Fusarium graminearum rapid alkalinization factor peptide negatively regulates plant immunity and cell growth via the FERONIA receptor kinase.

The plant rapid alkalinization factor (RALF) peptides function as key regulators in cell growth and immune responses through the receptor kinase FERONIA (FER). In this study, we report that the transcription factor FgPacC binds directly to the promoter of FgRALF gene, which encodes a functional homologue of the plant RALF peptides from the wheat head blight fungus Fusarium graminearum (FgRALF). More importantly, FgPacC promotes fungal infection via host immune suppression by activating the expression of FgRALF. The FgRALF peptide also exhibited typical activities of plant RALF functions, such as inducing plant alkalinization and inhibiting cell growth, including wheat (Triticum aestivum), tomato (Solanum lycopersicum) and Arabidopsis thaliana. We further identified the wheat receptor kinase FERONIA (TaFER), which is capable of restoring the defects of the A. thaliana FER mutant. In addition, we found that FgRALF peptide binds to the extracellular malectin-like domain (ECD) of TaFER (TaFERECD) to suppress the PAMP-triggered immunity (PTI) and cell growth. Overexpression of TaFERECD in A. thaliana confers plant resistance to F. graminearum and protects from FgRALF-induced cell growth inhibition. Collectively, our results demonstrate that the fungal pathogen-secreted RALF mimic suppresses host immunity and inhibits cell growth via plant FER receptor. This establishes a novel pathway for the development of disease-resistant crops in the future without compromising their yield potential.

Phase I/II clinical trial of efficacy and safety of EGCG oxygen nebulization inhalation in the treatment of COVID-19 pneumonia patients with cancer.

BACKGROUND: The antiviral drug Nirmatrelvir was found to be a key drug in controlling the progression of pneumonia during the infectious phase of COVID-19. However, there are very few options for effective treatment for cancer patients who have viral pneumonia. Glucocorticoids is one of the effective means to control pneumonia, but there are many adverse events. EGCG is a natural low toxic compound with anti-inflammatory function. Thus, this study was designed to investigate the safety and efficacy of epigallocatechin-3-gallate (EGCG) aerosol to control COVID-19 pneumonia in cancer populations. METHODS: The study was designed as a prospective, single-arm, open-label phase I/II trial at Shandong Cancer Hospital and Institute, between January 5, 2023 to March 31,2023 with viral pneumonia on radiographic signs after confirmed novel coronavirus infection. These patients were treated with EGCG nebulization 10 ml three times daily for at least seven days. EGCG concentrations were increased from 1760-8817umol/L to 4 levels with dose escalation following a standard Phase I design of 3-6 patients per level. Any grade adverse event caused by EGCG was considered a dose-limiting toxicity (DLT). The maximum tolerated dose (MTD) is defined as the highest dose with less than one-third of patients experiencing dose limiting toxicity (DLT) due to EGCG. The primary end points were the toxicity of EGCG and CT findings, and the former was graded by Common Terminology Criteria for Adverse Events (CTCAE) v. 5.0. The secondary end point was the laboratory parameters before and after treatment. RESULT: A total of 60 patients with high risk factors for severe COVID-19 pneumonia (factors such as old age, smoking and combined complications)were included in this phase I-II study. The 54 patients in the final analysis were pathologically confirmed to have tumor burden and completed the whole course of treatment. A patient with bucking at a level of 1760 umol/L and no acute toxicity associated with EGCG has been reported at the second or third dose gradients. At dose escalation to 8817umol/L, Grade 1 adverse events of nausea and stomach discomfort occurred in two patients, which resolved spontaneously within 1 hour. After one week of treatment, CT showed that the incidence of non-progression of pneumonia was 82% (32/39), and the improvement rate of pneumonia was 56.4% (22/39). There was no significant difference in inflammation-related laboratory parameters (white blood cell count, lymphocyte count, IL-6, ferritin, C-reactive protein and lactate dehydrogenase) before and after treatment. CONCLUSION: Aerosol inhalation of EGCG is well tolerated, and preliminary investigation in cancer population suggests that EGCG may be effective in COVID-19-induced pneumonia, which can promote the improvement of patients with moderate pneumonia or prevent them from developing into severe pneumonia. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05758571. Date of registration: 8 February 2023.

Epigallocatechin-3-gallate mouthwash protects mucosa from radiation-induced mucositis in head and neck cancer patients: a prospective, non-randomised, phase 1 trial.

Radiation-induced oral mucositis has a dismal outcome with limited treatment options. We conducted a phase I study to evaluate the safety and preliminary efficacy of epigallocatechin-3-gallate (EGCG) mouthwash when given along with radiation in head and neck cancer. Patients with pathologically confirmed head and neck cancer were eligible for this study. EGCG mouthwash was administered at the assigned dosage level (starting at 440 µmol/L, three times a day) in a standard 3 + 3 dose escalation design. Mucosal toxicity, patient satisfaction, and mucositis-related pain (MTP) were assessed weekly. The primary endpoint was safety of EGCG, and the secondary endpoint was to determine the relief of the mucositis symptom. The pre- and post-treatment parameters were compared using the paired t-test. 20 patients were enrolled. The maximum tolerated dose of the EGCG mouthwash was 2200 µmol/L. Burning (n = 1/20) and nausea (n = 3/20) were the most common toxicities. No patients experienced WHO Grade 3 or higher mucositis. MTP scores significantly decreased after EGCG administration over time (p < 0.05). Adding EGCG mouthwash to radiotherapy is feasible without increasing toxicities. The recommended dose for phase II study is determined to be 1760 µmol/L, and EGCG administration reduces radiation-induced oral mucosal injury in patients.

Relationships between the changes of skin temperature and radiation skin injury.

Background: Radiation skin injury (RSI) causes changes in skin temperature, but detailed information on the thermographic responses is currently lacking. We investigated thermographic patterns after radiotherapy. We hypothesized that skin temperature may be used as a diagnostic and early predictor of RSI severity.Method: All breast cancer patients received radiotherapy after unilateral postmastectomy. The contralateral supraclavicular area served as control, and the frontal thermal image of torso was taken by a thermal infrared imager weekly. We defined areas of interest on bilateral symmetrical supraclavicular area, and analyzed the difference of average and maximum skin temperature (DSTaverage and DSTmax) between them. The extent of the weekly variation in DST (DSTW) was calculated using a mathematical formula to represent a trend of skin temperature change. RSI and symptoms related to RSI were scored from baseline to 2 weeks after the end of radiotherapy.Results: Forty-one patients were enrolled in this study. In comparison to the baseline, the DSTaverage and DSTmax increased significantly over time during radiotherapy (p < .05). The onset of DST increase was accompanied by the onset of radiation dermatitis, and the maximal DST also appeared at the peak of Radiation Therapy Oncology Group (RTOG) and symptom scores. Radiation dose, DSTaverage, burning-feeling and pulling were the independent variables affecting RTOG score according to multivariate analysis (p < .001, p < .034, p < .001, p < .001). Patients with DSTWaverage >1.223 or DSTWmax >1.114 in second week showed a late higher dermatitis score (RTOG score ≥2).Conclusion: This study confirmed that RSI was associated with thermographic response. Our results suggested that the follow-up observations of skin temperature during radiotherapy could provide the objective evaluation criteria and prediction methods for RSI.

MRI In rectal cancer: Correlations between MRI features and molecular markers Ki-67, HIF-1α, and VEGF.

PURPOSE: To investigate whether the apparent diffusion coefficient (ADC) values acquired from diffusion-weighted magnetic resonance imaging (DW-MRI) are correlated with molecular markers Ki-67, hypoxia-inducible factor 1α (HIF-1α), and vascular endothelial growth factor (VEGF) in rectal cancer (RC). MATERIALS AND METHODS: Ninety-one patients (64 males and 27 females) diagnosed with rectal cancer underwent 3.0T DW-MRI before any anticancer treatment. DW-MRI was performed using the single-shot echo-planar imaging technique (b = 0 and b = 800 s/mm(2) ). The patients underwent surgery within 1 week after MRI. Ki-67, HIF-1α, and VEGF expression were assessed by immunohistochemistry at both the resected margins and the center of the tumor. RESULTS: We noted that ADC values correlated positively with histology differentiations (r = 0.336, P = 0.001) and negatively with carcinoembryonic antigen level (r = -0.217, P = 0.039) in RC. Both the value and the level of Ki-67 expression were correlated inversely with the ADC values (r = -0.475, P < 0.001 and r = -0.555, P < 0.001). There was a weak negative correlation between HIF-1α expression and the ADC values (r = -0.304, P = 0.003). VEGF expression was correlated inversely with the ADC values of the RCs (r = -0.290, P = 0.005). However, no significant correlation was observed between VEGF expression and the ADC values in pT4 RCs (r = -0.166, P = 0.255). CONCLUSION: Our results suggest that the ADC values on DW-MRI may be used as a measurement of cell proliferation and hypoxia in RC. J. Magn. Reson. Imaging 2016;44:594-600.

Temporally-coordinated bivalent histone modifications of BCG1 enable fungal invasion and immune evasion.

Bivalent histone modifications, including functionally opposite H3K4me3 and H3K27me3 marks simultaneously on the same nucleosome, control various cellular processes by fine-tuning the gene expression in eukaryotes. However, the role of bivalent histone modifications in fungal virulence remains elusive. By mapping the genome-wide landscape of H3K4me3 and H3K27me3 dynamic modifications in Fusarium graminearum (Fg) during invasion, we identify the infection-related bivalent chromatin-marked genes (BCGs). BCG1 gene, which encodes a secreted Fusarium-specific xylanase containing a G/Q-rich motif, displays the highest increase of bivalent modification during Fg infection. We report that the G/Q-rich motif of BCG1 is a stimulator of its xylanase activity and is essential for the full virulence of Fg. Intriguingly, this G/Q-rich motif is recognized by pattern-recognition receptors to trigger plant immunity. We discover that Fg employs H3K4me3 modification to induce BCG1 expression required for host cell wall degradation. After breaching the cell wall barrier, this active chromatin state is reset to bivalency by co-modifying with H3K27me3, which enables epigenetic silencing of BCG1 to escape from host immune surveillance. Collectively, our study highlights how fungal pathogens deploy bivalent epigenetic modification to achieve temporally-coordinated activation and suppression of a critical fungal gene, thereby facilitating successful infection and host immune evasion.

Efficacy and safety of epigallocatechin-3-gallate in treatment acute severe dermatitis in patients with cancer receiving radiotherapy: a phase I clinical trial.

To evaluate the safety and effectiveness of epigallocatechin-3-gallate (EGCG) solution treating the acute severe dermatitis in patients receiving radiotherapy. This phase I research enrolled patients with thoracic cancer receiving radiotherapy at Shandong Cancer Hospital and Institute in Shandong, China. EGCG solution was sprayed to the radiation field when grade III radiation-induced dermatitis (RID) first appearance. EGCG concentration escalated from 660 to 2574 µmol/L using modified-Fibonacci dose-escalation. RID and related symptoms were followed up every day. Between March 2021 and November 2021, 19 patients were enrolled in this phase I research. The median dose of grade III RID first observation was 44 Gy (30.6-52 Gy). As the EGCG treatment was performed continuously, all these grade III RID reactions were significantly decreased to grade I or grade II RID at three days after use of EGCG (p < 0.001). Significant relief can be observed in burning sensation (p < 0.001), tractive sensation (p < 0.001), tenderness (p < 0.001), erythema (p < 0.001), itching (p < 0.001) and pain (p < 0.001) after 15 days of EGCG treatment. No radiation therapy delay or interruption for all 19 patients. No adverse events were observed and reported associated with EGCG. The highest dose of this Phase I trial (2574 µmol/L) was recommended for continuous Phase II trial for further evaluation. In this phase I clinical research, use of EGCG solution is safe and can significantly relief grade III RID in patients receiving radiotherapy. Thus, EGCG might be a new choice for acute sever RID.Trial Registration: ClinicalTrials.gov Identifier: NCT02580279 (Full date of first registration: 12/2014).

The Mechanism of Stem Cell Aging.

Stem cells have self-renewal ability and multi-directional differentiation potential. They have tissue repair capabilities and are essential for maintaining the tissue homeostasis. The depletion of stem cells is closely related to the occurrence of body aging and aging-related diseases. Therefore, revealing the molecular mechanisms of stem cell aging will set new directions for the therapeutic application of stem cells, the study of aging mechanisms, and the prevention and treatment of aging-related diseases. This review comprehensively describes the molecular mechanisms related to stem cell aging and provides the basis for further investigations aimed at developing new anti-stem cell aging strategies and promoting the clinical application of stem cells.

Therapeutic Potential of Janus Kinase Inhibitors for the Management of Interstitial Lung Disease.

Interstitial lung disease (ILD) refers to a heterogeneous group of diseases characterized by lung fibroblast proliferation, interstitial inflammation, and fibrosis-induced lung damage. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway is known to be activated by pro-fibrotic/pro-inflammatory cytokines such as IL-6 and IL-13, whose levels are elevated in ILD. The overexpression of growth factors such as transforming growth factor ß1 in ILD activates the JAK/STAT pathway through classical or non-classical pathways, promotes macrophage activation, increases the release of pro-inflammatory and pro-fibrosis factors, and facilitates fibroblast differentiation into myofibroblasts. These findings implicate that the JAK/STAT pathway plays an important role in the course of ILD. Recent evidence also suggests that JAK inhibition alleviates excessive inflammation and pulmonary fibrosis. Accordingly, the JAK inhibitors may serve as promising drugs for the treatment of JAK/STAT-induced ILD.

Efficacy of Epigallocatechin-3-Gallate in Preventing Dermatitis in Patients With Breast Cancer Receiving Postoperative Radiotherapy: A Double-Blind, Placebo-Controlled, Phase 2 Randomized Clinical Trial.

Importance: Safe and effective prophylactic therapies for radiation-induced dermatitis (RID) remain an unmet need. Objective: To determine if epigallocatechin-3-gallate (EGCG) solution reduces the incidence of RID in patients undergoing radiotherapy after breast cancer surgery. Design, Setting, and Participants: This phase 2 double-blind, placebo-controlled randomized clinical trial enrolled 180 patients with breast cancer receiving postoperative radiotherapy at Shandong Cancer Hospital and Institute in Shandong, China, between November 2014 and June 2019. Data analysis was performed from September 2019 to January 2020. Interventions: Participants were randomly assigned (2:1) to receive either EGCG solution (660 µmol/L) or placebo (0.9% NaCl saline) sprayed to the whole radiation field from day 1 of the radiation until 2 weeks after radiation completion. Main Outcomes and Measures: The primary end point was incidence of grade 2 or worse RID, defined by the Radiation Therapy Oncology Group scale. The secondary end points included RID index (RIDI), symptom index, changes in the skin temperature measured by infrared thermal images, and safety. Results: A total of 180 eligible patients were enrolled, of whom 165 (EGCG, n = 111; placebo, n = 54) were evaluable for efficacy (median [range] age, 46 [26-67] years). The occurrence of grade 2 or worse RID was significantly lower (50.5%; 95% CI, 41.2%-59.8%) in the EGCG group than in the placebo group (72.2%; 95% CI, 60.3%-84.1%) (P = .008). The mean RIDI in the EGCG group was significantly lower than that in the placebo group. Furthermore, symptom indexes were significantly lower in patients receiving EGCG. Four patients (3.6%) had adverse events related to the EGCG treatment, including grade 1 pricking skin sensation (3 [2.7%]) and pruritus (1 [0.9%]). Conclusions and Relevance: In this randomized clinical trial, prophylactic use of EGCG solution significantly reduced the incidence and severity of RID in patients receiving adjuvant radiotherapy for breast cancer. It has the potential to become a new choice of skin care for patients receiving radiotherapy. Trial Registration: ClinicalTrials.gov Identifier: NCT02580279.

Evaluation of Epigallocatechin-3-Gallate as a Radioprotective Agent During Radiotherapy of Lung Cancer Patients: A 5-Year Survival Analysis of a Phase 2 Study.

BACKGROUND: Previous analysis of the study (NCT02577393) had demonstrated the application of epigallocatechin-3-gallate (EGCG) could be safe and effective in the prevention and treatment of acute radiation esophagitis in patients with advanced lung cancer. EGCG seemed to improve the response rate of small cell lung cancer (SCLC) to radiotherapy in a subgroup analysis. This research continued to analyze the impact of EGCG application on cancer-radiation efficacy and patient survival. METHODS: All patients with SCLC in the NCT02577393 study were included. Patients were randomized into EGCG group or conventional therapy group as protocol. The primary endpoints of the study were radiation response rate and progression-free survival (PFS). Overall survival (OS) and the efficacy of EGCG in the treatment of esophagitis were assessed as secondary endpoints. RESULTS: A total of 83 patients with lung cancer in the NCT02577393 study were screened, and all 38 patients with SCLC were eligible for analysis. No significant differences with regard to baseline demographic and clinical characteristics were observed between the two groups. The objective response rate (ORR) was higher than that of conventionally treated patients (84.6 vs 50%, P = 0.045), while the median PFS and OS were not significantly prolonged. At data cut-off (1 January 2021), 5-year PFS was 33% with EGCG versus 9.3% with conventional treatment, and 5-year OS was 30.3% versus 33.3%, respectively. The mean adjusted esophagitis index and pain index of patients with EGCG application were lower than conventional treatment (5.15 ± 2.75 vs 7.17 ± 1.99, P = 0.030; 8.62 ± 5.04 vs 15.42 ± 5.04, P < 0.001). CONCLUSION: The study indicates EGCG may alleviate some esophagitis-related indexes in SCLC patients exposed to ionizing radiation without reducing survival. However, this conclusion should be confirmed by further studies with large sample size.

Phase II Trial of Epigallocatechin-3-Gallate in Acute Radiation-Induced Esophagitis for Esophagus Cancer.

Acute radiation-induced esophagitis (ARIE) is among the most serious form of toxicities associated with definitive radiotherapy or chemoradiotherapy used for treatment of patients with esophageal cancer. Our preliminary phase I and II trials of lung cancer patients who received radiotherapy indicated epigallocatechin-3-gallate (EGCG) as a promising therapeutic option against ARIE. Therefore, we conducted a prospective phase II study to validate the efficacy and safety of EGCG in the treatment of ARIE. The patients who received chemoradiotherapy or definitive radiotherapy for treatment of esophageal cancer in the Shandong Cancer Hospital and Institute in China were enrolled for the present study. EGCG (440 µM) was administered with first onset of ARIE and then at weeks after final radiotherapy. The patients were monitored every week for dysphagia, Radiation Therapy Oncology Group (RTOG) score, and esophagitis-related pain. Moreover, tumor response and the effect on survival following the treatment were also evaluated. Comparison of the RTOG score in the first, second, third, fourth, fifth, and even sixth week after EGCG prescription and the first and second week after radiotherapy with baseline indicates a significant reduction. The tumor response rate was 86.3%. The overall survival rate in 1, 2, and 3 years was found to be 74.5%, 58%, and 40.5%. Oral administration of EGCG solution seems to be feasible for treating ARIE in patients with esophageal cancer who receive radiation therapy. EGCG might be an ARIE-reliever without compromising the efficacy of radiation therapy. A randomized study with a control group is needed for further evaluation.

A prospective, three-arm, randomized trial of EGCG for preventing radiation-induced esophagitis in lung cancer patients receiving radiotherapy.

BACKGROUND AND PURPOSE: This trial investigated whether epigallocatechin-3-gallate (EGCG), a radioprotector, could be effective in the prevention and treatment of acute radiation-induced esophagitis (ARIE). METHODS AND MATERIALS: This is a phase II study of EGCG combined with chemoradiation in unresectable stage III non-small-cell lung cancer or limited stage small cell lung cancer. Patients were randomized into a prophylactic EGCG group (arm A), a therapeutic EGCG group after the occurrence of esophagitis (arm B) or conventional therapy group (arm C). Esophagitis grades, pain and dysphagia scores were recorded weekly. Adjusted esophagitis index (AEI), pain index (API) and dysphagia index (ADI) were calculated to reflect changes in esophagitis grade, pain score and dysphagia score throughout treatment. RESULTS: A total of 83 patients were eligible for toxicity analysis (arm A vs arm B vs arm C: N = 28:27:28). There was no significant difference in the baseline characteristics among three arms of the patients. The difference in the maximum esophagitis grade among three groups was statistically significant (P = 0.004). The maximum ARIE for patients with EGCG was significantly lower than for those with conventional therapy. The mean AEI of arm A was lower than that of arm B, while the mean AEI of arm C was the highest (arm A vs arm B, P = 0.028; arm B vs arm C, P = 0.002). Furthermore, API and ADI were significantly lower in patients receiving EGCG than in conventionally treated patients. CONCLUSION: The application of EGCG could effectively alleviate acute radiation esophagitis in advanced lung cancer without obvious side effects. Prophylactic application of EGCG had a slight advantage over therapeutic use in treatment of acute esophagitis.

Epigallocatechin-3-gallate ameliorates radiation-induced acute skin damage in breast cancer patients undergoing adjuvant radiotherapy.

There are few effective treatment options for radiation-induced dermatitis in breast cancer patients. We conducted a single-arm trial to tested the hypothesis that topical epigallocatechin-3-gallate (EGCG) is effective against radiation-induced dermatitis in breast cancer patients undergoing radiotherapy. Forty-nine patients participated in this study. The patients underwent mastectomy followed by adjuvant radiotherapy. Topical EGCG was applied daily, starting when grade I dermatitis appeared and ending two weeks after radiotherapy. The maximum dermatitis observed during the EGCG treatment was as follows: Grade 1 toxicity, 71.4% (35 patients); grade 2 toxicity, 28.6% (14 patients); there were no patients with grade 3 or 4 toxicity. The majority of the radiation-induced dermatitis was observed 1 week after the end of radiotherapy. EGCG reduced the pain in 85.7% of patients, burning-feeling in 89.8%, itching in 87.8%, pulling in 71.4%, and tenderness in 79.6%. These findings suggest topical EGCG may be an effective treatment for radiation-induced dermatitis and has acceptable toxicity.

Phase I study of topical epigallocatechin-3-gallate (EGCG) in patients with breast cancer receiving adjuvant radiotherapy.

OBJECTIVE: The purpose of this study was to investigate the safety, tolerability and preliminary effectiveness of topical epigallocatechin-3-gallate (EGCG) for radiation dermatitis in patients with breast cancer receiving adjuvant radiotherapy. METHODS: Patients with breast cancer who received radiotherapy to the chest wall after mastectomy were enrolled. EGCG solution was sprayed to the radiation field from the initiation of Grade 1 radiation dermatitis until 2 weeks after completion of radiotherapy. EGCG concentration escalated from 40 to 660 µmol l(-1) in 7 levels with 3-6 patients in each level. EGCG toxicity was graded using the NCI (National Cancer Institute Common Terminology Criteria for Adverse Events) v. 3.0. Any adverse event >Grade 1 attributed to EGCG was considered dose-limiting toxicity. The maximum tolerated dose was defined as the dose level that induced dose-limiting toxicity in more than one-third of patients at a given cohort. Radiation dermatitis was recorded weekly by the Radiation Therapy Oncology Group scoring and patient-reported symptoms. RESULTS: From March 2012 to August 2013, 24 patients were enrolled. Acute skin redness was observed in 1 patient and considered to be associated with the EGCG treatment at 140 µmol l(-1) level. Three more patients were enrolled at this level and did not experience toxicity to EGCG. The dose escalation stopped at 660 µmol l(-1). No other reported acute toxicity was associated with EGCG. Grade 2 radiation dermatitis was observed in eight patients during or after radiotherapy, but all decreased to Grade 1 after EGCG treatments. Patient-reported symptom scores were significantly decreased at 2 weeks after the end of radiotherapy in pain, burning, itching and tenderness, p < 0.05. CONCLUSION: The topical administration of EGCG was well tolerated and the maximum tolerated dose was not found. EGCG may be effective in treating radiation dermatitis with preliminary investigation. ADVANCES IN KNOWLEDGE: EGCG solution seemed to be feasible for treating radiation dermatitis in patients with breast cancer after mastectomy. It should be tested as a way to reduce radiation-induced normal tissue toxicity and complications in future years.

Expression of Human Epidermal Growth Factor Receptor-2 in Resected Rectal Cancer.

The addition of trastuzumab to chemotherapy was demonstrated to be beneficial for advanced human epidermal growth factor receptor-2 (HER-2) positive gastric cancer. However, the HER-2 status of rectal cancer remains uncertain. This study aimed to determine the HER-2 expression in a large multicenter cohort of rectal cancer patients. The clinical and pathological features of 717 patients were retrospectively reviewed. All the patients were diagnosed with primary rectal adenocarcinoma without distant metastasis and took surgery directly without any preoperative anticancer treatment. HER-2 status was assessed on resected samples. A total of 99 cases with IHC3+ and 16 cases with IHC 2+ plus gene amplification were determined as HER-2 positive. 22.6% of HER-2 positive patients had local recurrence, whereas 16.9% of HER-2 negative patients did (P = 0.146). HER-2 positive tumors were more likely to have distant metastasis (P = 0.007). Univariate analysis revealed that pathological tumor stage, pathological node stage, positive margin, and lymphovascular invasion were significantly correlated with 5-year disease-free survival (DFS) and 5-year overall survival (OS). The patients with >10 dissected lymph nodes showed significantly longer OS (P = 0.045) but not DFS (P = 0.054). HER-2 negative patients had significantly better 5-year DFS (P < 0.001) and 5-year OS (P = 0.013) than those of the HER-2 positive patients. In the subgroup analysis for the early rectal cancer and locally advanced rectal cancer, HER-2 was also a poor predictor for survival. Multivariate analysis revealed that HER-2 was an independent prognostic factor for 5-year DFS (hazard ratio [HR] = 1.919, 95% confidence interval [CI] 1.415-2.605, P < 0.001) and for 5-year OS (HR = 1.549, 95% CI 1.097-2.186, P = 0.013). When the treatment was included in the analysis for locally advanced patients, HER-2 was a prognostic factor for 5-year DFS (P = 0.001) but not for 5-year OS (P = 0.106). This study confirmed that HER-2 was expressed in a part of patients with rectal cancers and might be used as a negative predictor. The results may support the trials to assess the efficacy of trastuzumab in treating HER-2 positive rectal cancer patients.

A prospective phase II trial of EGCG in treatment of acute radiation-induced esophagitis for stage III lung cancer.

BACKGROUND: Acute radiation-induced esophagitis (ARIE) is one of main toxicities complicated by thoracic radiotherapy, influencing patients' quality of life and radiotherapy proceeding seriously. It is difficult to be cured rapidly so far. Our phase I trial preliminarily showed that EGCG may be a promising strategy in the treatment of ARIE. MATERIALS AND METHODS: We prospectively enrolled patients with stage III lung cancer from the Shandong Tumor Hospital & Institute in China from January 2013 to September 2014. All patients received concurrent or sequential chemo-radiotherapy, or radiotherapy only. EGCG was administrated once ARIE appeared. EGCG was given with the concentration of 440µmol/L during radiotherapy and additionally two weeks after radiotherapy. RTOG score, dysphagia and pain related to esophagitis were recorded every week. RESULTS: Thirty-seven patients with stage IIIA and IIIB lung cancer were enrolled in this trial. In comparison to the original, the RTOG score in the 1st, 2nd, 3rd, 4th, 5th week after EGCG prescription and the 1st, 2nd week after radiotherapy decreased significantly (P=0.002, 0.000, 0.000, 0.001, 0.102, 0.000, 0.000, respectively). The pain score of each week was significantly lower than the baseline (P=0.000, 0.000, 0.000, 0.000, 0.006, 0.000, 0.000, respectively). CONCLUSION: This trial confirmed that the oral administration of EGCG is an effective and safe method to deal with ARIE. A phase III randomized controlled trial is expected to further corroborate the consequence of EGCG in ARIE treatment.

A phase I study of concurrent chemotherapy and thoracic radiotherapy with oral epigallocatechin-3-gallate protection in patients with locally advanced stage III non-small-cell lung cancer.

BACKGROUND AND PURPOSE: Patients with unresectable stage III non-small-cell lung cancer receiving concurrent chemoradiotherapy often develop esophagitis that may lead to unplanned treatment interruptions, which may severely reduce rates of locoregional tumor control and survival. No effectivetreatment that would reduce the incidence and severity of this complication has been identified up to now. Although acceleration of normal tissue protection using epigallocatechin-3-gallate (EGCG) has been reported, its actual clinical practicability remains obscure. METHODS AND MATERIALS: This is a phase I study of EGCG in combination with standard chemoradiation in surgically unresectable stage III non-small-cell lung cancer. Chemotherapy (cisplatin and etoposide) was given concurrently with radiation. EGCG solution was swallowed three times a day after the occurrence of grade 2 esophagitis at six concentration levels and dose escalation followed a standard phase I design. Esophageal toxicity and patient-reported pain was recorded weekly. RESULTS: Twenty-four patients with AJCC stage IIIA (six) and IIIB (eighteen) completed the course of therapy. Twelve had squamous histology, ten adenocarcinoma, and two not specified. Patients were treated in six cohorts at six dose levels of EGCG. RT was not interrupted with a median dose of 64 Gy. There were no dose-limiting toxicities reported in all EGCG dosing tiers. Dramatic regression of esophagitis to grade 0/1 was observed in 22 of 24 patients, whereas grade 2 esophagitis persisted in 2 of 24 patients at the end of radiotherapy. The pain score was also reduced from a mean of 4.58 (N=24), 1.29 (N=24), 1.42 (N=24), 0.96 (N=23) to 1.13 (N=16) every week in turn. CONCLUSION: We conclude that the oral administration of EGCG is feasible, safe and effective. The phase II recommended concentration is 440 µmol/L.