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Purpose/objective(s) Definitive chemoradiation is essential in non-operative thoracic esophageal cancer. Concerns have posed onto the possible radiation-induced lymphopenia and correlation with different survival outcomes. Neutrophil to lymphocyte ratio (NLR) is a simple way to surrogate the inflammation-immunity status and predict survival. We aim to evaluate the clinical variables and radiation dosimetric parameters associated with hematologic variables changes. Materials/methods Between 2010 and 2015, we identified 93 newly diagnosed thoracic esophageal squamous-cell cancer patients who had completed definitive concurrent chemoradiotherapy (CCRT). Patients' clinical, dosimetric, and hematological data, including absolute neutrophil count, absolute lymphocyte count, and NLR were analyzed at baseline and during CCRT. Cox regression model and Kaplan-Meier analyses were used to validate different survival outcomes. The possible relationships between clinical, hematologic, and dosimetric variables were tested using Spearman's rank or Pearson correlation coefficients, and a further multivariable logistic regression model was created to verify these significant variables. Results The participant group (mean age = 58.6 y) predominantly comprised males (94%) with 27% stage II (n = 25) and 73% stage III (n = 68). Median overall survival (OS) was 13 months (95% confidence interval: 10.304-15.696). We confirmed that baseline NLR (NLR-b) and highest NLR during CCRT (NLR-h) significantly predicted OS, progression-free survival, disease-specific survival, and freedom from distant metastasis. Dichotomized NLR-b with > 3.68 or ≤3.68 also predicted the survival outcomes. Primary esophageal tumor length (Spearman's correlation coefficient r = 0.324, P = 0.011) and baseline body weight (Spearman's r = -0.251, P = 0.019) were significantly correlated with baseline NLR > 3.68. In multivariable logistic regression, primary esophageal tumor length (OR = 1.345, P = 0.021) remained associated with a higher NLR-b. For NLR-h, lung V5 (Pearson r = 0.254, P = 0.014) and V10 (Pearson r = 0.317, P = 0.002) were significantly correlated. In the percentage of ALC nadir decreased during CCRT, lung V5 (Pearson r = 0.299, P = 0.005) and heart V10 (Pearson r = 0.273, P = 0.011) were significantly correlated. Conclusion Inflammation predicts survival outcomes and is correlated with tumor size. Low-dose thoracic irradiation affects inflammation-immunity dynamics because lung V5 and V10 are related to NLR-h; lung V5 and heart V10 with extent of lymphocyte decrease. A novel approach to decrease these unnecessary exposures may further improve survival outcomes in esophageal cancer treated with CCRT.

Objective: Cardiovascular events induced in breast cancer patients receiving radiotherapy (RT), chemotherapy (CT), or a combination of both (CRT) can increase the risk of death. This nationwide population-based study aims to estimate the risk of cardiovascular complications with a follow-up period of 5 years. Materials and Methods: The study cohorts consisted of all patients hospitalized with a principal diagnosis of breast cancer who underwent treatment in 2002. The Cox proportional hazard model and Kaplan–Meier plot were analyzed to compare the cardiovascular event-free survival rate among breast cancer patients treated with different modalities. Results: Of the 5514 breast cancer patients identified, 289 patients had cardiovascular disease (CVD): 110 (5.7%) from the surgery-alone group, 24 (4.1%) from the RT group, 79 (4.6) from the CT group, and 76 (5.8%) from the CRT group. Breast cancer patients who undergo CT and CRT at an age less than 55 years had a higher risk of CVD when compared with the surgery-alone group (for both groups, p

Objective Rituximab is a commonly used treatment for CD20-positive B-cell lymphoma. Late onset neutropenia (LON) has been identified as a complication associated with rituximab. FcgRIIIa 158 V/F polymorphism has been correlated with LON. We want to explore the relation between FcgRIIIa 158 V/F polymorphism and survival outcome. Materials and Methods We examined a cohort of patients with newly diagnosed CD20-positive B-cell lymphoma who were treated with rituximab-based therapy. We identified patients with LON and analyzed their characteristics and survival outcomes. Furthermore, we used a multiplex polymerase chain reaction to detect FcgRIIIa 158 V/F polymorphism and correlated this with LON. After a 10-year follow-up, we analyzed the survival outcomes between groups with different FcgRIIIa polymorphisms. Results Seventy-two consecutive patients with CD20-positive B-cell lymphoma patients were examined. Eleven (15.2%) of these patients developed LON. The V/V and V/F polymorphisms were significantly associated with the occurrence of LON (p = 0.031), yielding an odds ratio for the development of LON of 1.47 (95% confidence interval, 1.21–1.78). The log-rank test showed no overall survival difference both in the occurrence of LON and different polymorphisms. Conclusion The FcgRIIIa polymorphism was significantly associated with development of LON. Furthermore, neither FcgRIIIa polymorphism nor LON predicted a patient's survival outcome according to the results of a long-term follow-up study.

Summary Objectives In resected buccal cancer patients, an unexpected close surgical margin has been observed to correlate with poor clinical outcomes. However, close surgical margin alone does not independently guide post-operative therapies, revealing a clinical debate. Hence, the present study intended to explore epigenetic-based bio-predictors for further stratifying this debating patient population. Materials and methods Between 2000 and 2008, we retrospectively recruited 44 resected buccal cancer patients with a close surgical margin of ⩽5 mm. All patients had post-operative radiotherapy. Genomic DNA was extracted from tumor-enrich areas that contained cancer cells of >70%. Methylation-specific PCR was performed to detect promoter methylation of four tumor suppressor genes, including RASSF1A, DAPK, IRF8, and SFRP1. Post-irradiation locoregional control was defined as the primary end point. Results There were 40 males and 4 females, with a median age of 53.5 years (range, 32–82 years). Multivariate analysis identified two independent predictors for locoregional recurrence: very close margin of ⩽1 mm (HR: 4.96; 95% CI, 1.63–15.09; P = 0.018) and promoter hypermethylation of DAPK (HR: 2.83; 95% CI, 1.05–7.63; P = 0.042). The highest risk of locoregional recurrence was observed in patients with both of the two factors (HR, 8.05; 95% CI, 2.56–25.82; P = 0.002) when compared with patients with none. Shorter disease-free survival, but not overall survival, was also observed. Conclusion More aggressive managements should be considered in resected buccal cancer patients with both very close margin and DAPK promoter hypermethylation rather than post-operative observation or radiotherapy alone.

Objectives A close margin of ≤3 mm results in a high risk for locoregional recurrence, but still is not an independent factor that helps to guide the use of aggressive postoperative therapies in patients with resected buccal mucosa carcinoma. This suggests there is a diversity of clinical outcomes in this group of patients. The present study explores the predictors among this clinically debated group of patients. Materials and Methods From 2000 to 2008, 30 resected buccal mucosa carcinoma patients with a close margin of ≤3 mm were retrospectively included in this study. All patients were treated with radical surgery together with postoperative radiotherapy (RT) or chemoradiotherapy (CCRT). Locoregional/local/regional control, disease-free status, disease-specific survival and overall survival were the study end points. Results Two factors were observed that were able to predict 5-year locoregional control. These were a pathological N classification (pN0 vs. pN1-2, 71.5% vs. 30.0%, p = 0.044) and a very close margin (> 1 mm vs. ≤1 mm, 81.8% vs. 50.7%, p = 0.040). Remarkably, the predicting effect of a very close margin was well translated into disease-free status (81.8% vs. 47.1%, p = 0.024) and disease-specific survival (100% vs. 70.6%, p = 0.037). After multivariate analysis, a very close margin of ≤1 mm was found to independently predict a high risk of locoregional recurrence (HR, 9.528; 95% CI, 1.326–18.481; p = 0.025) and disease failure at any site (HR, 12.778; 95% CI, 1.934–25.217; p = 0.013). Conclusion More aggressive postoperative treatments should be considered for resected buccal mucosa carcinoma patients with a very close margin of ≤1 mm.

Purpose Increasing the sensitivity of tumor cells to radiation is a major goal of radiotherapy. The present study investigated the radiosensitizing effects of andrographolide and examined the molecular mechanisms of andrographolide-mediated radiosensitization. Methods and Materials An H- ras -transformed rat kidney epithelial (RK3E) cell line was used to measure the radiosensitizing effects of andrographolide in clonogenic assays, 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide assays, and a xenograft tumor growth model. The mechanism of andrographolide-sensitized cell death was analyzed using annexin V staining, caspase 3 activity assays, and terminal transferase uridyl nick end labeling assays. The roles of nuclear factor kappa B (NF-κB) and Akt in andrographolide-mediated sensitization were examined using reporter assays, electrophoretic mobility shift assays, and Western blotting. Results Concurrent andrographolide treatment (10 μM, 3 h) sensitized Ras-transformed cells to radiation in vitro (sensitizer enhancement ratio, 1.73). Andrographolide plus radiation (one dose of 300 mg/kg peritumor andrographolide and one dose of 6 Gy radiation) resulted in significant tumor growth delay (27 ± 2.5 days) compared with radiation alone (22 ± 1.5 days; p e.g., caspase-3, membrane reversion, DNA fragmentation), and andrographolide treatment did not promote radiation-induced apoptosis. However, the protein level of activated Akt was significantly reduced by andrographolide. NF-κB activity was elevated in irradiated Ras-transformed cells, and andrographolide treatment significantly reduced radiation-induced NF-κB activity. Conclusion Andrographolide sensitized Ras-transformed cells to radiation both in vitro and in vivo . Andrographolide-mediated radiosensitization was associated with downregulation of Akt and NF-κB activity. These observations indicate that andrographolide is a novel radiosensitizing agent with potential application in cancer radiotherapy.

Purpose To test, in a retrospective matched-pair study, whether necrosis-rescuing hyperbaric oxygen therapy (HBOT) increases the risk of cancer re-recurrence in patients with locoregionally recurrent and then successfully salvaged head-and-neck cancers. Methods and materials Between January 1995 and July 2004, we retrospectively identified 22 patients with locoregionally recurrent and then successfully salvaged head-and-neck cancers. We defined two groups: the HBOT group, 11 patients with HBOT for rescuing late radiation-associated tissue necroses; and the non-HBOT group, the other 11 matched-pair patients without HBOT. Between the two groups, the following four factors were matched for case pairing: primary cancer subsite, initial cancer stage, age, and gender. Results Three findings indicate that HBOT increases the risk of cancer re-recurrence. First, we observed more cancer re-recurrences in the HBOT group than in the non-HBOT group: 9 of 11 vs. 4 of 11, with 5-year disease-free survival rates after salvage of 32.7% vs. 70.0% (hazard ratio 3.2; 95% confidence interval 1.03–10.7; p = 0.048). Second, re-recurrences developed rapidly after HBOT in 6 patients. Third, 3 patients had unusual cancer re-recurrences after HBOT. Remarkably, of 9 patients with cancer re-recurrences in the HBOT group, 4 patients had cancer disease-free intervals of 9 months or less before HBOT. Conclusions Necrosis-rescuing HBOT should be given with caution in patients with locoregionally recurrent and then successfully salvaged head-and-neck cancers; if it cannot be omitted entirely, deferring HBOT 9 months or longer after cancer re-treatment may be prudent.

Background and purpose This study examined the efficacy of parotid gland sparing of three-dimensional conformal radiotherapy (3DCRT) compared with conventional radiotherapy for NPC patients. Both the dose given to the parotids and clinical assessment of dry mouth were conducted. Materials and methods Dry mouth was assessed for 108 patients treated with conventional technique and 72 treated with 3DCRT. Dose analysis was performed in 48 patients of the 3DCRT group. A dose of 70 Gy was given to the midplane in conventional radiotherapy and to 90% isodose volume in 3DCRT. Prognostic factors affecting the severity of dry mouth were analyzed using Generalized Estimating Equation (GEE). Results In the 3DCRT group about 50% of the patients' parotid glands received less than 25 Gy. Parallel analysis of dry mouth shows a significant decrease in the incidence of severe xerostomia after 3DCRT. The proportion of patients without dry mouth was also significantly higher in the 3DCRT group than the conventional group at 1–3 years after completion of radiotherapy. Although 3DCRT delivered a higher dose to the tumor, it spared the parotid gland significantly better than the conventional treatment. Late toxicities were mostly similar between the 2 groups while local control in T4 patients and survival were improved for 3DCRT. Conclusion Dosimetrically and clinically 3DCRT is better than conventional technique regarding parotid gland protection.

Purpose: To present our experience using a twice-daily radiotherapy (RT) technique, including hyperfractionated and accelerated-hyperfractionated RT, on nasopharyngeal carcinoma (NPC) patients. The dose to the primary tumor was increased in the hope that local control could be increased without the cost of increased late complications. We analyzed acute and late complications and local control and compared the results with the results of NPC patients treated during the same period using conventional once-daily RT. Methods and Materials: Between October 1991 and July 1998, 222 histologically confirmed, Stage M0, previously unirradiated NPC patients completed RT at our hospital. Most patients had American Joint Committee on Cancer (AJCC) 1992 Stage III and IV disease. Among them, 88 received altered fractionated, twice-daily RT; 76 patients received hyperfractionated RT and 12 accelerated-hyperfractionated RT. The remaining 134 patients received a conventional once-daily regimen. Hyperfractionated RT was delivered using 120 cGy b.i.d. separated by 6-h intervals throughout the course. For the accelerated-hyperfractionated patients, 160 cGy b.i.d. was given, also at 6-h intervals. The median dose in the twice-daily group was 7810 cGy (range 6840–8200). In the once-daily regimen, RT was delivered using 180–200 cGy q.d. The median tumor dose to the primary tumor was 7000 cGy (range 6560–8100) given during about 8 weeks. The median follow-up time was 70.5 and 72 months for the twice-daily and once-daily groups, respectively. Results: The incidence of acute toxicities was higher in the twice-daily group with more severe mucositis and moist desquamation than in the once-daily group. Both groups had a similar incidence of late complications, except for 3 cases of temporal lobe necrosis in the twice-daily group, all in patients treated with 160 cGy. No difference was noted in recurrence-free local control between the two groups when the individual T stage was compared using AJCC 1992 or 1997 criteria ( p = 0.51 and 0.59, respectively). The 5-year local control rate for T1-3 (AJCC 1997) was 93.2% for the twice-daily group and 86.4% for the once-daily group ( p = 0.45). In Stage T4 (AJCC 1997) patients, the local control rate dropped drastically to 43.5% and 36.9% for the twice-daily and once-daily groups, respectively. The overall neck control rate at 5 years was 87.3% and 80.3% for the twice-daily and once-daily patients, respectively ( p = 0.16). The overall locoregional control rate was 82.7% for the twice-daily group and 66.6% for the once-daily group. The difference was again not statistically significant, but showed a tendency in favor of the twice-daily regimen ( p = 0.055). Locoregional failure occurred mainly in Stage T4 patients with central nervous invasion for whom local control was particularly poor, with a failure rate of about 60%. Conclusion: The present data suggest that NPC patients can be safely treated using a 120-cGy twice-daily program with a 6-h interval up to 8000 cGy. The accelerated-hyperfractionated technique is not recommended. A large discrepancy in local control between patients with T1-3 and T4 disease was noted. For T1-3 disease, an excellent local control rate >90% was achieved using the twice-daily regimen. In contrast, failure in the T4 patients was as high as 55% in the twice-daily group and reached 65% in the once-daily group. More rigorous treatment is needed using either additional dose escalation or other strategies for T4 NPC patients. With a dose escalation of 1000 cGy using 120-cGy twice-daily RT, a trend toward better locoregional control and disease-specific survival was noted in the twice-daily group. Whether this difference was truly the result of an increased dose needs additional confirmation in studies with larger patient numbers.

analyses the independent prognostic factors according to the histology of the primary tumor are as follows: Breast e KPS < 70% (HR Z 1.84); no PTC (HR Z 1.47), no chemotherapy [CT] (HR Z 1.49); no RS (HR Z 2.34). Lung e KPS < 70% (HR Z 1.80); no PTC (HR Z 2.10); no FT (HR Z 2.90 for RS and 1.72 for SG, respectively). Melanoma e no FT (HR Z 4.38 for RS and 2.28 for SG, respectively). GI e no SG (HR Z 4.19). All tumors e KPS < 70% (HR Z 1.70); no PTC (HR Z 1.42); no CT (HR Z 1.42), no FT (HR Z 2.48 for RS and 2.11 for SG, respectively); ECM (HR Z 1.48). *All p value < 0.05. Conclusions: Comparing our data to DS-GPA we observe differences in prognostic factors for breast cancer (PTC, CT and FT), lung cancer (PTC and FT), melanoma (FT) and GI (FT). ECM was just significant when it was analyzed all tumor types together and the number of BM was not an independent factor in this study. The FT was correlated with improved survival in all tumor histology. The inclusion of new prognostic factors could further refine DS-GPA. Author Disclosure: M.G. Silva: None. D.F.G. Neves: None. F.L.C. Faustino: None. D.F. Ferreira: None. A.C.A. Pellizon: None. R.C. Fogaroli: None. D.G. Castro: None. M.J. Chen: None.

Background Radiotherapy is an important modality in treating head and neck cancers. Clinically, predicting radiation response is essential. Stem-like cancer cells have been reported as having a high degree of radiation resistance. However, whether stem cell markers, such as OCT4 and NANOG, can predict clinical outcomes in patients with resected-then-irradiated oral cancer is still unknown. Methods We established a radioresistant cell subline, OML1_R, from OML-1 oral cancer cells by using sequent 5-Gy irradiations, with a total dose of 50 Gy. Between each irradiation, cancer cells were allowed to regrow for 5–7 days, then PCR was used to detect mRNA expression of stem cell markers. Paraffin-embedded human tissue sections were used for validation of the role of stem cell markers in predicting post-resection, post-irradiation clinical outcomes. Findings A 10-Gy radiation stress test confirmed the radioresistance of OML1_R. PCR showed upregulation of OCT4 (4-fold) and NANOG (6-fold) in OML1_R cells compared with their parent OML-1 cells. In 44 patients with resected-but-close-margined oral cancer, higher locoregional control was observed in the low OCT4/NANOG expression group compared with the high OCT4/NANOG expression group (92% versus 62%, p = 0.03). Multivariate analysis confirmed that this stem cell marker is an independent factor in predicting locoregional control (adjusted hazard ratio 6.76; 95% confidence interval 1.87–24.43; p = 0.04). Interpretation Our data showed that stem cell markers OCT4 and NANOG are potential bio-predictors in patients with resected-then-irradiated oral cancer.