Xiangjiao Meng

Predictive biomarkers in PD-1/PD-L1 checkpoint blockade immunotherapy.

Checkpoint blockades turn on a new paradigm shift in immunotherapy for cancer. Remarkable clinical efficacy, durable response and low toxicity of programmed death 1 (PD-1)/programmed death ligand-1 (PD-L1) checkpoint blockades have been observed in various malignancies. However, a lot of cancer patients failed to respond to the PD-1/PD-L1 checkpoint blockades. It is crucial to identify a biomarker to predict the response to checkpoint blockades. The overexpression of PD-L1 is an important and widely-explored predictive biomarker for the response to PD-1/PD-L1 antibodies. However PD-L1 staining cannot be used to accurately select patients for PD-1/PD-L1 pathway blockade due to the low prediction accuracy and dynamic changes. Tumor-infiltrating immune cells and molecules in the tumor microenvironment, or along with PD-L1 expression, may be important in predicting clinical benefits of PD-1/PD-L1 checkpoint blockades. Gene analysis has proven to be new approach for judging the potential clinical benefit of immune checkpoint inhibitors, such as mutational landscape and mismatch-repair deficiency. Further preclinical and clinical studies are necessary to carry out before its application in clinical practice. Challenges should be overcome to identify patients accurately who will benefit from PD-1/PD-L1 checkpoint blockades. In this review, we focus on the predictive biomarkers for checkpoint blockades of PD-1/PD-L1 pathway.

Security enhancement of double-random phase encryption by amplitude modulation

Conventional double-random phase encoding is vulnerable to a chosen or known plaintext attack owing to the linearity of the system. We introduce a technique to break down this linearity with an undercover amplitude modulation in the encryption scheme. As an additional key, this operation can significantly enhance the security of the system. A series of computer simulations have shown the effectiveness of this method and its resistance against the known plaintext attack. The design and parameter choice of the amplitude modulator is also discussed.

Simple direct extraction of unknown phase shift and wavefront reconstruction in generalized phase-shifting interferometry: algorithm and experiments

An algorithm to extract the arbitrary unknown phase shift and then reconstruct the complex object wave in generalized phase-shifting interferometry (GPSI) without the iteration process and measurement of object wave intensity is proposed. This method can be used for GPSI of any frame number >or=2. Both computer simulations with smooth and diffusing object surfaces and optical experiments have verified the effectiveness of this method over a wide range of phase shifts with very satisfactory results.

Generalized phase-shifting interferometry with arbitrary unknown phase shifts: Direct wave-front reconstruction by blind phase shift extraction and its experimental verification

A simple wave-front reconstruction method by generalized phase-shifting interferometry (PSI) with arbitrary unknown phase shift between 0 and π for two adjacent frames is proposed. In this method the unknown phase shifts are extracted by a noniterative algorithm with the use of the interferograms and the intensities of object and reference waves, and then the original object field can be further obtained. This method is applicable for generalized PSI of any frame number N (N⩾2) and for both the amplitude and phase objects. Its effectiveness and accuracy are verified by both the computer simulations and optical experiments.

Circulating lymphocytes as predictors of sensitivity to preoperative chemoradiotherapy in rectal cancer cases.

OBJECTIVE The objective of this study was to identify clinical predictive factors for tumor response after neoadjuvant chemoradiotherapy (nCRT) in locally advanced rectal cancer (LARC). METHODS All factors were evaluated in 88 patients with LARC treated with nCRT. After a long period of 4-8 weeks of chemoradiotherapy, 3 patients achieved clinical complete response (cCR) and thus aggressive surgery was avoided, and the remaining 85 patients underwent a curative-intent operation. The response to nCRT was evaluated by tumor regression grade (TRG) system. RESULTS There were 32 patients (36.4%) with good tumor regression (TRG 3-4) and 56 (63.6%) with poor tumor regression (TRG 0-2). Lymphocyte counts and ratios were higher in good response cases (P=0.01, 0.03, respectively) while neutrophil ratios and N/L ratios were higher in poor response cases (P=0.04, 0.02, respectively). High lymphocyte ratios before nCRT and good tumor regression (TRG3-4) were significantly associated with improved 5-year disease-free survival (P<0.05). Pretreatment nodal status was also significantly associated with 5-year disease-free survival and 5-year overall survival (P<0.05). Multivariate analysis confirmed that the pretreatment lymphocyte ratio and lymph nodal status were independent prognostic factors. CONCLUSION Our study suggested that LARC patients with high lymphocyte ratios before nCRT would have good tumor response and high 5-year DFS and OS.

Tumor-infiltrating lymphocytes, forkhead box P3, programmed death ligand-1, and cytotoxic T lymphocyte–associated antigen-4 expressions before and after neoadjuvant chemoradiation in rectal cancer

Preclinical studies have suggested that cytotoxic agents and radiation may partly deliver their antitumor activities by activating antitumor immune response. However, the alterations of tumor immune microenvironment including immunosuppressive molecules during chemoradiotherapy and their associations with clinical features and prognosis in rectal cancer have not been thoroughly investigated. Therefore, we investigate the densities of cluster of differentiation 8 (CD8) positive tumor-infiltrating lymphocytes (TILs), CD4+TILs, natural killer cell (NK)-TILs, myeloid-derived suppressor cells (MDSCs), transcription factor forkhead box P3 (FOXP3)+TILs, programmed death ligand-1 (PD-L1), and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) before and after neoadjuvant chemoradiotherapy (nCRT) in rectal cancer patients to determine their predictive and prognostic effects. We screen 62 rectal cancer patients who underwent nCRT followed by radical surgery. Pretreatment biopsy specimens and posttreatment surgically resected specimens of all patients are retrieved to perform the immunohistochemistry of CD8, CD4, CD56, FOXP3, CD33, CD11b, PD-L1, and CTLA-4. The CD8+TILs and CD4+TILs in post-nCRT resected specimens are significantly higher than that in pre-nCRT biopsy specimens (P = 0.004 and 0.005, respectively). Expressions of MDSC, FOXP3+TILs, and CTLA-4 are relative stable after nCRT. Tumors with high density of CD8+TILs, CD4+TILs, and low MDSC-TILs are more sensitive to nCRT (P = 0.022, 0.022 and 0.005, respectively). High pretreatment CD8+TILs are associated with better disease-free survival and overall survival (P = 0.016 and 0.022, respectively). NK-TILs are detected only in 6 of 62 rectal cancer specimens evaluated. Cell surface PD-L1 positive by tumor cells (1 of 62) and stroma cells (3 of 62) are very low. We may conclude that tumor immunity is activated after nCRT by increased infiltrating CD8+ and CD4+ T cells and relative stable numbers MDSC-TILs, FOXP3+TILs, and coinhibitory molecules. Pre-nCRT CD8+TILs, CD4+TILs, and MDSC-TILs are sensitive predictive marker for response to CRT, and high CD8+TILs are associated with better prognosis.

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.

Predictors of sensitivity to preoperative chemoradiotherapy of rectal adenocarcinoma.

OBJECTIVES The purpose of the study was to identify predictive factors of tumor response to preoperative chemoradiotherapy for rectal adenocarcinoma. METHODS Ninety-eight patients with nonmetastatic rectal adenocarcinoma received preoperative concurrent chemoradiotherapy and underwent mesorectal excision. After treatment, tumor response according to tumor regression grade were evaluated. The correlation of clinicopathologic factors to tumor response was analyzed. RESULTS The results from a univariate analysis indicated that pretreatment carcinoembryonic antigen level ≤3.0 ng/ml (P = 0.002), non-fixed tumor (P = 0.001), and tumor circumferential extent ≤50% (P = 0.001) were associated significantly with a good tumor response. They also indicated that pretreatment positive lymph nodes (P = 0.032) were associated significantly with a poor tumor response. In multivariate analysis, the results indicated that pretreatment carcinoembryonic antigen level (hazard ratio, 2.930; P = 0.003), tumor mobility (hazard ratio, 2.651; P = 0.002) and circumferential extent of tumor (hazard ratio, 2.394; P = 0.019) independently predicted a good pathologic response rate. Pretreatment positive lymph nodes were not significantly associated with a good response (hazard ratio, 0.361; P = 0.191). CONCLUSIONS Pretreatment carcinoembryonic antigen level, tumor mobility and circumferential extent of tumor may be helpful in predicting responsiveness in rectal adenocarcinoma to preoperative chemoradiotherapy, although the results should be confirmed in larger, more homogeneous studies.

Correction of wavefront reconstruction errors caused by light source intensity instability in phase-shifting interferometry

In the recording process of phase-shifting interferometry, intensity fluctuation caused by light source instability may occur and then introduce amplitude and phase errors to the reconstructed object wavefront. A simple direct algorithm of digital data processing to correct these errors is proposed and satisfactorily verified by both computer simulations and optical experiments. This method can work without specific knowledge of the source intensity fluctuation, and it reduces both the amplitude and phase errors of the reconstructed wavefront by about two orders of magnitude in computer simulations.

The prognostic role of EZH2 expression in rectal cancer patients treated with neoadjuvant chemoradiotherapy

BackgroundNeoadjuvant chemoradiotherapy (nCRT) combined with surgery has been implemented as a standard treatment strategy in locally advanced rectal cancer (LARC). However, there is a wide spectrum of response to nCRT. The aim of this study was to determine whether enhancer of zeste homologue 2 (EZH2 ) expression could predict response to nCRT and outcomes for patients in LARC.MethodThe study examined the EZH2 expression in 112 biopsies by immohistochemistry. The associations between EZH2 and clinical characters were analyzed.ResultsEZH2 expression in biopsy tissue was significantly related to increased tumor cell proliferation, as assessed by Ki-67 expression with a cutoff value of 37% (p <0.001). High EZH2 expression was correlated closely with low differentiation (p = 0.029), high CEA level (p = 0.041), T4 status (p = 0.011) and node metastasis (p =0.045). By univariate and multivariate analysis, we observed low EZH2 expression could reliably and independently predict the good response to nCRT ( p = 0.026 and p = 0.023) and down-staging ( p = 0.021 and p = 0.027). In univariate analysis, high EZH2 expression was significantly associated with poor 5-year disease-free survival (p = 0.025) and 5-year overall survival (p = 0.032). In multivariate analysis, EZH2 was a prognostic factor for 5-year DFS (HR = 2.287; 95% CI 1.137-4.602, p = 0.020) but not for 5-year OS (HR = 2.182; 95% CI 0.940-5.364, p = 0.069).ConclusionOur study revealed that low EZH2 expression in biopsy tissue might be a useful predictive factor of good tumor response to nCRT and longer 5-year DFS in patients with LARC. However this is a relatively small retrospective study, to further validate the role of EZH2 in rectal cancer, large consistent cohort studies are needed.