Heating technology for malignant tumors: a review

The therapeutic application of heat is very effective in cancer treatment. Both hyperthermia, i.e., heating to 39-45 degrees C to induce sensitization to radiotherapy and chemotherapy, and thermal ablation, where temperatures beyond 50 degrees C destroy tumor cells directly are frequently applied in the clinic. Achievement of an effective treatment requires high quality heating equipment, precise thermal dosimetry, and adequate quality assurance. Several types of devices, antennas and heating or power delivery systems have been proposed and developed in recent decades. These vary considerably in technique, heating depth, ability to focus, and in the size of the heating focus. Clinically used heating techniques involve electromagnetic and ultrasonic heating, hyperthermic perfusion and conductive heating. Depending on clinical objectives and available technology, thermal therapies can be subdivided into three broad categories: local, locoregional, or whole body heating. Clinically used local heating techniques include interstitial hyperthermia and ablation, high intensity focused ultrasound (HIFU), scanned focused ultrasound (SFUS), electroporation, nanoparticle heating, intraluminal heating and superficial heating. Locoregional heating techniques include phased array systems, capacitive systems and isolated perfusion. Whole body techniques focus on prevention of heat loss supplemented with energy deposition in the body, e.g., by infrared radiation. This review presents an overview of clinical hyperthermia and ablation devices used for local, locoregional, and whole body therapy. Proven and experimental clinical applications of thermal ablation and hyperthermia are listed. Methods for temperature measurement and the role of treatment planning to control treatments are discussed briefly, as well as future perspectives for heating technology for the treatment of tumors

새로운 가압 복강 내 에어로졸 화학 요법에 의한 인간 복강을 모방 한 Ex Vivo 모델에서의 약물 확산의 효과와 한계

학위논문(박사) -- 서울대학교대학원 : 의과대학 의학과, 2021.8. 이마리아.Background: Pressurized intra-peritoneal aerosol chemotherapy (PIPAC) has been introduced as a novel technique of intraperitoneal chemotherapy for the treatment of peritoneal metastasis (PM) caused by advanced or recurrent solid tumors. PIPAC has been implemented in clinical medicine mainly in Europe. But the PIPAC machine has not been imported to South Korea and is not affordable in market. So, before conducting this part of ex vivo experiment, we collaborated with medical biomechanics and design laboratory in Seoul National University redesigned and reconstructed the well-established prototype and this project implemented to investigate the pattern of tissue penetration according to different nozzle position and to find the best position resulting in best drug delivery. Material and Methods: Fresh postmortem peritoneum tissues were cut into 8 identical pieces and fixed at different spatial places A-H considering the asymmetrical abdominal cavity in 2cm-,4cm- and 8cm- ex vivo models. Ex vivo experiment performed using a novel prototype, that sprayed about 30-μm droplets at flow rate of 30ml/min under the pressure of 7 bars. Methylene blue staining aera on six faces in the three ex vivo models were observed with naked eyes. The penetration depth was evaluated with the depth of concentrated diffusion (DCD) and the depth of maximal diffusion (DMD) of doxorubicin using confocal laser scanning microscopy after the application of 4’,6-diamidino-2-phenylindole to the tissue specimens. The counted highest number of DCD and DMD was performed to compare the score of three ex vivo models. Results: In terms of the distribution, the 4cm- and 8cm-ex vivo models showed more stained faces than the 2cm-ex vivo model, the closer nozzle to the bottom of the model, the more unevenly distributed methylene blue was observed. With different nozzle positions, the best tissue penetration found at different tissue sample and the pattern of doxorubicin penetration in the 8 sample tissues change accordingly. After we counted the number of the highest DCD and DMD values and found that 4cm-ex vivo model showed the highest score of 5 (62.5%). Conclusion: Drug delivery into the peritoneum tissue during PIPAC differs according to different nozzle position and the optional nozzle position for best drug delivery should be determined in consideration of the three-dimensional structure of the abdominal cavity. Further in vivo study is needed to determine optional nozzle position and rotated nozzle can be expected to improve diffusion and penetration of aerosol during PIPAC배경: 가압복강내에어로졸항암요법은 solid종양의 복강내 전이종양의 새로운 치료방법으로 잘 알려져 있다. 가압복강내에어로졸항암요법은 현재 주로 유럽에서 잘 사용되고 있다. 그러나 가압복강내에어로졸항암요법은 현재 국내에 도입이 되여있지 않고 시중에서 구매할수 없다. 본 실험을 진행하기 앞서 서울대학교 의공학과와 콜라보를 하여 새로운 PIPAC prototype을 만들었으며 본 prototype을 사용해 prototype의 노즐의 위치가 변함에 따라 조직의 penetration이 어떻게 변화를 하는지 어떤 위치에 있을 경우에 가장 이상적인 delivery를 얻어낼 수 있는지 알아보려고 한다. 자료와 방법: 8개의 똑 같은 크기의 신선한 사후 실험돼지의 복막조직(A-H)을 인체의 비대칭구조를 모방하여 만든 ex vivo 모델의 부동한 공간위치에 부착을 하였다. 노즐과 ex vivo모델의 밑부분과의 거리 2cm-,4cm-,8cm를 선택했다. 본 ex vivo 모델에서 새로운 prototype를 사용했으며 본 prototype은 30-μm 크기의 에어로졸들을 30ml/min의 유속으로 7 bar의 압력아래 분사한다. Ex vivo 모델내에 약물의 분포도는 methylene blue로 축정했으며 눈으로 관찰하여 측정하였다. 조직의 약물 침투는 depth of concentrated diffusion (DCD)와 depth of maximal diffusion (DMD)를 측정하여 confocal laser scanning microscopy로 관찰하였고 부동한 ex vivo 모델끼리 비교 분석하였다. 각 모델의 가장 높은 DCD와 DMD를 카운트한결과 4cm-ex vivo 모델에서 가장 이상적인 약물delivery가 측정되었다. 결과: 4cm-와8cm-ex vivo모델에서 2cm-ex vivo모델보다 약물의 분포가 가장 잘 측정되었다. 노즐위치가 다름에 따라 각 조직의 약물침투패턴이 다르며 각 위치에서 가장 높은 약물침투가 측정되는 조직 또한 다르다. 항암제의 약물전달은 4cm-ex vivo 모델에서 가장 훌륭한 DCD와 DMD 5 (62.5%)이 측정되었다. 결론: 본 prototype을 사용했을 때 노즐위치에 따본 ex vivo model의 각 타깃조직의 penetration패턴이 다르며 노즐위치가 다름에 따라 약물침투가 가장 많이 되는 조직 또한 다르다. 인체 복강의 복잡한 three-dimensional구조를 고려했을 때 노즐위치를 위아래로 바꾸거나 각도를 바꾸는 방법으로 더 우월한 delivery를 얻을 수 있을 것이다. 향후 in vivo실험을 더 진행해야 할 필요성이 있다.Chapter 1. Ex vivo Experiment of Pressurized Intraperitoneal Aerosol Chemotherapy: A Review 6 1.1 Introduction 6 1.1.1 Ovarian cancer 6 1.1.2 Peritoneal metastasis 6 1.2 Diagnosis of Peritoneal Metastasis 7 1.3 Treatment of Peritoneal Metastasis 8 1.3.1 Intravenous chemotherapy (IV) 8 1.3.2 Intraperitoneal chemotherapy (IP) 8 1.3.3 Hyperthermic intraperitoneal chemotherapy 10 1.3.4 Pressurized intraperitoneal aerosol chemotherapy 11 1.4 Methodological Aspects of PIPAC 12 1.5 The Microinjection Pump 13 1.6 Ex Vivo Experiment of PIPAC 14 1.6.1 Ex vivo model of PIPAC 15 1.6.2 Position to detect drug penetration depth 16 1.6.3 Nozzle position 16 1.7 Previous Studies of Ex Vivo Experiment of PIPAC 16 1.7.1 Effect of MIP position on drug delivery in the ex vivo model of PIPAC 16 1.7.2 Effect of internal pressure on the drug delivery in the ex vivo model of PIPAC 17 1.7.3 Effect of drug dosage on drug delivery in the ex vivo model of PIPAC 17 1.7.4 Exploring drug distribution in the ex vivo model 17 1.7.5 Effect of irradiation on the tissue penetration depth in the ex vivo model of PIPAC 18 1.7.5 Exploring particle stability and structure during the ex vivo experiment of PIPAC 18 1.7.6 Research about particle application range during ex vivo experiment of PIPAC 19 1.8 Discussion 19 1.9 Conclusion 21 Chapter 2. Evaluation of Drug Delivery into the Peritoneum Based on Nozzle Position during Pressurized Intraperitoneal Aerosol Chemotherapy in an ex vivo Model 22 2.1 Study Background 22 2.2 Purpose of Research 24 2.3 Materials and Method 26 2.3.1 Novel PIPAC system developed in Seoul National University 26 2.3.2 Novel ex vivo model of PIPAC 27 2.3.3 Procedure of ex vivo experiment of PIPAC 29 2.3.4 The distance between nozzle and the bottom of the model 30 2.3.5 Detection of doxorubicin penetration depth using confocal fluorescence microscopy 30 2.3.6 Distribution analysis 31 2.3.7 Statistical analysis 31 2.4 Results 32 2.4.1 Microscopic confocal laser analysis of DCD and DMD at various nozzle positions according to the distance between nozzle and the bottom 32 2.4.2 Comparison of DCD at various nozzle positions according to the distance between the nozzle and the bottom 32 2.4.3 Comparison of DMD at various nozzle positions according to distance between the nozzle and the bottom 33 2.4.4 Spatial distribution pattern of methylene blue in the novel ex vivo model of PIPAC 34 2.5 Discussion 44 2.6 Acknowledgements 49 References 50 Chapter 3. 초록 56 Chapter 4. Thank You Letters 57 Chapter 5. Abbreviations 58박

Multimodality treatment of colorectal peritoneal metastases:Towards evidence-based practice

This thesis focuses on patients with peritoneal metastases of colorectal cancer. Part 1 shows that the hospital of diagnosis with this disease seems to influence the probability of undergoing curative intent surgery and survival. Part 2 focuses on patients with operable peritoneal metastases undergoing curative intent surgery. Internationally, these patients increasingly receive chemotherapy before and after surgery, while nothing is known about the benefits of chemotherapy in this setting. This thesis shows that chemotherapy before and after surgery is safe, tolerable, and potentially effective. Part 3 focuses on patients with inoperable peritoneal metastases who cannot be cured. Internationally, these patients increasingly undergo PIPAC (i.e. intra-abdominal aerosol chemotherapy), while there is no available research supporting the use of PIPAC in this setting. This thesis shows that PIPAC is feasible and seems biologically active, but leads to (sometimes severe) adverse events and transient worsening of quality of life

The current and potential future role of peritonectomy and hyperthermic intraperitoneal chemotherapy (HIPEC) for treatment of advanced epithelial ovarian cancer in Australia

Background and Aims: Ovarian cancer is the most common cause of death due to gynaecological malignancy. Most cases (70%) present as advanced disease (stage III/IV), where cancer has spread to peritoneal surfaces. Standard treatment is optimal cytoreductive surgery and intravenous platinum-based chemotherapy, with selective use of targeted treatments. However, peritonectomy (extended cytoreductive surgery) and hyperthermic intraperitoneal chemotherapy (HIPEC) is being increasingly used. This thesis aims to investigate the current and potential future role of peritonectomy and HIPEC in treating advanced ovarian cancer in Australia. Methods: A review of literature on the treatment of primary and recurrent epithelial ovarian cancer, and a systematic review of the use of cytoreductive surgery and HIPEC for this disease, were performed. A survey of Australian gynaecological oncologists was conducted to determine changes in surgical practices for ovarian cancer over the past decade. A retrospective review of 41 cases of peritonectomy with/without HIPEC for ovarian cancer in the largest Australian centre was undertaken. The attitudes of gynaecological oncologists towards this treatment were investigated with an online survey. A multicentre Australian phase II clinical trial of HIPEC for the treatment of primary ovarian cancer was developed, and a grant application was submitted to the Medical Research Future Fund (NHMRC). Results: There is good evidence for the use of extended cytoreductive surgery, but a paucity of quality studies of HIPEC, for treatment of ovarian cancer. Australian gynaecological oncologists report a lack of surgical training and abilities, but increased neoadjuvant chemotherapy use, for treating advanced disease. In an Australian centre performing peritonectomy and HIPEC there were good outcomes for primary ovarian cancer, but poorer results for recurrent disease, primarily due to a lack of strict selection criteria. Gynaecological oncologists report concerns around potential toxicities and effectiveness of HIPEC and indicate a need for quality clinical trials. This knowledge was used to design HyNOVA, a randomised multicentre trial comparing HIPEC with normothermic chemotherapy (NIPEC) for stage III ovarian cancer. HyNOVA received NHMRC funding and commenced in 2022. Conclusion: This thesis has produced new knowledge about peritonectomy and HIPEC for the treatment of ovarian cancer and will help define its future role through an Australian clinical trial, HyNOVA

Magneettikuvauksella ohjattu korkean intensiteetin kohdennettu ultraääniteknologia syöpätautien liitännäishoidoissa ja syöpälääkkeiden annostelussa

Ablative hyperthermia (more than 55 °C) has been used as a stand-alone treatment for accessible solid tumors not amenable to surgery, whereas mild hyperthermia (40-45 °C) has been shown effective as an adjuvant for both radiotherapy and chemotherapy. An optimal mild hyperthermia treatment is noninvasive and spatially accurate, with precise and homogeneous heating limited to the target region. High-intensity focused ultrasound (HIFU) can noninvasively heat solid tumors deep within the human body. Magnetic resonance imaging (MRI) is ideal for HIFU treatment planning and monitoring in real time due to its superior soft-tissue contrast, high spatial imaging resolution, and the ability to measure temperature changes. The combination of MRI and HIFU therapy is known as magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU). Low temperature-sensitive liposomes (LTSLs) release their drug cargo in response to heat (more than 40 °C) and may improve drug delivery to solid tumors when combined with mild hyperthermia. MR-HIFU provides a way to image and control content release from imageable low-temperature sensitive liposomes (iLTSLs). This ability may enable spatiotemporal control over drug delivery - a concept known as drug dose painting. The objectives of this dissertation work were to develop and implement a clinically relevant volumetric mild hyperthermia heating algorithm, to implement and characterize different sonication approaches (multiple foci vs. single focus), and to evaluate the ability to monitor and control heating in real time using MR-HIFU. In addition, the ability of MR-HIFU to induce the release of a clinical-grade cancer drug encapsulated in LTSLs was investigated, and the potential of MR-HIFU mediated mild hyperthermia for clinical translation as an image-guided drug delivery method was explored. Finally, drug and contrast agent release of iLTSLs as well as the ability of MR-HIFU to induce and monitor the content release were examined, and a computational model that simulates MR-HIFU tissue heating and drug delivery was validated. The combination of a multifoci sonication approach and the mild hyperthermia heating algorithm resulted in precise and homogeneous heating limited to the targeted region both in vitro and in vivo. Heating was more spatially confined compared to the use of single focus sonication method. The improvement in spatial control suggests that multifoci heating is a useful tool in MR-HIFU mediated mild hyperthermia applications for clinical oncology. Using the mild hyperthermia heating algorithm, LTSL + MR-HIFU resulted in significantly higher tumor drug concentrations compared to free drug and LTSL alone. This technique has potential for clinical translation as an image-guided drug delivery method. MR-HIFU also enabled real-time monitoring and control of iLTSL content release. Finally, computational models may allow quantitative in silico comparison of different MR-HIFU heating algorithms as well as facilitate therapy planning for this drug delivery technique.Ablatiivista hypertermiaa (yli 55 °C) on perinteisesti käytetty leikkauksiin soveltumattomien kasvainten hoitoon. Lievän hypertermian (40-45 °C) on sen sijaan todettu olevan tehokas liitännäishoito syöpätautien säde- ja lääkehoidoille. Suotuisa hypertermiahoito on kajoamatonta ja täsmällisesti kohdistettua. Lämmityksen tulisi lisäksi olla tarkkaa, tasalaatuista ja kohdealueeseen rajoittunutta. Korkean intensiteetin kohdennettu ultraääni (HIFU) -hoito mahdollistaa kasvainten kajoamattoman lämmityksen. Magneettikuvauksen (MK) etuina ovat erinomainen pehmytkudoskontrasti, korkea paikkaresoluutio ja kyky mitata lämpötilan muutoksia. Näin ollen MK soveltuu erinomaisesti HIFU -hoitojen suunnitteluun ja seurantaan. MK:n ja HIFU:n yhdistelmää kutsutaan magneettikuvauksella ohjatuksi korkean intensiteetin kohdennetuksi ultraääniteknologiaksi (MR-HIFU). Lämpötilaherkät liposomit ovat suunniteltuja vapauttamaan lääkeainesisältönsä hieman normaalia ruumiinlämpötilaa korkeammissa lämpötiloissa (yli 40 °C). Yhdessä lievän hypertermian kanssa tämänkaltaiset liposomit voivat mahdollistaa kohdistetun lääkeaineen vapauttamisen. Liposomien sisällön vapautumisen tarkkailu voi myös mahdollistaa tarkan lääkemäärän kohdistetun annostelun kasvaimessa. Väitöskirjatyössä kehitettiin kliinisesti merkittävä lämmitysalgoritmi lievän hypertermian aikaansaamiseksi, toteutettiin usean samanaikaisen kohteen sonikaatio (ultraäänialtistus) menetelmä sekä arvioitiin algoritmin ja menetelmän kykyä kontrolloida kudoksen lämpötilaa käyttäen kliinistä MR-HIFU laitetta. Lisäksi tutkittiin HIFU:n kykyä vapauttaa lääkeaine lämpötilaherkistä liposomeista, karakterisoitiin lääke- ja kontrastiaineen vapautuminen kuvannettavissa olevista lämpötilaherkistä liposomeista sekä tarkasteltiin MR-HIFU:lla aikaansaadun lievän hypertermian potentiaalia kohdentaa lääkeaineen vapautuminen kasvaimeen. Tässä työssä myös validoitiin laskennallinen malli, joka simuloi MR-HIFU:lla aikaansaatua lämmitystä ja siitä johtuvaa lääkeaineen vapautumista, sekä todennettiin MR-HIFU:n sopivuus lämpöablaatioon perustuvaan kohdun pehmytkudoskasvainten hoitomenelmään kliinisessä käytössä. Lievän hypertermian lämmitysalgoritmi yhdessä usean kohteen sonikaatiomenetelmän kanssa tuotti täsmällisen, tasalaatuisen sekä paikallisesti rajoitetun lämmityksen kohdealueessa. Usean kohteen sonikaatiomenetelmä voi siis olla hyödyllinen työkalu MR-HIFU:n lievän hypertermian syöpähoidon sovelluksissa. MR-HIFU yhdessä lämpötilaherkkien liposomien kanssa sai aikaan merkittävästi korkeamman kasvaimen lääkeainekonsentraation verrokkiryhmiin nähden, ja saattaa siten soveltua kliiniseen käyttöön kuvantamisavusteisena lääkehoitona. Liposomien sisällön (lääkeaine + MK-kontrastiaine) vapautumisen kuvannettavuus merkitsee, että MR-HIFU saattaa lisäksi mahdollistaa tarkan lääkeannoksen kohdistetun vapauttamisen

Doctor of Philosophy

dissertationThermal ablation is widely used, first line local-regional therapy for unresectable hepatocellular carcinoma (HCC). Although high temperature delivered by thermal energy results in efficient coagulation necrosis in tumor cells, various factors including tumor size, shape, location, and cirrhosis can lead to un-uniform heat distribution and inefficient cell damage. As a result, the incomplete ablation causes high rates of tumor recurrence and poor survival for HCC patients. Cells that are not completely ablated can induce heat shock proteins (HSPs), which are cellular gatekeepers to protect tumor cells from thermal damage and prepare them for future neoplastic growth. Synchronous adjuvant chemotherapy targeting those cells can achieve more complete tumor abrogation and prevent future tumor recurrence. This dissertation describes a strategy to combat postablation recurrence by synchronous inhibition of heat shock protein 90 (HSP90) by thermo-responsive, elastin-like polypeptide (ELP)-based biopolymer conjugates. ELP copolymer carries high concentrations of a potent HSP90 inhibitor, geldanamycin (GA), which inhibit the induction of HSP90 and further destabilize numerous HSP90 client proteins critical for cell survival. It is hypothesized that combination of thermal ablation with concomitant inhibition of HSP90 via ELP-GA conjugates can achieve synergistic anticancer effect. Specifically, the ablation-created hyperthermia will sensitize tumor cells to be more vulnerable to the drug, which will be conjugated with high concentrations through thermally targeted, ELP-based biopolymer systems. The ELP conjugates, in turn, will reach and kill the remaining viable cells to prevent future recurrence. ELP-GA conjugates that ferry multiple GAs and rapidly respond to hyperthermia were synthesized, characterized, and evaluated for activity in HCC models. The cytotoxicity of ELP-GA conjugates was enhanced with hyperthermia treatment, and effective HSP90 inhibition was achieved in HCC cell lines. In a tumor-bearing mouse model, electrocautery-based thermal ablation offered effective destruction of tumor core and created a hyperthermia zone for targeted delivery and accumulation of ELP-GA conjugates. Results demonstrate that the combination of thermal ablation and targeted HSP90 inhibition can enhance the anticancer effect and cellular delivery of macromolecular chemotherapeutics to achieve safe, synergistic, and long-term anticancer effect with no tumor recurrence observed. The combination approach paves the way for developing molecular-targeted intervention to increase the efficacy of first-line local-regional therapies for HCC

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

Klinikai és kísérletes, molekuláris és multimodalitású képalkotó vizsgálatok B sejtes malignus lymphomában

Doktori munkám során olyan képalkotó módszereket alkalmaztam, amelyek igazoltan hasznosak limfómás betegeknél a diagnózis felállításában és a terápiára adott válasz értékelésében. A disszertáció egy klinikai és egy preklinikai részre osztható. A szakirodalom alapján a PET-képekből származó radiomikai adatok hozzájárulhatnak a tumor részletgazdagabb in vivo jellemzéséhez, és így segíthetnek az egyénre szabott tumorkezelésben. A klinikai részben kétéves eseménymentes túlélést előrejelző modellt építettünk fel DLBCL-ben szenvedő betegek kezelés előtti FDG-PET/CT vizsgálatából származó radiomikai adatok segítségével. Az első preklinikai vizsgálatban egy új és pontos egérmodell (spontán limfóma) segítségével vizsgáltam egy képalkotás-által szigorúan irányított mintavételi módszert. PET/SPECT és CLI képalkotást kombináló új módszert fejlesztettünk ki egérmodellben, amely lehetővé teszi a legfontosabb érintett nyirokcsomó és/vagy az érintett nyirokcsomó legfontosabb részének irányított kivételét és feldolgozását. A limfómasejtek terjedési mechanizmusai és útvonalai még mindig tisztázatlanok. Célom volt a daganat terjedésének és heterogenitásának a jellemzése mind a preklinikai vizsgálatok első, mind a második részében. Dolgozatom második preklinikai részében a lymphoma peritoneális terjedésének korai kimutatására megvizsgáltuk különböző nukleáris medicina módszerek alkalmazhatóságát és kiválasztottuk ezek közül a legjobban használhatót egérmodell segítségével. Védésem során a klinikai és preklinikai kutatásaink során felmerülő új diagnosztikai lehetőségeket mutatom be a publikált közleményeink alapján