Search

Background: Coronary heart disease (CHD) and heart failure (HF) are the major causes of morbidity and mortality worldwide. Early and accurate diagnoses of CHD and HF are essential for optimal management and prognosis. However, conventional diagnostic methods such as electrocardiography, echocardiography, and cardiac biomarkers have certain limitations, such as low sensitivity, specificity, availability, and cost-effectiveness. Therefore, there is a need for simple, noninvasive, and reliable biomarkers to diagnose CHD and HF., Aim: To investigate serum cystatin C (Cys-C), monocyte/high-density lipoprotein cholesterol ratio (MHR), and uric acid (UA) diagnostic values for CHD and HF., Methods: We enrolled 80 patients with suspected CHD or HF who were admitted to our hospital between July 2022 and July 2023. The patients were divided into CHD ( n = 20), HF ( n = 20), CHD + HF ( n = 20), and control groups ( n = 20). The serum levels of Cys-C, MHR, and UA were measured using immunonephelometry and an enzymatic method, respectively, and the diagnostic values for CHD and HF were evaluated using receiver operating characteristic (ROC) curve analysis., Results: Serum levels of Cys-C, MHR, and UA were significantly higher in the CHD, HF, and CHD + HF groups than those in the control group. The serum levels of Cys-C, MHR, and UA were significantly higher in the CHD + HF group than those in the CHD or HF group. The ROC curve analysis showed that serum Cys-C, MHR, and UA had good diagnostic performance for CHD and HF, with areas under the curve ranging from 0.78 to 0.93. The optimal cutoff values of serum Cys-C, MHR, and UA for diagnosing CHD, HF, and CHD+HF were 1.2 mg/L, 0.9 × 10 9 , and 389 µmol/L; 1.4 mg/L, 1.0 × 10 9 , and 449 µmol/L; and 1.6 mg/L, 1.1 × 10 9 , and 508 µmol/L, respectively., Conclusion: Serum Cys-C, MHR, and UA are useful biomarkers for diagnosing CHD and HF, and CHD+HF. These can provide information for decision-making and risk stratification in patients with CHD and HF., Competing Interests: Conflict-of-interest statement: We all authors jointly declare that there is no conflict of interest., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Lymphoma-associated hemophagocytic syndrome is aggressive with rapid progression, particularly in NK/T cell lymphoma. The MINE regimen is a salvage treatment for aggressive non-Hodgkin lymphoma. In our center, the modified MINE regimen was applied to treat three patients with hemophagocytic syndrome secondary to aggressive NK cell leukemia and T-cell lymphoma. The modified MINE regimen showed good efficacy against NK/T cell lymphoma, control of the inflammatory state of secondary hemophagocytic syndrome, and good tolerability.

Cavity optomechanical (COM) entanglement, playing an essential role in building quantum networks and enhancing quantum sensors, is usually weak and easily destroyed by noises. As feasible and effective ways to overcome this obstacle, optical or mechanical parametric modulations have been used to improve the quality of quantum squeezing or entanglement in various COM systems. However, the possibility of combining these powerful means to enhance COM entanglement has yet to be explored. Here, we fill this gap by studying a COM system containing an intra-cavity optical parametric amplifier (OPA), driven optically and mechanically. By tuning the relative strength and the frequency mismatch of optical and mechanical driving fields, we find that constructive interference can emerge and significantly improve the strength of COM entanglement and its robustness to thermal noises. This work sheds what we believe to be a new light on preparing and protecting quantum states with multi-field driven COM systems for diverse applications.

Cell signaling is highly integrated for the process of various cell activities. Although previous studies have shown how individual genes contribute to cell migration, it remains unclear how the integration of these signaling pathways is involved in the modulation of cell migration. In our two-hit migration screen, we revealed that serine-threonine kinase 40 (STK40) and mitogen-activated protein kinase (MAPK) worked synergistically, and the suppression of both genes could further lead to suppression in cell migration. Furthermore, based on our analysis of cellular focal adhesion (FA) parameters using MATLAB analysis, we are able to find out the synergistic reduction of STK40 and MAPK that further abolished the increased FA by shSTK40. While FA identification in previous studies includes image analysis using manual selection, our protocol provides a semi-automatic manual selection of FAs using MATLAB. Here, we provide a method that can shorten the amount of time required for manual identification of FAs and increase the precision for discerning individual FAs for various analyses, such as FA numbers, area, and mean signals., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (©Copyright : © 2023 The Authors; This is an open access article under the CC BY-NC license.)

N 6 -methyladenosine (m 6 A) in messenger RNA (mRNA) regulates immune cells in homeostasis and in response to infection and inflammation. The function of the m 6 A reader YTHDF2 in the tumor microenvironment (TME) in these contexts has not been explored. We discovered that the loss of YTHDF2 in regulatory T (Treg) cells reduces tumor growth in mice. Deletion of Ythdf2 in Tregs does not affect peripheral immune homeostasis but leads to increased apoptosis and impaired suppressive function of Treg cells in the TME. Elevated tumor necrosis factor (TNF) signaling in the TME promotes YTHDF2 expression, which in turn regulates NF-κB signaling by accelerating the degradation of m 6 A-modified transcripts that encode NF-κB-negative regulators. This TME-specific regulation of Treg by YTHDF2 points to YTHDF2 as a potential target for anti-cancer immunotherapy, where intratumoral Treg cells can be targeted to enhance anti-tumor immune response while avoiding Treg cells in the periphery to minimize undesired inflammations., (© 2023 The Authors.)

Background: Detectable Epstein-Barr virus (EBV) DNA levels and unsatisfactory tumor response to induction chemotherapy (IC) could be used to guide the risk-adapted treatment strategy of locoregionally advanced nasopharyngeal carcinoma (LANPC) before concurrent chemoradiotherapy. We aim to compare the efficacy and safety of concurrent chemotherapy using taxane plus cisplatin [double-agent concurrent chemotherapy (DACC) group] with those of cisplatin alone [single-agent concurrent chemotherapy (SACC) group] in high-risk LANPC., Methods: Overall, 197 LANPC patients with detectable EBV DNA or stable disease (SD) after IC were retrospectively included. Potential confounders between the DACC and SACC groups were adjusted by propensity score matching. Short-term efficacy and long-term survival were assessed in the two groups., Results: Although the objective response rate of the DACC group was marginally higher than that of the SACC group, the difference was not significant (92.7% versus 85.3%, p  = 0.38). Concerning long-term survival, DACC did not show superiority to SACC after patient matching: 3-year progression-free survival: 87.8% versus 81.7%, p  = 0.80; overall survival: 97.6% versus 97.3%, p  = 0.48; distant metastasis-free survival: 87.8% versus 90.5%, p  = 0.64, and; locoregional relapse-free survival: 92.3% versus 86.9%, p  = 0.77. The incidence of grade 1-4 hematological toxicities was significantly higher in the DACC group., Conclusion: Due to the small sample size, we do not have sufficient evidence that concurrent chemotherapy using taxane plus cisplatin provides additional survival benefits in LANPC patients with an unfavorable response (detectable EBV DNA levels or SD) after IC. But concurrent taxane and cisplatin chemotherapy is associated with a higher rate of hematologic adverse events. Further clinical trials will be required to establish evidence and identify more effective treatment modalities for high-risk LANPC patients., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2023.)

The transcription factor Prdm16 functions as a potent suppressor of transforming growth factor-beta (TGF-β) signaling, whose inactivation is deemed essential to the progression of pancreatic ductal adenocarcinoma (PDAC). Using the KrasG12D-based mouse model of human PDAC, we surprisingly found that ablating Prdm16 did not block but instead accelerated PDAC formation and progression, suggesting that Prdm16 might function as a tumor suppressor in this malignancy. Subsequent genetic experiments showed that ablating Prdm16 along with Smad4 resulted in a shift from a well-differentiated and confined neoplasm to a highly aggressive and metastatic disease, which was associated with a striking deviation in the trajectory of the premalignant lesions. Mechanistically, we found that Smad4 interacted with and recruited Prdm16 to repress its own expression, therefore pinpointing a model in which Prdm16 functions downstream of Smad4 to constrain the PDAC malignant phenotype. Collectively, these findings unveil an unprecedented antagonistic interaction between the tumor suppressors Smad4 and Prdm16 that functions to restrict PDAC progression and metastasis., (© 2023 Hurwitz et al.)

Purpose: To evaluate the long-term local control, failure patterns, and toxicities after individualized clinical target volume (CTV) delineation in unilateral nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiotherapy (IMRT)., Methods: Unilateral NPC was defined as a nasopharyngeal mass confined to one side of the nasopharynx and did not exceed the midline. From November 2003 to December 2017, 95 patients were retrospectively included. All patients received IMRT. The CTVs were determined based on the distance from the gross tumor. The contralateral para-pharyngeal space and skull base orifices were spared from irradiation., Results: There were three local recurrences and eight regional recurrences in 10 patients during an 84-month follow-up. All local recurrences were within PGTVnx, and all in-field recurrences. No recurrences were found in traditional high-risk areas including contralateral the para-pharyngeal space and skull base orifices. The 10-year local-recurrence-free survival, regional-recurrence-free survival and overall survival were 96.2%, 90.5% and 84.7%, respectively. The dosimetry parameters of the tumor-contralateral organs were all lower than the values of the tumor-ipsilateral side (P < 0.05). The late toxicities occurred mainly in the tumor-ipsilateral organs, including radiation-induced temporal lobe injury, impaired visuality, hearing loss and subcutaneous fibrosis., Conclusion: Individualized CTV delineation in unilateral NPC could yield excellent long-term local control with limited out-of-field recurrences, reduced dose to tumor- contralateral organs and mild late toxicities, which is worthy of further exploration., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: The current recommendation for patients with locoregionally advanced nasopharyngeal carcinoma (NPC) is cisplatin-based induction chemotherapy (IC) or adjuvant chemotherapy (AC) plus concurrent chemoradiotherapy (CRT). However, data on the optimal platinum doses for each phase of combined regimens are lacking., Experimental Design: 742 patients with NPC in the NPC-0501 trial treated with CRT plus IC/AC and irradiated with intensity-modulated radiotherapy (IMRT) were analyzed. The optimal platinum dose to achieve the best overall survival (OS) in the concurrent and induction/adjuvant phases was studied., Results: Evaluation of the whole series shows the optimal platinum dose was 160 mg/m2 in the concurrent and 260 mg/m2 in the induction/adjuvant phase. Repeating the analyses on 591 patients treated with cisplatin throughout (no replacement by carboplatin) confirmed the same results. The cohort with optimal platinum doses in both phases had better OS than the cohort suboptimal in both phases (stage III: 90% vs. 75%; stage IVA-B: 80% vs. 56%, at 5-year). Multivariable analyses confirmed optimal platinum doses in both phases versus suboptimal dose in each phase are significant independent factors for OS, with HR of 0.61 [95% confidence interval (CI), 0.41-0.91] and 0.67 (95% CI, 0.48-0.94), respectively. Treatment sequence was statistically insignificant after adjusting for platinum doses., Conclusions: Both concurrent and IC/AC are needed for locoregionally advanced NPC, even for patients irradiated by IMRT; the concurrent platinum dosage could be set at ≥160 mg/m2 when coupled with adequate induction/adjuvant dosage at ≥260 mg/m2 (or at least ≥240 mg/m2). To achieve these optimal dosages, IC-CRT at conventional fractionation is favored., (©2022 American Association for Cancer Research.)

Objective: In treating patients with inflammatory bowel disease (IBD), how concomitant medications influence the response to infliximab is largely unexplored. We aim to evaluate whether proton pump inhibitors (PPIs) affect the response to infliximab therapy in patients with IBD., Design: Patient-level data of adult patients with moderate-to-severe IBD treated with infliximab were obtained from the Yale Open Data Access Framework. Multivariable analysis and propensity score-matched analysis were performed to assess week 30 remission rates, week 54 remission rates and hospitalisation rates in patients on infliximab therapy with and without PPI exposure., Results: Among the five randomised controlled studies, there were 147 and 889 patients on infliximab with and without PPI therapy, respectively. Patients on PPI were older, more likely to be Caucasian and were less likely to be on immunomodulator therapy. Patients on PPI were significantly less likely to achieve week 30 remission on multivariable analysis (OR 0.45, p<0.001). Following propensity score matching adjusting for baseline difference in patient characteristics, the week 30 remission rates were 30% and 49% in patients with and without PPI therapy, respectively (p<0.001). Analysing separately for disease, the findings remained statistically significant in Crohn's disease but did not reach significance in UC. Similar results were seen with week 54 remission rates. Patients on PPI were also more likely to be hospitalised (15% vs 8%, p=0.007). Rates of adverse events such as gastroenteritis were not different between the two groups., Conclusion: In this patient-level meta-analysis of randomised controlled studies, we found that patients with IBD taking PPI were less likely to achieve remission while on infliximab therapy. The results of our study warrant further investigation into the effect of PPI on IBD outcomes and therapies., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Integrating signals is essential for cell survival, leading to the concept of synthetic lethality. However, how signaling is integrated to control cell migration remains unclear. By conducting a "two-hit" screen, we revealed the synergistic reduction of cell migration when serine-threonine kinase 40 (STK40) and mitogen-activated protein kinase (MAPK) were simultaneously suppressed. Single-cell analyses showed that STK40 knockdown reduced cell motility and coordination by strengthening focal adhesion (FA) complexes. Furthermore, STK40 knockdown reduced the stability of yes-associated protein (YAP) and subsequently decreased YAP transported into the nucleus, while MAPK inhibition further weakened YAP activities in the nucleus to disturb FA remodeling. Together, we unveiled an integrated STK40-YAP-MAPK system regulating cell migration and introduced "synthetic dysmobility" as a novel strategy to collaboratively control cell migration., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Purpose: Reirradiation for locally recurrent nasopharyngeal carcinoma (NPC) is challenging because prior radiation dose delivered in the first course is often close to the tolerance limit of surrounding normal structures. A delicate balance between achieving local salvage and minimizing treatment toxicities is needed. However, high-level evidence is lacking because available reports are mostly retrospective studies on small series of patients. Pragmatic consensus guidelines, based on an extensive literature search and the pooling of opinions by leading specialists, will provide a useful reference to assist decision-making for these difficult decisions., Methods and Materials: A thorough review of available literature on recurrent NPC was conducted. A set of questions and preliminary draft guideline was circulated to a panel of international specialists with extensive experience in this field for voting on controversial areas and comments. A refined second proposal, based on a summary of the initial voting and different opinions expressed, was recirculated to the whole panel for review and reconsideration. The current guideline was based on majority voting after repeated iteration for final agreement., Results: The initial round of questions showed variations in clinical practice even among the specialists, reflecting the lack of high-quality supporting data and the difficulties in formulating clinical decisions. Through exchange of comments and iterative revisions, recommendations with high-to-moderate agreement were formulated on general treatment strategies and details of reirradiation (including patient selection, targets contouring, dose prescription, and constraints)., Conclusion: This paper provides useful reference on radical salvage treatment strategies for recurrent NPC and optimization of reirradiation through review of published evidence and consensus building. However, the final decision by the attending clinician must include full consideration of an individual patient's condition, understanding of the delicate balance between risk and benefits, and acceptance of risk of complications., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose : Orbital fibroblasts are involved in pathogenesis of Graves' orbitopathy (GO). Fibroblast growth factor (FGF) affects fibroblasts of GO. This study aims to investigate the roles of FGF and FGF receptor (FGFR) in GO. Methods : Serum FGF proteins and orbital fibroblast FGFR proteins and mRNAs were measured in GO patients and controls. Orbital fibroblasts of GO were cultured and accessed for changes in proliferation (by nuclei number and MTT), myofibroblastic differentiation (by α-SMA), and adipogenesis (by oil droplets using Oil Red O stain) under FGF1 with or without FGFR inhibitors (FGFRi). Results : Serum FGF1 and FGF2 were increased in GO patients. FGFR1 was the most abundantly expressed FGFR in GO orbital fibroblasts. FGF1 increased GO fibroblast proliferation/adipogenesis and suppressed myofibroblastic differentiation, while FGFRi reversed these effects. Conclusion : FGF signaling may be involved in GO pathogenesis. Manipulation of FGF-FGFR pathway for GO treatment is worthy of further investigation. Registration number on Clinicaltrials.gov : NCT03324022.

Background: A current recommendation for the treatment of patients with locoregionally advanced nasopharyngeal carcinoma (NPC) is conventional fractionated radiotherapy (RT) with concurrent cisplatin followed by adjuvant cisplatin and 5-fluorouracil (PF). This randomized NPC-0501 trial evaluated the therapeutic effect of changing to an induction-concurrent sequence or accelerated-fractionation sequence, and/or replacing 5-fluorouracil with capecitabine (X)., Methods: Patients with American Joint Committee on Cancer/International Union Against Cancer stage III to stage IVB NPC initially were randomly allocated to 1 of 6 treatment arms (6-arm full-randomization cohort). The protocol was amended in 2009 to permit centers to opt out of randomization regarding fractionation (3-arm chemotherapy cohort)., Results: A total of 803 patients were accrued (1 of whom was nonevaluable) from 2006 to 2012. Based on the overall comparisons, neither changing the chemotherapy sequence nor accelerated fractionation improved treatment outcome. However, secondary analyses demonstrated that when adjusted for RT parameters and other significant factors, the induction-concurrent sequence, especially the induction-PX regimen, achieved significant improvements in progression-free survival (PFS) and overall survival. Efficacy varied among different RT groups: although no impact was observed in the accelerated-fractionation group and the 3-arm chemotherapy cohort, a comparison of the induction-concurrent versus concurrent-adjuvant sequence in the conventional-fractionation group demonstrated a significant benefit in PFS (78% vs 62% at 5 years; P = .015) and a marginal benefit in overall survival (84% vs 72%; P = .042) after adjusting for multiple comparisons. Comparison of the induction-PX versus the adjuvant-PF regimen demonstrated better PFS (78% vs 62%; P = .027) without an increase in overall late toxicity., Conclusions: For patients irradiated using conventional fractionation, changing the chemotherapy sequence from a concurrent-adjuvant to an induction-concurrent sequence, particularly using induction cisplatin and capecitabine, potentially could improve efficacy without an adverse impact on late toxicity. However, further validation is needed for confirmation of these findings., (© 2020 American Cancer Society.)

The dual expression of CD5 and MYC protein (DECM) on B-lymphocytes may arise at a specific stage of de novo diffuse large B-cell lymphoma (DLBCL). This study retrospectively reviewed 210 patients with de novo DLBCL at the Affiliated Hospital of Jiangnan University between 2006 and 2017. DECM was significantly correlated with a worse prognosis than that in either the CD5 + or MYC + or CD5 - MYC - patients. Furthermore, patients with DECM showed a similar outcome to MYC + BCL2 + lymphoma patients who have extremely poor survival rates. Multivariate analysis demonstrated that DECM was a significant independent predictor for overall survival (P < .0001) and progression-free survival (P < .0001) in DLBCL. DLBCL patients with DECM showed significantly inferior clinical outcomes compared to the CD5 + , MYC + or CD5 - MYC - patients. Combinational therapeutic modalities might be a candidate approach to improve the prognosis of these patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflicts of interest., (Copyright © 2019 Elsevier Inc. All rights reserved.)

CD44 is widely expressed in most vertebrate cells, whereas the expression of CD44v6 is restricted to only a few tissues and has been considered to be associated with tumor progression and metastasis. Thus, CD44v6 has been recognized as a promising prognostic biomarker and therapeutic target for various cancers for more than a decade. However, despite many experimental studies, the structural dynamics and differences between CD44s and CD44v6, particularly in their stem region, still remain elusive. Here, a computational study was conducted to address these problems. We found that the stem of CD44s adopted predominantly two conformations, one featuring antiparallel β-sheets and the other featuring parallel β-sheets, whereas the stem of CD44v6 adopted mainly one conformation with relatively highly suppressed β-sheet contents. Moreover, Phe215 was found to be essential in the β-sheets of both CD44s and CD44v6. We finally found intramolecular Phe215-Trp224 hydrogen-bonding interactions and hydrophobic interactions with Phe215 that cooperatively drove conformational differences upon the addition of the v6 region to CD44. Our study elucidated the structural differences between the stem regions of CD44s and CD44v6 and thus can offer useful structural information for drug design to specifically target CD44v6 in promising clinical applications.

Background and Aims: Mouse models of colitis have been used to study the pathogenesis of inflammatory bowel disease (IBD) and for pre-clinical development of therapeutic agents. Various epigenetic pathways have been shown to play important regulatory roles in IBD. Reversible N 6 -methyladenosine (m 6 A) methylation represents a new layer of post-transcriptional gene regulation that affects a variety of biological processes. We aim to study how deletion of a critical component of m 6 A writer complex, METTL14, in T cells affects the development of colitis., Methods: Conditional Mettl14 was lineage specifically deleted with CD4-regulated Cre in T cells. Colitis phenotype was determined by H&E staining, colon weight-to-length ratio and cytokine expression. We additionally utilized T cell transfer model of colitis and adoptive transfer of regulatory T cells. Mice were treated with antibiotics to determine if the colitis could be attenuated., Results: METTL14 deficiency in T cells induced spontaneous colitis in mice. This was characterized by increased inflammatory cell infiltration, increased colonic weight-to-length ratio and increased Th1 and Th17 cytokines. The colitis development was due to dysfunctional regulatory T (T reg ) cells, as adoptive transfer of WT T reg cells attenuated the colitis phenotype. The METTL14-deficient T reg cells have decreased RORγt expression compared with WT controls. METTL14 deficiency caused impaired induction of naïve T cells into induced T reg cells. Antibiotic treatment notably attenuated the colitis development., Conclusion: Here we report a new mouse model of spontaneous colitis based on perturbation of RNA methylation in T cells. The colitis is T cell-mediated and dependent on the microbiome. This model represents a new tool for elucidating pathogenic pathways, studying the contribution of intestinal microbiome and preclinical testing of therapeutic agents for inflammatory bowel disease., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: The treatment of nasopharyngeal carcinoma requires high radiation doses. The balance of the risks of local recurrence owing to inadequate tumor coverage versus the potential damage to the adjacent organs at risk (OARs) is of critical importance. With advancements in technology, high target conformality is possible. Nonetheless, to achieve the best possible dose distribution, optimal setting of dose targets and dose prioritization for tumor volumes and various OARs is fundamental. Radiation doses should always be guided by the As Low As Reasonably Practicable principle. There are marked variations in practice. This study aimed to develop a guideline to serve as a global practical reference., Methods and Materials: A literature search on dose tolerances and normal-tissue complications after treatment for nasopharyngeal carcinoma was conducted. In addition, published guidelines and protocols on dose prioritization and constraints were reviewed. A text document and preliminary set of variants was circulated to a panel of international experts with publications or extensive experience in the field. An anonymized voting process was conducted to rank the proposed variants. A summary of the initial voting and different opinions expressed by members were then recirculated to the whole panel for review and reconsideration. Based on the comments of the panel, a refined second proposal was recirculated to the same panel. The current guideline was based on majority voting after repeated iteration for final agreement., Results: Variation in opinion among international experts was repeatedly iterated to develop a guideline describing appropriate dose prioritization and constraints. The percentage of final agreement on the recommended parameters and alternative views is shown. The rationale for the recommendations and the limitations of current evidence are discussed., Conclusions: Through this comprehensive review of available evidence and interactive exchange of vast experience by international experts, a guideline was developed to provide a practical reference for setting dose prioritization and acceptance criteria for tumor volumes and OARs. The final decision on the treatment prescription should be based on the individual clinical situation and the patient's acceptance of optimal balance of risk., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: To define the clinical characteristics and prognostic value of pre-retreatment plasma Epstein-Barr virus (EBV) DNA, we investigated EBV status in locoregional recurrent nasopharyngeal carcinoma (lrNPC) patients., Methods: Between April 2008 and August 2016, the data of patients with nonmetastatic lrNPC were retrospectively reviewed. The survival indexes of patients between different pre-retreatment EBV status groups were compared., Results: A total of 401 patients with nonmetastatic lrNPC were enrolled, and 197 (49.1%) patients had detectable pre-retreatment plasma EBV DNA. Treatment included radiotherapy alone (n = 37 patients), surgery alone (n = 105), radiotherapy (n = 208), surgery combined with radiotherapy (n = 20), chemotherapy and targeted therapy (n = 31). Median follow-up was 32 months. The 3-year locoregional relapse-free survival (LRRFS), distant metastasis-free survival (DMFS), and overall survival (OS) rates for the entire cohort were 64.8%, 89.4%, and 58.8%, respectively. The estimated 3-year LRRFS, DMFS, and OS rates for the pre EBV-positive group vs the pre EBV-negative group were 54.2% vs 75.0% (P < 0.001), 86.6% vs 91.9% (P = 0.05), 51.6% vs 65.9% (P = 0.01), respectively. Among patients in the clinical stage rI/II, there were 17 patients in the radiotherapy alone group and 49 patients in the surgery alone group. And there was no significant difference in overall survival between radiotherapy and surgery, even among the different pre-EBV statuses (P > 0.05). In terms of long-term toxic and side effects, the incidence of radioactive temporal lobe injury in the radiotherapy group was higher than that in the surgery group (35.3% vs 8.2%, P < 0.001), and no statistically significant difference was found in other long-term toxic and side effects., Conclusions: The positive rate of pre-retreatment plasma EBV DNA in lrNPC is lower than primary NPC. The prognosis of EBV DNA negative group is better than positive group. For locally early-stage lrNPC, regardless of EBV DNA status, radiotherapy and surgery are available options and both can achieve better long-term survival., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Liver function is routinely assessed in clinical practice as liver function tests provide sensitive indicators of hepatocellular injury. However, the prognostic value of enzymes that indicate hepatic injury has never been systematically investigated in lymphoma, including diffuse large B-cell lymphoma (DLBCL)., Methods: This study examined the prognostic value of baseline aspartic transaminase (AST) in DLBCL patients. The association between AST and clinical features was analyzed in 179 DLBCL patients treated from 2006 to 2016. All enrolled patients were treated with R-CHOP or R-CHOP-like chemotherapy. Log-rank test, univariable analysis, and subgroup analysis were performed to evaluate the impact of AST on survival., Results: AST 33.3 U/L was considered to be the optimal threshold value for predicting prognosis. A higher AST level was associated with advanced stage (P = 0.001), poorer performance status (P = 0.014), elevated lactate dehydrogenase level (P <  0.0001), presence of B symptoms (P = 0.001), high-risk International Prognostic Index (IPI, IPI 3-5) (P = 0.002), non-germinal center B-cell subtypes (P = 0.038), hepatitis B virus surface antigen positivity (P = 0.045) and more extra nodal involvement (ENI, ENI ≥ 2) (P = 0.027). Patients with a higher AST level had a shorter overall survival (OS) (2-year OS rate, 53.6% vs. 83.6%, P <  0.001). Subgroup analysis indicated that higher AST levels have poorer prognostic values in patients without B symptoms and LDH positive groups., Conclusion: A pretreatment AST level is associated with OS in DLBCL patients treated with R-CHOP or similar chemotherapy regimens. A high pretreatment AST level might be a reliable prognostic factor for predicting a dismal outcome in DLBCL patients. Serum AST levels may be investigated for use as an easily determinable, inexpensive biomarker for risk assessment in patients with DLBCL.

Purpose: To analyze the long-term outcome and pattern of failure for patients with nasopharyngeal carcinoma (NPC) after intensity-modulated radiotherapy (IMRT)., Methods and Materials: Patients with NPC after IMRT from 2001 to 2008 were recruited (n = 865). Clinical features, laboratory data, and treatments were collected., Results: The 10-year local recurrence-free survival, distant metastasis-free survival, and disease-specific survival (DSS) were 92.0%, 83.4%, and 78.6%, respectively. A total of 209 patients died: 59% of whom died from distant metastasis. The 10-year DSS was higher in patients who received chemoradiotherapy than those who received IMRT alone for patients with high-risk stage III disease, while there was no survival difference for patients with stage II and low-risk stage III disease., Conclusions: IMRT provides satisfactory long-term survival for patients with NPC. Distant metastasis has been the most common reason for failure. Adding chemotherapy did not improve survival in patients with stage II and low-risk stage III disease., (© 2019 Wiley Periodicals, Inc.)

Purpose of Review: Crohn's disease management has changed significantly with increasing use of biologics. We review the recent literature on the clinical management of Crohn's disease and new approaches in selecting and optimizing therapy., Recent Findings: Recent studies have addressed the efficacy of proactive anti-TNFα trough level monitoring, the efficacy of biosimilars, and the efficacy and immunogenicity of newer biologics including anti-integrin therapy and anti-IL12/23 therapy. Optimizing anti-TNFα therapy according to trough concentrations correlates with improved remission rates. Patients can be switched from the reference drug to a biosimilar, or vice versa, without a measurable change in efficacy, safety, or immunogenicity. Immunomodulators are effective in decreasing immunogenicity and boosting anti-TNFα drug level. The anti-integrin and anti-IL12/23 therapies are effective as induction and maintenance therapy with low immunogenicity and excellent safety profiles. Patients at high risk for post-operative recurrence should be started on a biologic therapy within 4 weeks post-op. Multiple biologic therapies are currently available for treatment of Crohn's disease including anti-TNFα therapy, anti-integrin therapy, and anti-IL12/23 therapy. The choice of first-line therapy should be based on individual risk-benefit analysis, route of administration, and patient preference. Patient with inadequate response should have their trough level checked and therapy optimized. Therapeutic prophylaxis for post-operative recurrence should be based on patient's risk factors for recurrence.

Background: Systemic inflammation has been implicated in cancer development and progression. This study examined the best cutoff value of erythrocyte sedimentation rate (ESR) in diffuse large B-cell lymphoma (DLBCL) patients., Methods: The relationship between ESR and clinical characteristics was analyzed in 182 DLBCL patients from 2006 to 2017. The log-rank test, univariate analysis, and Cox regression analysis were applied to evaluate the relationship between ESR and survival. An ESR of more than 37.5 mm/hour was found to be the optimal threshold value for predicting prognosis., Results: ESR was associated with more frequent advanced Ann Arbor stage, poorer performance status, elevated lactate dehydrogenase level, the presence of B symptoms, high-risk International Prognostic Index (IPI 3-5), more extranodal involvement (ENI ≥2), non-germinal-center B-cell (non-GCB) subtypes, and more frequent Myc protein positivity. Shorter overall survival (OS) and progression-free survival (PFS) were found for patients with higher ESRs. Multivariate analysis demonstrated that ESR level is an independent prognostic factor of both OS and PFS. In addition, dynamic changes in ESR are valuable in assessing curative effect and predicting disease recurrence., Conclusion: High ESR in DLBCL patients indicated unfavorable prognosis that may require alternative treatment regimens.

Aim: CD30+ diffuse large B-cell lymphoma (DLBCL) has emerged as a new immunophenotypic variant of de novo DLBCLs. However, the prevalence of CD30 positivity is variable according to different studies, and the prognostic significance of CD30 is also controversial. This study aimed to investigate the positive expression rate and prognostic impact of CD30 in de novo DLBCLs and try to find the correlated influences., Methods: A total of 241 patients with de novo DLBCL in east China from 2008 to 2015 were included to investigate the prevalence, clinicopathological features and outcomes of CD30+ de novo DLBCLs. Immunohistochemical evaluation for CD10, CD30, BCL2, BCL6, MUM1/IRF4, MYC and Ki67, and fluorescence in situ hybridisation for MYC and BCL2 gene alterations were performed., Results: Using a >0% threshold, CD30 expression was detected in approximately 10% patient with de novo DLBCL. These predominately presented with centroblastic or anaplastic morphological patterns, less frequently showing immunoblastic morphology or 'starry sky' pattern, mutually exclusive with MYC gene rearrangement, and negatively associated with BCL2 protein expression. CD30 expression was associated with a favourable prognosis of patients' outcomes. However, the multivariate analysis revealed that it was not an independent prognostic factor in de novo DLBCLs. The impact of CD30 might be influenced by the international prognostic index and the expression of MYC and BCL2 proteins., Conclusion: CD30+ DLBCL may be a subset of de novo DLBCLs with characteristic clinicopathological features, but the prognostic role of CD30 is limited., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Purpose: This is an updated combined analysis of 2 randomized studies (NPC-9901 and NPC-9902 trials) to evaluate the 10-year outcome attributed to the addition of concurrent-adjuvant chemotherapy for advanced locoregional nasopharyngeal carcinoma (NPC)., Patients and Methods: Eligible patients with stage III-IVB nonkeratinizing NPC were randomly assigned to radiation therapy alone (RT: 218 patients) or chemoradiation therapy (CRT: 223 patients) using 3 cycles of cisplatin (100 mg/m 2 ) concurrent with RT, followed by 3 cycles of cisplatin (80 mg/m 2 ) and fluorouracil (1000 mg/m 2 /day for 4 days). All of the patients were irradiated with conventional fractionation to ≥66 Gy. The median follow-up was 13.9 years., Results: Intention-to-treat analysis confirmed that the CRT group achieved significant improvement in 10-year failure-free rate (FFR: 62% vs 52%, P = .016), progression-free survival rate (PFS: 56% vs 44%, P = .008), and overall survival rate (OS: 60% vs 50%, P = .044). There was no significant increase in overall late toxicity rate (51% vs 48%, P = .34) or noncancer deaths (19% vs 16%, P = .52). Exploratory studies showed no difference in disease control between 2 or 3 cycles of concurrent cisplatin; however, patients given 3 concurrent cycles had a significant increase in hearing impairment (40% vs 24%, P = .017). Only those who continued to receive 2 or more cycles of adjuvant cisplatin-fluorouracil achieved significant improvement in distant control (73% vs 65%, P = .037) and maximal survival gain., Conclusion: The addition of concurrent cisplatin plus adjuvant cisplatin-fluorouracil could significantly improve overall survival and disease control without incurring a significant increase in late toxicity or noncancer deaths. Exploratory analyses suggested that both the concurrent and the adjuvant phases contributed to tumor control. Furthermore, the number of concurrent cycles could be reduced from 3 to 2 cycles in order to achieve a similar survival benefit without incurring an excessive increase in hearing impairment. This is a useful hypothesis that warrants further validation., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: To investigate the diagnostic value of shear wave elastography (SWE) in identifying cervical small lymph node metastases in nasopharyngeal carcinoma (NPC) patients., Materials and Methods: This prospective study was approved by the local institutional review board. From July 2014 to March 2016, 114 sLNs from 62 newly diagnosed NPC patients (47 men, 15 women) were assessed. Target small lymph nodes (sLNs), which were undiagnosed by magnetic resonance imaging (MRI), were defined as scattered cervical lymph nodes that had no evidence of central necrosis or extracapsular spread and exhibited a maximum transverse diameter ≥5 mm and <10 mm in MRI. The mean (Emean), minimum (Emin) and maximum (Emax) of the elasticity indices (EIs) were measured by SWE at the stiffest part of the sLN (kPa). Biopsy pathology was served as the reference standard. Diagnostic performances were assessed using receiver operating curve (ROC) analysis on a node-by-node basis., Results: Of the 114 small cervical lymph nodes, 88 (77.2%) were benign, and 26 (22.8%) were malignant. All SWE EIs were significantly higher in malignant sLNs than in benign sLNs (p < 0.001). Emean exhibited the highest diagnostic value (area under the curve = 0.879 ± 0.036) (p < 0.001) and the corresponding sensitivity, specificity, positive predictive value, negative predictive value and accuracy of 84.6%, 83.0%, 59.5%, 94.8% and 83.3%, respectively. The intra-observer reproducibility of all SWE EIs were significant, with intra-class correlation coefficient (ICC) of 0.745 in Emean, 0.716 in Emax and 0.702 in Emin., Conclusion: Shear wave elastography is an optional supplementary imaging modality to routine MRI examination to diagnose cervical lymph nodes in NPC patients., (Copyright © 2018 Elsevier B.V. All rights reserved.)

MicroRNAs (miRNAs) are small endogenous RNAs that regulate gene-expression posttranscriptionally. MiRNA research in allergy is expanding because miRNAs are crucial regulators of gene expression and promising candidates for biomarker development. MiRNA mimics and miRNA inhibitors currently in preclinical development have shown promise as novel therapeutic agents. Multiple technological platforms have been developed for miRNA isolation, miRNA quantitation, miRNA profiling, miRNA target detection, and modulating miRNA levels in vitro and in vivo. Here we will review the major technological platforms with consideration given for the advantages and disadvantages of each platform., (Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: The purpose of this study is to assess the feasibility of volumetric-modulated arc therapy (VMAT) for nasopharyngeal carcinoma (NPC) patients by comparing the physical dosimetry, delivery efficiency and clinical outcomes with intensity-modulated radiotherapy (IMRT). Methods: A prospective matched study was performed for patients with newly diagnosed NPC who underwent VMAT or IMRT. The patients in two groups were equally matched in terms of gender, age, tumor stage and chemotherapy. The target coverage, homogeneity index (HI) and conformity index (CI) of the planning target volume (PTV), organs at risk (OARs) sparing, average treatment time and clinical outcomes were analyzed. Results: From June 2013 to August 2015, a total of 80 patients were enrolled in this study, with 40 patients in each group. The coverage of PTV was similar for both groups. D2 was observed slight difference only in early stage disease (T1-2) (VMAT vs. IMRT, 7494±109 cGy vs. 7564±92 cGy; p=0.06). The HI of VMAT group was better than that of IMRT group (p=0.001), whereas CI was slightly worse (p=0.061). The maximum doses received by the brain stem, spinal cord, and optic nerve of VMAT were higher than those of IMRT (p<0.05). But the irradiation volumes in healthy tissue were generally lower for VMAT group, with significant differences in V20, V25 and V45 (p<0.05). With regard to the delivery efficiency compared with IMRT (1160 ± 204s), a 69% reduction in treatment time was achieved by VMAT (363 ± 162s). Both groups had 5 cases of nasopharyngeal residual lesions after radiotherapy. The 2-year estimated local relapse-free survival, regional relapse-free survival and locoregional relapse-free survival, distant metastasis-free survival, disease-free survival and overall survival were similar between two groups, with the corresponding rates of 100%, 97.4%, 97.4%, 90.0%, 90.0% and 92.4% in VMAT group, and 100%, 100%, 100%, 95.0%, 95.0% and 97.5% in IMRT group, respectively. Conclusions: Both VMAT and IMRT can meet the clinical requirements for the treatment of NPC. The short-term tumor regression rates and 2-year survival rates with the two techniques are comparable. The faster treatment time benefits of VMAT will enable more patients to receive precision radiotherapy., Competing Interests: Competing Interests: The authors declare no competing financial interests.

Purpose: Target delineation in nasopharyngeal carcinoma (NPC) often proves challenging because of the notoriously narrow therapeutic margin. High doses are needed to achieve optimal levels of tumour control, and dosimetric inadequacy remains one of the most important independent factors affecting treatment outcome., Method: A review of the available literature addressing the natural behaviour of NPC and correlation between clinical and pathological aspects of the disease was conducted. Existing international guidelines as well as published protocols specified by clinical trials on contouring of clinical target volumes (CTV) were compared. This information was then summarized into a preliminary draft guideline which was then circulated to international experts in the field for exchange of opinions and subsequent voting on areas with the greatest controversies., Results: Common areas of uncertainty and variation in practices among experts experienced in radiation therapy for NPC were elucidated. Iterative revisions were made based on extensive discussion and final voting on controversial areas by the expert panel, to formulate the recommendations on contouring of CTV based on optimal geometric expansion and anatomical editing for those structures with substantial risk of microscopic infiltration., Conclusion: Through this comprehensive review of available evidence and best practices at major institutions, as well as interactive exchange of vast experience by international experts, this set of consensus guidelines has been developed to provide a practical reference for appropriate contouring to ensure optimal target coverage. However, the final decision on the treatment volumes should be based on full consideration of individual patients' factors and facilities of an individual centre (including the quality of imaging methods and the precision of treatment delivery)., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Phytochemical investigation on the whole plants of Ypsilandra parviflora led to the isolation of seven new spirostanol saponins, named ypsiparosides A-G, together with 14 known saponins. Their structures were unambiguously established based on extensive spectroscopic evidence and chemical methods. The induced rabbit platelet aggregation activities of the isolates were tested. Compounds 4, 15, and 17 showed maximal platelet aggregation rates ranging from 43 to 55% at a concentration of 300μg/mL. Further experiments exhibited that compounds 4, 15, and 17 possessed EC 50 values of 642.9, 95.3, and 300.8μg/mL, respectively., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Chemoresistance, the major obstacle in breast cancer chemotherapy, results in unnecessary chemotherapy and wasting of medical resources. No feasible method has been available to predict chemoresistance before chemotherapy. In our previous study, elevated expression of transient receptor potential channel TRPC5 was found to be an essential element for chemoresistance in breast cancer cells, and it was determined that it could be transferred to chemosensitive breast cancer cells through releasing extracellular vesicles (EV) containing TRPC5 from chemoresistant cells, resulting in acquired chemoresistance. Exosomes, a type of EV, are secreted membrane-enclosed vesicles of 50-150-nm diameter. In this study we found that circulating exosomes in peripheral blood from breast cancer patients carried TRPC5. In the present study, circulating exosome-carrying TRPC5 (cirExo-TRPC5) level was significantly correlated with TRPC5 expression level in breast cancer tissues and tumor response to chemotherapy. Furthermore, increased cirExo-TRPC5 level after chemotherapy preceded progressive disease (PD) based on imaging examination and strongly predicted acquired chemoresistance. Taken together, our study demonstrated that cirExo-TRPC5 might act as a noninvasive chemoresistance marker and might serve as an adjuvant to the current imaging examination-based chemoresistance., (© 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Given the distinct biological characteristics and regional distribution of nasopharyngeal carcinoma (NPC) compared with other head and neck cancers, and uncertainties regarding therapeutic strategies, physicians require high-quality clinical practice guidelines (CPGs) to provide transparent recommendations for NPC treatment. This study aimed to critically appraise the quality of NPC CPGs and assess the consistency of their recommendations. Methods: We identified CPGs that provided recommendations on the diagnosis and management of NPC published up to December 2015. Four investigators independently appraised CPG quality using the Appraisal of Guidelines for Research & Evaluation (AGREE) II instrument. Key recommendations by CPGs were also evaluated. Results: A total of 7 CPGs were eligible for this study: 5 produced by professional organizations or governmental agencies and 2 were developed based on expert consensus. Of the 6 AGREE II domains, the applicability domain scored consistently low across CPGs (range, 13.5%-30.2%); no CPG achieved a score of >50% in all 6 domains. The scope and purpose domain (≥73.6% for 4 CPGs) and editorial independence domain (≥75.0% for 6 CPGs) scored highest. Of the 23 AGREE II items, 9 scored less than half of the points available in all 7 CPGs. The recommendations by CPGs were consistent in general; heterogeneity mainly existed among recommended therapeutic strategies. Conclusions: Variation exists in NPC CPG development processes and recommendations. Increased efforts are required to make comprehensive resources available to guide healthcare providers and enhance delivery of high-quality, evidence-based care for NPC. International collaboration is necessary to enable the development of high-quality and regionally relevant CPGs for NPC., (Copyright © 2017 by the National Comprehensive Cancer Network.)

Synchronous front-face fluorescence spectroscopy has been developed for the discrimination of used frying oil (UFO) from edible vegetable oil (EVO), the estimation of the using time of UFO, and the determination of the adulteration of EVO with UFO. Both the heating time of laboratory prepared UFO and the adulteration of EVO with UFO could be determined by partial least squares regression (PLSR). To simulate the EVO adulteration with UFO, for each kind of oil, fifty adulterated samples at the adulterant amounts range of 1-50% were prepared. PLSR was then adopted to build the model and both full (leave-one-out) cross-validation and external validation were performed to evaluate the predictive ability. Under the optimum condition, the plots of observed versus predicted values exhibited high linearity (R(2)>0.96). The root mean square error of cross-validation (RMSECV) and root mean square error of prediction (RMSEP) were both lower than 3%., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Reprogramming of energy metabolism (aerobic glycolysis) is thought to play an essential role in cancer. Compared to oxidative phosphorylation, aerobic glycolysis consumes more glucose through the upregulation of glucose transporters, notably glucose transporter 1 (GLUT1). Elevated glycolysis occurs in chemoresistant cancer cells, but the detailed mechanism is not well understood. The upregulation of the Ca2+-permeable transient receptor potential channel 5 (TrpC5) activates the Wnt/β-catenin signaling pathway in 5-fluorouracil (5-Fu)-resistant human colorectal cancer (CRC) HCT-8 (HCT-8/5-Fu) cells. In the present study, TrpC5 was overexpressed at the mRNA and protein levels along with GLUT1 in HCT-8/5-Fu cells. Suppression of TrpC5 expression with a TrpC5-specific shRNA reduced the induction of GLUT1 in the HCT-8 cells. The inhibition of the Wnt/β-catenin signaling pathway with XAV939 resulted in a decreased GLUT1 and nuclear c-Myc expression. Further study using clinical specimens validated the positive correlation between TrpC5 and GLUT1 protein levels and showed that a high TrpC5/GLUT1 expression was significantly correlated with chemoresistance. Taken together, we demonstrated the essential role of TrpC5 in GLUT1 induction and revealed that a high TrpC5/GLUT1 expression is associated with chemoresistance in human CRC.

Phytochemical investigation of the rhizomes of Paris polyphylla var. stenophylla led to the isolation of two new highly oxygenated spirostanol saponins, named paristenosides A (1) and B (2), together with seven known compounds. Their structures were established mainly on the base of NMR spectroscopic techniques and mass spectrometry, as well as chemical methods. In addition, the cytotoxicity of the two new saponins was tested. Two new highly oxygenated spirostanol saponins, paristenosides A (1) and B (2), were isolated from the rhizomes of Paris polyphylla var. stenophylla. Their structures were established mainly based on NMR spectroscopic techniques and mass spectrometry, as well as chemical methods.

Background: The current World Health Organization (WHO) classification of nasopharyngeal carcinoma (NPC) conveys little prognostic information. This study aimed to propose an NPC histopathologic classification that can potentially be used to predict prognosis and treatment response., Methods: We initially developed a histopathologic classification based on the morphologic traits and cell differentiation of tumors of 2716 NPC patients who were identified at Sun Yat-sen University Cancer Center (SYSUCC) (training cohort). Then, the proposed classification was applied to 1702 patients (retrospective validation cohort) from hospitals outside SYSUCC and 1613 patients (prospective validation cohort) from SYSUCC. The efficacy of radiochemotherapy and radiotherapy modalities was compared between the proposed subtypes. We used Cox proportional hazards models to estimate hazard ratios (HRs) with 95% confidence intervals (CI) for overall survival (OS)., Results: The 5-year OS rates for all NPC patients who were diagnosed with epithelial carcinoma (EC; 3708 patients), mixed sarcomatoid-epithelial carcinoma (MSEC; 1247 patients), sarcomatoid carcinoma (SC; 823 patients), and squamous cell carcinoma (SCC; 253 patients) were 79.4%, 70.5%, 59.6%, and 42.6%, respectively (P < 0.001). In multivariate models, patients with MSEC had a shorter OS than patients with EC (HR = 1.44, 95% CI = 1.27-1.62), SC (HR = 2.00, 95% CI = 1.76-2.28), or SCC (HR = 4.23, 95% CI = 3.34-5.38). Radiochemotherapy significantly improved survival compared with radiotherapy alone for patients with EC (HR = 0.67, 95% CI = 0.56-0.80), MSEC (HR = 0.58, 95% CI = 0.49-0.75), and possibly for those with SCC (HR = 0.63; 95% CI = 0.40-0.98), but not for patients with SC (HR = 0.97, 95% CI = 0.74-1.28)., Conclusions: The proposed classification offers more information for the prediction of NPC prognosis compared with the WHO classification and might be a valuable tool to guide treatment decisions for subtypes that are associated with a poor prognosis.

Background: Salvage treatment for locally recurrent nasopharyngeal carcinoma (NPC) is complicated and relatively limited. Radiotherapy, combined with effective concomitant chemotherapy, may improve clinical treatment outcomes. We conducted a phase II randomized controlled trial to evaluate the efficacy of intensity-modulated radiotherapy with concomitant weekly cisplatin on locally recurrent NPC., Methods: Between April 2002 and January 2008, 69 patients diagnosed with non-metastatic locally recurrent NPC were randomly assigned to either concomitant chemoradiotherapy group (n = 34) or radiotherapy alone group (n = 35). All patients received intensity-modulated radiotherapy. The radiotherapy dose for both groups was 60 Gy in 27 fractions for 37 days (range 23-53 days). The concomitant chemotherapy schedule was cisplatin 30 mg/m(2) by intravenous infusion weekly during radiotherapy., Results: The median follow-up period of all patients was 35 months (range 2-112 months). Between concomitant chemoradiotherapy and radiotherapy groups, there was only significant difference in the 3-year and 5-year overall survival (OS) rates (68.7% vs. 42.2%, P = 0.016 and 41.8% vs. 27.5%, P = 0.049, respectively). Subgroup analysis showed that concomitant chemoradiotherapy significantly improved the 5-year OS rate especially for patients in stage rT3-4 (33.0% vs. 13.2%, P = 0.009), stages III-IV (34.3% vs. 13.2%, P = 0.006), recurrence interval >30 months (49.0% vs. 20.6%, P = 0.017), and tumor volume >26 cm(3) (37.6% vs. 0%, P = 0.006)., Conclusion: Compared with radiotherapy alone, concomitant chemoradiotherapy can improve OS of the patients with locally recurrent NPC, especially those with advanced T category (rT3-4) and stage (III-IV) diseases, recurrence intervals >30 months, and tumor volume >26 cm(3).

Using an immunohistochemistry (IHC) based method, diffuse large B-cell lymphoma (DLBCL) can be classified into germinal center B-cell (GCB) and non-GCB subtypes. However, the prognostic value of Hans algorithm was contradictory in the literature. Using IHC and fluorescence in situ hybridization, we analyzed the antibodies applied in Hans algorithm and other genetic factors in 601 DLBCL patients and prognostic value of Hans algorithm in 306 cases who were treated with chemoimmunotherapy. The results showed that patients with GCB subtype have better overall survival (OS) and progression-free survival (PFS) than non-GCB cases. However, to some extent, double positive (CD10(+)MUM1(+), DP) and triple negative (CD10(-)Bcl6(-)MUM(-), TN) showed different clinical characteristics and prognosis to others that were assigned to the same cell-of-origin group. The DP group showed similar OS (median OS: both not reached, P = 0.3650) and PFS (median PFS: 47.0 vs. 32.7 months, P = 0.0878) with the non-GCB group while the TN group showed similar OS (median OS: both not reached, P = 0.9278) and PFS (median PFS: both not reached, P = 0.9420) with the GCB group. In conclusion, Recognition of specific entities in Hans algorithm could help us to accurately predict outcome of the patients and choose the best clinical management for them.

Background: We investigated the feasibility of reirradiation with intensity-modulated radiotherapy (IMRT) for recurrent T1 to T2 nasopharyngeal carcinoma (NPC) by assessing long-term survival and late complication rates., Methods: Sixty patients who had been previously irradiated were diagnosed with locally recurrent T1 to T2 NPC and underwent reirradiation with IMRT. Severe radiation toxicities were assessed., Results: The median follow-up time was 40.0 months. The 5-year local failure-free survival (LFFS), distant failure-free survival (DFFS), and overall survival (OS) rates were 85.7%, 96.1%, and 67.2%, respectively. Independent prognostic factors included primary gross tumor volume >20 cm and the presence of significant complications. The most common severe complications were headache (31.6%), mucosal necrosis (30.0%), cranial neuropathy (25.0%), and temporal lobe necrosis (21.6%). Thirty-nine patients (65.0%) developed at least one severe complication and 18 patients died as a result., Conclusion: Excellent disease control can be achieved by reirradiation with IMRT for recurrent T1 to T2 NPC. However, the main challenge remains severe late complications., (© 2015 Wiley Periodicals, Inc.)

The aberrations of TP53 gene and dysregulation of the TP53 pathway are important in the pathogenesis of many human cancers, including malignant lymphomas, especially for diffuse large B cell lymphoma (DLBCL). By regulating many downstream target genes or molecules, TP53 governs major defenses against tumor growth and promotes cellular DNA repair, apoptosis, autophagy, cell cycle arrest, signaling, transcription, immune or inflammatory responses and metabolism. Dysfunction of TP53, including microRNA regulations, copy number alterations of TP53 pathway and TP53 itself, dysregulation of TP53 regulators, and somatic mutations by abnormal TP53 function modes, play an important role in lymphoma generation, progression and invasion. The role of TP53 in DLBCL has been widely explored recently. In this review, we summarized recent advances on different mechanisms of TP53 in DLBCL and new therapeutic approaches to overcome TP53 inactivation., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease that great efforts had been made in to build up molecular and immunophenotypic subgroups that could relatively accurate indicate prognosis and give clue to therapy. Recently, CD30 was reported as a useful predictor with favorable clinical outcome. However, CD30 expression patterns and the clinicopathologic features of CD30 positive DLBCL are not well described thus far, especially in Asian patients. Here, we studied 232 cases of de novo DLBCL in East China to investigate the prevalence and clinicopathological features of CD30-positive DLBCL using a panel of immunohistochemical markers. Applying a >0% threshold, CD30 was expressed in approximately 12% patients with Epstein-Barr virus (EBV) negative DLBCL, affecting younger people and showing a lower frequency of BCL2 expression and MYC/BCL2 co-expression. Patients with CD30-positive DLBCLs showed better progression-free survival and overall survival compared with patients with CD30-negative DLBCLs, although the superior outcome of CD30 positivity had minimal effects on BCL2+ DLBCL or DLBCL with MYC/BCL2 co-expression. Moreover, CD30 could express in CD5+ DLBCL. We concluded that CD30 may be useful as a prognostic marker in rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) treated DLBCLs, indicating favorable outcomes in a Chinese population. Further studies with larger samples should be performed to investigate the function of CD30 expression in BCL2+ DLBCLs, DLBCLs with MYC/BCL2 co-expression, and CD5+ DLBCLs, and to evaluate the feasibility of anti-CD30 targeted treatment in DLBCL therapy.

Purpose: To establish accurate prognostic score models to predict survival for patients with nasopharyngeal carcinoma (NPC), treated with intensity-modulated radiotherapy (IMRT) and chemotherapy., Materials and Methods: Six hundred and seventy-five patients with newly diagnosed, nonmetastatic and histologically proven NPC who were treated with IMRT and chemotherapy were analyzed retrospectively. Samples were split randomly into a training set (n = 338) and a test set (n = 337) to analyze. All data from the training set were used to perform an extensive survival analysis and to develop multivariate nomograms based on Cox regression. Data from the test set was used as an external validation set. Risk group stratification was proposed for the nomograms., Results: The nomograms are able to predict survival with a C-index for external validation of local recurrence-free survival (LRFS; 0.66, 95% CI: 0.58-0.74), distant metastasis-free survival (DMFS; 0.73, 95% CI: 0.66-0.79), and disease-specific survival (DSS; 0.73, 95% CI: 0.67-0.79). The calibration curve for probability of survival showed good agreement between prediction by nomogram and actual observation. The C-index of the nomogram for LRFS, DMFS and DSS were statistically higher than the C-index values of the AJCC seventh edition (P < 0.001). In the test set, the nomogram discrimination was also superior to the AJCC Staging systems (P < 0.001). The stratification in risk groups allows significant distinction between Kaplan-Meier curves for outcome., Conclusions: Prognostic score models were successfully established and validated to predict LRFS, DMFS, and DSS over a 5-year period after IMRT and chemotherapy, which will be useful for individual treatment.

Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma (NHL). Patients with DLBCL harboring MYC aberrations concurrent with BCL2 or/and BCL6 aberrations constitute a specific group with extremely poor outcome. In this study, we retrospectively investigated the incidence and prognosis of MYC, BCL2, and BCL6 aberrations with DLBCL patients in Chinese population. We applied fluorescence in situ hybridization and immunohistochemical analysis in 246 DLBCL patients. The results showed that patients with MYC or BCL2 copy number aberration (CNA) had significantly worse overall survival (OS) and progression-free survival (PFS) than negative cases (P < 0.0001). Patients with both MYC and BCL2 CNA had similar outcomes to those with classic double hit lymphoma or protein double expression lymphoma (MYC and BCL2/BCL6 coexpression). By multivariate analysis, MYC CNA, BCL2 CNA and double CNA were the independent worse prognostic factors. In conclusions, patients with MYC or BCL2 CNA constituted a unique group with extremely poor outcome and may require more aggressive treatment regimens.

Epstein-Barr virus (EBV) positive diffuse large B-cell lymphoma (DLBCL) of the elderly is defined as patients older than 50 years alone. However, recent studies showed young patients with sound immune status could also be affected. In this study, we investigated the clinical features and outcomes of patients with EBV positive DLBCL in the different age groups using different EBER cut-off values. The prevalence of EBV positive DLBCL was 14.0% (35/250) and 10.4% (26/250) for EBER cut-off of 20% and 50%, respectively. With both EBER cut-off values, patients with EBV DLBCL shared many unfavorable prognostic characteristics, regardless of age. EBV positive patients, both in the elderly and young groups, showed significantly worse overall survival and progression-free survival than negative cases. Moreover, no significant differences of outcomes were identified between different age groups with EBV positive DLBCL. In conclusion, EBV positive DLBCL patients, regardless of age, shared similar poor prognostic features and showed worse outcome than negative cases. We suggest that the age criterion of EBV positive DLBCL of the elderly, and possibly the name itself, be modified in future.

Rituximab was widely used in clinical practice. Some chronic lymphocytic leukemia (CLL) patients were primary or secondary resistance to rituximab, but the mechanism has not been yet clear. CD20 gene coding region was amplified by PCR in 92 cases of newly diagnosed CLL patients and 200 healthy donors. The expression of CD20 was conducted in peripheral blood specimens of CLL patients. Proportions of CD20 expression and fluorescence intensity were detected by flow cytometry. Exon-3 c.246C>T (rs17155019) and Exon-4 c.632C>T (rs2070770) were present in 4.35% (4/92) and 9.78% (9/92) of newly diagnosed CLL patients. The mutations were not found in remaining exons. The frequency of C/C genotype and C allele of rs2070770 were significantly higher than the normal control population (90.22% vs 81.00%, P=0.04; 95.11% vs 90%, P=0.04). There was no significant relationship between genotypes with CLL development (P>0.05), however, C allele of rs2070770 may be associated with CLL (P=0.04, OR=0.46, 95% CI=0.22-0.98). The expression CD20 mRNA, proportion and intensity of CD20 were no significant different between genotypes of two polymorphic loci (P>0.05). Low expression of CD20 for CLL was not associated with mutation of CD20 gene coding region. Other mechanisms, such as promoter methylation, may result in low expression of CD20.

Purpose: To identify predictors for the development of temporal lobe injury (TLI) after intensity-modulated radiation therapy (IMRT) for nasopharyngeal carcinoma., Materials and Methods: Data in 351 patients with nasopharyngeal carcinoma treated with IMRT were reviewed retrospectively according to institutional ethics committee approval. Clinical factors associated with TLI were analyzed. Dose-volume histograms for 550 evaluable temporal lobes were analyzed, and the predictive value of therapy-associated and patient-associated factors for the occurrence of TLI was evaluated. Survival curves were depicted by using the Kaplan-Meier method and compared by using the log-rank test. Logistic regression analysis was used for multivariate analyses., Results: Median follow-up was 76 months (range, 6-100 months). Twenty-nine of 351 patients (8.3%) developed TLI; 21 patients had unilateral TLI, and eight had bilateral TLI. Median latency from IMRT until first TLI was 33 months (range, 12-83 months) among patients with TLI. The actuarial TLI-free survival rates were 94.4% and 91.3% at 3 and 5 years after radiation therapy, respectively. Logistic regression analysis demonstrated that dose delivered to a 1-cm(3) volume of the temporal lobe (D1cc) was the only independent predictor for TLI. The biologically equivalent tolerance doses at 2 Gy for a 5% and 50% probability of developing TLI were 62.83-Gy equivalents (95% confidence interval: 59.68, 65.97) and 77.58-Gy equivalents (95% confidence interval: 74.85, 80.32), respectively., Conclusion: D1cc is predictive for radiation-induced TLI, suggesting that delivery of a high dose of radiation to a small volume of the temporal lobe is unsafe. A D1cc of 62.83 Gy by using a correction formula for varying fraction size may be the dose tolerance of the temporal lobe.

Introduction: The properties of a tumor itself were considered the main factors determining the survival of patients with locally recurrent nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiotherapy (IMRT). However, recurrent tumors were mainly evaluated by using the American Joint Committee on Cancer staging system, which was modeled on primary tumors and did not incorporate the tumor volume. This study aimed to investigate the prognostic values of the primary tumor location and tumor volume, and to determine whether evaluating these parameters could improve the current staging system., Methods: Magnetic resonance (MR) images for 229 patients with locally recurrent NPC who underwent IMRT were analyzed retrospectively., Results: The skull base, parapharyngeal space, and intracranial cavity were the most common sites of tumors. There was a difference in the survival between patients with T1 and T2 diseases (77.6% vs. 50.0%, P<0.01) and those with T3 and T4 diseases (33.0% vs. 18.0%, P=0.04) but no difference between patients with T2 and T3 diseases (50.0% vs. 33.0%, P=0.18). Patients with a tumor volume≤38 cm3 had a significantly higher survival rate compared with those with a tumor volume>38 cm3 (48.7% vs. 15.2%, P<0.01)., Conclusions: A new staging system has been proposed, with T3 tumors being down-staged to T2 and with the tumor volume being incorporated into the staging, which may lead to an improved evaluation of these tumors. This new system can be used to guide the treatment strategy for different risk groups of recurrent NPC.