Magnetic resonance guided focused ultrasound surgery - a novel treatment for uterine fibroids

Uterine fibroids are the most common tumour of the reproductive tract in women of reproductive age. Although they are benign tumours that are often asymptomatic, they may cause debilitating symptoms in many women, such as abnormal uterine bleeding, abdominal pain, increased abdominal girth, urinary frequency, constipation, pregnancy loss, dyspareunia, and in some cases infertility. Several approaches are available for the treatment of uterine fibroids. These include pharmacologic options, such as hormonal therapies and gonadotropinreleasing hormone agonists; surgical approaches, such as hysterectomy, myomectomy; myolysis, laparoscopic uterine artery occlusion, uterine artery embolisation and magnetic resonance imaging-guided focused ultrasound surgery. The choice of approach may be dictated by factors such as the patient’s desire to become pregnant in the future, the importance of uterine preservation, symptom severity, and tumour characteristics. There is however, no widely agreed therapeutic strategy. There is a widespread view that hysterectomy is overused in the UK; the Chief Medical Officer in his annual report ‘On the state of public health’ in 2005, highlighted that hysterectomy in younger women is associated with complications, hospital stays, procedure-related interference with normal life and is costly. In addition he outlined the need to reduce the number of hysterectomies. This, along with the change in cultural attitudes amongst patients, who are becoming increasingly reluctant to undergo these conventional invasive procedures, has increased the need for new treatment options. Ideally new treatment options for uterine fibroids would be minimally invasive, have long-term data demonstrating efficacy and safety, have minimal or no incidence of fibroid recurrence, be easy to perform, preserve fertility, and be cost effective. New treatment approaches are under investigation, with the goals of being effective, safe, and less invasive. MRgFUS is a non-invasive thermo-ablative hybrid technique which uses both MR and ultrasound to destroy tumours. It is an outpatient procedure, which avoids the need for an anaesthetic, has a short recovery period, and is uterine sparing. The main objective of this work was to set out the rationale for using Magnetic Resonance guided Focused Ultrasound Surgery (MRgFUS) for the treatment of uterine fibroids. In order to achieve this aim, four main bodies of work are necessary; 1) Identifying patient selection criteria and investigating mitigating techniques to increase the pool of women for whom this treatment can be offered. 2) Investigating a method designed to overcome the problem of safely treating women with abdominal scars for whom this treatment can cause potential morbidity. 3) Investigating the potentiality of using MRgFUS to prolong the tumour shrinkage effect of GnRH analogue injections. 4) Investigating the safety of MRgFUS in treating symptomatic women who wish to preserve fertility. Results: the first aim of this project was to identify patient selection criteria and to investigate methods to widen the selection criteria. In our retrospective review it was found that 74% of women presenting were deemed technically suitable to proceed with treatment and several mitigating techniques that solved current technical difficulties were identified and allowed for less restrictive MRgFUS selection criteria for treatment of symptomatic uterine fibroids. These less restrictive criteria are expected to expand the pool of patients for whom MRgFUS is a viable treatment option for uterine fibroid symptoms. The second aim was to identify a method of overcoming the problem of treating women with previous abdominal scars safely. We identified a unique method of highlighting the scar by painting it with a paramagnetic iron oxide material which clearly outlined the scar on MR scanning allowing complete avoidance of the scar using MR guidance. In this small pilot study, all women were treated safely with no skin burns. The third aim of this project looked at the potentiality of prolonging the shrinkage effect of GnRH analogues by following a course of 3 injections with MRgFUS treatment. In this prospective study of fifty women, there was a 50% reduction in the mean symptoms severity score at 6 months which was maintained for 24 months post treatment. There was an average reduction in target fibroid volume which was maintained for 24 months. The final aim of the project was to investigate the safety of using MRgFUS as a treatment option for those women who wished to preserve their fertility. In this multicentre international study, One hundred and sixteen women were recruited from five centres. There were sixty four reported pregnancies in Sixty one women, with 30 completed deliveries. There were no reported cases of uterine rupture, premature labour, abnormal placentation or placental abruption. Conclusion: There is a growing body of data from clinical trials and more than four years of clinical experience to validate the safety and efficacy of MRgFUS for the treatment of uterine fibroids. MRgFUS is a totally non-invasive outpatient procedure that is not associated with the typical surgical risks of bleeding, infection and has minimal recovery time. Additionally, the procedure allows women to address their symptoms whilst preserving the uterus. Consequently, MRgFUS is an alternative treatment option for suitable patients who have refused other interventions due to concerns about lost productivity, risks of surgical complications or future fertility

Imaging findings after meniscal repair with degradable polyurethane scaffold: preliminary results.

Purpose / Introduction: To date, there are no satisfactory solutions to the meniscal originated knee pain post meniscal tear repair. In this study a newly developed polyurethane material that has the intended properties of reducing pain and inducing tissue growth in a damaged meniscus is tested. Materials and Methods: All patients will be imaged using conventional and dynamic MR imaging techniques at 1 week and 3, 12 and 24 months after surgery. The influx of gadolinium contrast in a tissue during the first three minutes after injection gives a measure of the vascularisation, capillary permeability, perfusion and composition of the interstitial fluid. It can be measured using dynamic MRI and is represented as a Time Intensity Curve (TIC). This curve permits an evaluation of the healing process after surgery. Discussion / Conclusion: Thus far 11 patients have received meniscal implants. Eight medial and three lateral menisci were operated. All implants covered the posterior horn with 3 reaching halfway into the meniscal body and one extending into the anterior horn. The average length of the scaffold meniscus measured on MR imaging was 45mm. In the first week after surgery, the capsule and suture area display fast and intense enhancement typical for post-operative inflammation and the formation of early scar-tissue. There is no enhancement in the base or the tip of the scaffold meniscus. After three months the speed and intensity of enhancement in the capsule and suture area between the remnants of the native meniscus and the scaffold have decreased indicating maturation of scar-tissue. However, the base of the scaffold meniscus now shows enhancement. This can only be explained by proliferation of blood vessels from the capsule and theresidual meniscus wall into the scaffold meniscus. The tip of the matrix shows limited enhancement in some patients after three months. On anatomical MR images, the signal intensity (SI) of the implanted scaffold is close to that of water on both T1- and T2-weighted spin echo and turbo spin echo sequences in the first week. After three months the SI decreases but is still clearly higher than that of the native meniscus. The implants in the posterior horn all had a normal position and no loosening of the sutures or tears of the scaffold were found. After three months, one of the patients had slight expulsion of body of the scaffold meniscus but this is a common finding in transplanted menisci

Interstitial laser thermotherapy (ILT) of breast cancer - Methodology and immunological responce

Interstitial laser thermotherapy (ILT) is an attractive form of local therapy against cancer because of its anti-tumor immune activity. The aim of this work was to evaluate ILT in breast cancer with respect to technique, changes in tissue immunocompetent cells and effect on prognosis. The method is dependent on accurate assessment of the tumor, and another aim was therefore to evaluate if MRI is better than ultrasound (US) for imaging. Twenty-four patients were treated with ILT, followed by surgical resection about two weeks later. Pre-treatment US estimated the average tumor diameter to be 14 (range 5-35) mm. ILT was performed at 48Cº for 30 minutes under local anesthesia. Three patients were radically treated with ILT and the average tumor necrosis was 33% (0-100). Microscopic examination of the resected specimen showed that the average tumor diameter was 23 (range 7-55) mm. US underestimation of tumor size contributed to the rather poor local efficacy. ILT-induced changes in tissue immunocompetent cells were assessed by comparing findings in pre-treatment core biopsies and post-treatment pathologic specimens (paired comparisons). Changes in regional lymph nodes were assessed by comparison with a control group undergoing surgery only. ILT induced a significant increase of mature dendritic cells, B lymphocytes and macrophages at the tumor border and of cytotoxic T lymphocytes and macrophages within the tumor. In the lymph nodes there was a significant decrease in T regulatory cells. Most of these changes are considered to have a favorable prognostic value. Follow up after ILT was 116 (91-136) months. No patient had local recurrence of disease. Five patients developed distant metastases, and three of them have died. The number of cytotoxic T cells within the tumor was higher in patients with recurrence than in patients without recurrence. Patients with recurrent disease had a lower number of NK cells in tumor-free lymph nodes than patients without recurrence. Possible clinical benefit of ILT should be examined in a larger and less heterogenous patient population. MRI has been used preoperatively in most patients (68%) with breast cancer in Iceland during 2007-2009, in addition to mammography and US. Invasive tumor was measurable on all imaging methods in 267 patients. The study revealed that MRI and US both under- and overestimated size. Routine MRI was not shown to be a better radiological method than US for estimating tumor size in local ablative therapy

Novel imaging and image-guided therapy of prostate cancer

Whole-gland prostate surgery and radiotherapy, the established approaches to localised prostate cancer (PCa), usually cause substantial adverse effects. Targeted image-guided cancer therapy has gained acceptance through improved PCa detection, localization and characterization by magnetic resonance imaging (MRI) and prostate-specific membrane antigen positron emission tomography-computed tomography (PSMA PET-CT). Focal therapy offers a potentially better trade-off between disease control and preservation of genitourinary and bowel function. MRI-guided transurethral ultrasound ablation (TULSA), a recently introduced treatment modality, uses therapeutic ultrasound directed through the urethra to thermally ablate the prostate under real-time MRI control. The applicability of TULSA to focal therapy of primary PCa, palliative therapy of symptomatic locally advanced PCa, and treatment of locally radiorecurrent PCa was investigated in a prospective setting. TULSA was shown to be a safe and effective method for local PCa control. Thermal injury was restricted to the planned treatment volume. This method enabled whole-gland ablation and focal ablation anywhere in the prostate. Furthermore, TULSA achieved local symptom relief in palliative care and encouraging preliminary oncological control in salvage care. These promising phase 1 study results enabled progression to phase 2 studies of patients with localised PCa and salvage of patients with radiorecurrent PCa. The diagnostic accuracy of MRI and PSMA PET-CT was studied to determine the extent of primary PCa, to plan TULSA treatment and evaluate treatment response. PSMA PET-CT was found to be a more sensitive method for detecting metastatic disease and appeared to accurately reflect the extent of local disease before and after TULSA treatment. PSMA PET-CT appears to detect some falsepositive bone lesions. The advantages of using MRI and PSMA PET-CT in treatment planning and monitoring treatment response are under further investigation. These studies have shown 18F-PSMA-1007 PET-CT to be effective in PCadiagnosis and TULSA to be effective in PCa therapyModernit kuvantamismenetelmät ja kuvantamisohjatut hoidot eturauhassyövässä Vakiintuneet paikallisen eturauhassyövän (PCa) hoitomenetelmät, leikkaus ja sädehoito, kohdistuvat koko rauhaseen ja aiheuttavat merkittäviä haittavaikutuksia. Magneettikuvantamisella (MRI) ja eturauhassyövän entsyymikuvantamisella (PSMA PET-TT) PCa:n havaitseminen, paikallistaminen ja karakterisointi ovat tarkentuneet. Kohdennetut kuvantamisohjatut syöpähoidot ovat siksi saaneet hyväksynnän ja tarjoavat mahdollisesti optimaalisemman vaihtoehdon hoidon hyödyn ja sen virtsa- ja sukupuolielimiin kohdistuvien haittojen suhdetta ajatellen. MRI-ohjattu eturauhasen kuumennushoito (TULSA) on uusi menetelmä, jossa virtsaputken kautta kudosta tuhoavaa ultraääntä ohjataan eturauhaseen reaaliaikaisessa MRI-ohjauksessa ja -valvonnassa. TULSA:n käyttökelpoisuutta primaarin PCa:n kohdennetussa hoidossa, paikallisesti edenneen PCa:n palliatiivisessa hoidossa ja sädehoidon jälkeen paikallisesti uusiutuneen PCa:n hoidossa tutkittiin prospektiivisessa tutkimusasetelmassa. TULSA-menetelmän todettiin tuhoavan turvallisesti ja tehokkaasti eturauhaskudosta. Lämpövaurio rajautui suunnitellulle hoitoalueelle. Menetelmä mahdollisti kuumennushoidon käytön kaikkialla eturauhasessa, koko rauhasessa tai paikallisemmin. Lisäksi TULSA-hoito lievensi paikallisoireita palliatiivisilla potilailla ja oli tehokas sädehoidon jälkeen paikallisesti uusiutuneessa PCa:ssä. Lupaavien ensimmäisen vaiheen tutkimustulosten takia olemme siirtyneet toisen vaiheen tutkimuksiin näillä uusilla indikaatioilla. MRI:n ja PSMA PET-TT:n diagnostista tarkuutta tutkittiin primaarin PCa:n levinneisyyden selvittelyssä ja TULSA-hoidon suunnittelussa sekä hoitovasteen arvioinnissa. PSMA PET-TT:n havaittiin olevan herkempi menetelmä etäpesäkkeiden tunnistamisessa ja se näytti tarkasti taudin laajuuden ennen ja jälkeen TULSAhoidon. PSMA PET-TT tunnistaa myös vääriä positiivisia luustomuutoksia. MRI:n ja PSMA PET-TT:n kliinistä hyötyä TULSA-hoidon suunnittelussa ja hoitovasteen seurannassa tutkitaan edelleen. Tutkimuksemme ovat osoittaneet PSMA PET-TT:n hyödyllisyyden PCa:n diagnostiikassa ja TULSA:n turvallisuuden ja tehon PCa:n hoidossa

Interstitial diagnosis and treatment of breast tumours

This thesis exploits the interaction of light with breast tissue for diagnosis and therapy. Optical biopsy is an experimental technique, based on Elastic Scattering Spectroscopy (ESS), being developed for characterising breast tissue. An optical probe interrogates tissue with a white light pulse, with spectral analysis of the reflected light. 264 spectral measurements (50 patients) were obtained from a range of breast tissues and axillary lymph nodes and correlated with conventional histology of biopsies from the same sites. Algorithms for spectral analysis were developed using ANN (Artificial Neural Network), HCA (Hierarchical Cluster Analysis) and MBA (Model Based Analysis). The sensitivity and specificity for cancer detection in breast and lymph nodes were: [diagram]. Interstitial Laser Photocoagulation (ILP) involves image guided, thermal coagulation of lesions within the breast using laser energy delivered via optical fibres positioned percutaneously under local anaesthetic. Two groups were studied: 1) Nineteen patients with benign fibroadenomas underwent ILP and the results compared with 11 treated conservatively. Thirteen ILP patients (14 fibroadenomas) and 6 controls (11 fibroadenomas) have reached their one-year review: [diagram]. These differences are statistically significant (P<0.001). 2)Six patients with primary breast cancers underwent ILP (with pre- and post-ILP contrast enhanced MRI) within 3 weeks of diagnosis and were then treated with Tamoxifen. Four underwent surgery at 3 months, two showing complete tumour ablation. MRI was reasonably accurate at detecting residual tumour. In conclusion: a) optical biopsy is a promising 'real time' diagnostic tool for breast disease. b) ILP could provide a simple and safe alternative to surgery for fibroadenomas. c) ILP with MRI monitoring may be an alternative to surgery in the management of some patients with localised primary breast cance

Minimally-invasive breast interventions : methods for high yield, low risk, precision biopsy and curative thermal ablation

Advances in medical imaging and the introduction of population-based screening programs have increased the detection rate and overall proportion of small breast tumors. In addition, progress in technology and medical science, in combination with efforts to minimize morbidity, have resulted in the emergence of minimally invasive image-guided interventional procedures for both diagnosis and treatment of breast cancer. The aim of this thesis was to develop and validate new technologies for minimally-invasive diagnosis and treatment of breast cancer. Specifically, to develop and validate a new biopsy system incorporating novel mechanisms for needle insertion and tissue acquisition designed for accurate lesion targeting and high yield tissue sampling; to clinically validate a biopsy enhancement technology using radiofrequency (RF) pulses to counteract dissemination of tumor cells; and to improve and validate radiofrequency ablation (RFA) for the treatment of small carcinoma and demonstrate feasibility in non-operable elderly patients. During the course of this work a new biopsy device has been developed which incorporates a pneumatic insertion mechanism combined with a novel needle design. Paper I presented the device, compared sampling performance to a standard core needle biopsy (CNB) device in three representative bench models, measured needle dynamics on a specially designed needle trajectory test and evaluated ex vivo sample quality. Mean weight of samples were 3.5, 4.6, and 4.3 times higher (p <0.01) than standard CNB device in turkey breast, calf thymus and swine pancreas. The method of tissue acquisition had no negative impact on the histopathologic quality of samples obtained from resected specimens. Maximum measured needle velocity was 21.2 ±2.5 m/s on a stroke length of 2.5 mm. Paper II investigated whether a technology incorporating the application of RF pulses to the biopsy needle could counteract dissemination of tumor cells. In this proof-of-principle setting the technology was adapted to fine needle aspiration (FNA) and prospectively used in 31 patients. Eighty-eight patients underwent routine FNA. Blood emerging from the skin orifice was analyzed for the presence of tumor cells. Viable tumor cells were found in 74% (65/88) of cases for routine FNA and in 0% (0/31) of cases (p <0.001) when RF pulses where applied. It was observed that application of RF pulses had a hemostatic effect, did not degrade the cytological sample inside the needle and caused no additional pain compared with standard FNA. In Papers III, IV & V, the technology, method and protocol for RFA in breast cancer were successively developed and evaluated in a total of 55 patients. Specifically, in Paper III the feasibility of a newly developed RF device for ablation of unifocal breast carcinoma <16 mm immediately prior to partial mastectomy was assessed. In 84% (26/31) of cases complete ablation was achieved as assessed by Hematoxylin and Eosin (H&E) staining. Non-complete ablation was associated with incorrect electrode positioning within the lesion and underestimation of lesion extent due to inaccurate preoperative imaging. In Paper IV, tumors ≤20 mm were included and the feasibility under local anesthesia three weeks prior to planned resection using improved technology and protocol was assessed. Magnetic resonance imaging (MRI) was utilized for patient selection. Exclusion criteria included multifocality, diffuse growth patterns, >25% intraductal components and lobular histology. Magnetic resonance imaging, H&E staining and cytokeratine 8 (CK8) immunostaining were used to determine complete ablation. A pneumatic–mechanical insertion mechanism was developed to improve electrode insertion and positioning. Pain was assessed using the Visual Analogue Scale (VAS). In 100% (18/18) of cases MRI showed no residual tumor growth and devitalization of the entire tumor was shown by at least one histologic method. Pain was reported to be a median of 2 and 2.5 for injection of anesthetics and during ablation, respectively, and the difference was not significant (p =0.512). In Paper V the feasibility of RFA as an alternative to surgical resection in elderly breast cancer patients with severe comorbidities that were unfit for or refused surgery was assessed. Six patients aged ≥85 years were included. In all cases, complete ablation was confirmed using MRI and contrast enhanced ultrasound (CEUS) at 1 month as well as staining assays for H&E and CK8 in tissue samples at 6 months. The procedure was well tolerated with mild to moderate pain during the ablation procedure. Follow-up was a median (range) of 54 months (11 to 94 months). Three patients died of non-cancer related causes. Three patients remained alive at 74, 86 and 94 months of which one experienced a loco-regional recurrence at 59 months. In conclusion, this thesis demonstrates that the newly developed biopsy system enables for a novel method of precision needle insertion and achieves high yield tissue sampling. Furthermore, this thesis demonstrates that the presented biopsy enhancement technology can prevent dissemination of tumor cells. Finally, it demonstrates that RF ablation of small breast carcinoma has a high rate of complete ablation, can be performed under local anesthesia with mild to moderate pain, and is feasible as an individualized treatment option in elderly patients with severe co-morbidity who are refusing, or are unfit for surgery

Understanding Nanoparticle Toxicity to Direct a Safe-by-Design Approach in Cancer Nanomedicine

Nanomedicine is a rapidly growing field that uses nanomaterials for the diagnosis, treatment and prevention of various diseases, including cancer. Various biocompatible nanoplatforms with diversified capabilities for tumor targeting, imaging, and therapy have materialized to yield individualized therapy. However, due to their unique properties brought about by their small size, safety concerns have emerged as their physicochemical properties can lead to altered pharmacokinetics, with the potential to cross biological barriers. In addition, the intrinsic toxicity of some of the inorganic materials (i.e., heavy metals) and their ability to accumulate and persist in the human body has been a challenge to their translation. Successful clinical translation of these nanoparticles is heavily dependent on their stability, circulation time, access and bioavailability to disease sites, and their safety profile. This review covers preclinical and clinical inorganic-nanoparticle based nanomaterial utilized for cancer imaging and therapeutics. A special emphasis is put on the rational design to develop non-toxic/safe inorganic nanoparticle constructs to increase their viability as translatable nanomedicine for cancer therapies

Macrophage COX-2 As a Target For Imaging And Therapy of Inflammatory Diseases Using Theranostic Nanoemulsions

Personalized medicine can be an approach to address the unsatisfactory treatment outcomes in inflammatory conditions such as cancer, arthritis, and cardiovascular diseases. A common feature of chronic diseases is the infiltration of pro-inflammatory macrophages at the disease loci. Infiltrating macrophages have been previously utilized for disease diagnosis. These features suggest that macrophages can be broadly applicable targets for simultaneous therapy and diagnosis. Cyclooxygenase-2 (COX-2), an enzyme involved in the biosynthesis of a lipid inflammatory mediator, prostaglandin E2 (PGE2), is over expressed in macrophages infiltrating the pathological site. Inhibition of PGE2 leads to reduced inflammation, pain and macrophage infiltration. To utilize macrophages for the purpose of simultaneous therapy and diagnosis, we proposed to integrate therapeutic and imaging capabilities on a single nanomedicine platform, referred as theranostics. A stable 19F MRI visible nanoemulsion platform was developed, incorporating celecoxib for COX-2 inhibition and near-infrared fluorescent dye(s) for fluorescence imaging. We hypothesized that inhibition of COX-2 in macrophages using a theranostic nanoemulsion will reduce the inflammation (and pain), and that this response can be visualized by monitoring changes in macrophage infiltration. In vitro characterization demonstrated that the theranostic displays excellent stability with no toxicity, and significant uptake in macrophages. Furthermore, it delivers celecoxib to macrophages and reduces PGE2 production from these cells. In vivo studies in a murine paw inflammation model showed nanoemulsion presence at the inflamed site, specifically in COX-2 expressing macrophages compared to neutrophils. Supporting our hypothesis, celecoxib delivered through a nanoemulsion demonstrated time-dependent reduction in fluorescence from the inflamed paw, indicative of reduced macrophage infiltration. In a neuropathic pain model, celecoxib delivered to macrophages led to reduced pain concomitant with reduced macrophage infiltration at the inflamed site compared to free drug control (cross reference: Kiran Vasudeva, Dissertation, 2015). In conclusion, inhibition of COX-2 in macrophages using theranostic nanoemulsions proves to be an effective and generalized strategy facilitating simultaneous therapy and diagnosis, which can be applied to many chronic diseases. The diagnostic information during therapy can be used to tailor the treatment and reduce patient variability leading to personalized medicine