Since human tumour virus (HPV) is an infectious pathogen, some people have regained interest in the degree of host inflammatory response to persistent HPV infection that contributes to tumor transformation, cancer treatment response and patient prognosis. Although inflammation has antitumor effects in the initial stage, activation of the innate immune system and recruiting primitive immune cells (such as neutrophils) promotes tumor occurrence and cancer development. In addition, capillary leakage caused by inflammatory cascades may increase tumor proangiogenesis and increase its potential for metastasis. The neutrophil-lymphocyte ratio (NLR) is a simple biomarker of systemic inflammation and has also been shown to be a prognostic marker for several solid tumors, including prostate tumors, renal tumors, gastric cancer, brain tumors and hypopharyngeal carcinoma. This study evaluates the impact of nlr values ​​on prognosis in contemporary oropharyngeal patients before initiation of treatment.

Research Methods

Between 2002 and 2013, all patients with oropharyngeal squamous cell carcinoma who had completed therapeutic radiotherapy over the age of 18 were included in this study and blood cell counts were performed within 2 weeks before radiotherapy. All patients received radical radio doses. Patients with distant metastatic disease (M1) at the time of diagnosis, patients who did not undergo blood counts within 2 weeks before radiotherapy, or patients with hematologic diseases such as affecting lymphocytes and/or neutrophil counts were excluded. Patients, tumor and treatment characteristics, clinical results, and total neutrophil and lymphocytes (TNC and TLC) were recorded. Patients' hpv status was collected as much as possible and if p16 immunohistochemistry or HPV in situ hybridization was positive, it was considered positive. NLR was post hoc and collected by dichotomy based on the median found (rounded to the closest integer).

Overall survival (OS) from the date of completion of radiotherapy to the date of death was calculated using kaplan-meier. Patients who did not have local treatment failure were analyzed from the end of radiotherapy to the first local failure. The degree of freedom of distant metastasis was calculated from the completion of radiotherapy to the first time of distant disease. The recurrence rate was calculated from the completion of radiotherapy to the first time of distant disease. Patients who did not have any events were excluded at the last follow-up. The effect of NLR on survival and disease control was estimated using the kaplan-meier method and compared with the log-rank test. The potential prognostic factors of Os and relapse were evaluated using univariate and multivariate analyses, and the linear and cox proportional hazard regression model was used for analysis. The variables with p value ≤0.1 were included in the multivariate analysis and the two-tailed p value <0.05 were statistically significant.

From 2002 to 2013, a total of 1,124 local oropharyngeal carcinoma patients received radiotherapy. 276 of them were excluded from this analysis: 273 patients did not undergo hemocytogenes within 2 weeks of starting radiotherapy, 2 patients had chronic lymphocytic leukemia, and 1 patient had a high neutrophil count false positive. Therefore, a total of 848 patients met the enrollment criteria. Table 1 summarizes the patient characteristics, disease characteristics and treatment characteristics. The median age of the cohort was 5

7 years old (range: 29-87 years). Most (87%) were male, and about half of the cohort members had never smoked or had previously smoked, but had a history of <10 packs of years. The root of the tongue and tonsils were the main sites of the disease, accounting for 98% of the main sites of the cohort. 63 (71%) patients had hpv/p16 positive squamous cell carcinoma. The median radiation dose provided was 70gy, divided into 33 sessions. Almost half of the patients received induction chemotherapy and 88% received concurrent chemotherapy.

The median NLR before treatment was 2.52. The median follow-up time was 59 months. In the last follow-up, 183 (22%) patients died. 141 (17%) patients had a recurrence of the disease.

The OS for patients with nlr<3 was 85% for 5 years, while the 74% for patients with nlr≥3. The recurrence rate of patients with nlr<3 was higher, local treatment failure rate and distant metastasis degree (5-year recurrence rate 86       77%; 5-year local treatment failure rate 92      85%; 5-year distant metastasis rate 91     86%). To verify that our results were not affected by outliers, we only reanalysed the data for patients with nlr in 5-95%. The overall cohort analysis showed significant improvement in the prognosis of patients with nlr<3.

A total of 674 patients had hpv status that could be included in the study-603 hpv positive and 71 hpv negative. When stratified according to hpv status, the Os of patients with nlr<3 was still significantly better than those of patients with nlr≥3 (hpv positive: 5 years os    85      78%, hpv negative: 5 years os    88 vs     61%.)

nlr also had a similar effect on recurrence rate (hpv positive: 86% versus 80% in 5 years; hpv negative: 84% versus 69% in 5 years). In logistic regression analysis, nlr was associated with tumor cells in t and n phases, but there was no significant association with hpv status and smoking status. The last three figures show the effect of t-stage combined nlr on Os.

Among the 230 patients with higher NLR values ​​before chemotherapy, if NLR drops to <3.0 after first-line chemotherapy, Os is significantly better (median 32.2 vs 13.0 months). In the 228 patients with lower NLR values ​​before chemotherapy, if NLR increases to ≥3.0 after first-line chemotherapy, Os is significantly worse (median 20.1 months vs 33.7 months).

In multivariate analysis, nlr remained an independent prognostic factor for Os and relapse-free, with the hazard ratio of nlr ≥3 of 1.64 and 1.62, respectively. In addition to nlr, the patient's smoking status, age and t-phase were also related to Os results. Radiotherapy dose (higher dose) and nlr < 3 improved the relapse rate in patients. Nlr was analyzed as a continuous variable to determine whether the effect of the continuous degree of Nlr as a whole was relatively linear. In univariate analysis, lower Nlr was associated with better relapse degrees of freedom and local regional failure rates. However, Nlr as a continuous variable had no significant correlation with Os and whether there was distant metastasis.

discuss

1. The results of this study show that the effect of NLR on clinical outcomes is not related to the hpv status.

2. A large meta-analysis reported 100 studies involving 40,000 patients, and the results showed that patients with solid tumors had higher NLR (>4), poorer Os and disease prognosis, regardless of the cancer stage or its sub-site. Recently, a cohort of 104 HPV-related oropharyngeal cancer patients was reported in a smaller study than ours, and the results showed that patients with higher NLR had lower 5-year disease-free survival. Among patients with HPV-negative disease, an increase in NLR was associated with a reduced survival rate of 3 months after radiotherapy was completed.

3. Although inflammation has been identified as one of the hallmarks of cancer, there is still little understanding of the complex relationship between inflammation and the tumor microenvironment, namely, promoting angiogenesis and malignant transformation and subsequent cancer progression.

4. Continued HPV infection releases proinflammatory factors, leading to chronic inflammation, and subsequent cancerous development. However, the inflammatory tumor microenvironment between hpv-positive and hpv-negative tumors seems to be different because patients with hpv-positive oropharyngeal carcinoma are relatively effective compared to those with hpv-negative tumors. Necrosis promotes inflammation and can recruit immune cells to this area with the goal of clearing necrotic debris. Although the purpose of inflammatory infiltration is to remove debris and promote healing, interleukin-1α released by necrotic cells is used for cell proliferation and can inadvertently accelerate tumor transformation and progression.

limitation

1. There were only 71 patients with HPV-negative oropharyngeal carcinoma in this cohort (8.4%), which limited the statistical credibility of NLR for disease-specific results and further analysis:

2. Evaluation of objective responses or pathological diagnosis is carried out independently in each research institution, so the results are not uniformly processed and analyzed.

3. The pathological types were not distinguished and subgroup analysis was performed.

Summarize

In this large-sample-sized oropharyngeal carcinoma study cohort, it was emphasized that NLR before radiotherapy can be used as an independent prognostic factor in oropharyngeal patients (unrelated to the hpv status). Patients with lower nLR have better clinical benefits in survival and disease control. At the same time, NLR can be prospectively explored as a biomarker with potential research value to further stratify the risk of oropharyngeal patients before treatment, thereby achieving degradation/escalation of treatment.

According to the "Economic Reference Network", the People's Court of Pudong New District of Shanghai recently made a first-instance judgment on the case of a dispute over reputation rights between Researcher Geng Meiyu, Academic Director of the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, and rejected the plaintiff Geng Meiyu's lawsuit.

Geng Meiyu's lawsuit includes: the defendant Rao Yi issued an apology statement in his personal WeChat Moments, China Science and Technology Daily, Science and Technology Daily and Wenhui Daily, which is published once a day for fifteen days. He apologized to the plaintiff to eliminate the impact and restore his reputation.

On September 6, 2019, the English academic journal Cell Research published an article signed by Geng Meiyu and 26 people, "Ganlu Turner (gv-971) reshapes the intestinal bacterial amino acid-type neuroinflammation, and thus inhibits the progress of Alzheimer's disease" (Chinese translation).

In this article, Geng Meiyu proposed that gv-971 has been proven to be a sustainable and robust drug to improve patients' cognitive function in the Phase 3 clinical trial conducted in China, which can inhibit intestinal microbial disorders and related phenylalanine/isoleucine accumulation, control neuroinflammation and improve cognitive impairment.

On November 28, 2019, Rao Yi reported Geng Meiyu's fraud in a relevant WeChat group based on this research article: "This year, researcher Geng Meiyu from the Shanghai Institute of Materia Medica of the Chinese Academy of Sciences as the corresponding author, claiming that the drug GV-971 invented can treat Alzheimer's disease in mice through intestinal bacteria. This article is impossible without fraud. For a real name, please report it. Please ask your committee (National Natural Science Foundation of China) to do some good things to clean up the shame of the Chinese scientific community."

In this regard, Geng Meiyu believes that Rao Yi has objectively damaged her reputation and reduced social evaluation, which constitutes an infringement of her reputation rights.

On July 7, 2020, Professor Rao Yi published an article in Cell Research entitled "Authors should be corrected to ignore the citation of previous literature" (Chinese translation) and pointed out that all targets and effects of gv-971 help treat Alzheimer's disease, and a drug has so many targets to jointly treat a disease is extremely rare in the biomedical world. Geng Meiyu and others' 2019 papers were very strange, and they did not quote any of their 12 papers related to gv-971 published before... It is a wonder of the academic community.

On July 13, Geng Meiyu and others published a briefing in "Cell Research" to respond, saying that the research in his article mainly focuses on intestinal flora and related neurotic inflammation, which is a new mechanism for treating GV-971. The correlation between the previous 12 articles and the papers involved is really small and not enough to be cited.

In addition, Rao Yi also published an article on the "Rao Yi Science" public account to question gv-971. Related remarks include "the so-called gv-971 for treating Alzheimer's disease is considered a fake drug by many people." "If there is no strict investigation, the possibility that gv-971 will become the biggest fraud case in China in the 21st century cannot be ruled out."

On January 21, 2021, the Ministry of Science and Technology issued the "Notice on the Investigation and Handling of Suspicion of Falsification of Papers", which investigated the conclusions and handling opinions of Geng Meiyu's five papers: No fraud was found, but a small number of pictures were found to be misused in the paper. After review by the joint working mechanism, it was decided to criticize and educate them and remind them of scientific research integrity.

The court held that the main focus of the dispute between the two parties was: one is whether the defendant's statement on the plaintiff's paper in the WeChat group was infringing on the reputation rights of others or an academic criticism; the other is whether the defendant's above-mentioned behavior caused damage to the plaintiff's reputation.

Regarding the focus of dispute 1, the court believes that the research on Alzheimer's treatment is a continuous progressive process and requires the joint efforts of the medical community. Therefore, from the perspective of medical development, legitimate academic disputes and criticism should be allowed, and the law should not restrict or interfere. Therefore, as an industry expert, the defendant has the right to evaluate the plaintiff's research results.

The court held that Rao Yi's behavior did not exceed the reasonable boundaries of academic comments. Scholars commented on another scholar's research results based on their own knowledge and experience. Even if they had improper words, it was not a malicious infringement of the plaintiff's reputation. Judging from the fact that the plaintiff and the defendant later responded to each other in professional journals, this confrontation of views should fall within the scope of academic discussions, and Rao Yi did not have subjective intention to damage the plaintiff's reputation.

In addition, from the perspective of promoting academic debate and purifying the academic atmosphere, justice should set a relatively relaxed environment for academic criticism. Academic disputes can be clarified through debates between parties, publishing original data, and conducting repeated experiments, so as to encourage the truth to become clearer and clearer the more it is debated.

Regarding the second focus of the dispute, it is difficult for the court to determine that the defendant's behavior caused damage to the plaintiff's reputation. Judging from the fact that the defendants immediately published academic disputes in relevant academic journals and vectors afterwards, it has been shown that the dispute between the two parties on whether to commit fraud is essentially an academic dispute in medical research, rather than a dispute over whether the plaintiff's paper is intentionally falsified by research methods. Therefore, it is difficult to support the plaintiff's claim for infringement of reputation.

However, the court also pointed out that although the defendant's behavior did not cause any infringement, it did have problems such as excessive speech and improper methods, and should be criticized.

About gv-971: It has been listed and entered into medical insurance
Chapter completed!