Lymph node metastasis (LNM) is a significant prognostic factor in patients with head and neck cancer, and the ability to predict it accurately is essential to optimizing treatment. Positron emission ...tomography (PET) and computed tomography (CT) imaging are routinely used to identify LNM. Although large or highly active lymph nodes (LNs) have a high probability of being positive, identifying small or less reactive LNs is challenging. The accuracy of LNM identification strongly depends on the physician's experience, so an automatic prediction model for LNM based on CT and PET images is warranted to assist LMN identification across care providers and facilities. Radiomics and deep learning are the two promising imaging-based strategies for node malignancy prediction. Radiomics models are built based on handcrafted features, while deep learning learns the features automatically. To build a more reliable model, we proposed a hybrid predictive model that takes advantages of both radiomics and deep learning based strategies. We designed a new many-objective radiomics (MaO-radiomics) model and a 3D convolutional neural network (3D-CNN) that fully utilizes spatial contextual information, and we fused their outputs through an evidential reasoning (ER) approach. We evaluated the performance of the hybrid method for classifying normal, suspicious and involved LNs. The hybrid method achieves an accuracy (ACC) of 0.88 while XmasNet and Radiomics methods achieve 0.81 and 0.75, respectively. The hybrid method provides a more accurate way for predicting LNM using PET and CT.
Early-stage glottic larynx squamous cell carcinoma (GLC) is a relatively common disease with excellent oncologic control, but treatment is associated with acute dysphagia and long-term voice quality ...changes. This phase 1 study of hypofractionated radiation therapy for early-stage GLC increased the fraction size while reducing the number of fractions until 5-fraction stereotactic ablative radiation therapy (SABR) was delivered.
Eligible patients had received a diagnosis of stage Tis to T2 GLC. Patients who had undergone prior curative-intent surgery were excluded. The equipotent dose levels were as follows: (1) level 0, 50 Gy in 15 fractions (n = 4); (2) level 1, 45 Gy in 10 fractions (n = 13); and (3) level 2, 42.5 Gy in 5 fractions (SABR level, n = 12). Grade 3 or 4 laryngeal edema, voice, dyspnea, stridor, or cough were the predefined dose-limiting toxicities.
Twenty-nine patients were enrolled from November 2013 to March 2017. The median and minimum follow-up times were 39.2 and 13 months, respectively. Two actively smoking patients, 1 treated in level 1 (grade 4 laryngeal edema, grade 3 dysphagia) and 1 treated in level 2 (grade 3 laryngeal necrosis, dysphagia), developed dose-limiting toxicities. The former patient soon developed a local recurrence, and the latter patient recovered. There were a total of 5 local recurrences: 2 in level 0 and 3 in level 1. The Voice Handicap Index results showed robust long-term voice quality with median values of 7 and 0 at 6 and 12 months, respectively.
Given the tolerability, excellent voice outcomes, and preliminary efficacy data of 5-fraction glottic larynx SABR, this regimen warrants further study.
Determining the magnitude and kinetics, together with the phenotypic and functional characteristics of responding CD8 T cells, is critical for understanding the regulation of adaptive immunity as ...well as in evaluating vaccine candidates. Recent technical advances have allowed tracking of some CD8 T cells responding to infection, and a body of information now exists describing phenotypic changes that occur in CD8 T cells of known Ag-specificity during their activation, expansion, and memory generation in inbred mice. In this study, we demonstrate that Ag but not inflammation-driven changes in expression of CD11a and CD8alpha can be used to distinguish naive from Ag-experienced (effector and memory) CD8 T cells after infection or vaccination. Interestingly and in contrast to inbred mice, tracking polyclonal CD8 T cell responses with this approach after bacterial and viral infections revealed substantial discordance in the magnitude and kinetics of CD8 T cell responses in outbred hosts. These data reveal limitations to the use of inbred mouse strains as preclinical models at vaccine development and suggest the same dose of infection or vaccination can lead to substantial differences in the magnitude and timing of Ag-specific CD8 expansion as well in differences in protective memory CD8 T cell numbers in outbred individuals. This concept has direct relevance to development of vaccines in outbred humans.
Antigen presentation by mature dendritic cells (DCs) is the first step for initiating adaptive immune responses. DCs are composed of heterogeneous functional subsets; however, the molecular ...mechanisms that regulate differentiation of specific DC subsets are not understood. Here, we report that the basic leucine zipper transcription factor NFIL3/E4BP4 is essential for the development of CD8α+ conventional DCs (cDCs). Nfil3−/− mice specifically lack CD8α+ cDCs but not CD8α− cDCs or plasmacytoid DCs in lymphoid tissues. Flt3 ligand–dependent generation of CD8α+ cDCs in lymphoid tissues and CD8α+-equivalent cDCs from Nfil3−/− bone marrow cells was also impaired. NFIL3 regulates CD8α+ cDC development in part through Batf3 expression. Importantly, Nfil3−/− mice exhibited impaired cross-priming of CD8+ T cells against cell-associated antigen, a process normally performed by CD8α+ cDCs, and failed to produce IL-12 after TLR3 stimulation. Thus, NFIL3 plays an essential role in the development of CD8α+ cDCs.
T cell Ig and mucin domain (Tim) 3 is a surface molecule expressed throughout the immune system that can mediate both stimulatory and inhibitory effects. Previous studies have provided evidence that ...Tim-3 functions to enforce CD8 T cell exhaustion, a dysfunctional state associated with chronic stimulation. In contrast, the role of Tim-3 in the regulation of CD8 T cell responses to acute and transient stimulation remains undefined. To address this knowledge gap, we examined how Tim-3 affects CD8 T cell responses to acute Listeria monocytogenes infection. Analysis of wild-type (WT) mice infected with L. monocytogenes revealed that Tim-3 was transiently expressed by activated CD8 T cells and was associated primarily with acquisition of an effector phenotype. Comparison of responses to L. monocytogenes by WT and Tim-3 knockout (KO) mice showed that the absence of Tim-3 significantly reduced the magnitudes of both primary and secondary CD8 T cell responses, which correlated with decreased IFN-γ production and degranulation by Tim-3 KO cells stimulated with peptide Ag ex vivo. To address the T cell-intrinsic role of Tim-3, we analyzed responses to L. monocytogenes infection by WT and Tim-3 KO TCR-transgenic CD8 T cells following adoptive transfer into a shared WT host. In this setting, the accumulation of CD8 T cells and the generation of cytokine-producing cells were significantly reduced by the lack of Tim-3, demonstrating that this molecule has a direct effect on CD8 T cell function. Combined, our results suggest that Tim-3 can mediate a stimulatory effect on CD8 T cell responses to an acute infection.
Inflammatory cytokines induced by infection or vaccination with adjuvant act directly or indirectly on CD8 T cells to modulate their expansion, contraction, and acquisition of memory characteristics. ...Importantly, the initial exposure of naive T cells to inflammatory cytokines may occur before, during, or after their interaction with stimulating dendritic cells (DC) and it is unknown whether and how the timing of cytokine exposure impacts the CD8 T cell response. In this study, we use an immunization strategy with peptide-coated mature DC that, in the absence of inflammatory cytokines, results in a transient effector phase followed by the accelerated acquisition of memory characteristics by the responding CD8 T cells. Induction of inflammatory cytokines by TLR agonists, at the time of DC immunization or 2-4 days after DC immunization, prevented the early acquisition of memory characteristics by the responding CD8 T cells. Interestingly, although induction of inflammatory cytokines at the time of DC immunization increased the effector response, induction of inflammatory cytokines after DC immunization did not promote further expansion of the responding CD8 T cells but still prevented their early acquisition of memory characteristics. In contrast, induction of inflammatory cytokines 2 days before DC immunization did not prevent the CD8 T cells from early acquisition of memory characteristics. Furthermore, TLR ligand-induced inflammatory cytokines had the most significant impact on the phenotype and function of proliferating CD8 T cells. These data suggest that a default pathway of memory CD8 T cell differentiation is deflected toward sustained effector commitment by encounter with inflammatory cytokines during Ag-driven proliferation.
Radiotherapy is highly effective for treating squamous cell carcinoma of the head and neck but is often associated with significant toxicities and severe morbidity. Unplanned emergency department ...(ED) visits and hospitalizations are common during treatment and come with a substantial financial and health burden as well as the potential for impaired long-term outcomes due to treatment disruption.
The objective of this study was to identify patient, disease, and treatment characteristics that were associated with ED encounters and admissions.
A cohort of 462 patients with cancer of the head and neck treated with radiotherapy at UT Southwestern between 2010 and 2015 was retrospectively analyzed. The risks of ED visits, admissions, multiple admissions, and extended admissions were determined. Risk factors for an unplanned hospital encounter were analyzed using univariate and multivariate logistic regression.
Overall, 36% of patients had an unplanned hospital encounter during the treatment window. Patients with advanced disease, those with high comorbidity score, and those treated with concurrent chemotherapy were more likely to have unplanned admissions/ED visits. Social factors such as marital status, smoking status, and registration in the public hospital system were also strongly associated with admissions and multiple encounters.
The high rate of admissions and ED visits emphasizes the importance of anticipating and managing toxicities during treatment. Social factors have a strong association with unplanned encounters and may present opportunities for targeted interventions to reduce admissions for patients at highest risk.
•There were no differences in survival between surgery and CRT.•Primary CRT increased gastrostomy dependence but not osteonecrosis or stricture.•Chemotherapy improved survival in the definitive but ...not postoperative RT setting.•Only cisplatin- and taxane-based regimens improved survival.
To determine the comparative effectiveness of primary radiotherapy (RT) and primary surgery (PS) for locally advanced oropharyngeal squamous cell carcinoma (OPSCC).
Eligible individuals were patients in the SEER-Medicare registry diagnosed with locally advanced OPSCC between 2000 and 2011. Patients were categorized as receiving either primary RT ± chemotherapy, or PS ± adjuvant RT or chemoradiotherapy (CRT). Overall survival (OS) was analyzed using Cox multivariable analysis (MVA). Risks of gastrostomy dependence (GD), esophageal stricture (ES), and osteoradionecrosis (ORN) were analyzed using logistic regression.
A total of 2754 patients (69% RT, 31% PS) were included in this cohort, with a median age of 72 years. Patients treated with RT, CRT and PS experienced 3-year OS outcomes of 36.1%, 52.8%, and 54.9%, respectively (p < 0.001). Increasing age, unmarried status, increasing comorbidity, lower income, base of tongue (BOT) site, higher stage, no prior PET, and RT alone (but not CRT) were associated with inferior OS. Independent predictors of GD at 6 months included black race, BOT site, advanced stage, and CRT. The risks of ORN and stricture were not associated with treatment modality. Concurrent chemotherapy improved OS with definitive RT but had no impact in adjuvant RT. Only cisplatin- and taxane-containing regimens improved OS, but all concurrent agents, including cetuximab, significantly worsened GD.
Local therapy decisions for locally advanced OPSCC must be individualized, with CRT increasing acute and chronic GD. The differential survival impact of concurrent chemotherapy in the definitive and adjuvant setting may be a consideration in decision-making.
The number of memory CD8 T cells generated by infection or vaccination correlates strongly with the degree of protection observed in infection and tumor models. Therefore, rapid induction of ...protective numbers of effector and memory CD8 T cells may be crucial in the case of malignancy, pandemic infection, or bioterrorism. Many studies have shown that amplifying T-cell numbers by prime-boost vaccination is most effective with a substantial time interval between immunizations. In contrast, immunization with peptide-coated mature dentritic cells (DCs) results in a CD8 T-cell response exhibiting accelerated acquisition of memory characteristics, including the ability to respond to booster immunization within days of initial priming. However, personalized DC immunization is too costly, labor intensive, and time-consuming for large-scale vaccination. Here, we demonstrate that in vivo cross-priming with cell-associated antigens or antigen-coated, biodegradable microspheres in the absence of adjuvant quickly generates CD8 T cells that display the phenotype and function of long-term memory populations. Importantly, cross-primed CD8 T cells can respond to booster immunization within days of the initial immunization to generate rapidly large numbers of effector and memory T cells that can protect against bacterial, viral, and parasitic infections, including lethal influenza and malaria-causing Plasmodium infection. Thus, accelerated CD8 T-cell memory after in vivo cross-priming in the absence of adjuvant is generalizable and can be exploited to generate protective immunity rapidly.
•Ipsilateral IMRT for N+ tonsil cancer has a very low risk of contralateral failure.•Ipsilateral IMRT is associated with a highly favorable toxicity profile.•Ipsilateral IMRT should be therefore be ...considered even for bulky nodal disease.
To determine the risk of contralateral nodal failure following ipsilateral radiotherapy in a series of patients with node-positive tonsillar squamous cell carcinoma.
Retrospective review was used to identify 34 patients with well-lateralized node-positive tonsillar squamous cell carcinoma treated with definitive or adjuvant radiation to the primary site and ipsilateral neck between 2005 and 2015. Contralateral nodal failure, locoregional recurrence, distant metastasis, and overall survival were calculated using actuarial and/or cumulative incidence statistics.
At last follow-up, contralateral nodal failure was only observed in 1 patient (3%) with N1 disease. At median follow-up of 34 months for surviving patients, the 3-year overall survival probability was 87%, and the 3 year cumulative incidences of locoregional failure and distant metastasis were 6.5% and 7.2%, respectively. No disease-free patient was permanently gastrostomy-dependent.
Ipsilateral radiation treatment with IMRT is effective in node-positive patients with well-lateralized tonsillar cancer, resulting in a low risk of contralateral regional recurrence, even in patients with N2b disease.
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