Improving communication of the concept of 'treat-to target' in childhood lupus: a public and patient (PPI) engagement project involving children and young people.

BACKGROUND: A treat-to-target (T2T) approach, where treatment is escalated until a specific target is achieved, and re-escalated if the target is lost, has been proposed as a strategy to improve Childhood Systemic Lupus Erythematosus (cSLE) outcomes. Previous studies involving children and young people (CYP) have identified that the concept of T2T can be difficult to understand by CYP and their families. We aimed to explore the views of CYP participating in existing public and patient involvement (PPI) groups in relation to a proposed animation that is being developed to explain the concept of T2T to CYP who will be eligible for a future cSLE T2T trial. METHODS: An illustrated animation storyboard was developed on PowerPoint, to be used alongside a contemporaneous voiceover to simulate the animation for CYP participating in three existing CYP PPI groups (GenerationR, Lupus UK, and YOUR RHEUM). Mixed methods were used to generate CYP feedback on the resource, including on-line surveys and qualitative topic-guided discussion, noting CYP suggestions for improvement. Changes were made iteratively to the resources. Pre/post workshop questionnaires to assess the impact of the resource on their understanding of T2T were completed anonymously. RESULTS: 40 CYP were consulted; 16/40 (40%) from GenerationR (median age 15-years [IQR 12-15]), 12/40 (30%) from Lupus UK (median age 27-years [IQR 22-30]), and 12/40 (30%) from YOUR RHEUM (median age 17-years [IQR 16-21]). 62% of respondents had an underlying rheumatic condition. Pre-workshop median participant understanding of T2T was 2/10 [IQR 1-4], on a 1-10 scale (1 = "no understanding at all", 10 = "completely confident in my understanding"). After viewing the resource, participant understanding improved to a median of 9/10 [IQR 8-10], p < 0.0001). Overall, participants felt that the animation greatly improved their understanding of the concept of T2T, making several suggestions for improvement. CONCLUSION: Involvement of CYP in research is crucial to help improve the design/delivery of studies, ensuring relevance to CYP and their families. This manuscript demonstrates the involvement of CYP in the development of an animation that will be integral to a future clinical trial, helping to describe the T2T approach in a comprehensible way to eligible CYP and their families, supporting study recruitment.

The OpenKIM processing pipeline: A cloud-based automatic material property computation engine.

The Open Knowledgebase of Interatomic Models (OpenKIM) is a framework intended to facilitate access to standardized implementations of interatomic models for molecular simulations along with computational protocols to evaluate them. These protocols include tests to compute material properties predicted by models and verification checks to assess their coding integrity. While housing this content in a unified, publicly available environment constitutes a major step forward for the molecular modeling community, it further presents the opportunity to understand the range of validity of interatomic models and their suitability for specific target applications. To this end, OpenKIM includes a computational pipeline that runs tests and verification checks using all available interatomic models contained within the OpenKIM Repository at https://openkim.org. The OpenKIM Processing Pipeline is built on a set of Docker images hosted on distributed, heterogeneous hardware and utilizes open-source software to automatically run test-model and verification check-model pairs and resolve dependencies between them. The design philosophy and implementation choices made in the development of the pipeline are discussed as well as an example of its application to interatomic model selection.

Variability of heating patterns in animals by magnetic induction hyperthermia.

In a test of electromagnetic induction hyperthermia to deep viscera of a live dog model, we found that heating was not uniform to any depth, but was quite variable. In general, there was a thermal gradient between peripheral and central portions of the transposed spleen of about 1 degree C. Though heat generation within the abdomen was not uniform, its temperature pattern in the alive animal resulted in significant heating of that part of the organ that had been surgically placed at the center of the animal. This heating could not be explained by perfusion with regionally heated core blood. Our results indicate that extensive investigations in living systems and complex dynamic phantoms will be necessary before individual patient response can be predicted.

A comparison of deep-heating electrode concepts for hyperthermia.

There is mounting evidence that localized hyperthermia produced by electromagnetic waves may be useful in the treatment of cancer, and many innovative devices have been designed for this purpose. Most applicators employed for deep heating operate in the frequency region of 10-100MHz to provide greatest depth of penetration. Two basic categories of launching devices exist: E-field and H-field. The E-field applicators include conductive plates and fringing field devices; either may be used individually or in a multiple feed system. The H-field applicators include cylindrical and planar devices configured to produce specific heating patterns. We have analyzed and compared the performance of each of these devices, particularly in terms of engineering principles, design characteristics and their ability to transfer potentially therapeutic energy safely and at depth.

Clinical thermochemotherapy. A controlled trial in advanced cancer patients.

In vitro and in vivo animal studies and some clinical trials have shown apparent benefit from thermochemotherapy; however, this treatment modality has not been adequately tested in humans. This investigation evaluated response to and toxicity of secondary thermochemotherapy, using each patient as his own control. Patients with advanced cancer who had documented disease progression while receiving chemotherapy alone were subsequently treated with the same drug, by the same dose and route, combined with localized hyperthermia. Thirty-four patients whose diseases included metastatic colon carcinoma, melanoma, sarcoma and hepatoma in viscera (29) or surface tissues (5) were treated with combination thermochemotherapy for 1 hour daily for 5 days/month. Effective heating from 41 to 45 degrees C minimum tumor temperature was possible in 17/19 (89%) tumors in which temperatures could be measured safely. The authors observed 5 (15%) tumor regressions for 1 to 5 months (median, 2 months), and 19 (56%) tumor stabilizations (growth arrest of previously progressive disease) for 1 to 9 months (median, 4 months). Subjective improvement in activity and/or pain control occurred in 6 (18%) patients and 20 (59%) had no progression of symptoms during treatment. Moreover, there was no detectable morbidity from localized hyperthermia, and no evidence of increased chemotherapy toxicity. While the mechanism(s) of response is poorly understood, the documented disease regressions and stabilizations of previously progressive disease in 24 (71%) patients during secondary combination thermochemotherapy indicates that the addition of hyperthermia may have useful anticancer activity. Expanded trials are warranted.

Clinical radiofrequency hyperthermia: a review.

Localized radiofrequency (RF) hyperthermia is being investigated for potential use in cancer therapy, both as a single agent and in combination with radiation therapy and chemotherapy. Standard capacitive and inductive heating techniques and new technology, including magnetrode magnetic-loop induction, are being compared for safety and efficacy. Clinical trials suggest that effective localized RF hyperthermia may be administered safely to both superficial and deep visceral tumors with proper equipment. Temperatures of 42 degrees C or greater appear to be tumoricidal, though higher temperatures and longer and multiple treatments seem most beneficial. Effective heating of tumors has been independent of histology but could be related to size and blood flow. Combined with radiation therapy and chemotherapy, hyperthermia appears to have a synergistic or additive effect. These trials indicate that localized RF hyperthermia may soon provide a significant contribution to our armamentarium against cancer.

Thermal distribution of magnetic-loop induction hyperthermia in phantoms and animals: effect of the living state and velocity of heating.

Hyperthermia has shown promise for the treatment of cancer. The magnetrode radio-frequency magnetic-loop induction applicator was recently introduced and is being evaluated at many centers with encouraging initial results. This investigation was undertaken to delineate the thermal distribution patterns of magnetrode hyperthermia in both normal tissue phantoms and healthy dogs. Temperatures on homogeneous and heterogeneous tissue equivalents and animal tissue phantoms, a dead animal extremity, a dead dog and a live dog subjected to rapid high-dose heating showed preferential and potentially injurious peripheral heating with a central "cold spot." However, sequential moderate-dose heating in live dogs showed virtually uniform (less than 1 degree C) and potentially tumoricidal temperatures greater than or equal to 42 degrees C in both peripheral and central internal organs without injury to surface tissues. These data indicate that magnetic-loop induction can produce potentially safe and effective deep central heat in living, normal animals, but that safety and effectiveness are significantly influenced by the velocity of heat deposition. Furthermore, normal tissue phantom models and dead animals are unreliable predictors of magnetrode heat patterns in living systems.

Thermochemotherapy for melanoma metastases in liver.

Metastatic melanoma in the liver has carried an extremely poor prognosis regardless of therapy. Because transient responses (1/6 disease regressions and 2/6 disease stabilizations for four months) in selected patients treated with intraarterial (IA) DTIC infusion were encouraging and because localized hyperthermia may be both tumoricidal and synergistic with chemotherapy, these modalities were combined for treatment of patients with advanced liver metastases. Of 10 patients treated with IA-DTIC plus heat, three (30%) had disease-regression and five (50%) had disease stabilization for 3-14 months (median 6.5 months) and survived 3.5-18 months (median 8.5 months). During treatment, 4/5 patients had pain relief and 7/10 retained or acquired normal activities. Myelosuppression was minimal and no hyperthermia toxicity occurred. A retrospective review of 10 patients with similar disease levels who were treated with conventional intravenous (IV)-DTIC indicated no responses, and no responses were seen in five patients treated with IV-DTIC plus heat. However, this latter group may have been selected patients due to the inability to place a percutaneous hepatic artery infusion catheter. This pilot study suggests that combination IA-DTIC and hyperthermia has a high response rate, is safe, and can provide quality survival for many patients.

Radio frequency hyperthermia of advanced human sarcomas.

Hyperthermia greater than or equal to 42 degrees C is tumoricidal in vitro and in many animal models, although such temperatures have only recently been achieved experimentally in some human cancers. A recently developed radio frequency device that provides safe hyperthermia to any depth without surface tissue injury now permits evaluation of the effects of hyperthermia on advanced human sarcomas. Twelve patients with large sarcomas located intraabdominally [7], in the chest wall [2], proximal extremity [2], and the neck [1], were evaluated in this study. Tumor types include liposarcoma [3], rhabdomyosarcoma [2], leiomyosarcoma [2], neurofibrosarcoma [2], and one each malignant mesothelioma, undifferentiated sarcoma, and osteosarcoma. Intratumor temperatures greater than or equal to 42 degrees C were observed in all tumors, with virtually no normal tissue injury. Selective tumor heating greater than or equal to 45 degrees C occurred in 9/12 (75%) and greater than or equal to 50 degrees C in 6/12 (50%). One to five weekly treatments greater than or equal to 50 degrees C and ten daily treatments greater than or equal to 45 degrees C resulted in significant tumor necrosis and pain relief in some patients. Hyperthermia of advanced sarcomas is possible with little host toxicity and may be of potential therapeutic benefit.

Hyperthermic therapy for human neoplasms: thermal death time.

Hyperthermia greater than or equal to 42 C is tumoricidal, apparently a function of absolute temperature and duration of heating. However, because the technology for producing safe and effective deep hyperthermia did not exist, there was virtually no data on the thermal death times of human cancers. The development of a fundamentally new radio frequency device that produces uniform hyperthermia to any depth without surface tissue injury has allowed preliminary testing of this hypothesis in 38 patients with advanced cancer. Temperature measurements were taken in tumors and normal adjacent tissues. Tumors were heated from 40 C to greater than or equal to 50 C, one to ten times (13-600 minutes). Serial tumor biopsies compared percent necrosis (total absence of nuclei) by type of therapy. Of 44 tumors evaluated (21 superficial, 23 visceral), 31 (70%) were heated greater than or equal to 42 C, 23 (52%) greater than or equal to 45 C, and 14 (32%) greater than or equal to 50 C, with virtually no normal tissue injury. Single, short duration hyperthermia at greater than or equal to 50 C resulted in 20-100% tumor necrosis, while lower temperatures had no effect. Two or three treatments at 45-50 C produced 70-100% necrosis, while lower temperatures produced less necrosis at more than twice the duration of heating. Multiple treatments produced increased necrosis at lower temperatures; however, at the same temperature duration, higher temperatures were most effective. These clinical results support the hypothesis that the observed necrosis is related to both temperature and treatment time and suggest that higher temperatures and longer durations of therapy are most beneficial.

Human hyperthermic therapy: relation between tumor type and capacity to induce hyperthermia by radiofrequency.

There is mounting evidence that hyperthermia of 42 degrees C or greater is tumoricidal to cell cultures and to animal and human tumors. However, temperatures of 45 degrees C or greater may have greater potential therapeutic benefit. The ability to selectively achieve such highintratratumor temperatures without injury to normal tissue may be due to the relatively poor blood flow in tumors compared with that in normal tissues. While vascularity and blood flow are known to vary significantly among tumors, we found that of 52 tumors evaluated, temperatures of 42 degrees C or greater in 42 tumors (81 per cent) and of 45 degrees C or greater in 23 tumors (44 per cent) appeared to be independent of the histologic type of tumor. Therefore, therapeutic hyperthermia may be possible for most varieties of human solid cancer.

Normal tissue and solid tumor effects of hyperthermia in animal models and clinical trials.

Localized hyperthermia therapy by high-energy radio-frequency waves was evaluated in malignant and adjacent normal tissue of 30 patients with 10 types of cancer. Hyperthermia was delivered to superficial and deep visceral cancers in awake patients who had refractory disease. Histological and clinical responses were recorded serially. Toxicity tests in dogs, sheep, and pigs showed that progressive necrosis of normal and cancer tissue occurred at temperatures above 45 degrees C (113 degrees F). However, as normal tissues approached this temperature, intrinsic heat dissipation occurred (possibly due to augmented blood flow) so that temperatures below 45 degrees C could be maintained, whereas most solid tumors did not have this adaptive capacity and could be heated to 50 degrees C (122 degrees F) with virtually no injury to normal organs, s.c. tissue, or skin. To date, 69 treatments have been administered to 36 tumors in the 30 patients. Selective heating was observed in both primary and metastatic tumors located in surface tissues and internal organs. Response appeared to be related to tumor size in that differential heating was possible more often in the larger lesions. In tumors successfully heated, moderate to marked necrosis occurred. Radio-frequency hyperthermia appears to be a safe and potentially useful form of therapy for selected cancer patients. While other cancer treatments are more effective for small tumors, hyperthermia may be uniquely beneficial against larger lesions.