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Time-dependent ROC analyses, 2-year survival, DeepPET-OPSCC score, clinical factors, nomograms, clinical deployment test cohort

Purpose:Accurate prognostic stratification of patients with oropharyngeal squamous cell carcinoma (OPSCC) is crucial. We developed an objective and robust deep learning–based fully-automated tool called the DeepPET-OPSCC biomarker for predicting overall survival (OS) in OPSCC using [18F]fluorodeoxyglucose (FDG)-PET imaging.Experimental Design:The DeepPET-OPSCC prediction model was built and tested internally on a discovery cohort (n = 268) by integrating five convolutional neural network models for volumetric segmentation and ten models for OS prognostication. Two external test cohorts were enrolled—the first based on the Cancer Imaging Archive (TCIA) database (n = 353) and the second being a clinical deployment cohort (n = 31)—to assess the DeepPET-OPSCC performance and goodness of fit.Results:After adjustment for potential confounders, DeepPET-OPSCC was found to be an independent predictor of OS in both discovery and TCIA test cohorts [HR = 2.07; 95% confidence interval (CI), 1.31–3.28 and HR = 2.39; 95% CI, 1.38–4.16; both P = 0.002]. The tool also revealed good predictive performance, with a c-index of 0.707 (95% CI, 0.658–0.757) in the discovery cohort, 0.689 (95% CI, 0.621–0.757) in the TCIA test cohort, and 0.787 (95% CI, 0.675–0.899) in the clinical deployment test cohort; the average time taken was 2 minutes for calculation per exam. The integrated nomogram of DeepPET-OPSCC and clinical risk factors significantly outperformed the clinical model [AUC at 5 years: 0.801 (95% CI, 0.727–0.874) vs. 0.749 (95% CI, 0.649–0.842); P = 0.031] in the TCIA test cohort.Conclusions:DeepPET-OPSCC achieved an accurate OS prediction in patients with OPSCC and enabled an objective, unbiased, and rapid assessment for OPSCC prognostication.

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Background We compared the clinical outcomes of patients with oral cavity squamous cell carcinoma (OCSCC) with cN+pN0 versus cN0pN0 disease. Methods A total of 1309 OCSCC patients with pN0 disease were included. Of them, 1019 and 290 cases had cN0pN0 and cN+pN0 disease, respectively. For comparison purposes, we also examined 799 patients with pN+disease (cN0pN+/cN+pN+, n = 239/560). Subgroup analysis was performed in a propensity score‐matched cohort with cN0pN0 and cN+pN0 disease (n = 284 each). Results Compared with cN0pN0, patients with cN+pN0 had a higher prevalence of the following variables: betel chewing, pT3−4, depth ≥10 mm, perineural invasion, and treatment with surgery and adjuvant therapy. The prognosis of patients with cN+pN0 (mean: 52 nodes) and cN0pN0 (mean: 39 nodes) disease was similar both in the original cohort and after propensity score matching. However, the 5‐year outcomes were more favorable for cN+pN0/cN0pN0 compared with cN0pN+/cN+pN+ (local control, 88%/88%/83%/81%; neck control, 94%/93%/82%/76%; distant metastases, 4%/3%/13%/31%; disease‐free survival, 84%/83%/68%/52%; disease‐specific survival, 92%/92%/77%/57%; overall survival, 81%/82%/59%/42%; all p values 0.05). cN+pN0 disease (vs. cN0pN0) was not significantly associated with local control, neck control, distant metastases, and survivals either in univariable or multivariable analyses. Conclusions Despite a higher risk factor burden, the prognosis of patients with cN+pN0 disease did not differ from that of cases with cN0pN0. The higher nodal yield and the more frequent use of adjuvant therapy in cN+pN0 disease may explain the lack of significant differences in terms of neck control compared with cN0pN0 disease., Patients with oral cavity squamous cell carcinoma and cN+pN0 disease are characterized by a higher prevalence of adverse risk factors. However, this was not found to translate into a less favorable prognosis; therefore, the presence of cN+pN0 disease should not be considered as an adverse prognostic factor

To prospectively investigate the prognostic value of

Background The prognostic significance of the relapse interval in patients with resected oral cavity squamous cell carcinoma (OCSCC) is a matter of ongoing debate. In this large-scale, registry-based, nationwide study, we examined whether the time interval between surgery and the first disease relapse may affect survival outcomes in Taiwanese patients with OCSCC. Methods Data made available by the Taiwan Health Promotion Administration as of 2004 were obtained. The study cohort consisted of patients who were included in the registry between 2011 and 2017. Disease staging was performed according to the American Joint Committee on Cancer (AJCC) Staging Manual, Eight Edition. We retrospectively reviewed the clinical records of 13,789 patients with OCSCC who received surgical treatment. A total of 2327 (16.9%) patients experienced a first disease relapse. The optimal cutoff value for the relapse interval was 330 days when both 5-year disease-specific survival (DSS) and overall survival (OS) (≤ 330/>330 days, n = 1630/697) were taken into account. In addition, we undertook a propensity score (PS)-matched analysis of patients (n = 654 each) with early (≤ 330 days) versus late (> 330 days) relapse. Results The median follow-up time in the entire study cohort was 702 days (433 and 2001 days in the early and late relapse groups, respectively). Compared with patients who experienced late relapse, those with early relapse showed a higher prevalence of the following adverse prognostic factors: pT4, pN3, pStage IV, poor differentiation, depth of invasion ≥ 10 mm, and extra-nodal extension. Multivariable analysis revealed that early relapse was an independent adverse prognostic factor for both 5-year DSS and OS (average hazard ratios [AHRs]: 3.24 and 3.91, respectively). In the PS-matched cohort, patients who experienced early relapse showed less favorable 5-year DSS: 58% versus 30%, p versus 22%, p Conclusion After adjustment for potential confounders and PS matching, early relapse was an adverse prognostic factor for survival outcomes in patients with OCSCC. Our findings may have significant implications for risk stratification.

Simple Summary While the prognostic role of surgical margins in oral cavity squamous cell carcinoma is well-established, the optimal cutoff values for margin status remain controversial. This study addressed this issue in a large sample of 13,768 patients included in a nationwide registry in Taiwan. The identification of the most suitable cutoff value for surgical margins was conducted using 5-year local control as the outcome of interest. On analyzing the margin status—categorized as 0, 0.1–4 and > 4 mm—the 5-year outcomes were as follows: local control, 87, 89 and 92%; disease-specific survival, 57, 76 and 81%; overall survival, 47, 67 and 74%, respectively. Collectively, these data indicate that a margin status >4 mm can be considered as adequate. Abstract (1) Background: The optimal cutoff value that maximizes the prognostic value of surgical margins in patients with resected oral cavity squamous cell carcinoma has not yet been identified. (2) Methods: Data for this study were retrieved from the Taiwan Cancer Registry Database. A total of 13,768 Taiwanese patients with oral cavity squamous cell carcinoma were identified and stratified according to different margin statuses (0, 0.1–4 and > 4 mm). The five-year local control, disease-specific survival and overall survival rates were the main outcome measures. (3) Results: The 5-year local control, disease-specific survival and overall survival rates of patients with close margins (0 and 0.1–4 mm) were significantly lower than those observed in patients with clear margins (> 4 mm; all p values < 0.001). In multivariate analysis, margin status, depth of invasion and extra-nodal extension were identified as independent adverse prognostic factors for 5-year local control. (4) Conclusions: A thorough assessment of surgical margins can provide a reliable prognostic prediction in patients with OCSCC. This has potential implications for treatment approaches tailored to the individual level. The achievement of clear margins (>4 mm) should be considered a key surgical goal to improve outcomes in this patient group.

To determine the clinical impact of integrating Epstein-Barr virus (EBV) DNA and lymph node-to-primary tumor ratio (NTR) of positron emission tomography (PET) standardized uptake value (SUV) in predicting distant metastasis, such as distant metastasis-free survival (DMFS), in patients with nasopharyngeal carcinoma (NPC).We retrospectively reviewed patients diagnosed with non-disseminated NPC between 2010 and 2017. The optimal cut-off values of EBV DNA and SUV NTR were determined using receiver operating characteristic analysis. The prognostic values of SUV NTR and EBV DNA on DMFS and overall survival were evaluated using the Kaplan-Meier method. Univariate and multivariable analyses were performed using the Wald Chi-squared test and Cox proportional hazards regression, respectively.A total of 488 patients were included in the analysis. The median follow-up period was 61.6 months. The optimal cut-off values of EBV DNA and SUV NTR were 3377.5 copies per mL and 0.64, respectively. The five-year DMFS for patients with high vs low EBV DNA and SUV NTR levels were 64.9% vs 86.6% (p 0.001) and 78.7% vs 87.4% (p = 0.021), respectively. In subgroup analysis, the high-risk group with high levels of pretreatment EBV DNA and SUV NTR had worse DMFS in either American Joint Committee on Cancer (AJCC) stage I-III or IVA-B (p = 0.001 and0.001, respectively). Univariate and multivariable analyses showed the statistical significance of EBV DNA, SUV NTR, and their composite in DMFS (p 0.001 for EBV DNA; p = 0.022 for SUV NTR; p 0.001 for their composite).This study showed that EBV DNA and SUV NTR have independent and additive values as prognosticators for distant metastasis in patients with NPC, suggesting that these two individual factors, except the AJCC staging system, should be included in future studies.

While the NCCN guidelines maintain that T4b oral cavity squamous cell carcinoma (OCSCC) should undergo either non-surgical treatments or clinical trials, promising outcomes of T4b OCSCC having surgical excision have been reported. We analyzed and compared the clinical outcomes of Taiwanese patients with pT4a and pT4b OCSCC who had undergone surgical treatment.From 2011 to 2017, a total of 4031 and 355 patients with first primary pT4a and pT4b OCSCC were identified. A propensity score (PS)-matched analysis of patients (n = 351 each) for pT4a and pT4b tumors was also performed.The 5-year disease-specific and overall survival (DSS/OS) rates were more favorable in patients with pT4a than in those with pT4b OCSCC (64%/55%, p 0.0001; 55%/43%, p 0.0001, respectively). Compared with pT4a, those with pT4b tumors had a higher burden of the following risk factors: buccal/retromolar/hard palate subsite, male sex, depth ≥ 10 mm, and positive margins. Before PS matching, multivariable analyses revealed that pT4b tumors (versus pT4a) were an adverse prognosticator for both 5-year DSS and OS (hazard ratios: 1.32 and 1.39, respectively). However, in the PS-matched cohort, no significant differences in 5-year DSS and OS rates were observed between pT4a and pT4b OCSCC (57%/56%, p = 0.4024; 48%/44%, p = 0.1807, respectively) CONCLUSIONS: No significant outcome differences were evident between pT4b and pT4a OCSCC after PS matching. The most plausible hypothesis for the observed survival difference between T4a and T4b tumors is that it was driven by positive margins. We suggest that T4b OCSCC should undergo initial surgical excision if adequate resection is possible.

To prospectively investigate the prognostic value of 18F-FDG PET/MRI in patients with oropharyngeal or hypopharyngeal squamous cell carcinomas (OHSCC) treated by chemoradiotherapy. The study cohort consisted of patients with OHSCC who had undergone integrated PET/MRI prior to chemoradiotherapy or radiotherapy. Imaging parameters derived from intravoxel incoherent motion (IVIM), dynamic contrast-enhanced MRI (DCE-MRI), and 18F-FDG PET were analyzed in relation to overall survival (OS) and recurrence-free survival (RFS). In multivariable analysis, T classification (p < 0.001), metabolic tumor volume (p = 0.013), and pseudo-diffusion coefficient (p = 0.008) were identified as independent risk factors for OS. The volume transfer rate constant (p = 0.015), initial area under the curve (p = 0.043), T classification (p = 0.018), and N classification (p = 0.018) were significant predictors for RFS. The Harrell’s c-indices of OS and RFS obtained from prognostic models incorporating clinical and PET/MRI predictors were significantly higher than those derived from the traditional TNM staging system (p = 0.001). The combination of clinical risk factors with functional parameters derived from IVIM and DCE-MRI plus metabolic PET parameters derived from 18F-FDG PET in integrated PET/MRI outperformed the information provided by traditional TNM staging in predicting the survival of patients with OHSCC.

PURPOSE Previous studies have shown that SUVmax on F-FDG PET/CT predicts prognosis in patients with salivary gland carcinoma (SGC). Here, we sought to evaluate whether texture features extracted from F-FDG PET/CT images may provide additional prognostic information for SGC with high-risk histology. METHODS We retrospectively examined pretreatment F-FDG PET/CT images obtained from 85 patients with nonmetastatic SGC showing high-risk histology. All patients were treated with curative intent. We used the fixed threshold of 40% of SUVmax for tumor delineation. PET texture features were extracted by using histogram analysis, normalized gray-level co-occurrence matrix, and gray-level size zone matrix. Optimal cutoff points for each PET parameter were derived from receiver operating characteristic curve analyses. Recursive partitioning analysis was used to construct a prognostic model for overall survival (OS). RESULTS Receiver operating characteristic curve analyses revealed that SUVmax, SUV entropy, uniformity, entropy, zone-size nonuniformity, and high-intensity zone emphasis were significantly associated with OS. The strongest associations with OS were found for high SUVmax (>6.67) and high SUV entropy (>2.50). Multivariable Cox analysis identified high SUVmax, high SUV entropy, performance status, and N2c-N3 stage as independent predictors of survival. A prognostic model derived from multivariable analysis revealed that patients with high SUVmax and SUV entropy or with the presence of poor performance status or N2c-N3 were associated with worse OS. CONCLUSIONS A prognostic model that includes SUVmax and SUV entropy is useful for risk stratification and supports the additional benefit of texture analysis for SGC with high-risk histology.

Objective We sought to improve the prognostic stratification of patients with pN3b oral cavity squamous cell carcinoma (OCSCC) through a combined analysis of FDG-PET parameters and clinicopathological risk factors (RFs). Methods Complete data on maximum standardized uptake values derived from FDG-PET of neck metastatic nodes (SUV-nodal-max) and clinicopathological RFs were available for 257 patients with pN3b disease. Participants with pN0/pN1/pN2 (n = 1318/199/213) disease were included for comparison purposes. Results Using the 5-year disease-free survival (DFS) rate as the outcome of interest, the optimal cutoff points for SUV-nodal-max and lymph node ratio (LNR) were 15.9 and 0.17, respectively. After stratification with SUV-nodal-max and clinicopathological RFs, the 5-year DFS rates for patients with pN3 disease were as follows: SUV-nodal-max versus SUV-nodal-max ≥ 15.9 (n = 31), 49%/21%, p = 0.000003; LNR versus LNR ≥ 0.17 (n = 27), 49%/17%, p = 0.000117; absence (n = 230) versus presence (n = 27) of neck level IV/V metastases, 49%/15%, p = 0.000004. Multivariable analyses revealed that SUV-nodal-max ≥ 15.9, LNR ≥ 0.17, and the presence of level IV/V metastases were independent prognosticators for 5-year distant metastases (DM), DFS, disease-specific survival (DSS) and overall survival (OS) rates. Based on these variables, we devised a scoring system that identified three distinct prognostic subgroups of low (score 0, n = 190), intermediate (score 1, n = 51), and high (scores 2 − 3, n = 16) risk. The 5-year rates of pN0/pN1/pN2/pN3b of our cohort and the low/intermediate/high risk subgroups of pN3b were as follows: DM, 3%/12%/20%/38% and 31%/52%/89%; DFS, 83%/72%/65%/46% and 54%/26%/0%; DSS, 92%/79%/71%/52% and 59%/36%/8%; OS, 81%/62%/54%/38% and 42%/31%/6%, respectively; all p

pStage IVB oral cavity squamous cell carcinoma (OCSCC) is defined as either pT4b or pN3 disease. We sought to devise an improved prognostic stratification of this patient group.Between December 2003 and January 2018, we retrospectively reviewed the clinical records of 1331 consecutive patients with OCSCC who received tumor excision and neck dissection. The number of patients with pT4a/pT4b, pT1N3b/pT2N3b/pT3N3b/pT4N3b, and pStage IVA/IVB was 370/83, 3/49/42/142, and 332/295, respectively.The 5-year rates of disease-free survival (DFS) and disease-specific survival (DSS) for patients with pT4a/pT4b disease were 64%/63% (p = 0.973) and 72%/69% (p = 0.672), respectively. The 5-year DFS and DSS rates for patients with pT1N3b/pT2N3b/pT3N3b/pT4N3b disease were 67%/65%/40%/42% (p 0.001; pT1-2N3b versus pT3-4N3b, p = 0.002) and 100%/68%/45%/49% (p 0.001; pT1-2N3b versus pT3-4N3b, p = 0.002), respectively. We devised a new definition for pStage IV by considering patients with pT4bN0-2 and pT1-2N3b diseases as pStage-IVA. The number of patients with pStage IVA/IVB (pT3-4N3b) was 443/184. The 5-year rates of AJCC pStage IVA/IVB and the newly proposed pStage IVA/IVB (pT3-4N3b) were as follows: DFS, 74%/52% and 72%/42%; DSS, 83%/58% and 81%/47%; respectively, all p value 0.001.The clinical outcomes of pT4b and pT4a OCSCC are similar. However, patients with pT3-4N3b disease have a less favorable 5-year prognosis compared with cases with pT1-2N3b. In light of the unfavorable outcomes, pT3-4N3b disease should continue to be classified as pStage IVB. Conversely, pT4bN0-2 and pT1-2N3b diseases portend a less adverse prognosis and should therefore be downstaged to pStage IVA.

Purpose: Accurate prognostic stratification of patients with oropharyngeal squamous cell carcinoma (OPSCC) is crucial. We developed an objective and robust deep learning–based fully-automated tool called the DeepPET-OPSCC biomarker for predicting overall survival (OS) in OPSCC using [18F]fluorodeoxyglucose (FDG)-PET imaging. Experimental Design: The DeepPET-OPSCC prediction model was built and tested internally on a discovery cohort (n = 268) by integrating five convolutional neural network models for volumetric segmentation and ten models for OS prognostication. Two external test cohorts were enrolled—the first based on the Cancer Imaging Archive (TCIA) database (n = 353) and the second being a clinical deployment cohort (n = 31)—to assess the DeepPET-OPSCC performance and goodness of fit. Results: After adjustment for potential confounders, DeepPET-OPSCC was found to be an independent predictor of OS in both discovery and TCIA test cohorts [HR = 2.07; 95% confidence interval (CI), 1.31–3.28 and HR = 2.39; 95% CI, 1.38–4.16; both P = 0.002]. The tool also revealed good predictive performance, with a c-index of 0.707 (95% CI, 0.658–0.757) in the discovery cohort, 0.689 (95% CI, 0.621–0.757) in the TCIA test cohort, and 0.787 (95% CI, 0.675–0.899) in the clinical deployment test cohort; the average time taken was 2 minutes for calculation per exam. The integrated nomogram of DeepPET-OPSCC and clinical risk factors significantly outperformed the clinical model [AUC at 5 years: 0.801 (95% CI, 0.727–0.874) vs. 0.749 (95% CI, 0.649–0.842); P = 0.031] in the TCIA test cohort. Conclusions: DeepPET-OPSCC achieved an accurate OS prediction in patients with OPSCC and enabled an objective, unbiased, and rapid assessment for OPSCC prognostication.

Objectives The aim of this study was to develop and validate a prognostic model incorporating [18F]FDG PET/CT radiomics for patients of minor salivary gland carcinoma (MSGC). Methods We retrospectively reviewed the pretreatment [18F]FDG PET/CT images of 75 MSGC patients treated with curative intent. Using a 1.5:1 ratio, the patients were randomly divided into a training and validation group. The main outcome measurements were overall survival (OS) and relapse-free survival (RFS). All of the patients were followed up for at least 30 months or until death. Following segmentation of tumors and lymph nodes on PET images, radiomic features were extracted. The prognostic significance of PET radiomics and clinical parameters in the training group was examined using receiver operating characteristic curve analysis. Variables showing a significant impact on OS and RFS were entered into multivariable Cox regression models. Recursive partitioning analysis was subsequently implemented to devise a prognostic index, whose performance was examined in the validation group. Finally, the performance of the index was compared with clinical variables in the entire cohort and nomograms for surgically treated cases. Results The training and validation groups consisted of 45 and 30 patients, respectively. The median follow-up time in the entire cohort was 59.5 months. Eighteen relapse, 19 dead, and thirteen relapse, eight dead events were found in the training and validation cohorts, respectively. In the training group, two factors were identified as independently associated with poor OS, i.e., (1) tumors with both high maximum standardized uptake value (SUVmax) and discretized intensity entropy and (2) poor performance status or N2c-N3 stage. A prognostic model based on the above factors was devised and showed significant higher concordance index (C-index) for OS than those of AJCC stage and high-risk histology (C-index: 0.83 vs. 0.65, P = 0.005; 0.83 vs. 0.54, P < 0.001, respectively). This index also demonstrated superior performance than nomogram for OS (C-index: 0.88 vs. 0.70, P = 0.017) and that for RFS (C-index: 0.87 vs. 0.72, P = 0.004). Conclusions We devised a novel prognostic model that incorporates [18F]FDG PET/CT radiomics and may help refine outcome prediction in patients with MSGC.

Objectives Human papillomavirus-negative oropharyngeal squamous cell carcinoma (OPSCC) has unfavorable survival outcomes. Two outcomes have been identified based on smoking history and tumor stage. We investigate the prognostic role of pre-treatment positron emission tomography (PET) in high-risk OPSCC. Materials and Methods We enrolled 147 M0 OPSCC patients with p16-negative staining and a history of heavy smoking (>10 pack-years) or T4 disease. All patients completed primary chemoradiotherapy, and 42% maximum standard uptake values (SUVmax) were used as the threshold for primary tumor. Patients were classified into training and validation cohorts with a ratio of 1:1.5 according to the PET date. Heterogeneity and irregularity indices were obtained. PET parameters with significant impact on progression-free survival (PFS) in receiver operating characteristic curves and univariate Cox models were identified and included in recursive partitioning analysis (RPA) for constructing a prognostic model. The RPA-based prognostic model was further tested in the validation cohort using multivariate Cox models. Results Fifty-eight and 89 patients were in the training and validation groups, respectively. Heterogeneity parameter, SUV-entropy (derived from histogram analysis), and irregularity index, and asphericity were significantly associated with PFS. The RPA model revealed that patients with both high SUV-entropy and high asphericity experienced the worst PFS. Results were confirmed in the validation group. The overall concordance index for PFS of the model was 0.75, which was higher than the clinical stages, performance status, SUVmax, and metabolic tumor volume of PET. Conclusions PET prognostic model provided useful prediction of PFS for patients with high-risk OPSCC.

The prognosis of pN3b oral cavity squamous cell carcinoma (OCSCC) remains heterogeneous. We sought to improve the prognostic stratification of patients with pN3b OCSCC through a combined analysis of FDG-PET parameters and clinicopathological risk factors (RFs).From 2001 to 2019, complete data on maximum standardized uptake values derived from FDG-PET of neck metastatic nodes (SUV-nodal-max) and clinicopathological RFs were available for 257 patients with pN3b disease.Using the 5-year disease-free survival (DFS) as the outcome of interest, the optimal cutoff points for SUV-nodal-max and lymph node ratio (LNR) were 15.9 and 0.17, respectively. The 5-year DFS rates/(number of cases) for patients with pN3b disease were as follows: SUV-nodal-max 15.9 versus ≥ 15.9, 49%(226)/21%(31), p = 0.000003; LNR 0.17 versus ≥ 0.17, 49%(230)/17%(27), p = 0.000117; absence versus presence of neck level IV/V metastases, 49%(230)/15%(27), p = 0.000004. Multivariable analyses revealed that SUV-nodal-max ≥ 15.9, LNR ≥ 0.17, and level IV/V metastases were independent prognosticators for 5-year distant metastases (DM), DFS, disease-specific survival (DSS), and overall survival (OS) rates. Based on these variables, we devised a scoring system that identified three distinct prognostic subgroups at low (score 0, n = 190), intermediate (score 1, n = 51), and high (scores 2-3, n = 16) risk. The 5-year rates of patients with pN3b disease deemed to be at low/intermediate/high risk were as follows: DM, 31%/52%/89%; DFS, 54%/26%/0%; DSS, 59%/36%/8%; OS, 42%/31%/6%, respectively; all p 0.001.A scoring system based on SUV-nodal-max, LNR, and level IV/V metastases improves the prognostic stratification of OCSCC patients with pN3b disease.

// Sheng-Chieh Chan 1,2,* , Nai-Ming Cheng 2,3,* , Chia-Hsun Hsieh 4 , Shu-Hang Ng 5,6 , Chien-Yu Lin 7 , Tzu-Chen Yen 2,3 , Cheng-Lung Hsu 4 , Hung-Ming Wan 4 , Chun-Ta Liao 8 , Kai-Ping Chang 8 and Jiun-Jie Wang 6 1 Department of Nuclear Medicine, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan 2 Molecular Imaging Center, Linkou Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan 3 Department of Nuclear Medicine, Linkou Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan 4 Department of Internal Medicine, Division of Medical Oncology, Linkou Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan 5 Department of Diagnostic Radiology, Linkou Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan 6 Department of Medical Imaging and Radiological Sciences, Chang Gung University, Taoyuan, Taiwan 7 Department of Radiation Oncology, Linkou Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan 8 Department of Otorhinolaryngology, Linkou Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan * These authors have contributed equally to this work Correspondence to: Shu-Hang Ng, email: // Jiun-Jie Wang, email: // Keywords : PET, heterogeneity, DCE-MRI, DWI, head and neck cancer Received : July 22, 2016 Accepted : February 20, 2017 Published : March 04, 2017 Abstract Background: In this study, PET heterogeneity was combined with functional MRI techniques to refine the prediction of prognosis in patients with oropharyngeal or hypopharyngeal squamous cell carcinoma (OHSCC). Methods: A total of 124 patients with primary advanced OHSCC who underwent pretreatment 18 F-FDG PET/CT, dynamic contrast-enhanced MR imaging (DCE-MRI), and diffusion-weighted MR imaging (DWI) were enrolled. Conventional and heterogeneity parameters from 18 F-FDG PET as well as perfusion parameters from DCE-MRI and diffusion parameter from DWI of primary tumors were analyzed in relation to recurrence-free survival (RFS) and overall survival (OS). Results: Multivariate analysis identified hypopharyngeal tumors ( P = 0.038), alcohol drinking ( P = 0.006), K trans ≤ 0.5512 ( P = 0.017), and K ep ≤ 0.8872 ( P = 0.005) as adverse prognostic factors for RFS. Smoking ( p = 0.009), K trans ≤ 0.5512 ( P = 0.0002), K ep ≤ 0.8872 ( P = 0.004), and the PET heterogeneity parameter uniformity ≤ 0.00381 ( P = 0.028) were independent predictors of poor OS. The combination of PET uniformity with DCE-MRI parameters and smoking allowed distinguishing four prognostic groups, with 3-year OS rates of 100%, 76.6%, 57.4%, and 7.1%, respectively ( P < 0.0001). This prognostic system appeared superior to both the TNM staging system ( P = 0.186) and the combination of conventional PET parameters with DCE-MRI ( P = 0.004). Conclusions: Multiparametric imaging based on PET heterogeneity and DCE-MRI parameters combined with clinical risk factors is superior to the concomitant use of functional MRI coupled with conventional PET parameters. This approach may improve the prognostic stratification of OHSCC patients.

The aim of the present study was to evaluate whether texture features extracted fromWe retrospectively examined 52 patients with metastatic NPC who underwent assessment of EBV DNA titers and pretreatmentOn multivariate analysis, EBV DNA titers 3500 copies/mL and TLG of metastatic lesions 138 mL were identified as independent predictors of overall survival (OS) (P = 0.036 and P = 0.047, respectively). Patients were divided into two subgroups based on their EBV DNA titers (high versus low). In the high EBV DNA titer group, a lower homogeneity of distant metastatic lesions and higher TLG values of distant metastatic lesions were independent risk factors for OS (P = 0.033 and P 0.001, respectively). In the low EBV DNA titer group, a reduced uniformity of distant metastatic lesions and a higher SUVmax of distant metastatic lesions were unfavorable risk factors for OS (P = 0.004 and P = 0.005, respectively). Based on these results, we devised two prognostic scoring systems for the prediction of 2-year OS in each EBV DNA titer group.Some of the PET-derived texture parameters are independent predictors of outcomes in patients with metastatic NPC and provide complementary information to EBV DNA titers.

Supplemental Digital Content is available in the text, The utility of multimodality molecular imaging for predicting treatment response and survival of patients with hypopharyngeal carcinoma remains unclear. Here, we sought to investigate whether the combination of different molecular imaging parameters may improve outcome prediction in this patient group. Patients with pathologically proven hypopharyngeal carcinoma scheduled to undergo chemoradiotherapy (CRT) were deemed eligible. Besides clinical data, parameters obtained from pretreatment 2-deoxy-2-[fluorine-18]fluoro-D-glucose positron emission tomography/computed tomography (18F-FDG PET/CT), dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI), and diffusion-weighted MRI were analyzed in relation to treatment response, recurrence-free survival (RFS), and overall survival (OS). A total of 61 patients with advanced-stage disease were examined. After CRT, 36% of the patients did not achieve a complete response. Total lesion glycolysis (TLG) and texture feature entropy were found to predict treatment response. The transfer constant (Ktrans), TLG, and entropy were associated with RFS, whereas Ktrans, blood plasma volume (Vp), standardized uptake value (SUV), and entropy were predictors of OS. Different scoring systems based on the sum of PET- or MRI-derived prognosticators enabled patient stratification into distinct prognostic groups (P

Clinical outcomes of patients with resected oral cavity squamous cell carcinoma (OCSCC) chiefly depend on the presence of specific clinicopathological risk factors (RFs). Here, we performed a combined analysis of FDG-PET, genetic markers, and clinicopathological RFs in an effort to improve prognostic stratification. We retrospectively reviewed the clinical records of 2036 consecutive patients with first primary OCSCC who underwent surgery between 1996 and 2016. Of them, 345 underwent ultra-deep targeted sequencing (UDTS, between 1996 and 2011) and 168 whole exome sequencing (WES, between 2007 and 2016). Preoperative FDG-PET imaging was performed in 1135 patients from 2001 to 2016. Complete data on FDG-PET, genetic markers, and clinicopathological RFs were available for 327 patients. Using log-ranked tests based on 5-year disease-free survival (DFS), the optimal cutoff points for maximum standardized uptake values (SUV-max) of the primary tumor and neck metastatic nodes were 22.8 and 9.7, respectively. The 5-year DFS rates were as follows: SUVtumor-max ≥ 22.8 or SUVnodal-max ≥ 9.7 (n = 77) versus SUVtumor-max

In this retrospective review of prospectively collected data, we sought to investigate whether early FDG-PET assessment of treatment response based on total lesion glycolysis measured using a systemic approach (TLG-S) would be superior to either local assessment with EORTC (European Organization for Research and Treatment of Cancer) criteria or single-lesion assessment with PERCIST (PET Response Criteria in Solid Tumors) for predicting clinical outcomes in patients with metastatic lung adenocarcinoma treated with erlotinib. We also examined the effect of bone flares on tumor response evaluation by single-lesion assessment with PERCIST in patients with metastatic bone lesions. We performed a retrospective review of prospectively collected data from 23 patients with metastatic lung adenocarcinoma treated with erlotinib. All participants underwent FDG-PET imaging at baseline and on days 14 and 56 after completion of erlotinib treatment. In addition, diagnostic CT scans were performed at baseline and on day 56. FDG-PET response was assessed with TLG-S, EORTC, and PERCIST criteria. Response assessment based on RECIST 1.1 (Response Evaluation Criteria in Solid Tumors) from diagnostic CT imaging was used as the reference standard. Two-year progression-free survival (PFS) and overall survival (OS) served as the main outcome measures. We identified 13 patients with bone metastases. Of these, four (31 %) with persistent bone uptake due to bone flares on day 14 were erroneously classified as non-responders according to the PERCIST criteria, but they were correctly classified as responders according to both the EORTC and TLG-S criteria. Patients who were classified as responders on day 14 based on TLG-S criteria had higher rates of 2-year PFS (26.7 % vs. 0 %, P = 0.007) and OS (40.0 % vs. 7.7 %, P = 0.018). Similar rates were observed in patients who showed a response on day 56 based on CT imaging according to the RECIST criteria. Patients classified as responders on day 14 according to the EORTC criteria on FDG-PET imaging had better rates of 2-year OS than did non-responders (36.4 % vs. 8.3 %, P = 0.015). TLG-S criteria may be of greater help in predicting survival outcomes than other forms of assessment. Bone flares, which can interfere with the interpretation of treatment response based on PERCIST criteria, are not uncommon in patients with metastatic lung adenocarcinoma treated with erlotinib.

Purpose The aim of the present study was to evaluate whether texture features extracted from 18F-FDG PET/CT images may provide additional prognostic information in patients with metastatic nasopharyngeal carcinoma (NPC). Materials and Method We retrospectively examined 52 patients with metastatic NPC who underwent assessment of EBV DNA titers and pretreatment 18F-FDG PET/CT imaging. All participants were followed up for at least two years. The following 18F-FDG PET parameters were analyzed: standardized uptake value (SUV), metabolic tumor volume (MTV), total lesion glycolysis (TLG), and texture parameters. Independent predictors of outcomes were identified using receiver operating characteristic curve analysis and multivariate Cox proportional hazards models. Results On multivariate analysis, EBV DNA titers > 3500 copies/mL and TLG of metastatic lesions > 138 mL were identified as independent predictors of overall survival (OS) (P = 0.036 and P = 0.047, respectively). Patients were divided into two subgroups based on their EBV DNA titers (high versus low). In the high EBV DNA titer group, a lower homogeneity of distant metastatic lesions and higher TLG values of distant metastatic lesions were independent risk factors for OS (P = 0.033 and P Conclusion Some of the PET-derived texture parameters are independent predictors of outcomes in patients with metastatic NPC and provide complementary information to EBV DNA titers.

PURPOSE To assess whether primary tumor and nodal F-FDG uptake may predict prognosis in patients with salivary gland carcinoma. METHODS We conducted a 2-center, retrospective study on 117 patients with salivary gland carcinoma who underwent F-FDG PET/CT before treatment and were subsequently treated with curative intent between 2004 and 2014. Pretreatment SUVmax of the primary tumor (SUVmax-T) and that of positive nodes (SUVmax-N) were analyzed in relation to clinical outcomes. RESULTS Patients were followed up for a median of 61 months. The following 5-year rates were observed: locoregional control (LRC), 78%; distant metastasis-free survival (DMFS), 67%; progression-free survival (PFS), 62%; and overall survival (OS), 68%. A cutoff value of 7.0 maximized the prognostic impact of both SUVmax-T and SUVmax-N for PFS. Compared with patients with SUVmax-T and SUVmax-N values below the optimal cutoff, those with SUVmax-T and SUVmax-N of 7 or greater showed less favorable 5-year LRC (P < 0.001 and P < 0.001), DMFS (P < 0.001 and P < 0.001), PFS (P < 0.001 and P < 0.001), and OS (P < 0.001 and P < 0.001) rates. Both SUVmax-T of 7 or greater and SUVmax-N of 7 or greater were identified as independent predictors of LRC (P = 0.010 and 0.022), DMFS (P = 0.001 and P = 0.001), PFS (P < 0.001 and P = 0.007), and OS (P = 0.007 and P = 0.002) in multivariable analysis. We therefore devised a prognostic scoring system based on these 2 variables, which was found to be strongly associated with 5-year LRC (P < 0.001), DMFS (P < 0.001), PFS (P < 0.001), and OS (P < 0.001) rates. CONCLUSIONS SUVmax of the primary tumor and SUVmax-N on pretreatment F-FDG PET/CT images may be a useful guide in predicting treatment outcomes, especially when combined in a prognostic scoring system.

The Ang's risk profile (based on p16, smoking and cancer stage) is a well-known prognostic factor in oropharyngeal squamous cell carcinoma (OPSCC). Whether heterogeneity in (18)F-fluorodeoxyglucose (FDG) positron emission tomographic (PET) images and epidermal growth factor receptor (EGFR) expression could provide additional information on clinical outcomes in advanced-stage OPSCC was investigated. Patients with stage III-IV OPSCC who completed primary therapy were eligible. Zone-size nonuniformity (ZSNU) extracted from pretreatment FDG PET scans was used as an index of image heterogeneity. EGFR and p16 expression were examined by immunohistochemistry. Disease-specific survival (DSS) and overall survival (OS) served as outcome measures. Kaplan-Meier estimates and Cox proportional hazards regression models were used for survival analysis. A bootstrap resampling technique was applied to investigate the stability of outcomes. Finally, a recursive partitioning analysis (RPA)-based model was constructed. A total of 113 patients were included, of which 28 were p16-positive. Multivariate analysis identified the Ang's profile, EGFR and ZSNU as independent predictors of both DSS and OS. Using RPA, the three risk factors were used to devise a prognostic scoring system that successfully predicted DSS in both p16-positive and -negative cases. The c-statistic of the prognostic index for DSS was 0.81, a value which was significantly superior to both AJCC stage (0.60) and the Ang's risk profile (0.68). In patients showing an Ang's high-risk profile (N = 77), the use of our scoring system clearly identified three distinct prognostic subgroups. It was concluded that a novel index may improve the prognostic stratification of patients with advanced-stage OPSCC.

Human papillomavirus-negative oropharyngeal squamous cell carcinoma (OPSCC) has unfavorable survival outcomes. Two outcomes have been identified based on smoking history and tumor stage. We investigate the prognostic role of pre-treatment positron emission tomography (PET) in high-risk OPSCC.We enrolled 147 M0 OPSCC patients with p16-negative staining and a history of heavy smoking (10 pack-years) or T4 disease. All patients completed primary chemoradiotherapy, and 42% maximum standard uptake values (SUVFifty-eight and 89 patients were in the training and validation groups, respectively. Heterogeneity parameter, SUV-entropy (derived from histogram analysis), and irregularity index, and asphericity were significantly associated with PFS. The RPA model revealed that patients with both high SUV-entropy and high asphericity experienced the worst PFS. Results were confirmed in the validation group. The overall concordance index for PFS of the model was 0.75, which was higher than the clinical stages, performance status, SUVPET prognostic model provided useful prediction of PFS for patients with high-risk OPSCC.

Objectives We investigated the relationships of cystic nodal metastasis, human papillomavirus (HPV) status, and treatment failure patterns in patients with oropharyngeal squamous cell carcinoma (OPSCC) treated with chemoradiotherapy. Methods We retrospectively reviewed pretreatment MRI and clinical courses of patients with OPSCC whose tumors were tested for HPV-induced p16 expression via immunohistochemistry and who completed chemoradiotherapy. Cervical cystic nodal metastasis and necrotic nodal metastasis were classified on MRI. Results Of 98 patients eligible for analysis, 33 were p16-positive. Cystic nodal metastasis was significantly more prevalent in p16-positive than in p16-negative patients (39.4% versus 18.5%, respectively; p = 0.025). Necrotic nodal metastasis was significantly more prevalent in p16-negative than in p16-positive patients (73.8% versus 51.5%, respectively; p = 0.027). On multivariate analysis, necrotic nodal metastasis (odds ratio [OR] = 7.310, p = 0.011) was an independent predictor of regional failure, while advanced nodal stage (OR = 4.119, p = 0.022) and cystic nodal metastases (OR = 0.087, p = 0.026) were independent positive and negative predictors of distant failure, respectively. Conclusions Cervical cystic and necrotic nodal metastases are associated with HPV-induced p16-positive and p16-negative OPSCC, respectively. Patients with necrotic nodal metastasis at presentation have an increased risk of regional failure. Distant failure is directly and inversely correlated with advanced nodal stage and cystic nodal metastasis, respectively.

The question as to whether the regional textural features extracted from PET images predict prognosis in oropharyngeal squamous cell carcinoma (OPSCC) remains open. In this study, we investigated the prognostic impact of regional heterogeneity in patients with T3/T4 OPSCC.We retrospectively reviewed the records of 88 patients with T3 or T4 OPSCC who had completed primary therapy. Progression-free survival (PFS) and disease-specific survival (DSS) were the main outcome measures. In an exploratory analysis, a standardized uptake value of 2.5 (SUV 2.5) was taken as the cut-off value for the detection of tumour boundaries. A fixed threshold at 42 % of the maximum SUV (SUVmax 42 %) and an adaptive threshold method were then used for validation. Regional textural features were extracted from pretreatment (18)F-FDG PET/CT images using the grey-level run length encoding method and grey-level size zone matrix. The prognostic significance of PET textural features was examined using receiver operating characteristic (ROC) curves and Cox regression analysis.Zone-size nonuniformity (ZSNU) was identified as an independent predictor of PFS and DSS. Its prognostic impact was confirmed using both the SUVmax 42 % and the adaptive threshold segmentation methods. Based on (1) total lesion glycolysis, (2) uniformity (a local scale texture parameter), and (3) ZSNU, we devised a prognostic stratification system that allowed the identification of four distinct risk groups. The model combining the three prognostic parameters showed a higher predictive value than each variable alone.ZSNU is an independent predictor of outcome in patients with advanced T-stage OPSCC, and may improve their prognostic stratification.

Human papillomavirus type 16 (HPV-16) positivity is associated with favourable survival in oropharyngeal squamous cell carcinoma (OPSCC). We report here a study of the prognostic significance of 18F-FDG PET/CT functional parameters and HPV-16 infection in OPSCC patients. We retrospectively analysed 60 patients with stage III or IV OPSCC who had had a pretherapy 18F-FDG PET/CT scan and had completed concurrent chemoradiotherapy (n = 58) or curative radiotherapy (n = 2). All patients were followed up for ≥24 months or until death. We determined total lesion glycolysis (TLG) and the maximal standardized uptake values (SUVmax) of the primary tumour and neck lymph nodes from the pretherapy 18F-FDG PET/CT scan. Optimal cut-offs of the 18F-FDG PET/CT parameters were obtained by receiver operating characteristic (ROC) curve analyses. Pretherapy tumour biopsies were studied by polymerase chain reaction to determine HPV infection status. The pretherapy tumour biopsies were positive for HPV-16 in 12 patients (20.0 %). Cox regression analyses revealed HPV-16 positivity and tumour TLG >135.3 g to be independently associated with overall survival (p = 0.027 and 0.011, respectively). However, only tumour TLG >135.3 g was independently associated with progression-free survival, disease-free survival and locoregional control (p = 0.011, 0.001 and 0.034, respectively). A scoring system was formulated to define distinct overall survival groups using tumour TLG and HPV-16 status. Patients positive for HPV-16 and with tumour TLG ≤135.3 g experienced better survival than those with tumour TLG >135.3 g and no HPV infection (p = 0.001). Tumour TLG was an independent predictor of survival in patients with locally advanced OPSCC. A scoring system was developed and may serve as a risk stratification strategy for guiding therapy.