Prognostic value of lymph node-to-primary tumor ratio of PET standardized uptake value for nasopharyngeal carcinoma: a recursive partitioning risk stratification analysis.

Background: Induction chemotherapy (IC) combined with concurrent chemoradiotherapy has become the standard treatment for locoregionally advanced nasopharyngeal carcinoma (LA-NPC). Data on the prognostic value of the lymph node-to-primary tumor ratio (NTR) of positron emission tomography (PET) standardized uptake value (SUV) for patients treated with IC were limited. Objectives: To evaluate the prognostic value of the SUV NTR for patients with LA-NPC treated with IC. Design: In all, 467 patients with pretreatment 18F-fluorodeoxyglucose PET/computed tomography (CT) scans between September 2017 and November 2020 were retrospectively reviewed. Methods: The receiver operating characteristic (ROC) analysis was used to determine the optimal cut-off value of SUV NTR. Kaplan-Meier method was used to evaluate survival rates. The recursive partitioning analysis (RPA) was performed to construct a risk stratification model. Results: The optimal cutoff value of SUV NTR was 0.74. Multivariate analyses showed that SUV NTR and overall stage were independent predictors for distant metastasis-free survival (DMFS) and regional recurrent-free survival (RRFS). Therefore, an RPA model based on the endpoint of DMFS was generated and categorized the patients into three distinct risk groups: RPA I (low risk: SUV NTR < 0.74 and stage III), RPA II (medium risk: SUV NTR < 0.74 and stage IVa, or SUV NTR ⩾ 0.74 and stage III), and RPA III (high risk: SUV NTR ⩾ 0.74 and stage IVa), with a 3-year DMFS of 98.9%, 93.4%, and 84.2%, respectively. ROC analysis showed that the RPA model had superior predictive efficacy than the SUV NTR or overall stage alone. Conclusion: SUV NTR was an independent prognosticator for distant metastasis and regional recurrence in locoregionally advanced NPC. The RPA risk stratification model based on SUV NTR provides improved DMFS and RRFS prediction over the eighth edition of the TNM (Tumor Node Metastasis) staging system.

Multiply-mesoporous hydrophilic titanium dioxide nanohybrid for the highly-performed enrichment of N-glycopeptides from human serum.

N-glycopeptide is considered as one of significant biomarkers which provide guidance for the diagnosis and drug design of diseases. However, the direct analysis of N-glycopeptides is nearly impracticable mainly owing to their extremely low abundance and grave signal suppression from other interfering substances in the bio-samples. In this research, a multiply-mesoporous hydrophilic TiO2 nanohybrid (mM-TiO2@Cys) was synthesized by immobilizing Cys on a TiO2 substrate with hierarchical mesopores to achieve the highly-performed enrichment of N-glycopeptides. With the advantages of superior hydrophilicity and multiply-mesoporous structure, the obtained material exhibited an excellent selectivity (IgG digests and BSA digests at the molar ratio of 1/500), a high sensitivity (1 fmol µL-1 for IgG digests) and a good size-exclusion ability (IgG digests, IgG and BSA at the molar ratio of 1/500/500) in the enrichment of N-glycopeptides from IgG digests. As a result, 281 N-glycopeptides corresponded with 109 glycoproteins were identified from 2 µL serum digests of the patients with nasopharyngeal carcinoma, and 181 N-glycopeptides corresponded with 78 glycoproteins were identified from 2 µL serum digests of the healthy volunteers, revealing the potential application value of mM-TiO2@Cys in glycoproteomics.

Induction Toripalimab and Chemotherapy for Organ Preservation in Locally Advanced Laryngeal and Hypopharyngeal Cancer: A Single-Arm Phase II Clinical Trial.

PURPOSE: The aim of this study was to assess the efficacy, toxicities, and potential role of larynx preservation of induction chemotherapy combined with programmed cell death protein 1 (PD-1) inhibitor in locally advanced laryngeal and hypopharyngeal cancer. PATIENTS AND METHODS: This is a single-arm phase II study. Patients with histopathologically confirmed, resectable locally advanced laryngeal/hypopharyngeal squamous cell carcinoma and Eastern Cooperative Oncology Group Performance Status 0-1 were eligible. Three cycles of induction chemotherapy (paclitaxel 175 mg/m2 d1, cisplatin 25 mg/m2 d1-3) combined with PD-1 inhibitor (toripalimab 240 mg d0) were administered. Response assessment was performed after induction chemoimmunotherapy using RECIST 1.1 criteria. Patients with a complete/partial response of the primary tumor received concurrent chemoradiation, followed by maintenance therapy of toripalimab. Otherwise, patients were referred to surgery, followed by adjuvant (chemo) radiation and maintenance therapy of toripalimab. The primary endpoint is a larynx preservation rate at 3 months postradiation. RESULTS: Twenty-seven patients were enrolled. Most cases exhibited stage IV disease (81.5%), with T4 representing 37.0%. Five patients underwent pretreatment tracheostomy because of impaired larynx function. Overall response rate of induction chemoimmunotherapy was 85.2%. At 3 months postradiation, the larynx preservation rate was 88.9%. With a median follow-up of 18.7 months, the 1-year overall survival rate, progression-free survival rate, and larynx preservation rate were 84.7%, 77.6%, and 88.7%, respectively. When excluding those with pretreatment tracheostomy, the 1-year larynx preservation rate was 95.5%. Exploratory analysis revealed that relapse correlated with enrichment of RNA signature of hypoxia and M2 macrophage-associated genes. CONCLUSIONS: Induction toripalimab combined with chemotherapy provided encouraging activity, promising larynx preservation rate and acceptable toxicity in this cohort of extensively locally advanced laryngeal and hypopharyngeal cancer.

Radiation-induced nasopharyngeal ulcers after re-irradiation with intensity-modulated radiotherapy in locoregional recurrent nasopharyngeal carcinoma patients: a dose-volume-outcome analysis.

OBJECTIVE: To analyze the interrelation between radiation dose and radiation-induced nasopharyngeal ulcer (RINU) in locoregional recurrent nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiation therapy (IMRT). METHODS: Clinical data were collected from 363 patients with locoregional recurrent NPC who received re-irradiated with definitive IMRT from 2009 to 2017. Twenty-nine patients were diagnosed with RINU. Univariate and multivariate analyses were used to re-evaluate the first and second radiotherapy plans and to identify predictive dosimetric factors. RESULTS: All dosimetric parameters were notably associated with the progression to RINU (p < 0.01) using paired samples Wilcoxon signed rank tests. Multivariate analysis showed that EQD2_ [Formula: see text]D80 (dose for 80 percent volume of the unilateral nasopharynx lesion) was an independent prognostic factor for RINU (p = 0.001). The area under the ROC curve for EQD2_ [Formula: see text]D80 was 0.846 (p < 0.001), and the cutoff point of 137.035 Gy could potentially be the dose tolerance of the nasopharyngeal mucosa. CONCLUSIONS: The sum of equivalent dose in 2 Gy fractions (EQD2) in the overlapping volumes between initial and re-irradiated nasopharyngeal mucosal tissue can be effective in predicting the hazard of developing RINU in NPC patients undergoing radical re­irradiation with IMRT and we propose a EQD2_ [Formula: see text]D80 threshold of 137.035 Gy for the nasopharynx.

Nomograms containing body dose parameters for predicting survival in patients with nasopharyngeal carcinoma.

PURPOSE: To assess the impact of body dose on survival outcomes in nasopharyngeal carcinoma (NPC) patients and to create novel nomograms incorporating body dose parameters for predicting survival. METHODS: 594 of non-metastasis NPC patients (training group, 396; validation group, 198) received intensity-modulated radiation therapy at our institution from January 2012 to December 2016. Patient characteristics, body dose parameters in dose-volume histogram (DVH) and hematology profiles were collected for predicting overall survival (OS) and progression-free survival (PFS). Nomograms for OS and PFS were developed using the selected predictors. Each nomogram was evaluated based on its C-index and calibration curve. RESULTS: Body dose-based risk score for OS (RSOS), N stage, age, and induction chemotherapy were independent predictors for OS, with a C-index of 0.784 (95% CI 0.749-0.819) in the training group and 0.763 (95% CI 0.715-0.810) in the validation group for the nomogram. As for PFS, the most important predictors were the body dose-based risk score for PFS (RSPFS), N stage, and induction chemotherapy. C-index of PFS nomogram was 0.706 (95% CI 0.681-0.720) in the training group and 0.691 (95% CI 0.662-0.711) in the validation group. The two models outperformed the TNM staging system in predicting outcomes. CONCLUSIONS: Body dose coverage is a useful predictor of prognosis in clinical routine patients. The novel nomograms integrating body dose parameters can precisely predict OS and PFS in NPC patients.

Prognostic value of circulating Epstein-Barr virus DNA level post-induction chemotherapy for patients with nasopharyngeal carcinoma: A recursive partitioning risk stratification analysis.

BACKGROUND: To evaluate the prognostic value of plasma Epstein-Barr virus (EBV) DNA level post-induction chemotherapy (IC) for patients with nasopharyngeal carcinoma (NPC). METHODS: A total of 893 newly diagnosed NPC patients treated with IC were retrospectively reviewed. The recursive partitioning analysis (RPA) was performed to construct a risk stratification model. The receiver operating characteristic (ROC) analysis was applied to determine the optimal cut-off value of post-IC EBV DNA. RESULTS: Post-IC EBV DNA levels and overall stage were independent predictors for distant metastasis-free survival (DMFS), overall survival (OS), and progression-free survival (PFS). The RPA model base on post-IC EBV DNA and overall stage categorized the patients into three distinct risk groups: RPA I (low-risk: stage II-III and post-IC EBV DNA < 200 copies/mL), RPA II (median-risk: stage II-III and post-IC EBV DNA ≥ 200 copies/mL, or stage IVA and post-IC EBV DNA < 200 copies/mL), and RPA III (high-risk: stage IVA and post-IC EBV DNA ≥ 200 copies/mL), with 3-year PFS of 91.1%, 82.6%, and 60.2%, respectively (p < 0.001). The DMFS and OS rates in different RPA groups were also distinct. The RPA model showed better risk discrimination than either the overall stage or post-RT EBV DNA alone. CONCLUSIONS: Plasma EBV DNA level post-IC was a robust prognostic biomarker for NPC. We developed an RPA model that provides improved risk discrimination over the 8th edition of the TNM staging system by integrating the post-IC EBV DNA level and the overall stage.

Facile fabrication of hydrophilic covalent organic framework composites for highly selective enrichment of N-glycopeptides.

The development of facilely synthetic materials acts an essential role in glycoproteome analysis, especially for the highly efficient enrichment of N-linked glycopeptides. In this work, a facile and timesaving route was introduced in which COFTP-TAPT served as a carrier and poly (ethylenimine) (PEI) and carrageenan (Carr) were successively coated on the surface via electrostatic interaction. The resultant COFTP-TAPT@PEI@Carr showed remarkable performance in glycopeptide enrichment with high sensitivity (2 fmol µL-1), high selectivity (1:800, molar ratio of human serum IgG to BSA digests), large loading capacity (300 mg g-1), satisfactory recovery (102.4 ± 6.0%) and reusability (at least eight times). Due to the brilliant hydrophilicity and electrostatic interactions between COFTP-TAPT@PEI@Carr and positively charged glycopeptides, the prepared materials could be applied in the identification and analysis in the human plasma of healthy subjects and patients with nasopharyngeal carcinoma. As a result, 113 N-glycopeptides with 141 glycosylation sites corresponding to 59 proteins and 144 N-glycopeptides with 177 glycosylation sites corresponding to 67 proteins were enriched from 2 µL plasma trypsin digests of the control groups and patients with nasopharyngeal carcinoma, respectively. 22 glycopeptides were identified only from the normal controls and 53 glycopeptides were detected only from the other set. The results demonstrated that this hydrophilic material was promising on a large scale and further N-glycoproteome research.

Unraveling the patterns and pathways of local recurrence of nasopharyngeal carcinoma: evidence for individualized clinical target volume delineation.

BACKGROUNDS: Despite publication of international guidelines, there are notable controversial points of clinical target volume (CTV) delineation in nasopharyngeal carcinoma (NPC). Recently, scholars proposed a novel way of delineation of CTV in NPC-individualization of CTV delineation based on T classification and spread patterns, which yielded excellent long-term local control with limited late toxicities. The aim of this study was to clarify the anatomic patterns and pathways of local recurrence of NPC and provide a clinical reference for the delineation of CTV. METHODS: A total of 869 patients with non-metastatic NPC were treated with intensity-modulated radiation therapy (IMRT) at our institution between 2009 and 2010. Among the 57 cases of local/locoregional recurrence, 52 cases with traceable radiotherapy plans and magnetic resonance imaging at the time of the first diagnosis of recurrence were included. Anatomical structures and gross tumor volume of local recurrence were contoured. The incidence of relapse of each anatomic structure, route of local recurrence, and their correlation were analyzed. RESULTS: Locally advanced disease had a significantly increased risk of recurrence in the posterior nasal cavity and a trend towards higher risk of recurrence in the clivus, lateral pterygoid muscle, and hypoglossal canal. Based on the incidence of local recurrence, we constructed a high-risk map for the early and locally advanced stages. Local recurrences were classified into five routes, where anterior extension accounted for the majority (30.8%), and caudal tumor extension pathway had the lowest incidence (5.8%). There was a significant correlation between the local recurrences of neural foramina and neighboring anatomical structures along each pathway. All cases relapsed at unilateral cavernous sinus, most at the same side of primary tumor. Based on our findings, we proposed some suggestions on delineations of CTV, based on T classification and local extension pattern. CONCLUSIONS: Local recurrence of NPC varied according to T classification, followed a stepwise pattern, spread via neural foramina, and recurred at ipsilateral cavernous sinus. This provides meaningful clinical evidence for delineation of CTV, especially individualized delineation.

Radiotherapy Alone Versus Concurrent or Adjuvant Chemoradiotherapy for Nasopharyngeal Carcinoma Patients with Negative Epstein-Barr Virus DNA after Induction Chemotherapy.

The purpose of this study was to compare the efficacy and toxicity of induction chemotherapy (IC) plus radiotherapy (RT) and IC plus concurrent or adjuvant chemoradiotherapy (CCRT/AC) in nasopharyngeal carcinoma (NPC) patients with negative Epstein-Barr virus DNA (EBV DNA) after IC. A total of 547 NPC patients with negative plasma EBV DNA post-IC were included. Patients were classified into the IC + RT group and the IC + CCRT/AC group. Locoregional relapse-free survival (LRFS), distant metastasis-free survival (DMFS), overall survival (OS), and progression-free survival (PFS) were estimated and compared using the Kaplan-Meier method. Propensity score matching (PSM) was performed to balance the variables. The median follow-up time was 37 months. The 3-year LRFS, DMFS, OS, and PFS rates for the whole group were 92.2%, 92.4%, 96.4%, and 84.4%, respectively. There was no significant difference in LRFS, DMFS, OS, and PFS between the IC + RT and the IC + CCRT/AC groups, both before PSM (3-year rates of 91.1% vs. 92.6%, p = 0.94; 95.6% vs. 91.5%, p = 0.08; 95.2% vs. 96.8%, p = 0.80; 85.9% vs. 84.0%, p = 0.38) and after PSM (90.7% vs. 92.7%, p = 0.77; 96.8% vs. 93.7%, p = 0.29; 94.5% vs. 93.9%, p = 0.57; 84.7% vs. 85.6%, p = 0.96). Multivariate analysis demonstrated that the treatment schedule was not an independent predictor for survival rates. Patients in the IC + RT group had fewer treatment-related acute toxicities and better tolerance. IC + RT displayed similar survival outcomes as IC + CCRT/AC for NPC patients with negative post-IC EBV DNA.

Response to induction chemotherapy predicts survival outcomes in oropharyngeal cancer.

BACKGROUND: The role of induction chemotherapy (IC) in oropharyngeal squamous cell carcinoma (OPSCC) remains controversial. Its interpretation can be confounded by heterogeneity in chemosensitivity and human papillomavirus (HPV) status. This study aimed to investigate the prognostic impact of IC response in HPV-positive and -negative OPSCC. METHODS: Patients with OPSCC who underwent IC and concurrent chemoradiotherapy (CCRT) were retrospectively analyzed. Radiologic response to IC by ≥50% was defined as IC-sensitive (IC-s), while lesser response was deemed as IC-resistant (IC-r). Progression-free survival (PFS) and overall survival (OS) were compared between subgroups. RESULTS: A total of 51 HPV-positive and 57 HPV-negative patients were included. IC-s patients accounted for 55.6%, 62.7%, and 49.1% in the entire cohort, HPV-positive, and HPV-negative subgroup, respectively. Compared with IC-r subgroup, IC-s was associated with better clinical outcomes either in the entire cohort (3y-PFS 91.7%vs.43.7%, P < 0.001; 3y-OS 98.3% vs. 67.4%, P = 0.002), the HPV-positive subgroup (3-year PFS 94.7% vs. 47.9%, P < 0.001; 3-year OS 100% vs. 73.5%, P = 0.055) or the HPV-negative subgroup (3-year PFS 88.2% vs. 40.9%, P = 0.001; 3-year OS 96.4% vs. 63.1%, P = 0.026). Multivariate analysis demonstrated that response to IC represents an independent prognosticator for 3-year PFS (HR, 0.088; 95% CI, 0.027-0.289; P < 0.001) and 3-year OS (HR, 0.100; 95% CI, 0.021-0.477; P = 0.004). CONCLUSIONS: Response to IC exerts a critical predictive effect on prognosis of both HPV-positive and -negative OPSCC. Personalized treatment strategy based on IC response is worthy of further exploration in the future.

AntiPD-L1 antibody conjugated Au-SPIOs nanoplatform for enhancing radiosensitivity and triggering anti-tumor immune response.

To improve radiotherapy effect by inducing more toxicity for tumors and less for normal tissue and switching immunosuppressive microenvironment caused by expression of PD-L1 and tumor-associated macrophages (TAMs) to immunoreactive microenvironment, we designed a PD-L1-targeted nanoplatform consisting of gold nanoparticles and superparamagnetic iron oxide nanoparticles (antiPD-L1-SPIOs@PLGA@Au). In vivo T2-weighted images, the best contrast effect of tumor was achieved two hours after intravenous injection of antiPD-L1-SPIOs@PLGA@Au. The tumor control caused by irradiation combined with antiPD-L1-SPIOs@PLGA@Au was better than that by radiotherapy alone in clone formation assay and B16F10 subcutaneous tumor model. Radiosensitivity enhancement induced by the addition of antiPD-L1-SPIOs@PLGA@Au was achieved by increasing ROS production and attenuating DNA damage repair. AntiPD-L1-SPIOs@PLGA@Au could promote the polarization of tumor-associated macrophages (TAMs) to M1 and reverse the immunosuppression caused by TAMs. By increasing the expression of CRT in tumor and blocking the PD-L1/PD pathway, antiPD-L1-SPIOs@PLGA@Au with radiation activated the anti-tumor immune response. In conclusion, antiPD-L1-SPIOs@PLGA@Au could be used as a radiosensitizer and a MRI contrast targeting PD-L1, with the functions of blocking the PD-L1/PD-1 immune checkpoint pathway and reversing the immunosuppression caused by TAMs.

Failure pattern and suggestions for target volume delineation of carcinoma showing thymus-like differentiation treated with intensity-modulated radiotherapy.

BACKGROUND: To review our long-term clinical experience, analyze the failure patterns, and give suggestions for target volume delineation of carcinoma showing thymus-like differentiation (CASTLE) treated with intensity-modulated radiotherapy (IMRT). METHODS: From April 2008 to May 2019, 30 patients with CASTLE treated by postoperative or radical IMRT in our center were retrospectively reviewed. A total dose of 56-60 Gy in 28-30 fractions was prescribed to patients without residual disease and 66 Gy in 33 fractions for patients with residual or unresectable disease. Survival rates were calculated using the Kaplan-Meier method. Treatment-related toxicities were graded by National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 4.0. RESULTS: Among the 30 patients, 12 (40%) received partial resection or biopsy. Lateral lymph node metastasis was observed in 7 (23.3%) patients. During follow-up, regional lymph node recurrence occurred in 2 patients and distant metastasis in 5 patients. With a median follow-up time of 63.5 months, the 5-year local recurrence-free survival (LRFS), regional recurrence-free survival (RRFS), distant metastasis-free survival (DMFS), overall survival (OS) and progression-free survival (PFS) rates were 100, 88.9, 78.9, 93.1 and 78.9%, respectively. For patients with no lateral neck node metastasis, prophylactic radiotherapy for lateral neck nodal regions failed to improve RRFS (p = 0.381) and OS (p = 0.153). CONCLUSION: Distant metastasis was the major failure pattern for CASTLE after surgery and IMRT. For patients with no lateral neck node metastasis, the omission of irradiation for lateral neck nodal regions seems to be safe and feasible.

Revealing the crosstalk between nasopharyngeal carcinoma and immune cells in the tumor microenvironment.

Nasopharyngeal carcinoma (NPC) arises from the epithelial cells located in the nasopharynx and has a distinct geographic distribution. Chronic Epstein-Barr virus (EBV) infection, as its most common causative agents, can be detected in 100% of NPC types. In-depth studies of the cellular and molecular events leading to immunosuppression in NPC have revealed new therapeutic targets and diverse combinations that promise to benefit patients with highly refractory, advanced and metastatic NPC. This paper reviews the mechanisms by which NPC cells to circumvent immune surveillance and approaches being attempted to restore immunity. We integrate existing insights into anti-NPC immunity and molecular signaling pathways as well as targeting therapies in anticipation of broader applicability and effectiveness in advanced metastatic NPC.

Induction chemotherapy of modified docetaxel, cisplatin, 5-fluorouracil for laryngeal preservation in locally advanced hypopharyngeal squamous cell carcinoma.

BACKGROUND: Previous studies have investigated the value of induction chemotherapy (IC) in organ preservation strategies for head and neck cancers. This study evaluated the effectiveness of sequential IC with radiotherapy as a laryngeal preservation strategy for locally advanced hypopharyngeal carcinoma (LAHSCC). METHODS: One hundred and forty-two consecutive patients with LAHSCC were retrospectively analyzed who received three IC regimens from 2015 to 2019. RESULTS: In the TP (docetaxel plus cisplatin), TPF (TP plus 5-fluorouracil), and TPX (TP plus capecitabine) IC groups, there were 51, 29, and 62 patients, respectively. The primary tumor objective response rates were 51%, 55.2%, and 71%, and the 3-year survival rates with preserved larynx were 36.6%, 31.8%, and 51.2%, respectively (p = 0.03). There was no difference in overall survival and the adverse events were tolerable. CONCLUSIONS: The TPX regimen displayed good efficacy and safety, indicating its potential as a therapeutic IC regimen for LAHSCC.

Predictors of radiation-induced hypothyroidism in nasopharyngeal carcinoma survivors after intensity-modulated radiotherapy.

BACKGROUND: The aim of the study is to identify clinical and dosimetric factors that could predict the risk of hypothyroidism in nasopharyngeal carcinoma (NPC) patients following intensity-modulated radiotherapy (IMRT). METHODS: A total of 404 non-metastatic NPC patients were included in our study. All patients were treated with IMRT. The thyroid function were performed for all patients before and after radiation at regular intervals. The time onset for developing hypothyroidism was defined as the time interval between the completion of RT and the first recorded abnormal thyroid hormone test. The cumulative incidence rates of hypothyroidism were estimated using Kaplan-Meier method. Univariate and multivariate Cox regression analyses were performed to detect the most promising factors that were associated with hypothyroidism. RESULTS: Median follow up was 60.6 months. The 3-, 5- and 7- year cumulative incidence rate of hypothyroidism was 39.4%, 49.1% and 54.7%, respectively. The median time to primary hypothyroidism and central hypothyroidism were 15.4 months (range 2.9-83.8 months) and 29.9 months (range 19.8-93.6 months), respectively. Univariate and multivariate analyses revealed that younger age, female gender and small thyroid volume were the most important factors in predicting the risk of hypothyroidism. Dtmean (mean dose of thyroid), V30-V50 (percentage of thyroid volume receiving a certain dose level) and VS45-VS60 (the absolute volumes of thyroid spared from various dose levels) remained statistically significant in multivariate analyses. Cutoff points of 45 Gy (Dtmean), 80% (Vt40) and 5 cm3 (VS45Gy) were identified to classify patients as high-risk or low-risk group. CONCLUSION: Thyroid Vt40 highly predicted the risk of hypothyroidism after IMRT for NPC patients. We recommended plan optimization objectives to reduce thyroid Vt40 to 80%. TRIAL REGISTRATION: Retrospectively registered.

Dissecting the heterogeneity of the microenvironment in primary and recurrent nasopharyngeal carcinomas using single-cell RNA sequencing.

Nasopharyngeal carcinoma (NPC) has a 10-15% recurrence rate, while no long term or durable treatment options are currently available. Single-cell profiling in recurrent NPC (rNPC) may aid in designing effective anticancer therapies, including immunotherapies. For the first time, we profiled the transcriptomes of ∼60,000 cells from four primary NPC and two rNPC cases to provide deeper insights into the dynamic changes in rNPC within radiation fields. Heterogeneity of both immune cells (T, natural killer, B, and myeloid cells) and tumor cells was characterized. Recurrent samples showed increased infiltration of regulatory T cells in a highly immunosuppressive state and CD8+ T cells in a highly cytotoxic and dysfunctional state. Enrichment of M2-polarized macrophages and LAMP3+ dendritic cells conferred enhanced immune suppression to rNPC. Furthermore, malignant cells showed enhanced immune-related features, such as antigen presentation. Elevated regulatory T cell levels were associated with a worse prognosis, with certain receptor-ligand communication pairs identified in rNPC. Even with relatively limited samples, our study provides important clues to complement the exploitation of rNPC immune environment and will help advance targeted immunotherapy of rNPC.

Taxane/gemcitabine-containing chemotherapy plus locoregional IMRT for patients with de novo metastatic nasopharyngeal carcinoma: the treatment outcomes and prognostic factors analysis.

PURPOSE: To evaluate treatment outcomes of de novo metastatic nasopharyngeal carcinoma (mNPC) patients receiving taxane/gemcitabine-containing chemotherapy followed by locoregional intensity-modulated radiotherapy (IMRT) and analyze potential prognostic factors. METHODS: A total of 118 patients between March 2008 and November 2018 were retrospectively analyzed. All the patients were treated with taxane/gemcitabine-containing systemic chemotherapy followed by definitive locoregional IMRT. Potential prognostic factors including baseline absolute lymphocyte count (ALC) and the subdivision of metastasis were analyzed. RESULTS: The median follow-up time for the whole group was 31.5 months (range 5-138 months). Of the 118 patients, 9 (7.6%) patients experienced local regional failure and 60 (50.8%) patients had progression of distant metastasis. At the time of the last follow-up, 61 (51.7%) patients were dead. The 5-year actuarial progression free survival (PFS), overall survival (OS),distant metastasis relapse free survival (DMFS) and local regional recurrence free survival (LRFS) were 34.2%, 44%, 41.1% and 82.6%, respectively. Baseline lymphocyte count ≥ 1600/µl prior to the treatment conferred better locoregional control (5y-LRFS 96% vs. 64.7%, p < 0.001) and distant metastasis control (5y-MFS 50.4% vs. 32.4%, p = 0.023). The multivariate analysis showed that high lymphocyte count was the most relevant predictor of superior PFS (HR = 0.236, p < 0.001) and OS (HR = 0.518, p = 0.04). M subdivision was found as another independent prognostic factor for OS but not for PFS. CONCLUSION: Taxane/gemcitabine-containing chemotherapy combined with IMRT represents an effective treatment modality for mNPC. Baseline ALC is an independent significant prognostic factor for PFS and OS.

Local control and failure patterns after intensity modulated radiotherapy with reduced target volume delineation after induction chemotherapy for patients with T4 nasopharyngeal carcinoma.

BACKGROUND: The delineation of target volume after induction chemotherapy(IC) for nasopharyngeal carcinoma(NPC) is currently controversial. In this study, we aimed to analyze the long-term local control(LC) and failure patterns of T4 NPC treated with reduced target volume radiotherapy after IC. METHODS: From September 2007 to January 2013, 145 patients with T4 NPC were retrospectively reviewed. All patients received at least 1 cycle of IC followed by intensity modulated radiotherapy(IMRT). The gross tumor volume(GTV) was delineated according to the post-IC images for intracavity tumors and lymph nodes. The LC and overall survival (OS) rates were calculated using the Kaplan-Meier method. The location and extent of local failures were transferred to the pretreatment planning computed tomography (CT) for dosimetric analysis. RESULTS: With a median follow-up time of 95 months (range, 16-142 months), 23 local failures were found. The estimated 10-year LC and OS rates were 81.1%and 54.8% respectively. Among the 20 local failures with available diagnostic images, 18(90%) occurred within the 95% isodose lines and were considered in-field failures and 2(10%) were marginal. There was no outside-field failure. CONCLUSIONS: In-field failure was the major pattern of local failure for T4 NPC. IMRT with reduced target volume after IC seems to be feasible. Further researches exploring optimal volume and radiation dose for local advanced NPC in the era of IC are warranted.

Cancer of Pharyngoesophageal Junction: A Different Subtype From Hypopharyngeal and Cervical Esophageal Cancer?

BACKGROUND: Squamous cell cancers in the hypopharynx (HP) and cervical esophagus (CE) are different diseases with different staging systems and treatment approaches. Pharyngoesophageal junction (PEJ) tumor involves both the hypopharynx and the cervical esophagus simultaneously, but few reports focused on PEJ tumors. This study aimed to clarify clinical characteristics and the treatment approaches of PEJ tumors. PATIENTS AND METHODS: A total of 222 patients with squamous cell carcinoma in the HP, PEJ, and CE were collected between January 2008 and June 2018 in Fudan University Shanghai Cancer Center. We compared different lymph node metastatic patterns of three diseases above and the survival of different tumor locations, different lymph node metastasis, and different radiotherapy approaches. RESULTS: For HP, PEJ, and CE cancer, the upper and middle cervical lymph node metastatic rates were 85.7%, 47.1%, and 5.8%, respectively; the lower cervical lymph node metastatic rates were 36.7%, 42.9%, and 35.0%, respectively; and the mediastinal lymph node metastatic rates were 2.0%, 72.9%, and 80.6%, respectively. The 3-year overall survival rates were 69.5% in the HP group, 52.0% in the PEJ group, and 69.6% in the CE group (p = 0.024). No survival differences were found between the involved-field-irradiation and elective-node-irradiation subgroups among PEJ tumors (p = 0.717 for OS and p = 0.454 for PFS, respectively). CONCLUSION: HP cancers had a high prevalence in all cervical lymph node metastases, while CE cancers had a lower prevalence in the cervical and mediastinal lymph node metastases. PEJ cancer had the combined metastatic patterns of both HP and CE cancers. Involved field irradiation was feasible in chemoradiotherapy for PEJ cancers.

The impact of training sample size on deep learning-based organ auto-segmentation for head-and-neck patients.

To investigate the impact of training sample size on the performance of deep learning-based organ auto-segmentation for head-and-neck cancer patients, a total of 1160 patients with head-and-neck cancer who received radiotherapy were enrolled in this study. Patient planning CT images and regions of interest (ROIs) delineation, including the brainstem, spinal cord, eyes, lenses, optic nerves, temporal lobes, parotids, larynx and body, were collected. An evaluation dataset with 200 patients were randomly selected and combined with Dice similarity index to evaluate the model performances. Eleven training datasets with different sample sizes were randomly selected from the remaining 960 patients to form auto-segmentation models. All models used the same data augmentation methods, network structures and training hyperparameters. A performance estimation model of the training sample size based on the inverse power law function was established. Different performance change patterns were found for different organs. Six organs had the best performance with 800 training samples and others achieved their best performance with 600 training samples or 400 samples. The benefit of increasing the size of the training dataset gradually decreased. Compared to the best performance, optic nerves and lenses reached 95% of their best effect at 200, and the other organs reached 95% of their best effect at 40. For the fitting effect of the inverse power law function, the fitted root mean square errors of all ROIs were less than 0.03 (left eye: 0.024, others: <0.01), and theRsquare of all ROIs except for the body was greater than 0.5. The sample size has a significant impact on the performance of deep learning-based auto-segmentation. The relationship between sample size and performance depends on the inherent characteristics of the organ. In some cases, relatively small samples can achieve satisfactory performance.