Allele-Specific Reprogramming of Cancer Metabolism by the Long Non-coding RNA CCAT2.

Altered energy metabolism is a cancer hallmark as malignant cells tailor their metabolic pathways to meet their energy requirements. Glucose and glutamine are the major nutrients that fuel cellular metabolism, and the pathways utilizing these nutrients are often altered in cancer. Here, we show that the long ncRNA CCAT2, located at the 8q24 amplicon on cancer risk-associated rs6983267 SNP, regulates cancer metabolism in vitro and in vivo in an allele-specific manner by binding the Cleavage Factor I (CFIm) complex with distinct affinities for the two subunits (CFIm25 and CFIm68). The CCAT2 interaction with the CFIm complex fine-tunes the alternative splicing of Glutaminase (GLS) by selecting the poly(A) site in intron 14 of the precursor mRNA. These findings uncover a complex, allele-specific regulatory mechanism of cancer metabolism orchestrated by the two alleles of a long ncRNA.

Evolution of cisplatin resistance through coordinated metabolic reprogramming of the cellular reductive state.

BACKGROUND: Cisplatin (CDDP) is a mainstay treatment for advanced head and neck squamous cell carcinomas (HNSCC) despite a high frequency of innate and acquired resistance. We hypothesised that tumours acquire CDDP resistance through an enhanced reductive state dependent on metabolic rewiring. METHODS: To validate this model and understand how an adaptive metabolic programme might be imprinted, we performed an integrated analysis of CDDP-resistant HNSCC clones from multiple genomic backgrounds by whole-exome sequencing, RNA-seq, mass spectrometry, steady state and flux metabolomics. RESULTS: Inactivating KEAP1 mutations or reductions in KEAP1 RNA correlated with Nrf2 activation in CDDP-resistant cells, which functionally contributed to resistance. Proteomics identified elevation of downstream Nrf2 targets and the enrichment of enzymes involved in generation of biomass and reducing equivalents, metabolism of glucose, glutathione, NAD(P), and oxoacids. This was accompanied by biochemical and metabolic evidence of an enhanced reductive state dependent on coordinated glucose and glutamine catabolism, associated with reduced energy production and proliferation, despite normal mitochondrial structure and function. CONCLUSIONS: Our analysis identified coordinated metabolic changes associated with CDDP resistance that may provide new therapeutic avenues through targeting of these convergent pathways.

Cost-Effectiveness of [99mTc]Tilmanocept Relative to [99mTc]Sulfur Colloid for Sentinel Lymph Node Biopsy in Early Stage Oral Cavity Cancer.

BACKGROUND: Several studies have demonstrated varying rates of efficacy, reliability, and sensitivity of sentinel lymph node biopsy (SLNB) in identifying occult nodal disease for early stage oral cavity squamous cell carcinoma (OCSCC) depending on the radionuclide agent utilized. No head-to-head comparison of cost or clinical outcomes of SLNB when utilizing [99mTc]tilmanocept versus [99mTc]sulfur colloid has been performed. The goal of this study was to develop a decision model to compare the cost-effectiveness of [99mTc]tilmanocept versus [99mTc]sulfur colloid in early stage OCSCC. PATIENTS AND METHODS: A decision model of disease and treatment as a function of SLNB was created. Patients with a negative SLNB entered a Markov model of the natural history of OCSCC parameterized with published data to simulate five states of health and iterated over a 30-year time horizon. Treatment costs and quality-adjusted life-years (QALYs) for each health state were included. The incremental cost-effectiveness ratio (ICER) was then estimated using $100,000 per additional QALY as the threshold for determining cost-effectiveness. RESULTS: The base case cost-effectiveness analysis suggested [99mTc]tilmanocept was more effective than [99mTc]sulfur colloid by 0.12 QALYs (7.06 versus 6.94 QALYs). [99mTc]Tilmanocept was more costly, with a lifetime cost of $84,961 in comparison with $84,264 for sulfur colloid, however, the overall base case ICER was $5859 per additional QALY, well under the threshold for cost-effectiveness. Multiple one-way sensitivity analyses were performed, and demonstrated the model was robust to alternative parameter values. CONCLUSION: Our analysis showed that while [99mTc]tilmanocept is more costly upfront, these costs are worth the additional QALYs gained by the use of [99mTc]tilmanocept.

The combined profunda artery perforator-gracilis flap for immediate facial reanimation and resurfacing of the radical parotidectomy defect.

BACKGROUND: A radical parotidectomy with facial nerve sacrifice results in facial nerve paralysis as well as a volume and often cutaneous defect. Prior experience with nerve grafting and static suspension has yielded suboptimal results. The present report aims to examine the feasibility and outcomes of a combined free gracilis and profunda artery perforator (PAP) flap from a single donor site can reconstruct these extensive defects and potentially restore dynamic facial reanimation even in the setting of adjuvant radiation. PATIENTS AND METHODS: A retrospective review of 10 patients (6 males and 4 females) was performed from 2016 to 2020 that underwent a combined PAP-gracilis reconstruction of a radical parotidectomy defect. All patients (mean age: 71.3 years; range: 52-83 years) received adjuvant radiation. A chimeric PAP-gracilis flap requiring a single microvascular anastomosis was performed in three patients while the remaining patients underwent a double free flap reconstruction. RESULTS: The gracilis flap was innervated using the facial nerve stump, spinal accessory and massecteric nerve in three patients each. One patient's gracilis was innervated using the hypoglossal nerve. Three patients also underwent nerve grafting of the facial nerve. One patient was taken back to the operating room for a hematoma in the recipient site and there were not flap losses of either the PAP or gracilis flap. Two patients had delayed wound healing of the donor site that healed with conservative management. Average follow-up was 11.1 months (range: 8.1-19.5 months). Six patients were able to achieve dynamic animation while the others obtained a static reconstruction and did not have issues with drooling, eating, or speaking. CONCLUSIONS: Immediate functional muscle transfer can potentially restore dynamic facial reanimation even following radiation. Combining reconstruction using a PAP-gracilis flap addresses the soft tissue deficit and facial paralysis using a single donor site in a single operation.

Determinants of patient-reported xerostomia among long-term oropharyngeal cancer survivors.

BACKGROUND: This study was conducted to identify clinicodemographic risk factors for xerostomia among long-term oropharyngeal cancer (OPC) survivors. METHODS: This cross-sectional study included 906 disease-free, adult OPC survivors with a median survival duration at the time of survey of 6 years (range, 1-16 years); self-reported xerostomia scores were available for 877 participants. Study participants had completed curative treatment between January 2000 and December 2013 and responded to a survey administered from September 2015 to July 2016. The primary outcome variable was cancer patient-reported xerostomia measured with the MD Anderson Symptom Inventory Head and Neck Cancer Module. Clinicodemographic risk factors for moderate to severe xerostomia were identified via multivariable logistic regression. RESULTS: Moderate to severe xerostomia was reported by 343 of the respondents (39.1%). Female sex (odds ratio [OR], 1.82; 95% CI, 1.22-2.71; P = .003; Bayesian false-discovery probability [BFDP] = 0.568), high school or lower education (OR, 1.73; 95% CI, 1.19-2.52; P = .004; BFDP = 0.636), and current cigarette smoking at the time of survey (OR, 2.56; 95% CI, 1.19-5.47; P = .016; BFDP = 0.800) were risk factors for moderate to severe xerostomia, and bilateral intensity-modulated radiotherapy (IMRT) combined with proton therapy and ipsilateral IMRT were protective. CONCLUSIONS: In this large xerostomia study, modern radiotherapy was a protective factor, and continued cigarette smoking at the time of survey, female sex, and high school or lower education were identified as other contributing risk factors associated with moderate to severe xerostomia. Importantly, these findings need to be confirmed in prospective studies. These results can inform future research and targeted patient-centered interventions to monitor and manage radiation therapy-associated xerostomia and preserve quality of life among patients with OPC.

The impact of induction and/or concurrent chemoradiotherapy on acute and late patient-reported symptoms in oropharyngeal cancer: Application of a mixed-model analysis of a prospective observational cohort registry.

BACKGROUND: The goal of this study was to comprehensively investigate the association of chemotherapy with trajectories of acute symptom development and late symptom recovery in patients with oropharyngeal cancer (OPC) by comparing symptom burden between induction chemotherapy followed by concurrent chemoradiotherapy (ICRT), concurrent chemo-radiotherapy (CRT), or radiotherapy (RT) alone. METHODS: Among a registry of 717 patients with OPC, the 28-item patient-reported MD Anderson Symptom Inventory-Head and Neck Module (MDASI-HN) symptoms were collected prospectively at baseline, weekly during RT, and 1.5, 3 to 6, 12, and 18 to 24 months after RT. The effect of the treatment regimen (ICRT, CRT, and RT alone) was examined with mixed-model analyses for the acute and late period. In the CRT cohort, the chemotherapy agent relationship with symptoms was investigated. RESULTS: Chemoradiation (ICRT/CRT) compared with RT alone resulted in significantly higher acute symptom scores in the majority of MDASI-HN symptoms (ie, 21 out of 28). No late symptom differences between treatment with or without chemotherapy were observed that were not attributable to ICRT. Nausea was lower for CRT with carboplatin than for CRT with cisplatin; cetuximab was associated with particularly higher scores for acute and late skin, mucositis, and 6 other symptoms. The addition of ICRT compared with CRT or RT alone was associated with a significant increase in numbness and shortness of breath. CONCLUSION: The addition of chemotherapy to definitive RT for OPC patients was associated with significantly worse acute symptom outcomes compared with RT alone, which seems to attenuate in the late posttreatment period. Moreover, induction chemotherapy was specifically associated with worse numbness and shortness of breath during and after treatment. LAY SUMMARY: Chemotherapy is frequently used in addition to radiotherapy cancer treatment, yet the (added) effect on treatment-induced over time is not comprehensively investigated This study shows that chemotherapy adds to the symptom severity reported by patients, especially during treatment.

Development of a rational strategy for integration of lactate dehydrogenase A suppression into therapeutic algorithms for head and neck cancer.

BACKGROUND: Lactate dehydrogenase (LDH) is a critical metabolic enzyme. LDH A (LDHA) overexpression is a hallmark of aggressive malignancies and has been linked to tumour initiation, reprogramming and progression in multiple tumour types. However, successful LDHA inhibition strategies have not materialised in the translational and clinical space. We sought to develop a rational strategy for LDHA suppression in the context of solid tumour treatment. METHODS: We utilised a doxycycline-inducible short hairpin RNA (shRNA) system to generate LDHA suppression. Lactate and LDH activity levels were measured biochemically and kinetically using hyperpolarised 13C-pyruvate nuclear magnetic resonance spectroscopy. We evaluated effects of LDHA suppression on cellular proliferation and clonogenic survival, as well as on tumour growth, in orthotopic models of anaplastic thyroid carcinoma (ATC) and head and neck squamous cell carcinoma (HNSCC), alone or in combination with radiation. RESULTS: shRNA suppression of LDHA generated a time-dependent decrease in LDH activity with transient shifts in intracellular lactate levels, a decrease in carbon flux from pyruvate into lactate and compensatory shifts in metabolic flux in glycolysis and the Krebs cycle. LDHA suppression decreased cellular proliferation and temporarily stunted tumour growth in ATC and HNSCC xenografts but did not by itself result in tumour cure, owing to the maintenance of residual viable cells. Only when chronic LDHA suppression was combined with radiation was a functional cure achieved. CONCLUSIONS: Successful targeting of LDHA requires exquisite dose and temporal control without significant concomitant off-target toxicity. Combinatorial strategies with conventional radiation are feasible as long as the suppression is targeted, prolonged and non-toxic.

Self-Reported Trismus: prevalence, severity and impact on quality of life in oropharyngeal cancer survivorship: a cross-sectional survey report from a comprehensive cancer center.

OBJECTIVE: The purpose of this study was to estimate prevalence/severity of self-reported trismus, determine association with quality of life (QOL), and examine clinical risk factors in a large population of patients treated for oropharyngeal cancer. MATERIALS AND METHODS: A cross-sectional survivorship survey was conducted among patients who completed definitive treatment for oropharyngeal carcinoma, disease-free ≥ 1-year post-treatment (median survival, 7 years among 892 survivors). Associations between trismus and QOL were also analyzed using MDASI-HN, EQ-5D, and MDADI. Dietary and feeding tube status were also correlated to trismus status. RESULTS: Trismus was self-reported in 31%. Severity of trismus positively correlated (r = 0.29) with higher mean interference scores reflecting a moderate association with quality of life (p < 0.0001). There was a negative correlation for MDADI composite scores (r = - 0.33) indicating increased perceived dysphagia related to trismus severity (p < 0.0001). EQ-5D VAS scores were also negatively correlated with trismus severity (r = - 0.26, p < 0.0001). Larger T-stage (p ≤ 0.001), larger nodal stage (p = 0.03), tumor sub-site (p = 0.05), and concurrent chemoradiation (p = 0.01) associated with increased prevalence of trismus. Diet negatively correlated (r = - 0.27) with trismus severity (p = < 0.0001), and survivors with severe trismus were also more likely to be feeding tube-dependent. CONCLUSION: Severity of trismus appears to negatively impact quality of life and associate with various adverse functional outcomes in long-term oropharyngeal cancer survivorship. Trismus remains associated with advanced disease stages, tumor sub-site (tonsil), and addition of chemotherapy. Further investigation is merited for the dose-effect relationship to the muscles of mastication.

Recommendations for head and neck surgical oncology practice in a setting of acute severe resource constraint during the COVID-19 pandemic: an international consensus.

The speed and scale of the global COVID-19 pandemic has resulted in unprecedented pressures on health services worldwide, requiring new methods of service delivery during the health crisis. In the setting of severe resource constraint and high risk of infection to patients and clinicians, there is an urgent need to identify consensus statements on head and neck surgical oncology practice. We completed a modified Delphi consensus process of three rounds with 40 international experts in head and neck cancer surgical, radiation, and medical oncology, representing 35 international professional societies and national clinical trial groups. Endorsed by 39 societies and professional bodies, these consensus practice recommendations aim to decrease inconsistency of practice, reduce uncertainty in care, and provide reassurance for clinicians worldwide for head and neck surgical oncology in the context of the COVID-19 pandemic and in the setting of acute severe resource constraint and high risk of infection to patients and staff.

Cancer Surgery Scheduling During and After the COVID-19 First Wave: The MD Anderson Cancer Center Experience.

OBJECTIVE: To summarize the multi-specialty strategy and initial guidelines of a Case Review Committee in triaging oncologic surgery procedures in a large Comprehensive Cancer Center and to outline current steps moving forward after the initial wave. SUMMARY OF BACKGROUND DATA: The impetus for strategic rescheduling of operations is multifactorial and includes our societal responsibility to minimize COVID-19 exposure risk and propagation among patients, the healthcare workforce, and our community at large. Strategic rescheduling is also driven by the need to preserve limited resources. As many states have already or are considering to re-open and relax stay-at-home orders, there remains a continued need for careful surgical scheduling because we must face the reality that we will need to co-exist with COVID-19 for months, if not years. METHODS: The quality officers, chairs, and leadership of the 9 surgical departments in our Division of Surgery provide specialty-specific approaches to appropriately triage patients. RESULTS: We present the strategic approach for surgical rescheduling during and immediately after the COVID-19 first wave for the 9 departments in the Division of Surgery at The University of Texas MD Anderson Cancer Center in Houston, Texas. CONCLUSIONS: Cancer surgeons should continue to use their oncologic knowledge to determine the window of opportunity for each surgical procedure, based on tumor biology, preoperative treatment sequencing, and response to systemic therapy, to safely guide patients through this cautious recovery phase.

Tobacco exposure as a major modifier of oncologic outcomes in human papillomavirus (HPV) associated oropharyngeal squamous cell carcinoma.

BACKGROUND: The incidence of oropharyngeal squamous cell carcinoma (OPSCC) in the US is rapidly increasing, driven largely by the epidemic of human papillomavirus (HPV)-mediated OPSCC. Although survival for patients with HPV mediated OPSCC (HPV+ OPSCC) is generally better than that of patients with non-virally mediated OPSCC, this effect is not uniform. We hypothesized that tobacco exposure remains a critical modifier of survival for HPV+ OPSCC patients. METHODS: We conducted a retrospective analysis of 611 OPSCC patients with concordant p16 and HPV testing treated at a single institute (2002-2013). Survival analysis was performed using Kaplan-Meier analysis and Cox regression. Recursive partitioning analysis (RPA) was used to define tobacco exposure associated with survival (p < 0.05). RESULTS: Tobacco exposure impacted overall survival (OS) for HPV+ patients on univariate and multivariate analysis (p = 0.002, p = 0.003 respectively). RPA identified 30 pack-years (PY) as a threshold at which survival became significantly worse in HPV+ patients. OS and disease-free survival (DFS) for HPV+ > 30 PY patients didn't differ significantly from HPV- patients (p = 0.72, p = 0.27, respectively). HPV+ > 30 PY patients had substantially lower 5-year OS when compared to their ≤30 PYs counterparts: 78.4% vs 91.6%; p = 0.03, 76% vs 88.3%; p = 0.07, and 52.3% vs 74%; p = 0.05, for stages I, II, and III (AJCC 8th Edition Manual), respectively. CONCLUSIONS: Tobacco exposure can eliminate the survival benefit associated with HPV+ status in OPSCC patients. Until this effect can be clearly quantified using prospective datasets, de-escalation of treatment for HPV + OPSCC smokers should be avoided.

Development and application of an elastic net logistic regression model to investigate the impact of cardiac substructure dose on radiation-induced pericardial effusion in patients with NSCLC.

BACKGROUND: Typically, cardiac substructures are neither delineated nor analyzed during radiation treatment planning. Therefore, we developed a novel machine learning model to evaluate the impact of cardiac substructure dose for predicting radiation-induced pericardial effusion (PCE). MATERIALS AND METHODS: One-hundred and forty-one stage III NSCLC patients, who received radiation therapy in a prospective clinical trial, were included in this analysis. The impact of dose-volume histogram (DVH) metrics (mean and max dose, V5Gy[%]-V70Gy[%]) for the whole heart, left and right atrium, and left and right ventricle, on pericardial effusion toxicity (≥grade 2, CTCAE v4.0 grading) were examined. Elastic net logistic regression, using repeat cross-validation (n = 100 iterations, 75%/25% training/test set data split), was conducted with cardiac-based DVH metrics as covariates. The following model types were constructed and analyzed: (i) standard model type, which only included whole-heart DVH metrics; and (ii) a model type trained with both whole-heart and substructure DVH metrics. Model performance was analyzed on the test set using area under the curve (AUC), accuracy, calibration slope and calibration intercept. A final fitted model, based on the optimal model type, was developed from the entire study population for future comparisons. RESULTS: Grade 2 PCE incidence was 49.6% (n = 70). Models using whole heart and substructure dose had the highest performance (median values: AUC = 0.820; calibration slope/intercept = 1.356/-0.235; accuracy = 0.743) and outperformed the standard whole-heart only model type (median values: AUC = 0.799; calibration slope/intercept = 2.456/-0.729; accuracy = 0.713). The final fitted elastic net model showed high performance in predicting PCE (median values: AUC = 0.879; calibration slope/intercept = 1.352/-0.174; accuracy = 0.801). CONCLUSIONS: We developed and evaluated elastic net regression toxicity models of radiation-induced PCE. We found the model type that included cardiac substructure dose had superior predictive performance. A final toxicity model that included cardiac substructure dose metrics was developed and reported for comparison with external datasets.

Sebaceous carcinoma: evidence-based clinical practice guidelines.

Sebaceous carcinoma usually occurs in adults older than 60 years, on the eyelid, head and neck, and trunk. In this Review, we present clinical care recommendations for sebaceous carcinoma, which were developed as a result of an expert panel evaluation of the findings of a systematic review. Key conclusions were drawn and recommendations made for diagnosis, first-line treatment, radiotherapy, and post-treatment care. For diagnosis, we concluded that deep biopsy is often required; furthermore, differential diagnoses that mimic the condition can be excluded with special histological stains. For treatment, the recommended first-line therapy is surgical removal, followed by margin assessment of the peripheral and deep tissue edges; conjunctival mapping biopsies can facilitate surgical planning. Radiotherapy can be considered for cases with nerve or lymph node involvement, and as the primary treatment in patients who are ineligible for surgery. Post-treatment clinical examination should occur every 6 months for at least 3 years. No specific systemic therapies for advanced disease can be recommended, but targeted therapies and immunotherapies are being developed.

Single-item discrimination of quality-of-life-altering dysphagia among 714 long-term oropharyngeal cancer survivors: Comparison of patient-reported outcome measures of swallowing.

BACKGROUND: Two patient-reported outcomes (PROs) of swallowing and their correlation to quality of life (QOL) were compared in long-term survivors of oropharyngeal cancer (OPC). METHODS: Scores on the single dysphagia item from the 28-item, multisymptom MD Anderson Symptom Inventory-Head and Neck (MDASI-HN-S) were compared with scores on the dysphagia-specific composite MD Anderson Dysphagia Inventory (MDADI) and the EuroQol visual analog scale (EQ-VAS) in 714 patients who had received definitive radiotherapy ≥12 months before the survey. An MDASI-HN-S score ≥6 and an MDADI composite score <60 were considered representative of moderate/severe swallowing dysfunction. RESULTS: Moderate/severe dysphagia was reported by 17% and 16% of respondents on the MDASI-HN-S and the composite MDADI, respectively. Both swallow PROs were predictive of QOL, and the MDASI-HN-S model was slightly more parsimonious for the discrimination of EQ-VAS scores compared with MDADI scores (Bayesian information criteria, 6062 vs 6076, respectively). An MDASI-HN-S cutoff score of ≥6 correlated best with a declining EQ-VAS score (P < .0001) and was associated with increased radiotherapy dose to several normal swallowing structures. CONCLUSIONS: In this cohort, the single-item MDASI-HN-S performed favorably for the discrimination of QOL compared with the multi-item MDADI. A time-efficient model for PRO measurement of swallowing is proposed in which the MDADI may be reserved for patients who score ≥6 on the MDASI-HN-S.

Usefulness of surveillance imaging in patients with head and neck cancer who are treated with definitive radiotherapy.

BACKGROUND: The current study was performed to assess the efficacy of surveillance imaging in patients with head and neck cancer (HNC) who are treated definitively with radiotherapy. METHODS: Eligible patients included those with a demonstrable disease-free interval (≥1 follow-up imaging procedure without evidence of disease and a subsequent visit/imaging procedure) who underwent treatment of HNC from 2000 through 2010. RESULTS: A total of 1508 patients were included. The median overall survival was 99 months, with a median imaging follow-up period of 59 months. Of the 1508 patients, 190 patients (12.6%) experienced disease recurrence (107 patients had locoregional and 83 had distant disease recurrence). A total of 119 patients (62.6%) in the group with disease recurrence were symptomatic and/or had an adverse clinical finding associated with the recurrence. Approximately 80% of patients with locoregional disease recurrences presented with a clinical finding, whereas 60% of distant disease recurrences were detected by imaging in asymptomatic patients. Despite the earlier detection of disease recurrence via imaging, those patients in the group of patients with clinically detected disease recurrence were significantly more likely to undergo salvage therapy compared with those whose recurrence was detected on imaging (odds ratio, 0.35). There was no difference in overall survival noted between those patients with disease recurrences that were detected clinically or with imaging alone. Approximately 70% of disease recurrences occurred within the first 2 years. In those patients who developed disease recurrence after 2 years, the median time to recurrence was 51 months. After 2 years, the average number of imaging procedures per patient for the detection of a salvageable recurrence for the imaging-detected group was 1539. CONCLUSIONS: Surveillance imaging in asymptomatic patients with HNC who are treated definitively with radiotherapy without clinically suspicious findings beyond 2 years has a low yield and a high cost. Physicians ordering these studies must use judicious consideration and discretion.

Contemporary Approach to Locally Advanced Oral Cavity Squamous Cell Carcinoma.

PURPOSE OF REVIEW: Surgical management of locally advanced oral cavity squamous cell carcinomas (OCSCC) has long been recognized as a primary treatment modality. Technological advances have led to significant improvements in our surgical approach, from improvement in the visualization of tumors to more efficient and precise reconstruction. Here, we review the latest technological advances in surgical extirpation and reconstruction of locally advanced OCSCCs. RECENT FINDINGS: The focus of technological innovation in surgical extirpation has been on improving visualization, with the use of intraoperative ultrasound for margin delineation, intraoperative navigation, narrow-band imaging, and the use of fluorescence. Though early, these are promising steps to ensuring complete resection of the cancer. Advances in reconstruction have been centered on the incorporation of computer assisted design, manufacturing, and virtual surgical planning, allowing for more complex three-dimensional defects to be expeditiously reconstructed. As these technologies are still under development, their impact on oncologic outcomes are not yet robustly defined; however, as technology continues to advance and become more widely available, new technologies will undoubtedly become integrated into enhancing surgical precision and planning.

Influence of parameter accuracy on pharmacokinetic analysis of hyperpolarized pyruvate.

PURPOSE: To explore the effects of noise and error on kinetic analyses of tumor metabolism using hyperpolarized [1-13 C] pyruvate. METHODS: Numerical simulations were performed to systematically investigate the effects of noise, the number of unknowns, and error in kinetic parameter estimates on kinetic analysis of the apparent rate of chemical conversion from hyperpolarized pyruvate to lactate (kPL ). A pharmacokinetic model with two physical and two chemical pools of hyperpolarized spins was used to generate and analyze the synthetic data. RESULTS: The reproducibility of kPL estimates worsened quickly when peak signal-to-noise ratio for hyperpolarized pyruvate was below approximately 20. The accuracy of kPL estimates was most sensitive to errors in high excitation angles, the vascular blood volume fraction (vb ), and the rate of pyruvate extravasation (kve ), and was least sensitive to errors in the T1 of pyruvate. When vb and/or kve were fit as additional unknowns, the accuracy of kPL estimates suffered, and when the vascular input function of pyruvate was also fit, the reproducibility of kPL estimates worsened. CONCLUSIONS: The accuracy and precision of kPL estimates improve substantially for peak signal-to-noise ratio above approximately 20. Accurate estimates of perfusion parameters (combinations of vb , kve , and the pyruvate vascular input function) and transmit calibration at high excitation angles have the greatest effect on the accuracy of kinetic analyses. Magn Reson Med 79:3239-3248, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Predicting treatment Response based on Dual assessment of magnetic resonance Imaging kinetics and Circulating Tumor cells in patients with Head and Neck cancer (PREDICT-HN): matching 'liquid biopsy' and quantitative tumor modeling.

BACKGROUND: Magnetic resonance imaging (MRI) has improved capacity to visualize tumor and soft tissue involvement in head and neck cancers. Using advanced MRI, we can interrogate cell density using diffusion weighted imaging, a quantitative imaging that can be used during radiotherapy, when diffuse inflammatory reaction precludes PET imaging, and can assist with target delineation as well. Correlation of circulating tumor cells (CTCs) measurements with 3D quantitative tumor characterization could potentially allow selective, patient-specific response-adapted escalation or de-escalation of local therapy, and improve the therapeutic ratio, curing the greatest number of patients with the least toxicity. METHODS: The proposed study is designed as a prospective observational study and will collect pretreatment CT, MRI and PET/CT images, weekly serial MR imaging during RT and post treatment CT, MRI and PET/CT images. In addition, blood sample will be collected for biomarker analysis at those time intervals. CTC assessments will be performed on the CellSave tube using the FDA-approved CellSearch® Circulating Tumor Cell Kit (Janssen Diagnostics), and plasma from the EDTA blood samples will be collected, labeled with a de-identifying number, and stored at - 80 °C for future analyses. DISCUSSION: The primary objective of the study is to evaluate the prognostic value and correlation of weekly tumor response kinetics (gross tumor volume and MR signal changes) and circulating tumor cells of mucosal head and neck cancers during radiation therapy using MRI in predicting treatment response and clinical outcomes. This study will provide landmark information as to the utility of CTCs ('liquid biopsy) and tumor-specific functional quantitative imaging changes during treatment to guide personalization of treatment for future patients. Combining the biological information from CTCs and the structural information from MRI may provide more information than either modality alone. In addition, this study could potentially allow us to determine the optimal time to obtain MR imaging and/ or CTCs during radiotherapy to assess tumor response and provide guidance for patient selection and stratification for future dose escalation or de-escalation strategies. TRIAL REGISTRATION: Clinicaltrials.gov ( NCT03491176 ). Date of registration: 9th April 2018. (retrospectively registered). Date of enrolment of the first participant: 30th May 2017.