MST1 Negatively Regulates TNFα-Induced NF-κB Signaling through Modulating LUBAC Activity.

The nuclear factor (NF)-κB pathway plays a central role in inflammatory and immune responses, with aberrant activation of NF-κB signaling being implicated in various human disorders. Here, we show that mammalian ste20-like kinase 1 (MST1) is a previously unrecognized component of the tumor necrosis factor α (TNFα) receptor 1 signaling complex (TNF-RSC) and attenuates TNFα-induced NF-κB signaling. Genetic ablation of MST1 in mouse embryonic fibroblasts and bone marrow-derived macrophages potentiated the TNFα-induced increase in IκB kinase (IKK) activity, as well as the expression of NF-κB target genes. TNFα induced the recruitment of MST1 to TNF-RSC and its interaction with HOIP, the catalytic component of the E3 ligase linear ubiquitin assembly complex (LUBAC). Furthermore, MST1 activated in response to TNFα stimulation mediates the phosphorylation of HOIP and thereby inhibited LUBAC-dependent linear ubiquitination of NEMO/IKKγ. Together, our findings suggest that MST1 negatively regulates TNFα-induced NF-κB signaling by targeting LUBAC.

MST1 mediates the N-methyl-D-aspartate-induced excitotoxicity in mouse cortical neurons.

Excessive activation of the ionotropic N-methyl-D-aspartate (NMDA) receptor has been shown to cause abnormally high levels of Ca2+ influx, thereby leading to excitotoxic neuronal death. In this study, exposure of mouse primary cortical neurons to NMDA resulted in the cleavage and activation of mammalian sterile 20-like kinase-1 (MST1), both of which were mediated by calpain 1. In vitro cleavage assay data indicated that calpain 1 cleaves out the autoinhibitory domain of MST1 to generate an active form of the kinase. Furthermore, calpain 1 mediated the cleavage and activation of wild-type MST1, but not of MST1 (G339A). Intriguingly, NMDA/calpain-induced MST1 activation promoted the nuclear translocation of the kinase and the phosphorylation of histone H2B in mouse cortical neurons, leading to excitotoxicity. Thus, we propose a previously unrecognized mechanism of MST1 activation associated with NMDA-induced excitotoxic neuronal death.

Analysis of PET parameters as prognosticators of survival and tumor extent in Oropharyngeal Cancer treated with surgery and postoperative radiotherapy.

BACKGROUND: Positron-emission tomography (PET) is widely used to detect malignancies, but consensus on its prognostic value in oropharyngeal cancer has not been established. The purpose of this study was to analyze the PET parameters associated with tumor extent and survival in resectable oropharyngeal cancer. METHODS: The PET parameters in oropharyngeal cancer patients with regional node metastasis who underwent surgery and postoperative radiotherapy between January 2005 and January 2019 were analyzed. We calculated the SUVmax, tumor-to-liver ratio (TLR), metabolic tumor volume (MTV, volume over SUV 2.5), and total lesion glycolysis (TLG, MTV x mean SUV) of the primary lesion and metastatic nodes. Histologic findings, patient survival, and recurrence were reviewed in the medical records. RESULTS: Fifty patients were included, and the PET parameters were extracted for 50 primary lesions and 104 nodal lesions. In the survival analysis, MTV and TLG of the primary lesions showed significant differences in overall survival (OS) and recurrence-free survival (RFS). In the multiple regression analysis, TLG of the primary lesion was associated with the depth of invasion (DOI). MTV of the nodes was a significant factor affecting extranodal extension (ENE). CONCLUSIONS: PET parameters could be related with OS, RFS, DOI of the primary tumor, and ENE. PET would be expected to be a useful diagnostic tool as a prognosticator of survival and pathologic findings in oropharyngeal cancer.

Lymphovascular Invasion Increases the Risk of Nodal and Distant Recurrence in Node-Negative Stage I-IIA Non-Small-Cell Lung Cancer.

OBJECTIVES: Despite complete surgical resection, 30-40% of patients with stage I-IIA non-small-cell lung cancer (NSCLC) have recurrences. We aimed to elucidate the effect of lymphovascular invasion (LVI) on the prognosis and patterns of recurrence in patients with pathologically confirmed T1-2N0 NSCLC. METHODS: We evaluated 381 patients who underwent complete resection and were diagnosed with pathologic T1-2N0 NSCLC between March 2000 and January 2012. Local recurrence, nodal recurrence, and distant metastasis were defined and analyzed. RESULTS: LVI was present in 72 patients (18.9%). The 5-year disease-free survival (DFS) for all patients was 69.9%. Patients with LVI showed a significant decrease in 5-year DFS (47.3 vs. 74.4%, p < 0.001). LVI was a significant prognostic predictor in multivariate analysis (p = 0.003). The patients with LVI showed a significantly increased 5-year cumulative incidence of nodal recurrence (22.5 vs. 8.7%, p < 0.001) and distant metastasis (30.4 vs. 14.9%, p = 0.004). However, no difference was shown between the two groups in the 5-year cumulative incidence of local recurrence (p = 0.416). CONCLUSIONS: LVI is a negative prognostic factor in patients with stage I-IIA NSCLC. The presence of LVI significantly increases the risk of nodal and distant recurrence.

Intracranial control and survival outcome of tyrosine kinase inhibitor (TKI) alone versus TKI plus radiotherapy for brain metastasis of epidermal growth factor receptor-mutant non-small cell lung cancer.

INTRODUCTION: The efficacy of tyrosine kinase inhibitors (TKIs) with and without radiotherapy (RT) has not been determined in patients with brain metastases from epidermal growth factor receptor-mutant TKI naïve non-small cell lung cancer (NSCLC). METHODS: Between 2008 and 2016, 586 patients were diagnosed with NSCLC and treated with TKIs at a hospital in Seoul, South Korea; 81 of these patients met the eligibility criteria for our study. Outcomes analyzed included intracranial progression (ICP), neurological death, and overall survival (OS). RESULTS: The 2-year cumulative incidence of ICP was 36.5% in the TKI plus RT group and 62.2% in the TKI alone group (P = 0.006). The chronological pattern analysis indicated that 64.3% of ICP developed within 12 months of the start of TKI treatment in the TKI alone group. The multivariate analysis revealed that treatment group (P = 0.003) and duration of TKI treatment ≤ 12 months (P < 0.001) were significantly associated with ICP. However, no significant differences were observed in the 2-year OS rate (P = 0.267) or the 2-year cumulative incidence of neurological death (P = 0.740). CONCLUSIONS: Cumulative incidence of ICP was significantly lower with TKI plus RT than with TKI alone; however, there was no significant difference in OS or neurological death. Deferring brain RT may not compromise neurologic and survival outcome in selected patients, but close magnetic resonance imaging follow-up is recommended for patients who defer brain RT.

Chemoradiotherapy versus surgery followed by postoperative radiotherapy in tonsil cancer: Korean Radiation Oncology Group (KROG) study.

BACKGROUND: Treatment of tonsil cancer, a subset of oropahryngeal cancer, varies between surgery and radiotherapy. Well-designed studies in tonsil cancer have been rare and it is still controversial which treatment is optimal. This study aimed to assess the outcome and failure patterns in tonsil cancer patients treated with either approaches. METHODS: We retrospectively reviewed medical records of 586 patients with tonsil cancer, treated between 1998 and 2010 at 16 hospitals in Korea. Two hundred and one patients received radiotherapy and chemotherapy (CRT), while 385 patients received surgery followed by radiotherapy and/or chemotherapy (SRT). Compared with the SRT group, patients receiving CRT were older, with more advanced T stage and received higher radiotherapy dose given by intensity modulation techniques. Overall survival (OS), disease-free survival (DFS), locoregional recurrence-free survival (LRRFS), distant metastasis-free survival (DMFS), and clinicopathologic factors were analyzed. RESULTS: At follow-up, the 5-year OS, DFS, LRRFS and DMFS rates in the CRT group were 82, 78, 89, and 94%, respectively, and in the SRT group were 81, 73, 87, and 89%, respectively. Old age, current smoking, poor performance status, advanced T stage, nodal involvement, and induction chemotherapy were associated with poor OS. Induction chemotherapy had a negative prognostic impact on OS in both treatment groups (p = 0.001 and p = 0.033 in the CRT and SRT groups, respectively). CONCLUSIONS: In our multicenter, retrospective study of tonsil cancer patients, the combined use of radiotherapy and chemotherapy resulted in comparable oncologic outcome to surgery followed by postoperative radiotherapy, despite higher-risk patients having been treated with the definitive radiotherapy. Induction chemotherapy approaches combined with either surgery or definitive radiotherapy were associated with unfavorable outcomes.

Magnetic resonance imaging during definitive chemoradiotherapy can predict tumor recurrence and patient survival in locally advanced cervical cancer: A multi-institutional retrospective analysis of KROG 16-01.

OBJECTIVE: Definitive chemoradiotherapy (CRT) followed by brachytherapy is a standard treatment for locally advanced cervical cancer. During CRT, marked reduction of cervical tumor is often observed in magnetic resonance imaging (MRI). The primary aim of this study was to assess the association between tumor response in MRI using FIGO classification and clinical outcomes. METHODS: Multi-institutional data were retrospectively reviewed to identify the significance of MR tumor response on tumor recurrence and patient survival. 225 patients with histologically confirmed squamous cell carcinoma of the cervix, staged as FIGO Ib2-IVa on initial pelvic MRI, were included. Post-CRT MRI was performed median 35days after the beginning of CRT and before brachytherapy. A median 54Gy of external radiation was given with weekly cisplatin during CRT. RESULTS: 112 (49.7%) of the 225 patients showed a positive response in post-CRT MRI and were named the responsive arm. After a median follow-up time of 36.2months, the responsive arm had significantly lower para-aortic recurrence (7.5% vs. 12.4%; p=0.04) and distant metastasis (13.2% vs. 27.6%; p=0.03) rates than did the non-responsive arm. The responsive arm had significantly higher 3-year cause-specific survival rate (94.6% vs. 81.1%, p<0.01) than did the non-responsive arm. In the multivariate analysis, tumor size (hazard ratio, 1.91 and 95% confidence interval, 1.07-3.43; p=0.028) and positive MR response (hazard ratio, 1.75 and 95% confidence interval, 1.06-2.27; p=0.045) were significant factors for recurrence-free survival CONCLUSION: Early tumor response evaluation with MRI using FIGO classification effectively predicted distant tumor metastasis and disease-specific survival in locally advanced cervical cancer.

IMRT vs. 2D-radiotherapy or 3D-conformal radiotherapy of nasopharyngeal carcinoma : Survival outcome in a Korean multi-institutional retrospective study (KROG 11-06).

OBJECTIVE: We compared treatment outcomes of two-dimensional radiotherapy (2D-RT), three-dimensional conformal radiotherapy (3D-CRT), and intensity-modulated radiotherapy (IMRT) in patients with nasopharyngeal carcinoma (NPC). PATIENTS AND METHODS: In total, 1237 patients with cT1-4N0-3M0 NPC were retrospectively analyzed. Of these, 350, 390, and 497 were treated with 2D-RT, 3D-CRT, and IMRT, respectively. RESULTS: 3D-CRT and IMRT showed better 5-year overall survival (OS) rates (73.6 and 76.7 %, respectively) than did 2D-RT (5-year OS of 59.7 %, all p < 0.001). In T3-4 subgroup, IMRT was associated with a significantly better 5-year OS than was 2D-RT (70.7 vs. 50.4 %, respectively; p ≤ 0.001) and 3D-CRT (70.7 vs. 57.8 %, respectively; p = 0.011); however, the difference between the 2D-RT and 3D-CRT groups did not reach statistical significance (p = 0.063). In multivariate analyses of all patients, IMRT was a predictive factor for OS when compared with 2D-RT or 3D-CRT, as was 3D-CRT when compared with 2D-RT. CONCLUSION: Our study showed that 3D-CRT and IMRT were associated with a better local progression-free survival and OS than was 2D-RT in NPC. IMRT was significantly superior in terms of OS for advanced primary tumors (T3-4).

Safety and Efficacy of HL301 In Radiation Pneumonitis in Patients With Unresectable Non-Small Cell Lung Cancer Receiving Curative Concurrent Chemoradiotherapy: A Multicenter, Randomized, Double-Blinded, Placebo-Controlled, Phase 2a Clinical Trial.

PURPOSE: We aimed to investigate the safety and efficacy of HL301, a standardized combination product of 7 medicinal plants, in radiation pneumonitis in patients with unresectable non-small cell lung cancer undergoing curative concurrent chemoradiotherapy. METHODS AND MATERIALS: The target accrual was 87 and a total of 63 patients were enrolled due to poor accrual rate. We randomly assigned the 63 patients to receive a placebo (arm A), or 1200 mg HL301 (arm B), or 1800 mg HL301 (arm C). Patients received weekly paclitaxel and carboplatin concurrently with intensity-modulated radiation therapy at 60 to 66 Gy in conventional fractionation. Durvalumab was administered as a maintenance treatment according to standard clinical practice. HL301 was administered orally, daily for 12 weeks. The primary endpoint was incidence of grade ≥2 radiation pneumonitis at 24 weeks postchemoradiotherapy. RESULTS: The baseline characteristics of the patients were well balanced. The drug was tolerable with a compliance rate of 86.6%, 86.2%, and 88.8% in arms A, B, and C, respectively (P = .874). None of the patients experienced severe drug-related adverse events. No significant difference in the rate of adverse events were observed between the treatment arms. The incidence of grade ≥2 radiation pneumonitis at 24 weeks postchemoradiotherapy was 37.5% (95% CI, 18.5%-61.4%), 55.6% (95% CI, 33.7%-75.4%), and 52.4% (95% CI, 32.4%-71.7%) in arms A, B, and C, respectively (P = .535). CONCLUSIONS: This is the first exploratory clinical trial to test the safety and efficacy of HL301 in patients with non-small cell lung cancer. Safety and feasibility of HL301 were established but no signals of efficacy in reducing radiation pneumonitis was observed in this dose level.

Evidence-based clinical recommendations for hypofractionated radiotherapy: exploring efficacy and safety - Part 2. Lung (non-small cell lung cancer).

Several recent studies have investigated the use of hypofractionated radiotherapy (HFRT) for various cancers. However, HFRT for non-small cell lung cancer (NSCLC) with or without concurrent chemotherapy is not yet widely used because of concerns about serious side effects and the lack of evidence for improved treatment results. Investigations of HFRT with concurrent chemotherapy in NSCLC have usually been performed in single-arm studies and with a small number of patients, so there are not yet sufficient data. Therefore, the Korean Society for Radiation Oncology Practice Guidelines Committee planned this review article to summarize the evidence on HFRT so far and provide it to radiation oncology clinicians. In summary, HFRT has demonstrated promising results, and the reviewed data support its feasibility and comparable efficacy for the treatment of locally advanced NSCLC. The incidence and severity of esophageal toxicity have been identified as major concerns, particularly when treating large fraction sizes. Strategies, such as esophagus-sparing techniques, image guidance, and dose constraints, may help mitigate this problem and improve treatment tolerability. Continued research and clinical trials are essential to refine treatment strategies, identify optimal patient selection criteria, and enhance therapeutic outcomes.

Evidence-based clinical recommendations for hypofractionated radiotherapy: exploring efficacy and safety - Part 1. Brain and head and neck.

Advances in radiotherapy (RT) techniques, including intensity-modulated RT and image-guided RT, have allowed hypofractionation, increasing the fraction size over the conventional dose of 1.8-2.0 Gy. Hypofractionation offers advantages such as shorter treatment times, improved compliance, and under specific conditions, particularly in tumors with a low α/ß ratio, higher efficacy. It was initially explored for use in RT for prostate cancer and adjuvant RT for breast cancer, and its application has been extended to various other malignancies. Hypofractionated RT (HFRT) may also be effective in patients who are unable to undergo conventional treatment owing to poor performance status, comorbidities, or old age. The treatment of brain tumors with HFRT is relatively common because brain stereotactic radiosurgery has been performed for over two decades. However, re-irradiation of recurrent lesions and treatment of elderly or frail patients are areas under investigation. HFRT for head and neck cancer has not been widely used because of concerns regarding late toxicity. Thus, we aimed to provide a comprehensive summary of the current evidence for HFRT for brain tumors and head and neck cancer and to offer practical recommendations to clinicians faced with the challenge of choosing new treatment options.

When Should Spinal Surgery Be Considered for Spinal Metastasis from Non-Small Cell Lung Cancer?-Propensity Score Matched Study between Surgery with Radiotherapy and Radiotherapy Alone.

(1) Background: Although metastatic spine disease is increasing, the debate on therapeutic modality remains due to the heterogeneity of tumors and patients. This study aims to evaluate the efficacies of surgery and risk factors for patients' survival from potentially unstable spinal metastasis of non-small cell lung cancer; (2) Methods: Twenty-two patients undergoing surgery and radiotherapy (group I) were compared with 22 patients undergoing radiotherapy alone (group II) using propensity score matching in a 1-to-1 format. Clinical outcomes included the performance status and ambulatory status. In addition, independent risk factors for patients' survival were evaluated, including the molecular targeted therapy for mutations; (3) Results: deterioration in neurologic status was only observed in group II compared to group I (22.7% vs. 0%, p-value = 0.018). In addition, five patients in the surgery group showed improved Frankel grades. Regarding the patients' survival, a smoking history of more than ten pack-years (hazard ratio (HR) = 12.18), worse performance status (HR = 6.86), and absence of mutations (HR = 3.39) were the independent risk factors; (4) Conclusions: Spinal surgery with radiotherapy could have advantages for improving the neurologic status including ambulation for potentially unstable spine due to metastasis. Thus, surgery should be considered for patients with a longer life expectancy resulting from better performance status and use of the targeted therapy.

The Updated World Health Organization Classification Better Predicts Survival in Patients With Endocervical Adenocarcinoma (KROG 20-07).

PURPOSE: The 2020 World Health Organization classification divided endocervical adenocarcinoma (ADC) into human papillomavirus-associated (HPVA) and human papillomavirus-independent (HPVI) ADCs. This multi-institutional study aimed to investigate the clinical features and prognosis of patients with endocervical ADC based on the updated World Health Organization classification. METHODS AND MATERIALS: We retrospectively reviewed the 365 patients with endocervical ADC who underwent radical hysterectomy from 7 institutions. Tumor characteristics, patterns of failure, and survival outcomes were compared between HPVA and HPVI ADCs. RESULTS: Two hundred seventy-five (75.3%) and 90 (24.7%) patients had HPVA and HPVI ADC diagnoses, respectively. In all cases, the 5-year disease-free survival (DFS) and overall survival (OS) rates were 58.2% and 71.3%, respectively. HPVI ADC showed higher rates of local recurrence (25.6% vs 10.9%) and distant metastasis (33.3% vs 17.5%) than HPVA ADC. Multivariate survival analysis revealed that HPVI ADC showed significantly worse DFS (hazard ratio [HR], 1.919; 95% confidence interval [CI], 1.324-2.781; P < .001), distant metastasis-free survival (HR, 2.100; 95% CI, 1.397-3.156; P < .001), and OS (HR, 2.481; 95% CI, 1.586-3.881; P < .001) than HPVA ADC. Patients with gastric- and serous-type HPVI ADC had significantly worse OS than those with other HPVI ADCs (P = .020). Similarly, invasive stratified mucin-producing-type HPVA ADC showed significantly worse OS than other HPVA ADCs (P < .001). CONCLUSIONS: We demonstrated that HPVI ADC exhibited inferior DFS and OS and higher rates of local and distant recurrence compared with HPVA ADC. Gastric- and serous-type HPVI ADCs and invasive stratified mucin-producing-type HPVA ADC showed worse OS than other types of HPVI and HPVA ADCs, respectively. Our observation of significant differences in prognoses according to the histologic types needs to be validated in larger cohorts of patients with endocervical ADC.

Lymphovascular invasion is a significant prognosticator in rectal cancer patients who receive preoperative chemoradiotherapy followed by total mesorectal excision.

PURPOSE: This study was designed to identify the significance of lymphovascular invasion as a prognosticator for tumor recurrence and survival in rectal cancer patients treated with preoperative chemoradiotherapy (CRT) and total mesorectal excision (TME). METHODS: Between January 2003 and October 2010, the study included 328 patients with primary rectal cancer who had received preoperative CRT followed by TME. We analyzed the clinicopathologic factors that may be associated with survival, such as age, gender, carcinoembryonic antigen (CEA) value, pathologic T and N stage, tumor response, histologic grade, lymphovascular invasion (LVI), and perineural invasion. RESULTS: Higher pathologic T and N stage, poor tumor response, high-grade histology, and positive LVI were adverse prognostic factors for both disease-free survival (DFS) and overall survival (OS) on the multivariate analysis. Perineural invasion was a significant adverse prognostic factor affecting DFS (P=0.046) but not OS (P=0.08). Increased T and N stage and distant recurrence, but not local recurrence, were significant factors associated with LVI. The LVI-negative group had a higher DFS (71.4 vs. 56.2%, P=0.012) and OS rate (86.7 vs. 63.4%, P=0.020) at 5 years than the LVI-positive group did. CONCLUSIONS: Positive LVI had a negative impact on survival in patients with rectal cancer who received preoperative CRT and TME and is significantly associated with an increased chance of distant recurrence. Based on this finding, more tailored adjuvant chemotherapy is warranted for advanced rectal cancer patients with LVI to reduce the distant dissemination of tumor.

The relevance of serum carcinoembryonic antigen as an indicator of brain metastasis detection in advanced non-small cell lung cancer.

Although many biomarkers have emerged in non-small cell lung cancer (NSCLC), the predictive value of site-specific spread is not fully defined. We designed this study to determine if there is an association between serum biomarkers and brain metastasis in advanced NSCLC. We evaluated 227 eligible advanced NSCLC patients between May 2005 and March 2010. Patients who had been newly diagnosed with stage IV NSCLC but had not received treatment previously, and had available information on at least one of the following pretreatment serum biomarkers were enrolled: carcinoembryonic antigen (CEA), cytokeratin 19 fragments (CYFRA 21-1), cancer antigen 125 (CA 125), cancer antigen 19-9, and squamous cancer cell antigen. Whole body imaging studies and magnetic resonance imaging of the brain were reviewed, and the total number of metastatic regions was scored. Brain metastasis was detected in 66 (29.1%) patients. Although serum CEA, CYFRA 21-1, and CA 125 levels were significantly different between low total metastatic score group (score 1-3) and high total metastatic score group (score 4-7), only CEA level was significantly different between patients with brain metastasis and those without brain metastasis (p < 0.0001). The area under the receiver operating curve of serum CEA for the prediction of brain metastasis was 0.724 (p = 0.0001). The present study demonstrated that the pretreatment serum CEA level was significantly correlated with brain metastasis in advanced NSCLC. These findings suggested the possible role of CEA in the pathogenesis of brain invasion. More vigilant surveillance would be warranted in the high-risk group of patients with high serum CEA level and multiple synchronous metastasis.

Current Evidence of a Deintensification Strategy for Patients with HPV-Related Oropharyngeal Cancer.

Human papillomavirus (HPV)-related oropharyngeal cancer differs from HPV-negative oropharyngeal cancer in terms of etiology, epidemiology, and prognosis. Younger and lower comorbidity patient demographics and favorable prognosis allow HPV-related oropharyngeal cancer patients to anticipate longer life expectancy. Reducing long-term toxicities has become an increasingly important issue. Treatment deintensification to reduce toxicities has been investigated in terms of many aspects, and the reduction of radiotherapy (RT) dose in definitive treatment, replacement of platinum-based chemotherapy with cetuximab, response-tailored dose prescription after induction chemotherapy, and reduction of adjuvant RT dose after transoral surgery have been evaluated. We performed a literature review of prospective trials of deintensification for HPV-related oropharyngeal cancer. In phase II trials, reduction of RT dose in definitive treatment showed comparable survival outcomes to historical results. Two phase III randomized trials reported inferior survival outcomes for cetuximab-based chemoradiation compared with cisplatin-based chemoradiation. In a randomized phase III trial investigating adjuvant RT, deintensified RT showed noninferior survival outcomes in patients without extranodal extension but worse survival in patients with extranodal extension. Optimal RT dosage and patient selection require confirmation in future studies. Although many phase II trials have reported promising outcomes, the results of phase III trials are needed to change the standard treatment. Since high-level evidence has not been established, current deintensification should only be performed as part of a clinical study with caution. Implementation in clinical practice should not be undertaken until evidence from phase III randomized trials is available.

Oncologic outcomes according to the level of disease burden in patients with metachronous distant metastases from uterine cervical cancer: a Korean Radiation Oncology Group study (KROG 18-10).

OBJECTIVE: This study aimed to evaluate the oncologic outcomes according to disease burden in uterine cervical cancer patients with metachronous distant metastases. METHODS: Between 2005 and 2015, 163 patients with metachronous distant metastases from uterine cervical cancer after receiving a definitive therapy were evaluated at seven institutions in Korea. Low metastatic burden was defined as less than 5 metastatic sites, whereas high metastatic burden was others. Each metastasis site was divided based on the lymph node (LN) and organs affected. The overall survival (OS) and progression-free survival (PFS) were assessed. Cox proportional hazards models, including other clinical variables, were used to evaluate the survival outcomes. RESULTS: The median follow-up duration was 22.2 months (range: 0.3-174.8 months). Para-aortic LNs (56.4%), lungs (26.4%), supraclavicular LNs (18.4%), and peritoneum (13.5%) were found to be the common metastasis sites. Among 37 patients with a single metastasis, 17 (45.9%) had LN metastases and 20 (54.1%) had organ metastases. The 1- and 2-year OS rates were 73.9% and 55.0%, respectively, whereas the PFS rates were 67.2% and 42.9%, respectively. SCC Ag after recurrence and high metastatic burden were significant factors affecting the OS (p=0.004 and p<0.001, respectively). Distant organ recurrence, short disease-free interval (≤2 years), and high metastatic burden were unfavorable factors for PFS (p=0.003, p=0.011, and p=0.002, respectively). CONCLUSION: A favorable oncologic outcome can be expected by performing salvage treatments in selected patients with a long disease-free interval, low metastatic burden, and/or lymphatic-only metastasis.

Importance of lymph node ratio in HPV-related oropharyngeal cancer patients treated with surgery and adjuvant treatment.

OBJECTIVES: The pathologic nodal stage of human papillomavirus (HPV)-related oropharyngeal cancer (OPC) patients is classified according to the number of lymph nodes (LNs), as revised in 2018. Previous studies showed that the LN ratio (LNR) could be also a significant prognostic factor in head and neck cancer, but there are few studies on the LNR in HPV-related [HPV(+)] OPC. The aim of the present study was to analyze the predictive value of the LNR for survival and recurrence in HPV(+) OPC patients. MATERIALS AND METHODS: HPV(+) OPC patients treated with surgery with or without postoperative radiotherapy from January 2000 to March 2019 were evaluated. The patients were divided into two sets of three groups, according to LN numbers based on pathologic nodal stages, and LNRs by a cutoff value of 0.05. The medical records were reviewed, and the overall survival (OS), disease-free survival, locoregional recurrence, and distant metastasis incidence were analyzed. RESULTS: Ninty patients were included and the median follow-up period was 38.2 months. There were no significant differences in OS in the LN number groups. However, there was a significant difference in OS in the LNR groups (P = 0.010). The incidence of distant metastasis in the LNR groups was significantly different (P = 0.005). CONCLUSION: The LNR in HPV(+) OPC patients may be a more useful tool to predict survival and distant metastasis than the LN number. Additional research and consensus on surgical pathology are needed before applying the LNR to adjuvant treatment decisions and pathologic nodal staging.

Prognostic significance of expression of VEGF and Cox-2 in nasopharyngeal carcinoma and its association with expression of C-erbB2 and EGFR.

BACKGROUND AND OBJECTIVES: This study evaluated several tumor angiogenesis-related markers to examine their expression pattern and relation to clinicopathologic implications of nasopharyngeal carcinoma. METHODS: Paraffin sections from 69 nasopharyngeal carcinomas obtained before radiotherapy were prepared. The expression of vascular endothelial growth factor (VEGF), cyclooxygenase-2 (Cox-2), C-erbB2, and epidermal growth factor receptor (EGFR) were investigated by immunohistochemistry and then correlated with various clinicopathologic parameters. RESULTS: VEGF was inversely correlated with C-erbB2 (P = 0.036). In survival analysis, high mitosis (≥5/10 high power field) was significantly associated with worse relapse-free survival in univariate analysis (P = 0.048) but not in multivariate analysis (P = 0.153). High stage, high mitotic rate, absence of VEGF, and presence of Cox-2 were associated with worse survival in both univariate analysis (P = 0.002, P = 0.038, P = 0.044, and P = 0.028, respectively) and multivariate analysis (P = 0.007, P = 0.036, P = 0.047, and P = 0.004, respectively). CONCLUSIONS: Absence of VEGF is a useful indicator of poor prognosis in addition to Cox-2 expression, high stage, and high mitosis.

Early risk-assessment of patients with nasopharyngeal carcinoma: the added prognostic value of MR-based radiomics.

OBJECTIVES: To assess the additive prognostic value of MR-based radiomics in predicting progression-free survival (PFS) in patients with nasopharyngeal carcinoma (NPC) METHODS: Patients newly diagnosed with non-metastatic NPC between June 2006 and October 2019 were retrospectively included and randomly grouped into training and test cohorts (7:3 ratio). Radiomic features (n=213) were extracted from T2-weighted and contrast-enhanced T1-weighted MRI. The patients were staged according to the 8th edition of American Joint Committee on Cancer Staging Manual. The least absolute shrinkage and selection operator was used to select the relevant radiomic features. Univariate and multivariate Cox proportional hazards analyses were conducted for PFS, yielding three different survival models (clinical, stage, and radiomic). The integrated time-dependent area under the curve (iAUC) for PFS was calculated and compared among different combinations of survival models, and the analysis of variance was used to compare the survival models. The prognostic performance of all models was validated using a test set with integrated Brier scores. RESULTS: This study included 81 patients (training cohort=57; test cohort=24), and the mean PFS was 57.5 ± 43.6 months. In the training cohort, the prognostic performances of survival models improved significantly with the addition of radiomics to the clinical (iAUC, 0.72-0.80; p=0.04), stage (iAUC, 0.70-0.79; p=0.001), and combined models (iAUC, 0.76-0.81; p<0.001). In the test cohort, the radiomics and combined survival models were robustly validated for their ability to predict PFS. CONCLUSION: Integration of MR-based radiomic features with clinical and stage variables improved the prediction PFS in patients diagnosed with NPC.