Non-invasive Cancer Treatment Research Articles

MR-guided high-intensity focused ultrasound for noninvasive cancer treatment

Magnetic resonance (MR)-high-intensity focused ultrasound (HIFU) is an innovative, noninvasive tumour ablation technique. MR imaging and focused ultrasound are combined allowing real-time anatomic guidance and temperature mapping during treatment. Recently, the volumetric ablation approach has been introduced in order to reduce treatment length and provide more homogeneous tumour ablation. After successful treatment of uterine fibroids, MR-HIFU is currently being investigated for the treatment of malignant tumours. Palliative treatment of painful bone metastases is already applied in clinical practice. Several issues need to be further investigated for successful cancer treatment with MR-HIFU, including patient selection criteria, definition of treatment margins and optimal transducer technology.

Silicon phthalocyanine (pc 4) photodynamic therapy is a safe modality for cutaneous neoplasms: results of a phase 1 clinical trial

Photodynamic therapy (PDT) is a non-invasive treatment for non-melanoma skin cancer. However, PDT systems currently used clinically have limitations such as pain and superficial tissue penetration. The silicon phthalocyanine Pc 4 is a second-generation photosensitizer with peak absorption in the far red at 675 nm. To assess the safety and tolerability of topically applied Pc 4 followed by red light (Pc 4-PDT) in treating cutaneous neoplasms. Forty three adults with a diagnosis of neoplasms including actinic keratoses, Bowen's disease, squamous cell carcinoma, basal cell carcinoma, or mycosis fungoides were treated with a single administration of Pc 4-PDT and followed for 14 days. The study utilized a light and Pc 4 dose escalation design in sequential groups of three subjects each. Pc 4-PDT was well tolerated with no significant local toxicity or increased photosensitivity. It has promising biologic effects, particularly in mycosis fungoides where 14 of 35 subjects demonstrated a clinical response, which correlates with Pc 4-PDT-induced apoptosis, as measured by increased active caspase-3 in the treated skin lesions. Pc 4-PDT is a safe and tolerable treatment modality that effectively triggers apoptosis in cutaneous neoplasms such as mycosis fungoides.

Cancer-cell microsurgery using nonlinear optical endomicroscopy

Near-infrared laser-based microsurgery is promising for noninvasive cancer treatment. To make it a safe technique, a therapeutic process should be controllable and energy efficient, which requires the cancer cells to be identifiable and observable. In this work, for the first time we use a miniaturized nonlinear optical endomicroscope to achieve microtreatment of cancer cells labeled with gold nanorods. Due to the high two-photon-excited photoluminescence of gold nanorods, HeLa cells inside a tissue phantom up to 250 μm deep can be imaged by the nonlinear optical endomicroscope. This facilitates microsurgery of selected cancer cells by inducing instant damage through the necrosis process, or by stopping cell proliferation through the apoptosis process. The results indicate that a combination of nonlinear endomicroscopy with gold nanoparticles is potentially viable for minimally invasive cancer treatment.

3D computational study of non-invasive patient-specific microwave hyperthermia treatment of breast cancer

Non-invasive microwave hyperthermia treatment of breast cancer is investigated using three-dimensional (3D) numerical breast phantoms with anatomical and dielectric-properties realism. 3D electromagnetic and thermal finite-difference time-domain simulations are used to evaluate the focusing and selective heating efficacy in four numerical breast phantoms with different breast tissue densities. Beamforming is used to design and focus the signals transmitted by an antenna array into the breast. We investigate the use of propagation models of varying fidelity and complexity in the design of the transmitted signals. An ideal propagation model that is exactly matched to the actual patient's breast is used to establish a best-performance baseline. Simpler patient-specific propagation models based on a homogeneous breast interior are also explored to evaluate the robustness of beamforming in practical clinical settings in which an ideal propagation model is not available. We also investigate the performance of the beamformer as a function of operating frequency and compare single-frequency and multiple-frequency focusing strategies. Our study suggests that beamforming is a robust method of non-invasively focusing microwave energy at a tumor site in breasts of varying volume and breast tissue density.

Study of the stabilization of zinc phthalocyanine in sol-gel TiO 2 for photodynamic therapy applications

Photodynamic therapy (PDT) has emerged as an alternative and promising noninvasive treatment for cancer. It is a two-step procedure that uses a combination of molecular oxygen, visible light, and photosensitizer (PS) agents; phthalocyanine (Pc) was supported over titanium oxide but has not yet been used for cell inactivation. Zinc phthalocyanine (ZnPc) molecules were incorporated into the porous network of titanium dioxide (TiO 2) using the sol-gel method. It was prepared from stock solutions of ZnPc and TiO 2. ZnPc-TiO 2 was tested with four cancer cell lines. The characterization of supported ZnPc showed that phthalocyanine is linked by the N-pyrrole to the support and is stable up to 250°C, leading to testing for PDT. The preferential localization in target organelles such as mitochondria or lysosomes could determine the cell death mechanism after PDT. The results suggest that nanoparticulated TiO 2 sensitized with ZnPc is an excellent candidate as sensitizer in PDT against cancer and infectious diseases. From the Clinical Editor Photodynamic therapy is a two-step procedure that uses a combination of molecular oxygen, visible light and photosensitizer agents as an alternative and promising non-invasive treatment for cancer. The results of this study suggest that nanoparticulated TiO 2 sensitized with ZnPc is an excellent photosensitizer candidate against cancer and infectious diseases.

The value of transurethral resection of bladder tumor in one piece (TURBO).

e15143 Background: Since transurethral resection of bladder tumor in one piece (TURBO) was reported in the Journal of Urology in 2000 by Ukai, some urologists carried out TURBO. We analyzed treatment results of TURBO in our hospital and examined the value of this procedure. Methods: A total of 14 patients with bladder tumors carried out TURBO under spinal anesthesia, in some cases blocking the obtulater nerve, from April 2006 to June 2009 in our hospital. The procedure is 1. point marking, 2. circular incision, 3. level incision and 4. specimen retrieval using a needle electrode in accordance with the Ukai's method. We investigated pathological findings, operation time and complications. Results: It is possible to diagnose the precise pathlogical findings by TURBO. All resected edge had no cancer. There were no recurrence on the same location. There were no complications during and after the operation. Operation time of TURBO (35-223 min) was longer than TUR-BT. Urethral catheter holding period and hospitalization period after TURBO was the same as TUR-BT. TURBO is a relatively safe procedure even for beginners. Conclusions: TURBO is a safe and useful procedure that provides precise pathological findings with minimal complications. Second TUR is not necessary for TURBO. TURBO has a possibility to be gold standard of the treatment for non muscle invasive bladder cancer. No significant financial relationships to disclose.

Abstract 672: TumoraseTM: In vivo efficacy data for novel localized proteinase treatment applicable to solid tumors of varied tissue origins

Abstract To facilitate the development of noninvasive solid tumor cancer treatments, BioMedicure reports here the development of a specific proteinase treatment that when injected locally into solid tumors elicits a substantial tumor remission. Reported here is data indicating that intratumoral injection of TumoraseTM (T101, BioMedicure, San Diego, CA), a novel proteinase formulation, into solid tumors of various tissue origin destroys the tumor by digesting the solid-structure, killing cancer cells, including cancer stem cells, locally while not effecting normal tissues. The best route of TumoraseTM biochemical delivery to the tumor is intratumoral injection by a needle with a gauge 20-27. Before TumoraseTM intratumoral delivery, the tumor volume is estimated by 3-dimensional measurement and calculation: L x W X H in mm3, where “L” is the solid-tumor length, “W” solid-tumor width and “H” solid-tumor height. Tumorase works best when intratumorally injected at about 50-80% of solid-tumor volume delivered not by bolus but at about 200 uL per minute. The success rate of eliminating sparsely vascularized solid-tumors 50-400 mm3 in volume is high (over 70%). However, since inhibitory factors in serum diminish the activity of TumoraseTM, the success rate of eliminating a highly vascularized soft or liquid tumor is low (below 30%), though partial tumor mass decrease responses are observed. Multiple treatments can be applied to further diminish tumor mass. Data will be presented for the following tumor models, the human melanoma (CRL-1676 and WM-266-4), the human prostates (CRl-2505 and 22Rv1), human breast ductal carcinomas (HTB-129 and MDA-MB-435S), the human bronchioalveolar carcinomas (HTB-177 and NCI-H460) and the human colon adenocarcinomas (CCL-231 and SW48) xenografts. When a cancerous growth is found early and is accessible by a surgical knife, surgery is still the recommended treatment. However, if not accessible or there are multiple tumors, then, TumoraseTM would be a viable option, a local therapy that can be utilized for multiple tumors elimination. TumoraseTM contains proteases that cleave the extracellular matrix, including vital proteins required for cell survival, leading to cancer cell death. Presented here is in vivo data indicating the efficacy of this novel proteinase preparation for the elimination of solid tumors of multiple tumor classes by destroying tumors’ solid structure and killing cancer cells by cleaving the extracellular domains of vital cell membrane proteins. The wide range of solid cancerous tumors eliminated suggests a potential wide clinical applicability. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 672.

OPTIMAL CONSTRAINED FIELD FOCUSING FOR HYPERTHERMIA CANCER THERAPY: A FEASIBILITY ASSESSMENT ON REALISTIC PHANTOMS

Microwave hyperthermia is a non-invasive treatment for cancer which exploits a selective heating of tissues induced through focused electromagnetic flelds. In order to improve the treatment's e-ciency, while minimizing side efiects, it is necessary to achieve a constrained focusing of the fleld radiated by the sources. To address this issue, in this paper we present an innovative and computationally efiective approach to the fleld focusing for hyperthermia. The proposed method, after establishing the number of sources to be used, determines the excitations of the given set of sources such to produce a maximum fleld in a given region of space, subject to a completely arbitrary mask for the fleld amplitude in all other regions. As the approach relies on a formulation of the problem in terms of convex programming, it is able to achieve the globally optimal solution without the adoption of computationally intensive global optimization procedures. A preliminary assessment of feasibility is given on hyperthermia therapy of breast cancer by means of numerical examples run on realistic 2D phantoms of female breast.

Annular Array Transducer and Matched Amplifier for Therapeutic Ultrasound

The use of therapeutic ultrasound continues to grow. A focused ultrasonic wave can increase the tissue temperature locally for the non-invasive cancer treatment or other medical applications. The authors have designed a seven-element annular array transducer operating at 2.4 MHz. Each element was excited by sine burst supplied by a linear amplifier and FPGA control circuits. The acoustic field, generated by a transducer was initially numerically simulated in a computer and next compared to water tank hydrophone measurements performed at 20, 40 and 60 mm focal depth. The results showed good agreement of the measurements with theory and the possibility to focus the ultrasound in the preselected area. The total acoustic power radiated by the annular array was equal to 2.4 W.

A new hope for noninvasive cancer treatment? [Microwave Surfing

This paper reported the successful application of a 13.56-MHz external RF field (600-800 W for 1-2 min) to induce efficient heating in aqueous suspensions of single-walled carbon nanotubes (SWNTs). When the SWNT solution was injected into tumors in live rabbits and the animals exposed to RF fields, the tumor cells were successfully destroyed with relatively little damage to surrounding tissues. The exact RF heating mechanism of such electrically small nanotubes is not yet understood.

A new hope for noninvasive cancer treatment?

Tn 1946, when the late John Kraus was a new faculty member at Ithe Ohio State University, he attended a seminar on travelingwave- tube (TWT) amplifiers, presented by a well-known visiting scientist. These TWTs used a wire helix of a sub-wavelength diameter an a guiding structure. After the presentation, Kraus went up to the visitor and politely inquired if the visitor thought that the helix could have applications as an antenna. As Kraus relates it in his classic antenna text [I], the visitor told him, No. I have tried it and it does not work. finality of the answer sent Kraus scurrying to the basement workshop at his home, where he proceeded to invent the popular helical antenna. This inspiring story about defying conventional wisdom came to my mind as I read the transcript of a CBS News 60 Minutes segment [2], entitled The Kanzius Machine: A Cancer Cure? (broadcast originally on April 23, 2008). However, I am getting ahead of myself. Let me start at the beginning.

Wyniki leczenia wczesnych raków głośni

Early glottic cancer (stage T1, T2) is connected with very good prognosis as well as organ and function preservation. The aim of the study was the assessment of early glottic treatment results. Between 1999-2005 1007 patients with larynx cancer were treated in Dept. of Otolaryngology Head Neck Oncological Surgery Poznań University of Medical Sciences. The majority constitute the patients with II and III stage of clinical advancement of the disease. Early glottic cancer was diagnosed in 43 patients (4.3%). The diagnose of the larynx cancer was set upon indirect and direct laryngoscopy, histological examination of larynx samples and neck ultrasonography. In all 43 patients CO2 laser surgery in Klein1 sasser microlaryngoscopy set was performed. In all cases, confirmed in histological examination the resection was radical. Follow-up was conducted every month in the first year of observation, then every 2-3 months. The time of follow-up ranged from 40 to 64 month, mean 51 month. In 4 patients (9.3%) treated for early glottic cancer with CO2 laser surgery the local relapse occurred after 10, 15, 19 and 28 month respectively. In two patients total laryngectomy, in one reconstructive partial laryngectomy and in one radiotherapy was performed. The mean time of observation after salvage treatment is 29 months. All patients are alive and free of disease. The laser surgery is an effective and non-invasive treatment of early glottic cancer but the strict follow-up regimen is demanded.

MR guided cancer treatment system for an elevated therapeutic index – A macroscopic approach

Adjuvant therapy for cancer usually refers to surgery followed by chemotherapy and/or radiation treatment to decrease the risk of recurrence. But still, the absolute benefit for survival obtained with adjuvant therapy compared with control is only approximately 6%. The objective of this analysis is to formulate a non-invasive multimodal cancer treatment system related to cancer stem cells and hypoxic fractions of solid tumors, emphasizing MRI monitoring and guidance, to elevate the therapeutic index. Tumor hypoxia is a therapeutic concern since it can reduce the effectiveness of drugs and radiotherapy, where well oxygenated cells requiring one third of the dose of hypoxic cells to achieve a given level of cell killing. Cancer stem cells might be the cause of tumor recurrence, sometimes many years after the appearance of the successful treatment of a primary tumor. Thus, the primary objective of such a treatment system will be to provide sufficient selective toxicity to both kill cancer stem cells and cells of hypoxic fractions of the tumor. Active tumor targeting with the use of liposomally encapsulated drugs is the starting point of the treatment procedure. The system facilitates quality assurance means by MR monitoring of drug accumulation and drug release, in real time. Cavitation involves the nucleation, growth and oscillation of gaseous cavities. Selective drug release and/or hyperthermia are achieved by ultrasound induced cavitation well defined to the tumor region. Hyperthermic effects, increased vascularization and subsequent increase in pO2 levels to hypoxic regions, can be monitored by MRI. MRI monitoring of key physiological parameters facilitates optimization related to approximate real time concomitant treatments, including correct timing and various combinations of drug therapy, hyperthermia, ionizing radiation, ablation, other treatment options, before or after surgery. The likelihood of an improved therapeutic index with the use of such a system seems compelling. Further research related to optimal timing, combinations of responses between liposomally encapsulated drug dosage, ultrasound exposure, hyperthermia, pO2 response time, ionizing radiation fractionation and treatment time, have to be conducted.

UP-02.55: Transrectal non-invasive prostate cancer treatment by high intensity focused ultrasound (HIFU). Is available technology identical?

UP-02.55: Transrectal non-invasive prostate cancer treatment by high intensity focused ultrasound (HIFU). Is available technology identical?

Chronic Effect of Transrectal Split-Focus Ultrasonic Ablation on Canine Prostatic Tissue

The treatment time needed for high-intensity focused ultrasound (HIFU) ablation might be decreased substantially by using the split-focus approach, so we made a prototype 4.2-MHz split-focus therapeutic transducer combined with a small 6.5-MHz imaging ultrasonic probe for transrectally treatment of canine prostatic cancer and used it to experimentally evaluate the feasibility of using split-focus transrectal HIFU to ablate canine prostatic tissue without injuring surrounding tissues. The prostates of 5 dogs were transrectally treated with split-focus ablation at a peak intensity in the water of 1.7 kW/cm(2) for 4 s (4 shots) under the guidance of ultrasonic B-mode imaging. After ultrasonic exposure, the prostates became stiff because of thermal effect of HIFU. For the first 3-5 days after treatment, dogs were catheterized daily for urinary management and treated with oral antibiotics to prevent urinary tract infection. The dogs were able to urinate normally by a week after. Within two weeks a large centrally located cystic cavity had formed in the prostate by replacing the necrotic parenchyma around the prostatic urethra. Necropsy three months after treatment found the rectum and prostate capsule to be normal grossly and histologically. The 4 shots of split-focus HIFU destroyed the prostatic parenchyma and created a prostatic cavity 0.34-0.45 cm(3) in volume without injuring surrounding tissues. These results suggest that split-focus HIFU ablation could be used for noninvasive treatment of prostatic cancer in dogs.

CD4+ T Cell-Mediated Antigen-Specific Immunotherapy in a Mouse Model of Cervical Cancer

A major agenda for tumor immunology is the generation of specific immune responses leading to the destruction of incipient and frank neoplasia. In this report, we show that a novel HPV16 E7 fusion protein can produce objective therapeutic responses against incipient cervical cancer in genetically engineered mice that express in the cervix the HPV16 early region genes implicated as causative agents in human cervical cancer. Although nonresponsive toward the HPV16 E7 oncoprotein in the CD8+ T-cell compartment by virtue of MHC haplotype, the mice were capable of mounting an induced CD4+ T-cell response against E7, and in addition developed spontaneous anti-E7 antibodies. HPV16/CD4-/- mice showed increased tumor burden indicative of CD4-mediated immune surveillance. Seeking to enhance the CD4 response, we immunized mice bearing incipient cervical cancer with a recombinant protein fusing E7 with a mycobacterial heat shock protein. The incidences of cervical carcinoma and of high-grade dysplasia (CIN 3) were consequently reduced by comparison to control mice. Thus, an HPV16 E7 immunogen holds promise for noninvasive treatment and prevention of human cervical cancer.

The Role of Magnetic Resonance Imaging in Diagnosis and Management of Breast Cancer

A review of the literature on the current applications of breast magnetic resonance imaging (MRI) indications, their rationale and their place in diagnosis and management of breast cancer was given. Contrast-enhanced breast MRI is developing as a valuable adjunct to mammography and sonography. Its high sensitivity for invasive breast cancer establishes its superiority in evaluation of multifocality/multicentricity, tumor response to neoadjuvant chemotherapy, detection of recurrence, and staging. Emerging applications include spectroscopy, usage of new contrast agents, and MRI-guided interventions, including noninvasive treatment of breast cancer. Its potential benefit in screening high-risk women has yet to be established with prospective studies, particularly with regard to false positive results.

609. Highly Active, Cancer Specific Promoters for Gene Therapy of Small Cell Lung Cancer

One of the major problems in conventional, non-invasive cancer treatment is the lack of specific targeting to the cancer cells. For targeted gene therapy, the lack of cancer specific receptors has proven a major obstacle and therefore new strategies are being developed to increase the therapeutic index. This can be achieved by having the expression of the therapeutic gene regulated by a cancer specific promoter and will permit the use of less specific receptors for targeting. Most cancer specific promoters identified to date do not confer sufficient expression levels needed for effective therapy. Therefore the identification of novel highly active, cancer specific promoters would improve the potential of cancer gene therapy.

951. Antitumor Activity of AAV-2 Vector Encoding Modified TRAIL Gene

Prostate cancer is the second most prevalent cancer in men, with limited effective treatment options, especially for metastatic disease. We propose to address this problem by developing enhanced Fas-mediated apoptosis as a treatment modality for prostate cancer. It has been shown that Fas expression on some prostate tumor lines, including the murine RM-1 line, can be up-regulated by a variety of treatment regimens. In this study, primary T cells and functionally-defined subsets of these T cells will be engineered to over-express Fas and will be introduced into tumor-bearing mice in order to interact with normal or up-regulated Fas receptor on prostate tumors. To do this, three recombinant onco-retroviruses have been produced which engineer over-expression of FasL. The first carries only the FasL gene, while the second contains cDNA for a modified, non-cleavable form of FasL (ncFasL) with potentially reduced liver toxicity. The third, a bicistronic construct, includes the cDNA for c-FLIP, an inhibitor of the Fas-mediated apoptotic pathway, in addition to ncFasL. c-FLIP is included to prevent self-killing of transduced, FasL-expressing T cells. The constructs have been packaged in ecotropic E86 and amphotropic FLYRD18 cells and shown to direct production of FasL as well as produce infectious virions, as measured by staining with anti-FasL antibody and flow cytometric analysis. Assays have confirmed that the FasL and ncFasL produced by infected cells is able to mediate killing of Fas-expressing Jurkat cells, and is thus functional. Transduction of primary murine C57BL/6 pan-T cells has been optimized. Irradiation of several tumor cell lines, both murine and human, has shown this to be a plausible method to increase Fas expression. The ability of interferons and chemotherapeutic drugs, including mitoxantrone, to increase tumor Fas expression will also be examined. Experiments are underway in tumor-bearing mice to assess the efficiency of killing by these modified T cells, and to compare the effectiveness of the three viral constructs. We expect to see effective activation of death pathways, leading to tumor destruction. Finally, the relative abilities of the type 1 versus type 2 T lymphocytes as delivery vehicles for this treatment will be compared. This approach may provide a non-invasive treatment for prostate cancer and may also be extended to other malignancies such as breast cancer.

Trials of treatment for non-invasive breast cancer.

Non-invasive breast cancer can be of either the ductal or the lobular type. While the former is often associated with progression to invasive cancer at the same site, lobular carcinoma in situ (LCIS) is a risk factor for invasive cancer rather than a precursor. As a result, LCIS has been used as one entry criterion for the International Breast Intervention Study in which women at increased risk because of histological findings or family history are randomised to receive either tamoxifen 20 mg daily or placebo for 5 years. Four randomised trials have examined treatment options for ductal carcinoma in situ (DCIS) and all have demanded complete local excision as a necessary qualification for entry. Because of this, up to half the cases of DCIS were ineligible for entry since the disease was too extensive and was therefore usually treated by total mastectomy. In most studies--NSABP B-17, EORTC 10853 and Swedish trial--the randomisation was between breast irradiation and observation. Only one trial, NSABP B-17, has published results, and these suggest that progression to invasive cancer is reduced by irradiation. Withholding radiotherapy did not affect mortality. The UK DCIS trial is comparing the effects of both radiotherapy and tamoxifen, but as yet no results are available. At present, radiotherapy should not be used as standard treatment of completely excised DCIS. Appropriate indications for irradiation will be determined when results of histologically characterised cases participating in mature trials become available. Total mastectomy remains the standard treatment for extensive DCIS, but the next generation of trials may examine the role of endocrine manipulation in cases with estrogen-receptor-positive tumours.