LINC00324 suppresses apoptosis and autophagy in nasopharyngeal carcinoma through upregulation of PAD4 and activation of the PI3K/AKT signaling pathway.

BACKGROUND: Nasopharyngeal carcinoma (NPC) has high incidence in Southern China and is derived from the mucosal epithelium of the nasopharynx. Accumulating evidence has revealed that peptidyl arginine deiminase 4 (PAD4) exerts carcinogenic effect on certain cancers. We designed this study to probe the specific role that PAD4 plays in NPC and its molecular mechanism. METHODS: PAD4 expression in NPC cells was detected by RT-qPCR analysis. MTT, colony formation, flow cytometry, TUNEL staining, and LC3-II punctuation experiments were done to probe into the biological functions of PAD4 on NPC cellular behaviors in vitro. Subsequently, the upstream regulatory mechanism of PAD4 was investigated by luciferase reporter, RNA pull-down, and RIP assays. The impact of PAD4 on NPC tumor growth in mice was assessed by in vivo xenograft tumor assay. RESULTS: PAD4 was upregulated in NPC cells. PAD4 knockdown suppressed proliferative ability and promoted apoptosis and autophagy in NPC cells. Additionally, PAD4 expression was negatively regulated by microRNA 3164 (miR-3164). LINC00324 positively upregulated PAD4 expression by interacting with miR-3164 and recruiting HuR protein. The LINC00324/miR-3164/PAD4 axis modulated the PI3K/AKT pathway in NPC cells. Moreover, PAD4 upregulation countervailed the influences of LINC00324 deficiency on NPC cell proliferation, apoptosis, and autophagy and on NPC tumor growth in mice. CONCLUSION: LINC00324 promoted NPC malignancy by upregulation of PAD4 to activate the PI3K/AKT pathway.

PAD4 inhibitor promotes DNA damage and radiosensitivity of nasopharyngeal carcinoma cells.

Peptidylarginine deiminases 4 (PAD4), a kind of enzyme capable of converting protein arginine or mono-methylarginine into citrulline, has been identified to display a key role in diverse diseases. Radiotherapy is frequently used in nasopharyngeal carcinoma (NPC) treatment and induces DNA double strand breaks. In this study, whether PAD4 inhibitor YW3-56 affects the radiosensitivity of NPC cells was explored. RT-qPCR, immunofluorescence, western blot, clonogenic survival, and flow cytometry assays were used to assess the function of PAD4 and YW3-56 in NPC. We found the upregulation of PAD4 expression in NPC cells. PAD4 overexpression suppressed NPC cell apoptosis and promoted cell cycle, while PAD4 depletion had an opposite result. Moreover, the survival of NPC cells after irradiation was increased by overexpression of PAD4. PAD4 overexpression inhibited DNA damage and sensitivity of NPC cells to irradiation. Functional assays showed that YW3-56 treatment promoted DNA damage, apoptosis, and radiosensitivity of NPC cells. Importantly, YW3-56 treatment inhibited tumor growth in vivo. Overall, this study revealed the efficacy of PAD4 inhibitor YW3-56 in promoting sensitivity of NPC cells to irradiation.

MiR-30a-5p inhibits cell behaviors in esophageal cancer via modulating CBX2.

BACKGROUND: This investigation studied the impacts of the miR-30a-5p/CBX2 axis on esophageal cancer (EC). METHODS: Research objects were ascertained using The Cancer Genome Atlas database. Followed by qRT-PCR, western blot, dual-luciferase reporter, MTT, Transwell, and wound healing approaches, we tested gene expression and varying cell behaviors RESULTS: Conspicuously miR-30 family members (miR-30a-5p, miR-30b-5p, miR-30c-5p, miR-30d-5p, miR-30e-5p) downregulation and CBX2 upregulation were discovered in EC cells. miR-30 family members target CBX2 and inhibited CBX2 expression. EC cell behaviors were inhibited by miR-30a-5p/CBX2 axis. CONCLUSION: MiR-30a-5p draws a new inspiration for EC treatment.

Interobserver Variations in Target Delineation in Intensity-Modulated Radiation Therapy for Nasopharyngeal Carcinoma and its Impact on Target Dose Coverage.

BACKGROUND: To investigate the differences between physicians in target delineation in intensity-modulated radiation therapy for nasopharyngeal carcinoma as well as their impact on target dose coverage. METHODS: Ninety-nine in-hospital patients were randomly selected for retrospective analysis, and the target volumes were delineated by 2 physicians. The target volumes were integrated with the original plans, and the differential parameters, including the Dice similarity coefficient (DSC), Hausdorff distance (HD), and Jaccard similarity coefficient (JSC) were recorded. The dose-volume parameters to evaluate target dose coverage were analyzed by superimposing the same original plan to the 2 sets of images on which the target volumes were contoured by the 2 physicians. The significance of differences in target volumes and dose coverage were evaluated using statistical analysis. RESULTS: The target dose coverage for different sets of target volumes showed statistically significant differences, while the similarity metrics to evaluate geometric target volume differences did not. More specifically, for PGTVnx, the median DSC, JSC, and HD were 0.85, 0.74, and 11.73, respectively; for PCTV1, the median values were 0.87, 0.77, and 11.78, respectively; for PCTV2, the median values were 0.90, 0.82, and 16.12, respectively. For patients in stages T3-4, DSC, and JSC were reduced but HD was increased compared to those in stages T1-2. Dosimetric analysis indicated that, for the target volumes, significant differences between the 2 physicians were found in D95, D99, and V100 for all the target volumes (ie, PGTVnx, PCTV1, and PCTV2) across the whole group of patients, as well as in patients with disease stages T3-4 and T1-2. CONCLUSIONS: The target volumes delineated by the 2 physicians had a high similarity, but the maximal distances between the outer contours of the 2 sets were significantly different. In patients with advanced T stages, significant differences in dose distributions were found, stemming from the deviations of target delineation.

miR-3942-3p Increases the radiosensitivity of nasopharyngeal carcinoma through negatively regulating BARD1.

Nasopharyngeal carcinoma (NPC) has high incidence in China and East and Southeast Asia. The study was performed to investigate the effect of microRNA3942-3p (miR-3942-3p) on the radiosensitivity of NPC. Compared with non-cancer tissue, NPC had significantly lower miR-3942-3p expression. X-irradiation (IR) reduced the expression of miR-3942-3p in a dose-dependent way in NPC cells. Down-regulation of miR-3942-3p using miR-3942-3p inhibitor resulted in significantly increased cell viability, decreased apoptosis of CNE1 cells. Bax decreased and Bcl2 increased after IR. The expression of BARD1, a cancer predisposing gene, was elevated in NPC tissue. It was confirmed to be a target of miR-3942-3p using luciferase reporter assay. Down-regulation of BARD1 using siRNA significantly reduced cell viability and significantly increased apoptosis both before and after IR. The same response was observed when miR-3942-3p mimics was used to transfect BARD1-overexpressing CNE1 cells, suggesting the up-regulation of miR-3942-3p could sensitize CNE1 cells to X-rays via BARD1. Our data demonstrate that up-regulation of miR-3942-3p could sensitize NPC to X-rays via a downstream target BARD1, offering potential new strategies for radiotherapy of NPC.

Human papillomavirus infection can alter the level of tumour stemness and T cell infiltration in patients with head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) usually has a poor prognosis and is associated with a high mortality rate. Its etiology is mainly the result from long-term exposure to either alcohol, tobacco or human papillomavirus (HPV) infection or a combination of these insults. However, HNSCC patients with HPV have been found to show a survival advantage over those without the virus, but the mechanism that confers this advantage is unclear. Due to the large number of HPV-independent HNSCC cases, there is a possibility that the difference in prognosis between HPV-positive (HPV+) and negative (HPV-) patients is due to different carcinogens. To clarify this, we used scRNA data and viral tracking methods in order to identify HPV+ and HPV- cells in the tumour tissues of patients infected with HPV. By comparing HPV+ and HPV- malignant cells, we found a higher level of tumour stemness in HPV- tumour cells. Using tumour stemness-related genes, we established a six-gene prognostic signature that was used to divide the patients into low- and high-risk groups. It was found that HPV patients who were at low-risk of contracting HNSCC had a higher number of CD8+ T-cells as well as a higher expression of immune checkpoint molecules. Correspondingly, we found that HPV+ tumour cells expressed higher levels of CCL4, and these were highly correlated with CD8+ T cells infiltration and immune checkpoint molecules. These data suggest that the stemness features of tumour cells are not only associated with the prognostic risk, but that it could also affect the immune cell interactions and associated signalling pathways.

Tumor-Infiltrated CD8+ T Cell 10-Gene Signature Related to Clear Cell Renal Cell Carcinoma Prognosis.

Clear cell renal cell carcinoma (ccRCC) usually affects multiple organs (e.g., bone and brain), and patient prognosis is usually poor. Although it is known that CD8+ T cell infiltration can potentially alleviate ccRCC progression, few studies have concentrated on the correlation between CD8+ T cell infiltration and ccRCC prognosis. In this study, ten genes expressed by infiltrated CD8+ T cells (i.e., AMD1, CCSER2, CIB1, DRAP1, HMGB2, HMGN1, NPIPB5, PTP4A2, RORA, and SAP18) were suggested as potential ccRCC prognostic biomarkers, by using next-generation sequencing (i.e. bulk sequencing and single-cell sequencing) of ccRCC, papillary renal cell carcinoma (papRCC), and control kidney biopsies. Specifically, we identified four genes (i.e., CCSER2, DRAP1, NPIPB5, and SAP18) as potential novel prognostic biomarkers for ccRCC. It is noteworthy that SAP18 derived from CD8+ T cells negatively correlates to Atg7+ neutrophils in ccRCC, compared with papRCC, indicating a potential decreased neutrophil metabolic function in autophagy and fatty acids. This study elucidated the protective role of infiltrated CD8+ T cells in ccRCC and identified ten candidate genes related to an improved prognosis in patients with ccRCC.

Endostar, an Antiangiogenesis Inhibitor, Combined With Chemoradiotherapy for Locally Advanced Cervical Cancer.

This phase II randomized clinical trial aimed to assess the efficacy and toxicity of Endostar, an antiangiogenesis inhibitor, combined with concurrent chemoradiotherapy (CCRT) for locally advanced cervical cancer (LACC). Patients with LACC were randomly assigned to either CCRT plus Endostar (CCRT+E arm) or CCRT alone (CCRT arm). All patients received pelvic intensity-modulated radiation therapy (IMRT) and brachytherapy. Weekly cisplatin was administered concurrently with IMRT. Patients in the CCRT+E arm also received concurrent Endostar every 3 weeks for two cycles. The primary endpoint was progression-free survival (PFS) and acute toxicities. The exploratory endpoint was the impact of vascular endothelial growth factor receptor-2 (VEGFR2) expression on long-term survival. A total of 116 patients were enrolled. Patients in the CCRT+E arm and in the CCRT arm had similar acute and late toxicity profile. The 1- and 2-year PFS were 91.4% versus 82.1% and 80.8% versus 63.5% (p=0.091), respectively. The 1- and 2-year distance metastasis-free survival (DMFS) were 92.7% versus 81.1% and 86.0% versus 65.1% (p=0.031), respectively. Patients with positive VEGFR2 expression had significant longer PFS and overall survival (OS) compared with those with negative VEGFR2 expression. Patients in the CCRT+E arm had significantly longer PFS, OS, and DMFS than those in the CCRT arm when VEGFR2 expression was positive. In conclusion, CCRT plus Endostar significantly improved DMFS but not PFS over CCRT alone. The addition of Endostar could significantly improve survival for patients with positive VEGFR2 expression.

Hyperprogression After Immunotherapy for Primary Small Cell Neuroendocrine Carcinoma of the Ureter: A Case Report.

BACKGROUND: Primary small cell neuroendocrine carcinoma (SCNEC) in the ureter is extremely rare and has been sporadically reported in case reports. Its incidence, diagnosis, treatment, and outcomes have not yet been thoroughly understood. Here we present a patient with advanced SCNEC in the ureter who was treated by multimodal strategies. To the best of our knowledge, this is the first literature report about the clinical outcomes of the combination of programmed death ligand 1 (PD-L1) immune checkpoint inhibitors (ICIs) and radiotherapy in patient with primary ureteral SCNEC. CASE PRESENTATION: A 71-year old male presented with right flank pain and gross hematuria. A laparoscopic right nephroureterectomy was performed. He was diagnosed with primary ureteral SCNEC, pT3N0M0. Following the surgery, 4 cycles of adjuvant chemotherapy with carboplatin and etoposide (CE) were administered, with disease-free survival (DFS) of 10.1 months. He was then offered 4 cycles of palliative first-line chemotherapy with nedaplatin and irinotecan. The disease was continuously progressed, with progression-free survival (PFS) of 3.7 months. The patient subsequently received second-line treatment with PD-L1 ICI combined with radiotherapy. Unfortunately, hyperprogressive disease was found at the end of treatment. MRI and CT scan showed bilateral pubic bones, right acetabulum, and liver metastases. Without further intervention, the patient died from extensive metastatic disease 2 months after diagnosis, with overall survival (OS) of 18.2 months. CONCLUSION: Physicians must be aware of this rare and aggressive carcinoma at its initial presentation. Special attention should be paid to the potential likelihood of hyperprogression during the treatment.

A Clinical-Radiomics Nomogram Based on Computed Tomography for Predicting Risk of Local Recurrence After Radiotherapy in Nasopharyngeal Carcinoma.

Purpose: We aimed to establish a nomogram model based on computed tomography (CT) imaging radiomic signature and clinical factors to predict the risk of local recurrence in nasopharyngeal carcinoma (NPC) after intensity-modulated radiotherapy (IMRT). Methods: This was a retrospective study consisting of 156 NPC patients treated with IMRT. Radiomics features were extracted from the gross tumor volume for nasopharynx (GTVnx) in pretreatment CT images for patients with or without local recurrence. Discriminative radiomics features were selected after t-test and the least absolute shrinkage and selection operator (LASSO) analysis. The most stable model was obtained to generate radiomics signature (Rad_Score) by using machine learning models including Logistic Regression, K-Nearest neighbor, Naive Bayes, Decision Tree, Stochastic Gradient Descent, Gradient Booting Tree and Linear Support Vector Classification. A nomogram for local recurrence was established based on Rad_Score and clinical factors. The predictive performance of nomogram was evaluated by discrimination ability and calibration ability. Decision Curve Analysis (DCA) was used to evaluate the clinical benefits of the multi-factor nomogram in predicting local recurrence after IMRT. Results: Local recurrence occurred in 42 patients. A total of 1,452 radiomics features were initially extracted and seven stable features finally selected after LASSO analysis were used for machine learning algorithm modeling to generate Rad_Score. The nomogram showed that the greater Rad_Score was associated with the higher risk of local recurrence. The concordance index, specificity and sensitivity in the training cohort were 0.931 (95%CI:0.8765-0.9856), 91.2 and 82.8%, respectively; whereas, in the validation cohort, they were 0.799 (95%CI: 0.6458-0.9515), 79.4, and 69.2%, respectively. Conclusion: The nomogram based on radiomics signature and clinical factors can predict the risk of local recurrence after IMRT in patients with NPC and provide evidence for early clinical intervention.

Radiomics for Diagnosis and Radiotherapy of Nasopharyngeal Carcinoma.

Nasopharyngeal carcinoma (NPC) is a malignant tumor of the head and neck. The primary clinical manifestations are nasal congestion, blood-stained nasal discharge, headache, and hearing loss. It occurs frequently in Southeast Asia, North Africa, and especially in southern China. Radiotherapy is the main treatment, and currently, imaging examinations used for the diagnosis, treatment, and prognosis of NPC include computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET)-CT, and PET-MRI. These methods play an important role in target delineation, radiotherapy planning design, dose evaluation, and outcome prediction. However, the anatomical and metabolic information obtained at the macro level of images may not meet the increasing accuracy required for radiotherapy. As a technology used for mining deep image information, radiomics can provide further information for the diagnosis and treatment of NPC and promote individualized precision radiotherapy in the future. This paper reviews the application of radiomics in the diagnosis and treatment of nasopharyngeal carcinoma.

The Role of Dynamic Contrast-Enhanced Magnetic Resonance Imaging in Predicting Treatment Response for Cervical Cancer Treated with Concurrent Chemoradiotherapy.

PURPOSE: To evaluate the role of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in predicting early treatment response. MATERIALS AND METHODS: Patients with locally advanced cervical cancer (LACC) treated with concurrent chemoradiotherapy (CCRT) were enrolled. Pelvic DCE-MRI scans were performed before RT (pre-RT), in the middle of RT (mid-RT), and at the end of RT (post-RT), separately. Parameters (ie, Ktrans, Kep, and Ve) were measured. Pre-, mid-, and post-RT Ktrans were denoted as Ktrans-preTx, Ktrans-midTx, and Ktrans-postTx, respectively. And the same denoting rule also went for Kep and Ve. Difference for the same parameter such as Ktrans measured between two consecutive time points was calculated as second Ktrans value minus first Ktrans value. The differences in Ktrans between pre-RT and post-RT, between pre-RT and mid-RT, and between mid-RT and post-RT were denoted as ΔKtrans-post-preTx, ΔKtrans-mid-preTx, and ΔKtrans-post-midTx, respectively, and the same denoting rule was also applied to Kep and Ve. RESULTS: A total of 57 patients were enrolled. After the treatment, 31 patients had complete response (CR group). The remaining 26 patients had partial response (NCR group). Significant differences were found in Ktrans-postTx, Kep-postTx, Ve-midTx, ΔKtrans-post-preTx, ΔKtrans-post-midTx, ΔKep-post-preTx, ΔKep-mid-preTx and ΔKep-post-midTx between the two groups. Receiver operating characteristic (ROC) analysis for their performances in predicting treatment response showed an area under curve (AUC) of 0.656-0.849, sensitivity of 61.3-93.5%, specificity of 46.1-73.1%, and maximal Youden Index of 36.5-66.6. Among those parameters, Kep-postTx was the best, and its AUC, sensitivity, specificity, maximal Youden Index, and cutoff value were 0.849, 87.1%, 73.1%, 60.2, and 0.341, respectively. These combined parameters showed an AUC of 0.952, with sensitivity of 87.1%, specificity of 96.1%, and maximal Youden Index of 83.2. CONCLUSION: DCE-MRI parameters can predict early treatment outcome. Among those parameters, Kep-postTx is the best predictor. The combination of multi-parameters can increase the predictive potency.

Transcriptome Profiling Reveals B-Lineage Cells Contribute to the Poor Prognosis and Metastasis of Clear Cell Renal Cell Carcinoma.

Although immune therapy can improve the treatment of clear cell renal cell carcinoma (ccRCC) significantly, there are still a large proportion of ccRCC patients who progress to metastasis. Targeting the pro-metastatic immune cell in the ccRCC microenvironment could provide a solution to this problem. In this study, B cells in ccRCC biopsies were identified by using scRNA-seq and flow cytometry. The findings indicated the presence of a pro-metastatic B cell type which could be further classified into 3 subpopulations, MARCH3, B2M and DTWD1, based on their large-scaled genetic profiles, rather than traditional Immature/Mature ones. Although all of the 3 subpopulations appeared to contribute to distant metastasis, B cell (B2M) was deemed to be the most essential. Moreover, STX16, CLASRP, ATIC, ACIN1 and SEMA4B, were genes found to be commonly up-regulated in the 3 subpopulations and this was correlated to a poor prognosis of ccRCC. Furthermore, the heterogeneity of plasma cells in ccRCC was also found to contribute to metastasis of the disease. This study offers potential novel therapeutic targets against distant metastasis of cancers, and can help to improve the therapeutic efficiency of ccRCC patients.

Long-Term Results of Concurrent Chemoradiotherapy Combined with Anti-EGFR Monoclonal Antibody Prior to Surgery in Locally Advanced Cervical Cancer: A Single-Institute Prospective Study.

PURPOSE: We aimed to evaluate the long-term survival outcomes of concurrent chemoradiotherapy (CCRT) combined with nimotuzumab followed by surgery in patients with locally advanced cervical cancer (LACC). PATIENTS AND METHODS: Patients received whole pelvic intensity-modulated radiation therapy (IMRT) and concomitantly with weekly cisplatin (40 mg/m2) or nedaplatin (30 mg/m2) and weekly nimotuzumab (200 mg). After assessment of the treatment response, patients then underwent radical surgery. RESULTS: Between June 2013 and July 2016, 33 patients with FIGO IB2-IIIB cervical cancer were recruited. Clinical complete response and partial response were observed in 8 (24.3%) and 23 patients (69.7%), respectively. Twenty-seven patients (81.8%) were successfully treated with radical hysterectomy and pelvic lymphadenectomy: 9 (33.3%) showed pathological complete response; 10 (37.1%) showed partial response and 8 (29.6%) presented with persistent macroscopic/microscopic residual carcinoma. For the intention-to-treat population, the median follow-up time was 53.7 months. Locoregional recurrence and distant metastases were observed in three and seven patients, respectively. The 5-year overall survival, progression-free survival, locoregional recurrence-free survival, and distant metastasis-free survival were 81.5%, 72.7%, 90.9%, and 78.3%, respectively. Both acute and late toxicities were manageable and mainly limited to grade 1 or 2. CONCLUSION: Concurrent chemoradiotherapy combined with nimotuzumab followed by surgery for patients with LACC is safe and results in excellent long-term treatment outcomes. Further randomized controlled studies are warranted to confirm the findings.

Association of Twice-Daily Radiotherapy With Subsequent Brain Metastases in Adults With Small Cell Lung Cancer.

Importance: Although thoracic twice-daily radiotherapy (TDRT) is one of the standards of care for small cell lung cancer, its association with brain metastases remains unknown. Objective: To investigate the association of TDRT vs once-daily radiotherapy (ODRT) with brain metastases after prophylactic cranial irradiation in patients with small cell lung cancer. Design, Setting, and Participants: In this multicenter cohort study, data on 778 consecutive patients with small cell lung cancer who had undergone thoracic radiotherapy (609 received ODRT and 169 received TDRT), chemotherapy, and prophylactic cranial irradiation were retrieved from the databases of 8 hospitals in China between July 1, 2003, and June 30, 2016. A 1:1 propensity score matching approach was used to control for confounding between the ODRT and TDRT groups. Confounding covariates included 8 demographic variables and 8 treatment-related covariates. Data analysis was conducted from November 1, 2017, to May 31, 2018, and reanalyzed for revision. Exposures: The ODRT group received 50 to 66 Gy given in 25 to 33 fractions. The TDRT group received 45 Gy given in 30 fractions. Main Outcomes and Measures: The primary end point was brain metastases. Secondary end points included progression-free survival and overall survival. Results: Of the 778 patients (median age, 55 years [interquartile range, 48-61 years]), 204 were women and 574 were men. At a median follow-up of 23.6 months (interquartile range, 14.2-38.2 months), 131 patients (16.8%) experienced brain metastases. The rate of brain metastasis at 3 years in the TDRT group was significantly higher than in the ODRT group (26.0% vs 16.9%; hazard ratio, 1.55; 95% CI, 1.06-2.26; P = .03). Of the 338 matched patients (169 in the ODRT group vs 169 in the TDRT group), 60 (17.8%) experienced brain metastases, with a rate at 3 years of 14.9% in the ODRT group vs 26.0% in the TDRT group (hazard ratio, 1.71; 95% CI, 1.02-2.88; P = .04). Progression-free survival was similar in both the whole cohort and the matched cohort. Median overall survival in the ODRT group tended to be significantly longer than in the TDRT group after matching (47.2 vs 32.8 months; hazard ratio, 1.41; 95% CI, 0.99-2.01; P = .06). Conclusions and Relevance: In this study, patients with small cell lung cancer who received thoracic TDRT appeared to have a higher risk of brain metastases than those who received ODRT, which supports the need for further prospective randomized clinical trials, especially in China and other parts of Asia.

The current status of intensity-modulated radiation therapy in the treatment of nasopharyngeal carcinoma.

Radiation therapy is the mainstay of treatment in nasopharyngeal carcinoma, alone or in combination with chemotherapy. In the early stage, it can be managed by radiotherapy alone. For locally advanced-stage disease, several meta-analyses have demonstrated the role of concurrent chemoradiotherapy. Conventional radiation therapy results in significant side effects, particular xerostomia, leading to poor quality of life. With the maturity of intensity-modulated radiation therapy in the recent 10 years, more and more evidences have shown the advantages of intensity-modulated radiation therapy over conventional radiation therapy, regarding the local-regional control, survival rate and quality of life. This article reviews the utilization of intensity-modulated radiation therapy in the management of nasopharyngeal carcinoma with respect to its technical advantages, clinical outcome, critical organ sparing and quality of life, and the dilemma in target delineation. In particular, an issue of treatment-related dysphagia will also be discussed.

A prospective study on neoadjuvant chemoradiotherapy plus anti-EGFR monoclonal antibody followed by surgery for locally advanced cervical cancer.

BACKGROUND: To investigate the efficacy and safety of neoadjuvant chemoradiotherapy plus anti-epidermal growth factor receptor monoclonal antibody followed by surgery for locally advanced cervical cancer (LACC). PATIENTS AND METHODS: Patients with histologically proven LACC were enrolled into this prospective study. All patients received intensity-modulated radiation therapy with conventional fractionation. Weekly cisplatin or nedaplatin was administered concurrently with intensity-modulated radiation therapy. Nimotuzumab, a humanized anti-epidermal growth factor receptor monoclonal antibody, was given at a dose of 200 mg per week for 6 cycles. Approximately 1 month after the completion of neoadjuvant treatment, the patients were assessed for clinical tumor response and operability based on MRI and gynecological examination. For those who were considered to be candidates for surgery, radical hysterectomy, and pelvic lymph node dissection were performed 5-6 weeks after the completion of neoadjuvant therapy. RESULTS: Twenty-eight patients were enrolled. Clinical complete response and partial response were found in 8 (28.5%) and 20 (71.5%) patients, respectively. Four patients were not eligible for surgery and 2 patients refused surgery although they were assessed as surgical candidates. They were not included in this analysis. Radical hysterectomy and pelvic lymph node dissection were performed for the remaining 22 patients. Among them, 8 (36.4%) had complete pathology response, 9 (40.9%) presented with persistent atypical cells or cervical intraepithelial neoplasia, and 5 (22.7%) presented with macroscopic and/or microscopic residual disease, according to the pathological evaluation. Median follow-up time was 22 months (range, 5-39 months). The 2-year locoregional control rate, progression-free survival rate, distant metastasis-free survival rate, and overall survival rate were 95.0%, 85.2%, 84.0%, and 90.0%, respectively. Acute toxicities were mild in general and easily manageable. Chronic toxicities were mainly limited to grade 1. No severe late toxicities were observed. CONCLUSION: Concurrent chemoradiotherapy plus nimotuzumab followed by surgery is highly effective and safe in LACC. Further studies are warranted to confirm the findings.

Health-related quality-of-life outcomes following IMRT versus conventional radiotherapy for oropharyngeal squamous cell carcinoma.

PURPOSE: To compare health-related quality-of-life (HRQOL) outcomes of patients with oropharyngeal squamous cell carcinoma treated using intensity-modulated radiotherapy (IMRT) vs. conventional radiotherapy (CRT). PATIENTS AND METHODS: Patients with oropharyngeal squamous cell carcinoma were extracted from the database of an ongoing longitudinal Outcome Assessment Project. Eligible criteria included (1) treated with definitive radiation, and (2) provided 12-month posttreatment HRQOL data. Excluded were 7 patients who received IMRT before October 1, 2002, during this institution's developmental phase of the IMRT technique. The HRQOL outcomes of patients treated with IMRT were compared with those of patients who received CRT. RESULTS: Twenty-six patients treated using IMRT and 27 patients treated using CRT were included. Patients in the IMRT group were older and had more advanced-stage diseases and more patients received concurrent chemotherapy. However, the IMRT group had higher mean Head and Neck Cancer Inventory scores (which represent better outcomes) for each of the four head-and-neck cancer-specific domains, including eating, speech, aesthetics, and social disruption, at 12 months after treatment. A significantly greater percentage of patients in the CRT group had restricted diets compared with those in the IMRT group (48.0% vs. 16.0%, p = 0.032). At 3 months after treatment, both groups had significant decreases from pretreatment eating scores. However, the IMRT group had a significant improvement during the first year, but the CRT group had only small improvement. CONCLUSIONS: Proper delivery of IMRT can improve HRQOL for patients with oropharyngeal cancer compared with CRT.

The failure patterns of oral cavity squamous cell carcinoma after intensity-modulated radiotherapy-the university of iowa experience.

PURPOSE: Determine the failure patterns of oral cavity squamous cell carcinoma (SCC) treated with intensity-modulated radiotherapy (IMRT). METHODS AND MATERIALS: Between May 2001 and July 2005, 55 patients with oral cavity SCC were treated with IMRT for curative intent. Forty-nine received postoperative IMRT, 5 definitive IMRT, and 1 neoadjuvant. Three target volumes were defined (clinical target CTV1, CTV2, and CTV3). The failure patterns were determined by coregistration or comparison of the treatment planning computed tomography to the images obtained at the time of recurrence. RESULTS: The median follow-up for all patients was 17.1 months (range, 0.27-59.3 months). The median follow-up for living patients was 23.9 months (range, 9.3-59.3 months). Nine patients had locoregional failures: 4 local failures only, 2 regional failures only, and 3 had both local and regional failures. Five patients failed distantly; of these, 3 also had locoregional failures. The 2-year overall survival, disease-specific survival, local recurrence-free survival, locoregional recurrence-free survival, and distant disease-free survival was 68%, 74%, 85%, 82%, and 89%, respectively. The median time from treatment completion to locoregional recurrence was 4.1 months (range, 3.0-12.1 months). Except for 1 patient who failed in contralateral lower neck outside the radiation field, all failed in areas that had received a high dose of radiation. The locoregional control is strongly correlated with extracapsular extension. CONCLUSIONS: Intensity-modulated RT is effective for oral cavity SCC. Most failures are in-field failures. Further clinical studies are necessary to improve the outcomes of patients with high-risk features, particularly for those with extracapsular extension.

Three-Phase Adaptive Radiation Therapy for Patients With Nasopharyngeal Carcinoma Undergoing Intensity-Modulated Radiation Therapy: Dosimetric Analysis.

Patients with nasopharyngeal carcinoma undergoing intensity-modulated radiation therapy may experience significant anatomic changes throughout the entire treatment course, and adaptive radiation therapy may be necessary to maintain optimal dose delivered both to the targets and to the critical structures. The timing of adaptive radiation therapy, however, is largely unknown. This study was to evaluate the dosimetric benefits of a 3-phase adaptive radiation therapy technique for nasopharyngeal carcinoma. Twenty patients with nasopharyngeal carcinoma treated with intensity-modulated radiation therapy were recruited prospectively. After fractions 5 and 15, each patient had repeat computed tomography scans, and adaptive replans with recontouring the targets and organs at risk on the new computed tomography images were generated and used for subsequent treatment (replan 1 and replan 2). Two hybrid intensity-modulated radiation therapy plans (plan 1 and plan 2) were generated by superimposing the initial plan (plan 0) to each repeated new computed tomography image, reflecting the actual dose delivered to the targets and organs at risk if no changes were made to the original plan. Dosimetric comparisons were made between the adaptive replans (adaptive radiation therapy plans: plan 0 + replan 1 + replan 2) and their corresponding nonadaptive radiation therapy plans (plan 0 + plan 1 + plan 2). Comparing with the nonadaptive radiation therapy plans, the adaptive radiation therapy plans resulted in a significant improvement in conformity index for planning target volumes for primary disease, involved lymph node, high-risk clinical target volume, and low-risk clinical target volume (PTVnx, PTVnd, PTV1, and PTV2, respectively). Median V95 for PTVnx; D95, D99, V100, V95, and V93 for PTVnd; D99 and V100 for PTV1; and D95, D99, V100, V95, and V93 for PTV2 were increased significantly. There were significant dose-volume reductions, including maximum doses to the brainstem and temporal lobes, mean doses to the glottis, V50 for the supraglottis, Dmean and V30 for the left parotid, median dose to the right optic nerve, and V55 for the skin. The 3-phase adaptive intensity-modulated radiation therapy for patients with nasopharyngeal carcinoma results in improvements in target coverage and conformity index and decreased doses to some organs at risk.