Care at Your Fingertips: Codesign, Development, and Evaluation of the Oncology Hub App for Remote Symptom Management in Pediatric Oncology.

PURPOSE: To codesign, develop, and evaluate a smartphone app that includes patient-reported measures of symptoms and real-time advice in children's cancer. METHODS: The Oncology Hub is a comprehensive approach to symptom management that includes a suite of codesigned tools and resources including clinical algorithms to determine the level of concern, symptom management advice, and resources for families of children with cancer. The evaluation involved Think Aloud interviews with parent and adolescent patients to complete tasks in the app as well as a User Experience questionnaire (score range, 0-120) and qualitative feedback. The accuracy of algorithms was determined by repeated testing of inputs and outputs over 4 weeks. RESULTS: Design and wireframes were iteratively refined through consultation with parents and adolescents confirming the final design. Beta testing evaluation was then completed by 25 participants including two adolescents. Across all participants, 84% of tasks were easy to navigate, and the Oncology Hub demonstrated high usability, usefulness, and acceptability with participants' scores ranging between 90 and 120 (mean = 112.2, standard deviation = 9.43). Qualitative feedback was positive. Testing of algorithms identified inconsistencies in understanding between clinical research and coding teams; refinements were made until the expected response notifications were returned with 100% accuracy. CONCLUSION: Technology offers new ways to think about how clinicians and families communicate and share information to harness the best of community and hospital services. Understanding how information is exchanged using health apps, and how this affects clinical workflow is critical to successful implementation, and optimizing symptom assessment and management in children with cancer.

A platform for oncogenomic reporting and interpretation.

Manual interpretation of variants remains rate limiting in precision oncology. The increasing scale and complexity of molecular data generated from comprehensive sequencing of cancer samples requires advanced interpretative platforms as precision oncology expands beyond individual patients to entire populations. To address this unmet need, we introduce a Platform for Oncogenomic Reporting and Interpretation (PORI), comprising an analytic framework that facilitates the interpretation and reporting of somatic variants in cancer. PORI integrates reporting and graph knowledge base tools combined with support for manual curation at the reporting stage. PORI represents an open-source platform alternative to commercial reporting solutions suitable for comprehensive genomic data sets in precision oncology. We demonstrate the utility of PORI by matching 9,961 pan-cancer genome atlas tumours to the graph knowledge base, calculating therapeutically informative alterations, and making available reports describing select individual samples.

Evaluation of Alitretinoin for the Treatment of Mycosis Fungoides and Sézary Syndrome.

BACKGROUND: Mycosis fungoides (MF) and Sézary syndrome (SS) are the most common subtypes of cutaneous T-cell lymphoma (CTCL). There is currently no cure for CTCL, and treatment is aimed at limiting disease progression. This study evaluated the efficacy and tolerability of alitretinoin in CTCL management. METHODS: A retrospective, multicenter study was conducted on CTCL patients treated with alitretinoin as a primary agent or in combination with standard therapies. RESULTS: Forty-eight patients with MF (n = 40) and SS (n = 8) with a median age of 59.7 years (±14.3) were eligible for study inclusion. Treatment response data were evaluated in 40 patients and safety in 42 patients. 40.0% of the patients had early-stage, 43.8% had advanced-stage CTCL, and in 16.7% of patients there was insufficient information for staging. 40.0% (16/40) of the patients achieved a complete or partial response, whereas 47.5% (19/40) achieved stable disease, 12.5% (5/40) had progressive disease, and there were no cases of disease relapses in responders. Both early and advanced stages of CTCL were responsive to alitretinoin as a primary or combined modality. Alitretinoin was well tolerated, and 64.3% (27/42) of patients did not report any side effects. The most commonly observed side effect was hypertriglyceridemia. CONCLUSIONS: This retrospective analysis supports the efficacy and safety of alitretinoin in clearing skin disease and preventing disease progression in CTCL as a monotherapy or in combination with standard therapies.

Comorbidities in Mycosis Fungoides and Racial Differences in Co-Existent Lymphomatoid Papulosis: A Cross-Sectional Study of 580 Patients in an Urban Tertiary Care Center.

Background: Mycosis fungoides (MF) is a cutaneous T-cell lymphoma. Previous reports have suggested MF is associated with inflammatory conditions such as psoriasis, increased cardiovascular risk factors as well as secondary neoplasms. Methods: A cross-sectional study of MF patients seen from 2013 to 2019 was performed. Comorbidities were selected based on the 2015 Medicare report highlighting the most common chronic medical illnesses in the United States. Lifetime comorbidity occurrence in patients with MF were compared with that in patients with atopic dermatitis, psoriasis and patients without MF. Additional analyses were performed with patients sub-stratified by race. Results: Compared to control groups, MF was strongly associated with lymphomatoid papulosis and Hodgkin's disease, but not significantly associated with lung, breast or colon cancer. Interestingly, the association with lymphomatoid papulosis was observed in Caucasians (CI 1062-4338; p < 0.001) and not African Americans (p = 0.9). Patients with MF had a greater association with congestive heart failure, hypertension (HT) and hyperlipidemia (HLD) compared with the general population. However, they were significantly less likely to have HT and HLD when compared with psoriasis patients (HT CI: 0.6-0.9; p < 0.001, and HLD CI: 0.05-0.07; p < 0.001). MF patients were also significantly less likely to have concomitant vitamin D deficiency compared with atopic dermatitis (AD) and psoriasis (p < 0.001). Conclusions: Our results suggest that the association of MF with lymphomatoid papulosis varies by race. Compared to the general population, hypertension and hyperlipidemia were positively associated with MF, however, these were significantly less likely on comparison to psoriasis. Unlike previously described, vitamin D deficiency was found to be significantly less in patients with MF.

Analysis of CTCL cell lines reveals important differences between mycosis fungoides/Sézary syndrome vs. HTLV-1+ leukemic cell lines.

HTLV-1 is estimated to affect ~20 million people worldwide and in ~5% of carriers it produces Adult T-Cell Leukemia/Lymphoma (ATLL), which can often masquerade and present with classic erythematous pruritic patches and plaques that are typically seen in Mycosis Fungoides (MF) and Sézary Syndrome (SS), the most recognized variants of Cutaneous T-Cell Lymphomas (CTCL). For many years the role of HTLV-1 in the pathogenesis of MF/SS has been hotly debated. In this study we analyzed CTCL vs. HTLV-1+ leukemic cells. We performed G-banding/spectral karyotyping, extensive gene expression analysis, TP53 sequencing in the 11 patient-derived HTLV-1+ (MJ and Hut102) vs. HTLV-1- (Myla, Mac2a, PB2B, HH, H9, Hut78, SZ4, Sez4 and SeAx) CTCL cell lines. We further tested drug sensitivities to commonly used CTCL therapies and studied the ability of these cells to produce subcutaneous xenograft tumors in NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ mice. Our work demonstrates that unlike classic advanced MF/SS cells that acquire many ongoing balanced and unbalanced chromosomal translocations, HTLV-1+ CTCL leukemia cells are diploid and exhibit only a minimal number of non-specific chromosomal alterations. Our results indicate that HTLV-1 virus is likely not involved in the pathogenesis of classic MF/SS since it drives a very different pathway of lymphomagenesis based on our findings in these cells. This study also provides for the first time a comprehensive characterization of the CTCL cells with respect to gene expression profiling, TP53 mutation status, ability to produce tumors in mice and response to commonly used therapies.

Detection of in vivo enzyme activity with CatalyCEST MRI.

PURPOSE: CatalyCEST MRI compares the detection of an enzyme-responsive chemical exchange saturation transfer (CEST) agent with the detection of an unresponsive "control" CEST agent that accounts for other conditions that influence CEST. The purpose of this study was to investigate the feasibility of in vivo catalyCEST MRI. METHODS: CEST agents that were responsive and unresponsive to the activity of urokinase plasminogen activator were shown to have negligible interaction with each other. A CEST-fast imaging with steady state precession (FISP) MRI protocol was used to acquire MR CEST spectroscopic images with a Capan-2 pancreatic tumor model after intravenous injection of the CEST agents. A function of (super)-Lorentzian line shapes was fit to CEST spectra of a region-of-interest that represented the tumor. RESULTS: The CEST effects from each agent showed the same initial uptake into tumor tissues, indicating that both agents had the same pharmacokinetic transport rates. Starting 5 min after injection, CEST from the enzyme-responsive agent disappeared more quickly than CEST from the unresponsive agent, indicating that the enzyme responsive agent was being catalyzed by urokinase plasminogen activator, while both agents also experienced net pharmacokinetic washout from the tumor. CONCLUSION: CatalyCEST MRI demonstrates that dynamic tracking of enzyme-responsive and unresponsive CEST agents during the same in vivo MRI study is feasible.

Extraction chromatographic methods in the sample preparation sequence for thermal ionization mass spectrometric analysis of plutonium isotopes.

A sample preparation sequence for actinide isotopic analysis by thermal ionization mass spectrometry (TIMS) is described that includes column-based extraction chromatography as the first separation step, followed by anion-exchange column separations. The sequence is designed to include a wet ashing step after the extraction chromatography to prevent any leached extractant or oxalic acid eluent reagents from interfering with subsequent separations, source preparation, or TIMS ionization. TEVA resin and DGA resin materials, containing extractants that consist only of C, N, O, and H atoms, were investigated for isolation of plutonium. Radiotracer level studies confirmed expected high yields from column-based separation procedures. Femtogram-level studies were carried out with TIMS detection, using multiple monoisotopic spikes applied sequentially throughout the separation sequence. Pu recoveries were 87% and 86% for TEVA and DGA resin separations, respectively. The Pu recoveries from 400 µL anion-exchange column separation sequences were 89% and 93% for trial sequences incorporating TEVA and DGA resin. Thus, a prior extraction chromatography step in the sequence did not interfere with the subsequent anion-exchange separation when a simple wet ash step was carried out in between these column separations. The average measurement efficiency for Pu, encompassing the chemical separation recoveries and the TIMS ionization efficiency, was 2.73% ± 0.77% (2σ) for the DGA resin trials and 2.67% ± 0.54% for the TEVA resin trials, compared to 3.41% and 2.37% (average 2.89%) for two control trials. These compare with an average measurement efficiency of 2.78% ± 1.70%, n = 33 from process benchmark analyses using Pu spikes processed through a sequence of oxalate precipitation, wet ash, iron hydroxide precipitation, and anion-exchange column separations. We conclude that extraction chromatography can be a viable separation procedure as part of a multistep sequence for TIMS sample preparation.

Ultra-low level plutonium isotopes in the NIST SRM 4355A (Peruvian Soil-1).

For more than 20 years, countries and their agencies which monitor radionuclide discharge sites and storage facilities have relied on the National Institute of Standards and Technology (NIST) Standard Reference Material (SRM) 4355 Peruvian Soil. Its low fallout contamination makes it an ideal soil blank for measurements associated with terrestrial-pathway-to-man studies. Presently, SRM 4355 is out of stock, and a new batch of the Peruvian soil is currently under development as future NIST SRM 4355A. Both environmental radioanalytical laboratories and mass spectrometry communities will benefit from the use of this SRM. The former must assess their laboratory procedural contamination and measurement detection limits by measurement of blank sample material. The Peruvian Soil is so low in anthropogenic radionuclide content that it is a suitable virtual blank. On the other hand, mass spectrometric laboratories have high sensitivity instruments that are capable of quantitative isotopic measurements at low plutonium levels in the SRM 4355 (first Peruvian Soil SRM) that provided the mass spectrometric community with the calibration, quality control, and testing material needed for methods development and legal defensibility. The quantification of the ultra-low plutonium content in the SRM 4355A was a considerable challenge for the mass spectrometric laboratories. Careful blank control and correction, isobaric interferences, instrument stability, peak assessment, and detection assessment were necessary. Furthermore, a systematic statistical evaluation of the measurement results and considerable discussions with the mass spectroscopy metrologists were needed to derive the certified values and uncertainties. The one sided upper limit of the 95% tolerance with 95% confidence for the massic (239)Pu content in SRM 4355A is estimated to be 54,000 atoms/g.