cohort was 12 months from the time of CK-SRS. The 2-year LC, CSS, and OS rates were 26%, 26%, and 22%, respectively. After CK-SRS, symptoms were improved or stable in all but one patient who reported increasing pain. The treatment was well tolerated, with one case each of Grade 2 and 3 mucositis. There were no acute Grade 4 or 5 CTC toxicities. There were no late toxicities in this cohort. Frameless stereotactic radiosurgery for recurrent SCCHN is feasible and safe in the setting of high doses of prior irradiation. The majority of patients experienced palliation of disease without excess toxicity.
Wnt-1 is Dominant over Neu in Specifying Mammary Tumor Expression Profiles
Authors: Huang Shixia , Podsypanina Katrina , Chen Yidong , Cai Weiyan , Tsimelzon Anna , Hilsenbeck Susan , Li Yi
Published: October 2014

Wnt-1 and Neu collaborate to induce mammary tumors in bitransgenic mice carrying both MMTV- Wnt-1 and MMTV- Neu. In this report, gene expression profiles were determined for tumors from these bitransgenic mice, and compared with expression profiles of tumors from mice singly transgenic for MMTV- Wnt-1 or MMTV- Neu. While very different from tumors arising in MMTV- Neu transgenic mice, tumors from these bitransgenic mice were found not to have identifiable differences from tumors from MMTV- Wnt-1 transgenic mice, using clustering and multidimensional scaling analyses (unsupervised and supervised), One-way Analysis of Variance (ANOVA), and two sample t test (the later two of which were combined with false discovery rate computation). These observations suggest that Wnt-1 is dominant over Neu in specifying mammary tumor expression profiles.
Killing Two Birds with One Stone: A Dosimetric Study of Dual Target Radiosurgery Using a Single Isocenter
Authors: Roberge David , Ruo Russell , Souhami Luis
Published: October 2014

The treatment of hematogenous brain metastases is a frequent indication for stereotactic radiosurgery (SRS). It is common for more than one metastasis to be treated during the same SRS session.

We retrospectively identified four cases where our m3 micro multileaf collimator (mMLC) was used to create two distinct apertures and treat adjacent lesions using a single isocenter. For these four cases, single isocenter plans with static conformal beams were dosimetrically compared to plans utilizing two isocenters with static conformal beams or conformal arcs.

The effects on dose homogeneity, dose conformity, and the minimum isodose separating the two targets are minor and variable. On the other hand, the use of a single isocenter technique consistently halves delivery time and decreases the integral dose to normal tissue.

For small adjacent metastases, which can simultaneously be encompassed within the high-resolution portion of the m3/Novalis mMLC collimator, the use of a single rather than a dual isocenter technique is feasible and generally advantageous.
Concise Matrix Analysis of Point-Based Prostate Targeting for Intensity Modulated Radiation Therapy
Authors: Barbiere Joseph , Hanley Joseph , Song Yulin , Dhawan Atam P. , Chan Maria F.
Published: October 2014

Intensity Modulated Radiation Therapy (IMRT) has recently emerged as an effective clinical treatment tool to treat various types of cancers by limiting the external beam dose to the surrounding normal tissue. However, the process of limiting external radiation dose to the tissue surrounding the tumor volume is not a trivial task. Several parameters including tumor volume and inhomogeneity, position and shape of the tumor volume, and the geometrical distribution of the radiation beams directly affect the determination of the external radiation dose. In addition, a major variable in effective delivery of the radiation dose is “set-up error” caused by the changes in patient position. Any changes in the position of the patient affect the geometrical location of the tumor volume and, therefore, need to be accommodated in the delivery of radiation beams during the treatment. This work presents a complete matrix representation required to calculate the three-dimensional rigid body homogeneous transformation matrices corresponding to external beam radiotherapy setup error and subsequent corrections in treatment beam parameters. A new concise orthogonal rotation solution is presented for use with clinical noisy data. Monte Carlo simulations prove the new matrix results are consistently better than the standard inverse solution. The required corrections in beam table, gantry, and collimator angles as function of the planned beam gantry angle are derived. For transformations that include a rotation on the sagittal plane, the required offsets to beam parameters are complex functions of the planned gantry angle but are clearly documented graphically for clinical use. A case study is presented with an error analysis that supports the use of the presented method in a clinical environment. Clinical implementation and evaluation of the presented method with patient data is also included in the paper.
3D-Segmentation of the 18F-choline PET Signal for Target Volume Definition in Radiation Therapy of the Prostate
Authors: Ciernik I. Frank , Brown Derek W. , Schmid Daniel , Hany Thomas , Egli Peter , Davis J. Bernard
Published: October 2014

Volumetric assessment of PET signals becomes increasingly relevant for radiotherapy (RT) planning. Here, we investigate the utility of 18F-choline PET signals to serve as a structure for semi-automatic segmentation for forward treatment planning of prostate cancer. 18F-choline PET and CT scans of ten patients with histologically proven prostate cancer without extracapsular growth were acquired using a combined PET/CT scanner. Target volumes were manually delineated on CT images using standard software. Volumes were also obtained from 18F-choline PET images using an asymmetrical segmentation algorithm. PTVs were derived from CT 18F-choline PET based clinical target volumes (CTVs) by automatic expansion and comparative planning was performed. As a read-out for dose given to non-target structures, dose to the rectal wall was assessed. Planning target volumes (PTVs) derived from CT and 18F-choline PET yielded comparable results. Optimal matching of CT and 18F-choline PET derived volumes in the lateral and cranial-caudal directions was obtained using a background-subtracted signal thresholds of 23.0+/-2.6%. In antero-posterior direction, where adaptation compensating for rectal signal overflow was required, optimal matching was achieved with a threshold of 49.5+/-4.6%. 3D-conformal planning with CT or 18F-choline PET resulted in comparable doses to the rectal wall. Choline PET signals of the prostate provide adequate spatial information amendable to standardized asymmetrical region growing algorithms for PET-based target volume definition for external beam RT.
Irreversible Electroporation: A New Ablation Modality — Clinical Implications
Authors: Rubinsky Boris , Onik Gary , Mikus Paul
Published: October 2014

Irreversible electroporation (IRE) is a new tissue ablation technique in which micro to millisecond electrical pulses are delivered to undesirable tissue to produce cell necrosis through irreversible cell membrane permeabilization. IRE affects only the cell membrane and no other structure in the tissue. The goal of the study is to test our IRE tissue ablation methodology in the pig liver, provide first experience results on long term histopathology of IRE ablated tissue, and discuss the clinical implications of the findings. The study consists of: a) designing an IRE ablation protocol through a mathematical analysis of the electrical field during electroporation; b) using ultrasound to position the electroporation electrodes in the predetermined locations and subsequently to monitor the process; c) applying the predetermined electrotroporation pulses; d) performing histolopathology on the treated samples for up to two weeks after the procedure; and e) correlating the mathematical analysis, ultrasound data, and histology. We observed that electroporation affects tissue in a way that can be imaged in real time with ultrasound, which should facilitate real time control of electroporation during clinical applications. We observed cell ablation to the margin of the treated lesion with several cells thickness resolution. There appears to be complete ablation to the margin of blood vessels without compromising the functionality of the blood vessels, which suggests that IRE is a promising method for treatment of tumors near blood vessels (a significant challenge with current ablation methods). Consistent with the mechanism of action of IRE on the cell membrane only, we show that the structure of bile ducts, blood vessels, and connective tissues remains intact with IRE. We report extremely rapid resolution of lesions, within two weeks, which is consistent with retention of vasculature. We also document tentative evidence for an immunological response to the ablated tissue. Last, we show that mathematical predictions with the Laplace equation can be used in treatment planning. The IRE tissue ablation technique, as characterized in this report, may become an important new tool in the surgeon armamentarium.
Intensity-Modulated Radiosurgery for Patients with Brain Metastases: A Mature Outcomes Analysis
Authors: Wang Samuel J. , Choi Mehee , Fuller Clifton D. , Salter Bill J. , Fuss Martin
Published: October 2014

The purpose of this study was to evaluate the outcomes of patients with brain metastases treated by tomotherapeutic Intensity-modulated Radiosurgery (IMRS). Using retrospective chart review, we analyzed the outcomes of 78 patients (age 33–83 years, median 57 years) who underwent 111 sessions of IMRS (1 to 7 sessions per patient, median 1) for brain metastases (1 to 4 targets per IMRS session, median 1) treated between 2000 and 2005 using a serial tomotherapeutic intensity-modulated radiotherapy treatment (IMRT) planning and delivery system (Peacock, Nomos Corp., Cranberry Township, PA). Treatment planning was performed using an inverse treatment planning optimization algorithm that was optimized for IMRS. A median prescription dose of 15 Gy in combination with WBI, and median 20 Gy for IMRS alone was delivered using 2–4 couch angles over 4–24 rotational arcs. Overall survival was calculated using Kaplan-Meier analysis. To determine the effects of prognostic variables on survival, univariate and multivariate analyses using proportional hazards were performed to assess the effects of age, tumor size, the combination with whole brain irradiation, presence of multiple brain metastases, and presence of extracranial disease. The median overall survival was 6.5 months (95% CI, 5.5–7.9). One- and two-year survival rates were 24% and 10%. In multivariate analyses, age greater than 60 years was the only statistically significant variable that affected survival (hazard rate 1.29, p=0.049). We conclude that tomotherapeutic IMRS is safe and effective to treat patients with brain metastases.
Fractionated Stereotactic Radiotherapy Boost and Weekly Paclitaxel in Malignant Gliomas Clinical and Pharmacokinetics Results
Authors: Ashamalla H. , Zaki B. , Mokhtar B. , Lewis L. , Lavaf A. , Nasr H. , Colella F. , Dosik D. , Krishnamurthy M. , Saad N. , Guriguis A.
Published: October 2014

Management of Malignant Gliomas continues to be a challenge. We prospectively studied the role of adding weekly Paclitaxel to Fractionated Stereotactic Radiation Therapy (FSRT) in the treatment of Malignant Gliomas. Twenty-three Glioblastoma Multiforme and two Anaplastic Astrocytoma were studied. Patients received 46 Gy at 2 Gy/fraction followed by a boost utilizing FSRT at a fraction of 2.5 Gy for 8 fractions. Paclitaxel is delivered concomitantly at 150 mg/m2 weekly for six cycles. Eighteen patients had pharmacokinetic assays of Paclitaxel levels. All patients were followed until death or for a maximum of 36 months. The overall survival of the whole group was 14 months. The median survival for RPA prognostic classes III, IV, V, and VI were 20, 14, 12, and 11 months. Higher survival (14 months) was noted in the subtherapeutic phenytoin level group compared to 10 months in the therapeutic group (P=0.271). No grade 4 CTCAE (version 3.0) toxicities were observed. Enhanced survival was demonstrated with gross tumor resection (20.8 months), KPS ≥80 (18.7 months) and age ≤60 years (27 months) as compared to subtotal resection or biopsy (12.1 months, P< 0.005), KPS ≤70 (10.8 months, P=0. 005) and older age > 60 (10.46 months, P=0.006), respectively. Our study suggests that: i) the use of weekly Paclitaxel and FSRT in Gliomas is well tolerated with a survival of 14 months; ii) the regimen resulted in improvement of survival of RPA classes IV, V, VI; and iii) the use of FSRT boost may be studied with other chemotherapeutic agents to see if superior results can be attained.
Reducing Set-up Uncertainty in the Elekta Stereotactic Body Frame Using Stealthstation Software
Authors: Hinson William H. , Kearns William T. , Ellis Thomas L. , Sprinkle Denise , Cullen Tim , Smith Phillip G. , Stieber Volker W.
Published: October 2014

The Elekta Stereotactic Body Frame (SBF) is a device which allows extracranial targets to be localized and irradiated in a stereotactic coordinate system. Errors of positioning of the body relative to the frame are indirectly estimated by image fusion of multiple CT scans. A novel repositioning methodology, based on neurosurgical Stealth technology, is presented whereby accurate patient repositioning is directly confirmed before treatment delivery. Repositioning was performed on four extracranial stereotactic radiosurgery patients and a radiotherapy simulation phantom. The setup error was quantitatively measured by fiducial localization. A confirmatory CT scan was performed and the resulting image set registered to the initial scan to quantify shifts in the GTV isocenter. Alignment confirmation using Stealth took between 5 and 10 minutes. For the phantom studies, a reproducibly of 0.6 mm accuracy of phantom-to-SBF alignment was measured. The results on four actual patients showed setup errors of 1.5 mm or less. Using the Stealth Station process, rapid confirmation of alignment on the treatment table is possible.
Generation and Characterization of a Proton Microbeam for Experimental Radiosurgery
Authors: Moyers M. F. , Reder C. S. , Lau D. C.
Published: October 2014

A proton microbeam has been developed to support various research endeavors. Test subjects may be irradiated from any angle with respect to the vertical because the beamline is contained within a rotating gantry used for human patients. Converting from the treatment to experimental arrangement is quick and straightforward as is the reverse. Using a series of collimators, the final beam diameter at the surface of the subject is 1 mm. The depth from the surface to the Bragg peak in water is 15 mm. Fluence distributions perpendicular to the beam axis were determined by scanning radiographic film exposed at various depths with a scanner having a pixel size of 84.7 μm. The depth dose integrated over the beam area was measured using a parallel plate ionization chamber. Central axis depth doses were calculated by multiplying the ionization chamber signal by the ratio of film doses for the central axis pixels to the integrated beam doses at each depth. A Faraday cup was used to confirm the dose at the surface while TLDs, diodes, and film were used to verify the dose at depth. The usefulness of this beamline for experimental situations has been demonstrated in a feline neurological study. The dosimetry techniques are useful for narrow beams such as used for functional radiosurgery treatments of humans.
Detection of Metastases from Gastrointestinal Neuroendocrine Tumors: Prospective Comparison of 18F-TOCA PET, Triple-Phase CT, and PET/CT
Authors: Seemann Marcus D.
Published: October 2014

The purpose of the investigation was to assess positron emission tomography (PET), computed tomography (CT) and the image fusion of PET and CT (PET/CT) in the detection of metastases from gastrointestinal neuroendocrine tumors. In a prospective study, thirty-one patients were consecutively examined using a state-of-the-art PET/CT. PET was performed with a carbohydrated F-18-labeled somatostatin receptor ligand (Gluc-Lys([18F]FP-TOCA) from the base of the skull to the proximal thigh using a Pico-3D PET scanner. CT was performed with a noncontrast low-dose CT (LD-CT) and a venous-dominant contrast-enhanced CT (VD-CT) from the base of the skull to the proximal thigh and a hepatic arterial-dominant contrast-enhanced CT (AD-CT) from the epigastric region using a 16-slice CT. The data sets from PET and CT (LD-CT and VD-CT) were fused automatically. To assess a relative sensitivity of each imaging modality, the total number of metastases by summing the number of metastases depicted for each patient by the highest sensitive modality was used as reference standard. PET, LD-CT, AD-CT, VD-CT, PET/LD-CT and PET/VD-CT showed a lesion-by-lesion based overall detection rate for liver metastases (n=858) of 90.8% (P<0.001), 29.4% (P<0.001), 45.5% ( P<0.001), 73.9% ( P<0.001), 91.5% ( P<0.001) and 100%. PET, LD-CT, VD-CT, PET/LD-CT and PET/VD-CT showed an overall detection rate for lymph node metastases (n=193) of 93.8% ( P<0.001), 25.4% ( P<0.001), 64.8% ( P<0.001), 93.8% ( P<0.001) and 100% and for osseous metastases (n=567) of 98.6% ( P<0.005), 40.7% ( P<0.001), 40.7% ( P<0.001), 100% and 100%. Furthermore, PET revealed 2 (22.2%) of 9 intrapulmonal lesions seen on LD-CT, VD-CT, PET/LD-CT and PET/VD-CT. PET as single modality revealed most liver, lymph node and osseous metastases. The combination of molecular/metabolic with anatomical/morphological information improves the diagnostic accuracy for the detection of metastases in comparison to any single imaging modality. LD-CT cannot replace VD-CT in the detection of liver and lymph node metastases, but was equal in the detection of osseous metastases and identifying of pulmonary lesions.
Potential Long-Term Consequences of Fad Diets on Health, Cancer, and Longevity: Lessons Learned from Model Organism Studies
Authors: Ruden Douglas M. , Rasouli Parsa , Lu Xiangyi
Published: October 2014

While much of the third world starves, many in the first world are undergoing an obesity epidemic, and the related epidemics of type II diabetes, heart disease, and other diseases associated with obesity. The amount of economic wealth being directly related to a decline in health by obesity is ironic because rich countries contribute billions of dollars to improve the health of their citizens. Nevertheless, nutritional experiments in model organisms such as yeast, C. elegans, Drosophila, and mice confirm that “caloric restriction” (CR), which is defined generally as a 30–40% decrease in caloric intake, a famine-like condition for humans seen only in the poorest of countries, promotes good health and increases longevity in model organisms. Because caloric restriction, and dieting in general, requires a great deal of will power to deal with the feelings of deprivation, many fad diets, such as the Atkins, South Beach, and Protein Power, have been developed which allow people to lose weight purportedly without the severe feelings of deprivation. However, the long-term effects of such fad diets are not known and few experiments have been performed in the laboratory to investigate possible side affects and adverse consequences. In this paper, we review studies with fad-like dietary conditions in humans and model organisms, and we propose a “Dietary Ames Test” to rapidly screen fad diets, dietary supplements, and drugs for potential long-term health consequences in model organisms.
A Study of the Immunological Response to Tumor Ablation with Irreversible Electroporation
Authors: Al-Sakere B. , Bernat C. , André F. , Connault E. , Opolon P. , Davalos R. V. , Mir L. M.
Published: October 2014

Immune cell recruitment during the treatment of sarcoma tumors in mice with irreversible electroporation was studied by immunohistochemistry. Irreversible electroporation is a non-thermal tissue ablation technique in which certain short duration electrical fields are used to permanently permeabilize the cell membrane, presumably through the formation of nanoscale defects in the membrane. Employing irreversible electroporation parameters known to completely ablate the tumors without thermal effects we did not find infiltration of immune cells probably because of the destruction of infiltration routes. We confirm here that immune response is not instrumental in irreversible electroporation efficacy, and we propose that irreversible electroporation may be, therefore, a treatment modality of interest to immunodepressed cancer patients.
The Effect of Irreversible Electroporation on Blood Vessels
Authors: Maor Elad , Ivorra Antoni , Leor Jonathan , Rubinsky Boris
Published: October 2014

We present a pilot study on the long term effects of irreversible electroporation (IRE) on a large blood vessel. The study was motivated by the anticipated use of IRE for treatment of cancer tumors abutting large blood vessels. A sequence of 10 direct current IRE pulses of 3800 V/cm, 100μs each, at a frequency of 10 pulses per second, were applied directly to the carotid artery in six rats. Measuring tissue conductivity during the procedure showed, as predicted, an increase in conductivity during the application of the pulse, which suggests that this measurement can be used to control the application of IRE. All the animals survived the procedure and showed no side effects. Histology performed 28 days after the procedure showed that the connective matrix of the blood vessels remained intact and the number of vascular smooth muscle cells (VSMC) in the arterial wall decreased with no evidence of aneurysm, thrombus formation or necrosis. Average VSMC density was significantly lower following IRE ablation compared with control (24 ± 11 vs. 139 ± 14, P<0.001), with no apparent damage to extra cellular matrix components and structure. In addition to the relevance of this study to treatment of cancer near large blood vessels these findings tentatively suggest that IRE has possible applications to treatment of pathological processes in which it is desired to reduce the proliferation of VSMC population, such as restenosis and for attenuating atherosclerotic processes in clinical important locations such as coronary, carotid and renal arteries.
Design of an Irreversible Electroporation System for Clinical Use
Authors: Bertacchini Claudio , Margotti Pier Mauro , Bergamini Enrico , Lodi Andrea , Ronchetti Mattia , Cadossi Ruggero
Published: October 2014

Irreversible electroporation is an ablation modality in which microseconds, high-voltage electrical pulses are applied to induce cell necrosis in a target tissue. To perform irreversible electroporation it is necessary to use a medical device specifically designed for this use.

The design of an irreversible electroporation system is a complex task in which the effective delivery of high energy pulses and the safety of the patient and operator are equally important. Pulses of up to 3000 V of amplitude and 50 A of current need to be generated to irreversibly electroporate a target volume of approximately 50 to 70 cm3 with as many as six separate electrodes; therefore, a traditional approach based on high voltage amplifiers becomes hard to implement.

In this paper, we present the process that led to the first irreversible electroporator capable of such performances approved for clinical use. The main design choices and its architecture are outlined. Safety issues are also explained along with the solutions adopted.
CyberKnife Radiosurgery for Lesions of the Foramen Magnum
Authors: Cheshier Samuel H. , Hanft Simon J. , Adler John R. , Chang Steven D.
Published: October 2014

The region of the foramen magnum (FM) presents an especially difficult area for therapeutic intervention. Indeed, this location is challenging to access surgically, particularly in the case of intramedullary and anterior lesions. Therefore, the potential for morbidity associated with therapy to the foramen magnum, most frequently in the form of lower cranial nerve deficits, has encouraged the search for methods that can effectively treat lesions of this region while sparing the important neighboring structures. We report our experience in the use of Cyberknife radiosurgery as a treatment option for these lesions.

Thirty-five patients (17 men, 18 women; mean age, 51 yr; range, 18–83) with 35 lesions either spanning or approximating the foramen magnum were treated with the CyberKnife radiosurgical system. Histologies were determined either by prior surgery or radiographic criteria and included 25 benign tumors (nine meningiomas, five schwannomas, four neurofibromas, three hemangioblastomas, two ependymomas, one chordomas, and one pilocytic astrocytoma) along with 10 malignant growths (nine metastases and one chondrosarcoma). Twenty-seven (77%) patients presented with at least one sign and/or symptom, while eight (23%) patients were completely asymptomatic. The most common symptoms were headache, limb numbness, and limb/truncal ataxia, all of which were reported by ten (29%) patients. Among cranial neuropathies, CN XII dysfunction was evident in four (11%) patients. The specific fractionation schedule (mean of 1.8 sessions; range, 1–5) was based on the size of the treated lesion. The mean dose utilized was 19 Gy.

Radiographic follow-up was obtained for twenty-three (66%) patients. Nine of the twenty-three (39%) were stable in size, ten lesions decreased in size (43%), and four lesions increased in size (17%). In terms of symptom relief, follow-up was collected for twenty-four (69%) patients. Eleven (46%) of these patients experienced no change in their signs or symptoms, while seven (29%) patients experienced improvement. Six (25%) patients witnessed deterioration in their signs and symptoms. Overall, eighteen (75%) patients had their signs and symptoms either stabilize or improve. There were eleven (31%) deaths in our series, eight of which were related to the disease (though not directly related to CyberKnife treatment) and three of which were from unrelated causes. Complications directly related to CyberKnife radiosurgery were noted in four (11%) of the thirty-five patients. These included one case of temporary emesis immediately following treatment, one case of cystic enlargement two months out, and two cases of radiation necrosis (occurring 1.5 yrs and 2.5 yrs out from treatment).

Cyberknife radiosurgery can be an effective treatment for many foramen magnum lesions.