The knowns and unknowns of cardiac autoimmunity in viral myocarditis.

Myocarditis can result from various infectious and non-infectious causes that can lead to dilated cardiomyopathy (DCM) and heart failure. Among the infectious causes, viruses are commonly suspected. But the challenge is our inability to demonstrate infectious viral particles during clinical presentations, partly because by that point, the viruses would have damaged the tissues and be cleared by the immune system. Therefore, viral signatures such as viral nucleic acids and virus-reactive antibodies may be the only readouts pointing to viruses as potential primary triggers of DCM. Thus, it becomes hard to explain persistent inflammatory infiltrates that might occur in individuals affected with chronic myocarditis/DCM manifesting myocardial dysfunctions. In these circumstances, autoimmunity is suspected, and antibodies to various autoantigens have been demonstrated, suggesting that immune therapies to suppress the autoimmune responses may be necessary. From this perspective, we endeavoured to determine whether or not the known viral causes are associated with development of autoimmune responses to cardiac antigens that include both cardiotropic and non-cardiotropic viruses. If so, what their nature and significance are in developing chronic myocarditis resulting from viruses as primary triggers.

Adaptive frequency-domain filtering for neural signal preprocessing.

Electrical interference from various sources is a common issue for experimental extracellular electrophysiology recordings collected using multi-electrode array neural recording systems. This interference deteriorates the signal-to-noise ratio (SNR) of the raw electrophysiology signals and hampers the accuracy of data post-processing using techniques such as spike-sorting. Traditional signal processing methods to digitally remove electrical interference during post-processing include bandpass filtering to limit the signal to the relevant spectral range of the biological data, e.g., the spikes band (300 Hz - 7 kHz), targeted notch filtering to remove power line interference from standard alternating current mains electricity and common reference removal to minimize noise common to all electrodes. These methods require a priori knowledge of the frequency of the interfering signal source to address the unique electromagnetic interference environment of each experimental setup. We discuss an adaptive method for automatically removing narrow-band electrical interference through a spectral peak detection and removal (SPDR) step that can be applied during post-processing of the recorded data, based on the intuition that tall, narrowband signals localized in the signal spectrum correspond to interference, rather than the activity of neurons. A spectral peak prominence (SPP) threshold is used to detect these peaks in the frequency domain, which will then be removed via notch filtering. We applied this method to simulated waveforms and also experimental electrophysiology data collected from cerebral organoids to demonstrate its effectiveness for removing unwanted interference without significantly distorting the neural signals. We discuss that proper selection of the SPP threshold is required to avoid over-filtering, which can result in distortion of the electrophysiology data. We also compare the firing-rate activity in the filtered electrophysiology with fluorescence calcium imaging, a secondary cellular activity marker, to quantify signal distortion and provide bounds on SNR-based optimization of the SPP threshold. The adaptive filtering technique demonstrated in this paper is a powerful method that can automatically detect and remove interband interference in recorded neural signals, potentially enabling data collection in more naturalistic settings where external interference signals are difficult to eliminate.

2D optical confinement in an etchless stratified trench waveguide.

We demonstrate novel trapezoidal and rectangular stratified trench optical waveguide designs that feature low-loss two-dimensional confinement of guided optical modes that can be realized in continuous polymer thin film layers formed in a trench mold. The design is based on geometrical bends in a thin film core to enable two-dimensional confinement of light in the transverse plane, without any variation in the core thickness. Incidentally, the waveguide design would completely obviate the need for etching the waveguide core, avoiding the scattering loss due to the etched sidewall roughness. This new design exhibits an intrinsic leakage loss due to coupling of light out of the trench, which can be minimized by choosing an appropriate waveguide geometry. Finite-difference eigenmode simulation demonstrates a low intrinsic leakage loss of less than 0.15 dB/cm. We discuss the principle of operation of these stratified trench waveguides and present the design and numerical simulations of a specific realization of this waveguide geometry. The design considerations and tradeoffs in propagation loss and confinement compared with traditional ridge waveguides are discussed.

IL-10 as a Th2 Cytokine: Differences Between Mice and Humans.

The discovery of IL-10 more than 30 years ago marked the beginning of our understanding of how cytokines regulate immune responses, based on cross-regulation between Th1 and Th2 cytokines. Although multiple cell types were shown to produce IL-10, its identity as a Th2 cytokine remained strong because it was rigidly associated with Th2 clones in mice, whereas both Th1 and Th2 clones could secrete IL-10 in humans. However, as new Th1/Th2 cell functionalities emerged, anti-inflammatory action of IL-10 gained more attention than its inhibitory effect on Th1 cells, which may occur as an indirect consequence of suppression of APCs. This notion is also supported by the discovery of regulatory T cells, whose suppressor functions involve the mediation of IL-10, among other molecules. From this perspective, we discuss the functionalities of IL-10 by highlighting important differences between mice and humans with an emphasis on the Th1 and Th2 paradigm.

Correction: Paper spray mass spectrometry utilizing Teslin® substrate for rapid detection of lipid metabolite changes during COVID-19 infection.

Correction for 'Paper spray mass spectrometry utilizing Teslin® substrate for rapid detection of lipid metabolite changes during COVID-19 infection' by Imesha W. De Silva et al., Analyst, 2020, 145, 5725-5732, DOI: 10.1039/D0AN01074J.

Retinoic acid-induced autoantigen-specific type 1 regulatory T cells suppress autoimmunity.

Regulatory T (Treg) cells help to maintain tolerance and prevent the development of autoimmune diseases. Retinoic acid (RA) can promote peripheral conversion of naïve T cells into Foxp3+ Treg cells. Here, we show that RA can act as an adjuvant to induce antigen-specific type 1 Treg (Tr1) cells, which is augmented by co-administration of IL-2. Immunization of mice with the model antigen KLH in the presence of RA and IL-2 induces T cells that secrete IL-10, but not IL-17 or IFN-γ, and express LAG-3, CD49b and PD-1 but not Foxp3, a phenotype typical of Tr1 cells. Furthermore, immunization of mice with the autoantigen MOG in the presence of RA and IL-2 induces Tr1 cells, which suppress pathogenic Th1 and Th17 cells that mediate the development of experimental autoimmune encephalomyelitis (EAE), an autoimmune disease of the CNS. Furthermore, immunization with a surrogate autoantigen, RA and IL-2 prevents development of spontaneous autoimmune uveitis. Our findings demonstrate that the induction of autoantigen-specific Tr1 cells can prevent the development of autoimmunity.

An overview of the immune mechanisms of viral myocarditis.

Viral myocarditis has been identified as a major cause of dilated cardiomyopathy (DCM) that can lead to heart failure. Historically, Coxsackieviruses and adenoviruses have been commonly suspected in myocarditis/DCM patients in North America and Europe. However, this notion is changing as other viruses such as Parvovirus B19 and human herpesvirus-6 are increasingly reported as causes of myocarditis in the United States, with the most recent example being the severe acute respiratory syndrome coronavirus 2, causing the Coronavirus Disease-19. The mouse model of Coxsackievirus B3 (CVB3)-induced myocarditis, which may involve mediation of autoimmunity, is routinely used in the study of immune pathogenesis of viral infections as triggers of DCM. In this review, we discuss the immune mechanisms underlying the development of viral myocarditis with an emphasis on autoimmunity in the development of post-infectious myocarditis induced with CVB3.

Proton Therapy for HPV-Associated Oropharyngeal Cancers of the Head and Neck: a De-Intensification Strategy.

OPINION STATEMENT: The rise in the incidence of human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPC), the relatively young age at which it is diagnosed, and its favorable prognosis necessitate the use of treatment techniques that reduce the likelihood of side effects during and after curative treatment. Intensity-modulated proton therapy (IMPT) is a form of radiotherapy that de-intensifies treatment through dose de-escalation to normal tissues without compromising dose to the primary tumor and involved, regional lymph nodes. Preclinical studies have demonstrated that HPV-positive squamous cell carcinoma is more sensitive to proton radiation than is HPV-negative squamous cell carcinoma. Retrospective studies comparing intensity-modulated photon (X-ray) radiotherapy to IMPT for OPC suggest comparable rates of disease control and lower rates of pain, xerostomia, dysphagia, dysgeusia, gastrostomy tube dependence, and osteoradionecrosis with IMPT-all of which meaningfully affect the quality of life of patients treated for HPV-associated OPC. Two phase III trials currently underway-the "Randomized Trial of IMPT versus IMRT for the Treatment of Oropharyngeal Cancer of the Head and Neck" and the "TOxicity Reduction using Proton bEam therapy for Oropharyngeal cancer (TORPEdO)" trial-are expected to provide prospective, level I evidence regarding the effectiveness of IMPT for such patients.

Defining the dose-volume criteria for laryngeal sparing in locally advanced oropharyngeal cancer utilizing split-field IMRT, whole-field IMRT and VMAT.

PURPOSE: To determine the optimal dose-volume constraint for laryngeal sparing using three commonly employed intensity modulated radiation therapy (IMRT) approaches in patients with oropharyngeal cancer treated to the bilateral neck. MATERIALS AND METHODS: Thirty patients with stage II-IVA oropharynx cancers received definitive radiotherapy with split-field IMRT (SF-IMRT) to the bilateral neck between 2008 and 2013. Each case was re-planned using whole-field IMRT (WF-IMRT) and volumetric modulated arc therapy (VMAT) and plan quality metrics and dose to laryngeal structures was evaluated. Two larynx volumes were defined and compared on the current study: the Radiation Therapy Oncology Group (RTOG) larynx as defined per the RTOG 1016 protocol and the MDACC larynx defined as the components of the larynx bounded by the superior and inferior extent of the thyroid cartilage. RESULTS: Target coverage, conformity, and heterogeneity indices were similar in all techniques. The RTOG larynx mean dose was lower with WF-IMRT than SF-IMRT (22.1 vs 25.8 Gy; P < 0.01). The MDACC larynx mean dose was 17.5 Gy ± 5.4 Gy with no differences between the 3 techniques. WF-IMRT and VMAT plans were associated with lower mean doses to the supraglottic larynx (42.1 vs 41.2 vs 54.8 Gy; P < 0.01) and esophagus (18.1 vs 18.2 vs 36 Gy; P < 0.01). CONCLUSIONS: Modern whole field techniques can provide effective laryngeal sparing in patients receiving radiotherapy to the bilateral neck for advanced oropharyngeal cancers. SUMMARY: We evaluated laryngeal dose in patients with locally advanced oropharyngeal cancer treated to the bilateral neck using split-field IMRT (SF-IMRT), whole-field IMRT (WF-IMRT) and volumetric arc therapy (VMAT). All three techniques provided good sparing of laryngeal structures and were able to achieve a mean larynx dose < 33 Gy. There were no significant differences in dose to target structures or non-laryngeal organs at risk among techniques.

Reclassifying patients with early-stage Hodgkin lymphoma based on functional radiographic markers at presentation.

The presence of bulky disease in Hodgkin lymphoma (HL), traditionally defined with a 1-dimensional measurement, can change a patient's risk grouping and thus the treatment approach. We hypothesized that 3-dimensional measurements of disease burden obtained from baseline 18F-fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) scans, such as metabolic tumor volume (MTV) and total lesion glycolysis (TLG), would more accurately risk-stratify patients. To test this hypothesis, we reviewed pretreatment PET-CT scans of patients with stage I-II HL treated at our institution between 2003 and 2013. Disease was delineated on prechemotherapy PET-CT scans by 2 methods: (1) manual contouring and (2) subthresholding of these contours to give the tumor volume with standardized uptake value ≥2.5. MTV and TLG were extracted from the threshold volumes (MTVt, TLGt) and from the manually contoured soft-tissue volumes. At a median follow-up of 4.96 years for the 267 patients evaluated, 27 patients were diagnosed with relapsed or refractory disease and 12 died. Both MTVt and TLGt were highly correlated with freedom from progression and were dichotomized with 80th percentile cutoff values of 268 and 1703, respectively. Consideration of MTV and TLG enabled restratification of early unfavorable HL patients as having low- and high-risk disease. We conclude that MTV and TLG provide a potential measure of tumor burden to aid in risk stratification of early unfavorable HL patients.

To Maintain Formulation Composition Similarity of Coated Tablets of Different Strengths: Should Coating be Based on Core Tablet Weight or Surface Area?

PURPOSE: As per the Japanese or SUPAC guidance to maintain formulation composition similarity across tablet strengths, the coating should be applied based on the core tablet surface area or weight, respectively. These two coating approaches were compared by evaluating protective effects of coating on the light stability of three model compounds. METHODS: Core tablets of three light sensitive drugs, nifedipine, rosuvastatin calcium, and montelukast sodium were coated either with PVA-based Opadry® II white or Opadry® II beige. The coated tablets were exposed to light up to three ICH cycles. RESULTS: For Opadry® II white, the surface area based coating provided consistent light protection across tablet strengths when the coating amount was more than 0.1 mg/mm2 compared to that based on core tablet weights. For Opadry® II beige, both approaches gave comparable and better light protection due to presence of iron oxides. The light protection by Opadry® II white could be because of physical barrier of coating, which was uniform across the strengths when it was based on core tablet surface area. CONCLUSION: For a routine tablet formulation development with Opadry color coating, it does not matter whether the coating is applied based on the core tablet surface area or weight.

Paper spray mass spectrometry utilizing Teslin® substrate for rapid detection of lipid metabolite changes during COVID-19 infection.

The SARS-CoV-2 virus is known as the causal agent for the current COVID-19 global pandemic. The majority of COVID-19 patients develop acute respiratory distress syndrome (ARDS), while some experience a cytokine storm effect, which is considered as one of the leading causes of patient mortality. Lipids are known to be involved in the various stages of the lifecycle of a virus functioning as receptors or co-receptors that controls viral propagation inside the host cell. Therefore, lipid-related metabolomics aims to provide insight into the immune response of the novel coronavirus. Our study has focused on determination of the potential metabolomic biomarkers utilizing a Teslin® Substrate in paper spray mass spectrometry (PS-MS) for the development of a rapid detection test within 60 seconds of analysis time. In this study, results were correlated with PCR tests to reflect that the systemic responses of the cells were affected by the COVID-19 virus.

Epitope Mapping of SERCA2a Identifies an Antigenic Determinant That Induces Mainly Atrial Myocarditis in A/J Mice.

Sarcoplasmic/endoplasmic reticulum Ca2+ adenosine triphosphatase (SERCA)2a, a critical regulator of calcium homeostasis, is known to be decreased in heart failure. Patients with myocarditis or dilated cardiomyopathy develop autoantibodies to SERCA2a suggesting that they may have pathogenetic significance. In this report, we describe epitope mapping analysis of SERCA2a in A/J mice that leads us to make five observations: 1) SERCA2a contains multiple T cell epitopes that induce varying degrees of myocarditis. One epitope, SERCA2a 971-990, induces widespread atrial inflammation without affecting noncardiac tissues; the cardiac abnormalities could be noninvasively captured by echocardiography, electrocardiography, and magnetic resonance microscopy imaging. 2) SERCA2a 971-990-induced disease was associated with the induction of CD4 T cell responses and the epitope preferentially binds MHC class II/IAk rather than IEk By creating IAk/and IEk/SERCA2a 971-990 dextramers, the T cell responses were determined by flow cytometry to be Ag specific. 3) SERCA2a 971-990-sensitized T cells produce both Th1 and Th17 cytokines. 4) Animals immunized with SERCA2a 971-990 showed Ag-specific Abs with enhanced production of IgG2a and IgG2b isotypes, suggesting that SERCA2a 971-990 can potentially act as a common epitope for both T cells and B cells. 5) Finally, SERCA2a 971-990-sensitized T cells were able to transfer disease to naive recipients. Together, these data indicate that SERCA2a is a critical autoantigen in the mediation of atrial inflammation in mice and that our model may be helpful to study the inflammatory events that underlie the development of conditions such as atrial fibrillation in humans.

Quality by design (QbD) approach to match tablet glossiness.

A quality by design (QbD) approach was used for a polyvinyl alcohol (PVA)-based coating to develop a 'look-alike' placebo tablet, which can match the glossiness (shine) of an innovator tablet. Critical coating parameters such as exhaust temperature, drying capacity, solid concentration in coating dispersion, and plasticizer concentration were studied using a full factorial design of experiment (DoE). Total of 20 experimental coating runs was executed on a pilot scale using a perforated pan coater. Coated tablets were evaluated visually against the innovator product by a panel of 13 volunteers using an individual questionnaire about the tablet appearance. The tablet appearance included factors such as tablet surface shine, surface roughness, and logo bridging. These data were analyzed using JMP software. Solid concentration in coating dispersion and drying capacity were found to be the key contributing parameters for tablet surface shine. Human observations were more discerning in spotting subtle differences in tablet appearance than Munsell evaluation. By the judicious selection of a solid concentration in coating dispersion and drying conditions, a look-alike placebo tablet was successfully developed. Change in tablet shape or size did not affect the tablet shine. However, replacement of PVA-based coating with hydroxypropyl methylcellulose (HPMC)-based coating resulted in reduced shine irrespective of tablet shape and size.

Radiographic retropharyngeal lymph node involvement in HPV-associated oropharyngeal carcinoma: Patterns of involvement and impact on patient outcomes.

BACKGROUND: The objective of the current study was to characterize the incidence, pattern, and impact on oncologic outcomes of retropharyngeal lymph node (RPLN) involvement in HPV-associated oropharyngeal cancer (OPC). METHODS: Data regarding patients with HPV-associated OPC who were treated at The University of Texas MD Anderson Cancer Center with intensity-modulated radiotherapy from 2004 through 2013 were analyzed retrospectively. RPLN status was determined by reviewing pretreatment imaging and/or reports. Outcomes analysis was restricted to patients with lymph node-positive (+) disease. Kaplan-Meier survival estimates were generated and survival curves were compared using the log-rank test. Bayesian information criterion assessed model performance changes with the addition of RPLN status to current American Joint Committee on Cancer staging. Competing risk analysis compared modes of disease recurrence. RESULTS: The incidence of radiographic RPLN involvement was 9% (73 of 796 patients) and was found to vary by primary tumor site. The 5-year rates of freedom from distant metastases (FDM) and overall survival were lower in patients with RPLN(+) status compared with those with RPLN-negative (-) status (84% vs 93% [P = .0327] and 74% vs 87% [P = .0078], respectively). RPLN(+) status was not found to be associated with outcomes on multivariate analysis. Bayesian information criterion analysis demonstrated that current American Joint Committee on Cancer staging was not improved with the inclusion of RPLN. Locoregional and distant disease recurrence probabilities for those patients with RPLN(+) status were 8% and 13%, respectively, compared with 10% and 6%, respectively, for those with RPLN(-) status. RPLN(+) status portended worse 5-year FDM in the low-risk subgroup (smoking history of <10 pack-years) and among patients who received concurrent chemotherapy but not induction chemotherapy. CONCLUSIONS: RPLN(+) status was associated with worse overall survival and FDM on univariate but not multivariate analysis. In subgroup analyses, RPLN(+) status was associated with poorer FDM in both patients with a smoking history of <10 pack-years and those who received concurrent chemotherapy, suggesting that RPLN(+) status could be considered an exclusion criteria in treatment deintensification efforts seeking to omit chemotherapy.

Parameter estimation for roller compaction process using an instrumented vector TF mini roller compactor.

Using instrumented roll technology, statistical models relating process parameters such as hydraulic pressure, roll speed and screw speed of Vector TF mini roller compactor to ribbon normal stress and density were developed for placebo blends. Normal stress was found to be directly proportional to hydraulic pressure, roll speed and inversely to screw to roll speed ratio. A power-law relationship between ribbon density and normal stress was observed for placebo blends. Models developed for placebo were found to predict ribbon densities of active blends with good accuracy. Standard optimization of roller compaction process parameters involves the investment of a large amount of time and active ingredient. These models can, therefore, be utilized to predict starting instrument settings required to generate a ribbon of desired solid fraction during early-stage development where material availability & time is limited.

Pre-treatment neutrophil/lymphocyte ratio and platelet/lymphocyte ratio are prognostic of progression in early stage classical Hodgkin lymphoma.

To determine whether pre-treatment neutrophil/lymphocyte (NLR) or platelet/lymphocyte ratios (PLR) are predictive for progression in early-stage classical Hodgkin lymphoma (cHL), we derived NLR and PLR values for 338 stage I/II cHL patients and appropriate cut-off point values to define progression. Two-year freedom from progression (FFP) for patients with NLR ≥6·4 was 82·2% vs. 95·7% with NLR <6·4 (P < 0·001). Similarly, 2-year FFP was 84·3% for patients with PLR ≥266·2 vs. 96·1% with PLR <266·2 (P = 0·003). On univariate analysis, both NLR and PLR were significantly associated with worse FFP (P = 0·001). On multivariate analysis, PLR remained a significant, independent prognostic factor (P < 0·001).

Mammary stem cell and macrophage markers are enriched in normal tissue adjacent to inflammatory breast cancer.

INTRODUCTION: We hypothesized that breast tissue not involved by tumor in inflammatory breast cancer (IBC) patients contains intrinsic differences, including increased mammary stem cells and macrophage infiltration, which may promote the IBC phenotype. MATERIALS AND METHODS: Normal breast parenchyma ≥ 5 cm away from primary tumors was obtained from mastectomy specimens. This included an initial cohort of 8 IBC patients and 60 non-IBC patients followed by a validation cohort of 19 IBC patients and 25 non-IBC patients. Samples were immunostained for either CD44+CD49f+CD133/2+ mammary stem cell markers or the CD68 macrophage marker and correlated with IBC status. Quantitation of positive cells was determined using inForm software from PerkinElmer. We also examined the association between IBC status and previously published tumorigenic stem cell and IBC tumor signatures in the validation cohort samples. RESULTS: 8 of 8 IBC samples expressed isolated CD44+CD49f+CD133/2+ stem cell marked cells in the initial cohort as opposed to 0/60 non-IBC samples (p = 0.001). Similarly, the median number of CD44+CD49f+CD133/2+ cells was significantly higher in the IBC validation cohort as opposed to the non-IBC validation cohort (25.7 vs. 14.2, p = 0.007). 7 of 8 IBC samples expressed CD68 + histologically confirmed macrophages in initial cohort as opposed to 12/48 non-IBC samples (p = 0.001). In the validation cohort, the median number of CD68 + cells in IBC was 3.7 versus 1.0 in the non-IBC cohort (p = 0.06). IBC normal tissue was positively associated with a tumorigenic stem cell signature (p = 0.02) and with a 79-gene IBC signature (p < 0.001). CONCLUSIONS: Normal tissue from IBC patients is enriched for both mammary stem cells and macrophages and has higher association with both a tumorigenic stem cell signature and IBC-specific tumor signature. Collectively, these data suggest that IBC normal tissue differs from non-IBC tissue. Whether these changes occur before the tumor develops or is induced by tumor warrants further investigation.

Low-loss flexible Parylene photonic waveguides for optical implants.

We demonstrate compact, low-loss (<5 dB/cm) Parylene C photonic waveguides in a flexible, biocompatible, all-polymer platform suitable for implantable applications. The scattering loss due to the sidewall roughness resulting from the reactive ion etching of Parylene C was identified as the primary source of propagation loss. A fabrication process utilizing the conformal coating of Parylene C was developed to significantly reduce waveguide propagation loss (by more than 30 dB/cm). We also performed thermal annealing at 300°C to smoothen the sidewalls; however, it was found to adversely affect the waveguide performance.

Early-stage Hodgkin lymphoma outcomes after combined modality therapy according to the post-chemotherapy 5-point score: can residual pet-positive disease be cured with radiotherapy alone?

Early-stage classical Hodgkin lymphoma (HL) patients are evaluated by an end-of-chemotherapy positron emission tomography-computed tomography (eoc-PET-CT) after doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) and before radiation therapy (RT). We determined freedom from progression (FFP) in patients treated with ABVD and RT according to the eoc-PET-CT 5-point score (5PS). Secondarily, we assessed whether patients with a positive eoc-PET-CT (5PS of 4-5) can be cured with RT alone. The cohort comprised 174 patients treated for stage I-II HL with ABVD and RT alone. ABVD was given with a median of four cycles and RT with a median dose of 30·6 Gy. Five-year FFP was 97%. Five-year FFP was 100% (0 relapses/98 patients) for patients with a 5PS of 1-2, 97% (2/65) for a 5PS of 3, 83% (1/8) for a 5PS of 4, and 67% (1/3) for a 5PS of 5 (P < 0·001). Patients with positive eoc-PET-CT scans who were selected for salvage RT alone had experienced a very good partial response to ABVD. Risk factors for recurrence in this subgroup included a small reduction in tumour size and a 'bounce' in ≥1 PET-CT parameter (reduction then rise from interim to final scan). Thus, a positive eoc-PET-CT is associated with inferior FFP; however, appropriately selected patients can be cured with RT alone.