Complete Tumor Destruction Research Articles

Oncolytic herpes simplex viruses designed for targeted treatment of EGFR-bearing tumors

Oncolytic herpes simplex viruses (oHSVs) have emerged as leading cancer therapeutic agents. Effective oHSV virotherapy may ultimately require both intratumoral and systemic vector administration to target the primary tumor and distant metastases. An attractive approach to enhancing oHSV tumor specificity is engineering the virus envelope glycoproteins for selective recognition of and infection via tumor-specific cell surface proteins. We previously demonstrated that oHSVs could be retargeted to EGFR-expressing cells by the incorporation of a single-chain antibody (scFv) at the N terminus of glycoprotein D (gD). Here, we compared retargeted oHSVs generated by the insertion of scFv, affibody molecule, or VHH antibody ligands at different positions within the N terminus of gD. When compared to the scFv-directed oHSVs, VHH and affibody molecules mediated enhanced EGFR-specific tumor cell entry, spread and cell killing invitro, and enabled long-term tumor-specific virus replication following intravenous delivery invivo. Moreover, oHSVs retargeted via a VHH ligand reduced tumor growth upon intravenous injection and achieved complete tumor destruction after intratumoral injection. Systemic oHSV delivery is important for the treatment of metastatic disease, and our enhancements in targeted oHSV design are a critical step in creating an effective tumor-specific oHSVs for safe administration via the bloodstream.

Intraductal radiofrequency ablation for neoplasms of the major duodenal papilla with intraductal spread

To analyze the efficacy of intraductal radiofrequency ablation (RFA) for neoplasms of the major duodenal papilla with intraductal spread. Eleven patients with adenomas of the major duodenal papilla and intraductal spread underwent intraductal RFA between 2022 and 2023. Spread to the common bile duct ranged from 10 to 30 mm, to the main pancreatic duct - from 5 to 11 mm. Technical success was achieved in all cases. Complications after intraductal RFA occurred in 4 cases (post-manipulation pancreatitis - 2 cases, repeated intraductal RFA for residual adenomatous growths - 2 cases). Technical success of stenting of the main pancreatic and common bile ducts was achieved in all cases. Intraductal radiofrequency ablation for neoplasms of the major duodenal papilla with intraductal spread ensured complete destruction of intraductal tumor with adequate clinical effect and no need for highly traumatic surgery.

Metal-Organic Framework (MOF)-Based Ultrasound-Responsive Dual-Sonosensitizer Nanoplatform for Hypoxic Cancer Therapy.

Sonodynamic therapy (SDT), which uses reactive oxygen species to target tumors, has shown promise in the management of unresectable cancers. However, the hypoxic tumor environment limits SDT efficiency, making complete tumor destruction challenging. Here, a dual-sonosensitizer nanoplatform is developed by loading an alkyl radical generator (2,2-azobis[2-(2-imidazolin-2-yl)propane] dihydrochloride, AIPH) onto a zirconium metal-organic framework (Zr-MOF). The Zr-MOF@AIPH nanoparticles (NPs) can produce singlet oxygen, which can kill tumor cells under normoxic conditions, as well as alkyl radicals, which can kill tumor cells under both normoxic and hypoxic conditions. The combination of these free radicals further enhances SDT efficiency. Meanwhile, the nitrogen generated owing to AIPH decomposition can reduce the cavitation threshold and enhance the acoustic cavitation effect, thereby promoting NP penetration at the tumor site. Moreover, Zr-MOF@AIPH NPs exhibit good photoacoustic, fluorescence, and ultrasound imaging abilities due to their porphyrin-based structure and the nitrogen generated, which can remotely control NP delivery and determine the optimal therapeutic time window, ensuring the maximization of SDT efficiency. In vitro and in vivo examinations prove the superior antitumor efficacy, excellent biocompatibility, and favorable imaging ability of Zr-MOF@AIPH. This study spearheads the charge toward improving SDT efficacy in hypoxic environments via a combination of complementary sonosensitizers.

Assessment of a new 150 W single-antenna microwave ablation system in the treatment of malignant liver tumors: The first worldwide experience.

Data in literature regarding liver microwave ablation pertain to systems delivering 100 W of maximum power. Our aim is to assess a new 150 W microwave system for liver tumor ablation. This was an institutional review board-approved study of patients undergoing ablation of malignant liver tumors using a 150 W microwave system. Feasibility, safety, ablation algorithm, perioperative outcomes, and efficacy were analyzed. Comparison was made to historical patients undergoing ablation using a 100 W microwave system. There were 33 patients with 76 malignant liver lesions who underwent ablation with the 150 W system. Using a step-wise algorithm, ablations without intraoperative complications were performed for tumors ranging in size from 0.3 to 6.7 cm. Ninety-day morbidity was 5%, with no mortality. Compared to the 100 W system, the 150 W system shortened ablation time and created larger ablation zones with a single stick. This first worldwide experience showed that surgical ablations could be safely created at 150 W using a step-wise algorithm with complete tumor destruction achieved at short-term follow-up. Advantages versus 100 W systems include reduction in ablation time and creation of larger ablation zones with a single stick.

Abstract 6371: Gaseous nitric oxide at high concentration is a powerful anti-tumor agent both in-vitro and in-vivo

Abstract Nitric Oxide (NO) acts as a signaling molecule in the body in different pathologic conditions, including cancer. Beyond Air is developing an innovative gaseous Nitric Oxide (gNO) based tumor ablation method. The highly diffusible nature of NO may ease its spreading inside the tumor, while its short half-life may limit its effect to the tumor site and not affect the surrounding area. According to our preliminary data, exposure of gNO at 10,000-50,000ppm for a very short time (in some cases one minute or less) efficiently eradicates breast, colon, lung and prostate cancers and shows a potent mouse tumor's destruction in-vivo. Methods: Mouse colon and breast cancer cell lines were exposed to gNO at 150-50,000 ppm for 10 seconds - 180 seconds. Cell viability was examined 24hrs later by XTT assay. Mouse colon tumors were treated by gNO at 10,000ppm - 50,000ppm intratumorally by hypodermic needles or local exposure of the tumor using a plastic box or tube. Results: To test if gNO at 150-50,000ppm can decrease cancer cell viability, cells were exposed (I) directly to NO in a 96 well plate or (II) in an acrylic glass box. Cell viability was tested 24hrs later by XTT. According to our findings, less than 3% of 4T1 cells remain viable when exposed to 10,000ppm NO for 3 minutes or 50,000ppm NO for 1 minute in a 96-well plate. ~1% of CT26 cells remain viable after exposure to 50,000ppm NO for 10 seconds in a 96 well plate; while less than 10% remain viable after 1 minute of exposure of 50,000ppm NO in a box. To test if gNO at 10,000-50,000ppm can destroy mouse colon cancer tumors in-vivo, tumors were exposed to gNO locally by hypodermic needles or a plastic cover. Air treated tumor bearing mice served as the control group. A complete tumor destruction was observed when the skin was removed from the tumor and the entire tumor was exposed to 10,000ppm gNO for 10 minutes. Conclusion: In the current work, gNO at high concentration showed a substantial cytotoxic effect on cancer cells in-vitro and in-vivo. The proposed project represents development of a novel treatment for cancer. Our innovative gNO based treatment may serve to treat solid tumors locally or be used as an adjunctive therapy for surgery and can be synergized with common anticancer therapies, such as chemotherapy and radiotherapy, to further enhance the effect. Citation Format: Hila Confino, Steve Lisi, Rinat Kalaora, Matan Goldshtein, Amir Avniel. Gaseous nitric oxide at high concentration is a powerful anti-tumor agent both in-vitro and in-vivo [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6371.

Stereotactic Image-Guided Microwave Ablation for Malignant Liver Tumors-A Multivariable Accuracy and Efficacy Analysis.

Background: Therapeutic success of thermal ablation for liver tumors depends on precise placement of ablation probes and complete tumor destruction with a safety margin. We investigated factors influencing targeting accuracy and treatment efficacy of percutaneous stereotactic image-guided microwave ablation (SMWA) for malignant liver neoplasms.Materials and methods: All consecutive patients treated with SMWA for malignant liver tumors over a 3-year period were analyzed. A computed tomography-based navigation system was used for ablation probe trajectory planning, stereotactic probe positioning, and validation of probe positions and ablation zones. Factors potentially influencing targeting accuracy [target positioning error (TPE)] and treatment efficacy within 6 months [ablation site recurrence (ASR)] were analyzed in a multivariable regression model, including challenging lesion locations (liver segments I, VII, and VIII; subphrenic location).Results: Three hundred one lesions (174 hepatocellular carcinomas, 87 colorectal liver metastases, 17 neuroendocrine tumors, and 23 others) were targeted in 191 interventions in 153 patients. The median TPE per ablation probe was 2.9 ± 2.3 mm (n = 384). Correction of ablation probe positions by repositioning was necessary in 4 out of 301 lesions (1%). Factors significantly influencing targeting accuracy were cirrhosis (R 0.67, CI 0.22–1.12) and targeting trajectory length (R 0.21, CI 0.12–0.29). Factors significantly influencing early ASR were lesion size >30 mm (OR 5.22, CI 2.44–11.19) and TPE >5 mm (OR 2.48, CI 1.06–5.78). Challenging lesion locations had no significant influence on targeting accuracy or early ASR.Conclusions: SMWA allows precise and effective treatment of malignant liver tumors even for lesions in challenging locations, with treatment efficacy depending on targeting accuracy in our model. Allowing for many tumors to be safely reached, SMWA has the potential to broaden treatment eligibility for patients with otherwise difficult to target tumors.

Feasibility of co-registered ultrasound and acoustic-resolution photoacoustic imaging of human colorectal cancer.

Colorectal cancer is the second leading cause of cancer death in the United States. Significant limitations in screening and surveillance modalities continue to hamper early detection of primary cancers or recurrences after therapy. In this study, we describe a new registered ultrasound (US) and acoustic-resolution photoacoustic microscopy (AR-PAM) system and report its initial testing in ex vivo human colorectal tissue. A total of 8 colorectal specimens were imaged, which included 2 polyps, 4 malignant colon cancers, and 2 treated colorectal cancers. In each specimen, normal tissue was also imaged for internal control. Initial data have demonstrated the feasibility of identifying colorectal cancer imaging features and the invasion depth using co-registered US and an AR-PAM system. In normal tissue, we found that our system consistently demonstrates the multi-layer structure of normal colonic tissue while differentiating layers with elevated vascularity; these findings highly correlated with histologic findings of each specimen. For malignant colorectal samples, the tissue structure is highly disorganized as seen in US, and photoacoustic imaging revealed distorted vascular distribution inside the tumor. Notably, AR-PAM of tumor beds after complete tumor destruction by radiation and chemotherapy yielded a pattern identical to benign tissue. Quantitative analysis of photoacoustic spectral slope has demonstrated more high-frequency components in malignant tissue as compared to the normal colon tissue, which may be caused by significantly increased microvessel networks. In summary, we demonstrate the successful differentiation of benign and malignant colorectal tissue with our co-registered ultrasound and photoacoustic system.

Combined minimally invasive treatment of liver and bile ducts malignancies

Aim. To analyze radiofrequency ablation per se and in combination with other X-ray surgical procedures in patients with liver and bile ducts malignancies. Material and methods. Radiofrequency ablation was used in three groups: percutaneous intervention or in combination with liver resection – group 1 (n = 111); ablation combined with intra-arterial chemoembolization (n = 3) – group 2; RFA followed by right portal vein embolization (RALPPES) in order to induce liver hypertrophy to enable liver resection – group 3 (n = 20). Results. There were no recurrences after radiofrequency ablation. Two-year survival was 55% in patients with hepatocellular carcinoma and liver cirrhosis.Colorectal cancer metastases were followed by 4-year survival near 55%. RFA combined with intra-arterial chemoembolization were associated with complete tumor destruction in patients with hepatocellular carcinoma over 4–5 cm and stabilization in patients with progressive intrahepatic cholangiocarcinoma. Liver hypertrophy was over 50% in two weeks after RALPPES that enables liver resection in 95% of patients. Symptoms of liver failure after hemihepatectomy were not observed in any patients. Conclusion. Combination of interventional methods is able to improve outcomes in patients with liver and bile ducts malignancies.

A Facile Ion-Doping Strategy To Regulate Tumor Microenvironments for Enhanced Multimodal Tumor Theranostics.

Integration of multiple therapeutic/diagnostic modalities into a single system holds great promise to improve theranostic efficiency for tumors, but still remains a technical challenge. Herein, we report a new multimodal theranostic nanoconstruct based on Fe-doped polydiaminopyridine nanofusiforms, built easily and on a large scale, which can dual-regulate intracellular oxygen and glutathione levels, transport iron ions, and simultaneously be used for thermal imaging and magnetic resonance imaging. Co-loading of dihydroartemisinin and methylene blue generates a superior multifunctional theranostic agent with enhanced photochemotherapy efficiency and biodegradability, leading to almost complete destruction of tumors with near-infrared light irradiation. This represents an attractive route to develop multimodal anticancer theranostics.

FeIII -Doped Two-Dimensional C3 N4 Nanofusiform: A New O2 -Evolving and Mitochondria-Targeting Photodynamic Agent for MRI and Enhanced Antitumor Therapy.

Local hypoxia in tumors, as well as the short lifetime and limited action region of 1 O2 , are undesirable impediments for photodynamic therapy (PDT), leading to a greatly reduced effectiveness. To overcome these adversities, a mitochondria-targeting, H2 O2 -activatable, and O2 -evolving PDT nanoplatform is developed based on FeIII -doped two-dimensional C3 N4 nanofusiform for highly selective and efficient cancer treatment. The ultrahigh surface area of 2D nanosheets enhances the photosensitizer (PS) loading capacity and the doping of FeIII leads to peroxidase mimetics with excellent catalytic performance towards H2 O2 in cancer cells to generate O2 . As such tumor hypoxia can be overcome and the PDT efficacy is improved, whilst at the same time endowing the PDT theranostic agent with an effective T 1 -weighted in vivo magnetic resonance imaging (MRI) ability. Conjugation with a mitochondria-targeting agent could further increase the sensitivity of cancer cells to 1 O2 by enhanced mitochondria dysfunction. In vitro and in vivo anticancer studies demonstrate an outstanding therapeutic effectiveness of the developed PDT agent, leading to almost complete destruction of mouse cervical tumor. This development offers an attractive theranostic agent for in vivo MRI and synergistic photodynamic therapy toward clinical applications.

RNA disruption is associated with response to multiple classes of chemotherapy drugs in tumor cell lines.

BackgroundCellular stressors and apoptosis-inducing agents have been shown to induce ribosomal RNA (rRNA) degradation in eukaryotic cells. Recently, RNA degradation in vivo was observed in patients with locally advanced breast cancer, where mid-treatment tumor RNA degradation was associated with complete tumor destruction and enhanced patient survival. However, it is not clear how widespread chemotherapy induced “RNA disruption” is, the extent to which it is associated with drug response or what the underlying mechanisms are.MethodsOvarian (A2780, CaOV3) and breast (MDA-MB-231, MCF-7, BT474, SKBR3) cancer cell lines were treated with several cytotoxic chemotherapy drugs and total RNA was isolated. RNA was also prepared from docetaxel resistant A2780DXL and carboplatin resistant A2780CBN cells following drug exposure. Disruption of RNA was analyzed by capillary electrophoresis. Northern blotting was performed using probes complementary to the 28S and 18S rRNA to determine the origins of degradation bands. Apoptosis activation was assessed by flow cytometric monitoring of annexin-V and propidium iodide (PI) binding to cells and by measuring caspase-3 activation. The link between apoptosis and RNA degradation (disruption) was investigated using a caspase-3 inhibitor.ResultsAll chemotherapy drugs tested were capable of inducing similar RNA disruption patterns. Docetaxel treatment of the resistant A2780DXL cells and carboplatin treatment of the A2780CBN cells did not result in RNA disruption. Northern blotting indicated that two RNA disruption bands were derived from the 3’-end of the 28S rRNA. Annexin-V and PI staining of docetaxel treated cells, along with assessment of caspase-3 activation, showed concurrent initiation of apoptosis and RNA disruption, while inhibition of caspase-3 activity significantly reduced RNA disruption.ConclusionsSupporting the in vivo evidence, our results demonstrate that RNA disruption is induced by multiple chemotherapy agents in cell lines from different tissues and is associated with drug response. Although present, the link between apoptosis and RNA disruption is not completely understood. Evaluation of RNA disruption is thus proposed as a novel and effective biomarker to assess response to chemotherapy drugs in vitro and in vivo.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2197-1) contains supplementary material, which is available to authorized users.

Abstract B185: Induction of specific immunity to MUC1 antigen by tumor irradiation and cancer vaccines in murine tumor models

Abstract We have previously demonstrated that tumor irradiation potentiates cancer vaccines using genetic modification of tumor cells in murine tumor models. We showed that prior tumor irradiation enhanced the response of mice to intratumoral gene therapy with an IL-2 adenovector for non-immunogenic tumors. To investigate whether tumor irradiation augments the immune response to a specific tumor antigen, we have now tested the efficacy of tumor irradiation to enhance the therapeutic effect of MVA-MUC1-IL2 cancer vaccine (Transgene TG4010) for the treatment of murine renal adenocarcinoma Renca cells transfected with MUC1. Established subcutaneous (s.c.) Renca-MUC1 tumors (18mm3) were irradiated with 8 Gy on day 11 and peritumoral s.c. injections of MVA-MUC1-IL2 vector were administered at 106- 107 PFU on day 12 and 20. Tumor growth delays were monitored by tumor measurements and histological responses were evaluated following treatment with radiation alone, vector alone, radiation + MVA-MUC1-IL2 vector or radiation + MVA empty vector. Histological evaluation of tumors at an early time point, by 2-3 weeks after radiation and cancer vaccine, revealed that tumors treated with radiation and vaccine showed extensive areas of necrosis due to complete tumor destruction. Intense hemorrhages were observed due to disruption of tumor vasculature. Small areas of remaining tumor showed apoptotic tumor cells and degenerating giant tumor cells typical of radiation-induced changes. At the periphery of the tumor and infiltrating the tumor, we observed large bands of inflammatory cells including lymphocytes and macrophages as well as fibroblasts spindled shaped cells. Immuno-histochemical staining with CD45 leukocyte marker and F4/80 macrophage marker confirmed extensive infiltration of leukocytes and macrophages at the periphery and inside of areas of tumor destruction. These alterations were not as pronounced with radiation alone suggesting a drastic effect of the combined radiation + vaccine therapy on the tumor microenvironment. Radiation induced tumor growth delays for about 15 days but longer tumor growth delays of 30-35 days were observed with radiation + MVA-MUC1-IL2. By day 55, over 30% of the mice treated with radiation + MVA-MUC1-IL2 had a complete response with no sign of tumor whereas no responders were observed with either radiation alone or cancer vaccine alone. Complete responders were immune to rechallenge with Renca-MUC1 cells. These findings suggest that tumor irradiation given prior to cancer vaccine augments a specific immune response targeted at a specific tumor antigen that results in specific tumor immunity. The mechanisms of interaction between tumor irradiation and gene-mediated immunotherapy could include radiation-induced alterations in the tumor microenvironment, as those observed histologically in our studies, which could facilitate a more effective anti-tumor immune response. These include radiation-induced apoptosis and necrosis of tumor cells causing tumor-debulking and release of tumor antigens for APC presentation. Inflammatory cells mobilized in the tumor by radiation-induced tissue damage could subsequently be activated by the immune response triggered by the cancer vaccine. These studies support investing further pre-clinical and clinical efforts to combine radiotherapy with cancer vaccines for the treatment of cancer. Citation Format: Gilda Gali Hillman, Matthew D. Fountain, Shoshana E. Rothstein, Lyndsey Reich, Lisa Abernathy, Christopher K. Yunker, Fulvio Lonardo, Philippe Slos. Induction of specific immunity to MUC1 antigen by tumor irradiation and cancer vaccines in murine tumor models. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B185.

Extensive Use of Interventional Therapies Improves Survival in Unresectable or Recurrent Intrahepatic Cholangiocarcinoma.

Aim. To assess the outcomes of patients with unresectable intrahepatic cholangiocellular carcinoma (ICC) treated by a tailored therapeutic approach, combining systemic with advanced image-guided local or locoregional therapies. Materials and Methods. Treatment followed an algorithm established by a multidisciplinary GI-tumor team. Treatment options comprised ablation (RFA, CT-guided brachytherapy) or locoregional techniques (TACE, radioembolization, i.a. chemotherapy). Results. Median survival was 33.1 months from time of diagnosis and 16.0 months from first therapy. UICC stage analysis showed a median survival of 15.9 months for stage I, 9 months for IIIa, 18.4 months for IIIc, and 13 months for IV. Only the number of lesions, baseline serum CEA and serum CA19-9, and objective response (RECIST) were independently associated with survival. Extrahepatic metastases had no influence. Conclusion. Patients with unresectable ICC may benefit from hepatic tumor control provided by local or locoregional therapies. Future prospective study formats should focus on supplementing systemic therapy by classes of interventions (“toolbox”) rather than specific techniques, that is, local ablation leading to complete tumor destruction (such as RFA) or locoregional treatment leading to partial remission (such as radioembolization). This trial is registered with German Clinical Trials Registry (Deutsche Register Klinischer Studien), DRKS-ID: DRKS00006237.

The first clinical application of planning software for laparoscopic microwave thermosphere ablation of malignant liver tumours

BackgroundLiver tumour ablation is an operator‐dependent procedure. The determination of the optimum needle trajectory and correct ablation parameters could be challenging. The aim of this study was to report the utility of a new, procedure planning software for microwave ablation (MWA) of liver tumours. MethodsThis was a feasibility study in a pilot group of five patients with nine metastatic liver tumours who underwent laparoscopic MWA. Pre‐operatively, parameters predicting the desired ablation zones were calculated for each tumour. Intra‐operatively, this planning strategy was followed for both antenna placement and energy application. Post‐operative 2‐week computed tomography (CT) scans were performed to evaluate complete tumour destruction. ResultsThe patients had an average of two tumours (range 1–4), measuring 1.9 ± 0.4 cm (range 0.9–4.4 cm). The ablation time was 7.1 ± 1.3 min (range 2.5–10 min) at 100W. There were no complications or mortality. The patients were discharged home on post‐operative day (POD) 1. At 2‐week CT scans, there were no residual tumours, with a complete ablation demonstrated in all lesions. ConclusionsThis study describes and validates pre‐treatment planning software for MWA of liver tumours. This software was found useful to determine precisely the ablation parameters and needle placement to create a predicted zone of ablation.

Local ablative procedures of the liver.

Local ablative therapies have become an important part in the portfolio of treatment for patients with malignant tumors especially in the liver. Although percutaneous ethanol injection still plays a role, current guidelines favor radiofrequency ablation with a higher efficacy for complete tumor destruction. Nevertheless transplantation and surgical resection remain the gold standard due to their superiority in local control and improved survival. In this manuscript we discuss the technique in detail.

Complete destruction of deep-tissue buried tumors via combination of gene silencing and gold nanoechinus-mediated photodynamic therapy

Cancer is one of the major diseases leading to human deaths. Complete destruction of deep tissue-buried tumors using non-invasive therapies is a grand challenge in clinical cancer treatments. Many therapeutic modalities were developed to tackle this problem, but only partial tumor suppression or delay growths were usually achieved. In this study, we report for the first time that complete destruction of deep tissue-buried tumors can be achieved by combination of gold nanoechinus (Au NEs)-mediated photodynamic therapy (PDT) and gene silencing under ultra-low doses of near infra-red (NIR) light irradiation (915 nm, 340 mW/cm2; 1064 nm, 420 mW/cm2) in the first and second biological windows. The average lifespan of the mice treated by the above combined therapy is beyond 40 days, which are ∼2.6 times longer than that (15 days) observed from the anticancer drug doxorubicin-treated group. The current study points out a new direction for the therapeutic design to treat deeply seated tumors in future cancer treatments.

Styrene maleic acid copolymer–pirarubicin induces tumor-selective oxidative stress and decreases tumor hypoxia as possible treatment of colorectal cancer liver metastases

Pirarubicin, a derivative of doxorubicin, induces tumor destruction via the production of reactive oxygen species (ROS) but is associated with cardiotoxicity. As a macromolecule (conjugated to styrene-maleic acid [SMA]), SMA-pirarubicin is selective to tumors resulting in improved survival with decreased systemic toxicity. Tumor destruction is, however incomplete, and resistant cells at the periphery of the tumor contribute to recurrence. Tumor hypoxia is a major factor in tumor resistance. Understanding the effect of oxidative stress induced by SMA-pirarubicin on the tumor microenvironment may be key to overcoming resistance. This study investigated the pattern of ROS production and tumor hypoxia after treatment with SMA-pirarubicin in a murine model of colorectal liver metastases. Liver metastases were induced in male, CBA mice using a murine-derived colon cancer cell line. SMA-pirarubicin (maximum tolerated dose, 100 mg/kg) or pirarubicin, (maximum tolerated dose, 10 mg/kg) were administered intravenously 14 days after tumor induction. Systemic oxidative stress in serum, liver, and cardiac tissue was quantified using the thiobarbituric acid reactive substances assay. Flow cytometry and fluorescence microscopy were used to assess ROS production for 48 hours after treatment. Tumor hypoxia was quantified using immunohistochemistry for pimonidazole adducts. SMA-pirarubicin (100 mg/kg) induced ROS exclusively in tumors with minimal levels in serum and cardiac tissue. ROS levels were induced in a time-dependent and dose-dependent manner optimal between 4 and 24 hours after drug administration. Although tumor hypoxia was decreased overall, residual tumor cells adjacent to patent vessels were hypoxic. This study provides insight into the tumor microenvironment after chemotherapy. SMA-pirarubicin inhibits the growth of colorectal liver metastases by inducing ROS, which seems to be largely tumor selective. The temporal pattern of ROS production can be used to improve future dosing regimens. Furthermore, the observation that residual tumor cells are hypoxic clarifies the need for a multimodal approach with agents that can alter the hypoxic state to effect complete tumor destruction.

Lassa-vesicular stomatitis chimeric virus safely destroys brain tumors.

High-grade tumors in the brain are among the deadliest of cancers. Here, we took a promising oncolytic virus, vesicular stomatitis virus (VSV), and tested the hypothesis that the neurotoxicity associated with the virus could be eliminated without blocking its oncolytic potential in the brain by replacing the neurotropic VSV glycoprotein with the glycoprotein from one of five different viruses, including Ebola virus, Marburg virus, lymphocytic choriomeningitis virus (LCMV), rabies virus, and Lassa virus. Based on in vitro infections of normal and tumor cells, we selected two viruses to test in vivo. Wild-type VSV was lethal when injected directly into the brain. In contrast, a novel chimeric virus (VSV-LASV-GPC) containing genes from both the Lassa virus glycoprotein precursor (GPC) and VSV showed no adverse actions within or outside the brain and targeted and completely destroyed brain cancer, including high-grade glioblastoma and melanoma, even in metastatic cancer models. When mice had two brain tumors, intratumoral VSV-LASV-GPC injection in one tumor (glioma or melanoma) led to complete tumor destruction; importantly, the virus moved contralaterally within the brain to selectively infect the second noninjected tumor. A chimeric virus combining VSV genes with the gene coding for the Ebola virus glycoprotein was safe in the brain and also selectively targeted brain tumors but was substantially less effective in destroying brain tumors and prolonging survival of tumor-bearing mice. A tropism for multiple cancer types combined with an exquisite tumor specificity opens a new door to widespread application of VSV-LASV-GPC as a safe and efficacious oncolytic chimeric virus within the brain. Many viruses have been tested for their ability to target and kill cancer cells. Vesicular stomatitis virus (VSV) has shown substantial promise, but a key problem is that if it enters the brain, it can generate adverse neurologic consequences, including death. We tested a series of chimeric viruses containing genes coding for VSV, together with a gene coding for the glycoprotein from other viruses, including Ebola virus, Lassa virus, LCMV, rabies virus, and Marburg virus, which was substituted for the VSV glycoprotein gene. Ebola and Lassa chimeric viruses were safe in the brain and targeted brain tumors. Lassa-VSV was particularly effective, showed no adverse side effects even when injected directly into the brain, and targeted and destroyed two different types of deadly brain cancer, including glioblastoma and melanoma.

Image Guided Focal Therapy for Magnetic Resonance Imaging Visible Prostate Cancer: Defining a 3-Dimensional Treatment Margin Based on Magnetic Resonance Imaging Histology Co-Registration Analysis

We compared prostate tumor boundaries on magnetic resonance imaging and radical prostatectomy histological assessment using detailed software assisted co-registration to define an optimal treatment margin for achieving complete tumor destruction during image guided focal ablation. Included in study were 33 patients who underwent 3Tesla magnetic resonance imaging before radical prostatectomy. A radiologist traced lesion borders on magnetic resonance imaging and assigned a suspicion score of 2 to 5. Three-dimensional reconstructions were created from high resolution digitalized slides of radical prostatectomy specimens and co-registered to imaging using advanced software. Tumors were compared between histology and imaging by the Hausdorff distance and stratified by the magnetic resonance imaging suspicion score, Gleason score and lesion diameter. Cylindrical volume estimates of treatment effects were used to define the optimal treatment margin. Three-dimensional software based registration with magnetic resonance imaging was done in 46 histologically confirmed cancers. Imaging underestimated tumor size with a maximal discrepancy between imaging and histological boundaries for a given tumor of an average ± SD of 1.99 ± 3.1 mm, representing 18.5% of the diameter on imaging. Boundary underestimation was larger for lesions with an imaging suspicion score 4 or greater (mean 3.49 ± 2.1 mm, p <0.001) and a Gleason score of 7 or greater (mean 2.48 ± 2.8 mm, p = 0.035). A simulated cylindrical treatment volume based on the imaging boundary missed an average 14.8% of tumor volume compared to that based on the histological boundary. Asimulated treatment volume based on a 9 mm treatment margin achieved complete histological tumor destruction in 100% of patients. Magnetic resonance imaging underestimates histologically determined tumor boundaries, especially for lesions with a high imaging suspicion score and a high Gleason score. A 9 mm treatment margin around a lesion visible on magnetic resonance imaging would consistently ensure treatment of the entire histological tumor volume during focal ablative therapy.

A theranostic prodrug delivery system based on Pt(IV) conjugated nano-graphene oxide with synergistic effect to enhance the therapeutic efficacy of Pt drug

Due to their high NIR-optical absorption and high specific surface area, graphene oxide and graphene oxide-based nanocomposites have great potential in both drug delivery and photothermal therapy. In the work reported herein we successfully integrate a Pt(IV) complex (c,c,t-[Pt(NH3)2Cl2(OH)2]), PEGylated nano-graphene oxide (PEG-NGO), and a cell apoptosis sensor into a single platform to generate a multifunctional nanocomposite (PEG-NGO-Pt) which shows potential for targeted drug delivery and combined photothermal-chemotherapy under near infrared laser irradiation (NIR), and real-time monitoring of its therapeutic efficacy. Non-invasive imaging using a fluorescent probe immobilized on the GO shows an enhanced therapeutic effect of PEG-NGO-Pt in cancer treatment via apoptosis and cell death. Due to the enhanced cytotoxicity of cisplatin and the highly specific tumor targeting of PEG-NGO-Pt at elevated temperatures, this nanocomposite displays a synergistic effect in improving the therapeutic efficacy of the Pt drug with complete destruction of tumors, no tumor recurrence and minimal systemic toxicity in comparison with chemotherapy or photothermal treatment alone, highlighting the advantageous effects of integrating Pt(IV) with GO for anticancer treatment.