Clinical implication of pretreatment neutrophil to lymphocyte ratio in soft tissue sarcoma

Introduction: Elevated neutrophil to lymphocyte ratio has been identified as a prognostic indicator in malignancies whereas; its association with extremity and trunk soft tissue sarcoma remain unclear. The aim of this study is to determine the utility of full blood neutrophil lymphocyte ratio (NLR) in preoperative diagnosis and its predictive value for survival in patients managed for soft tissue sarcoma of the trunk and extremities.

Method: 223 patients who presented with a soft tissue tumor were retrospectively reviewed. The study period was from January 2002–December 2009. Preoperative NLR as well as demographics, clinical and histopathological data were analysed.

Results: Full blood NLR was significantly higher in patient with a soft tissue sarcoma compared to benign soft tissue tumors (p < 0.001). Cox regression analysis demonstrated that elevated NLR >5 (p < 0.05) may be an adverse prognostic factor for Overall Survival.

Conclusion: The preoperative NLR is a simple, investigation predicting the preoperative diagnosis of a soft tissue sarcoma and a predictor of worse overall survival for patient with a soft tissue sarcoma.     

Elevated neutrophil to lymphocyte ratio predicts survival in advanced pancreatic cancer

Background: Elevated neutrophil to lymphocyte ratio (NLR) is linked with worse survival in many malignancies, whereas its association with pancreatic cancer (PC) remains unclear.

Methods: We retrospectively reviewed 95 patients with locally advanced or metastatic PC receiving gemcitabine-based chemotherapy. The prognostic value of NLR was evaluated.

Results: Elevated pretreatment NLR (>5) was observed in 16 out of 89 eligible patients, which was identified as an independent prognostic factor for overall survival (OS). The median OS for patients with elevated and normal NLR were 2.4 months and 7.7 months, respectively (p <0.001).

Conclusions: Elevated NLR is a predictor of shorter survival in patients with advanced PC.     

Gemcitabine-mediated radiosensitization of human soft tissue sarcoma

Background/Purpose

Local and systemic control of soft tissue sarcoma (STS) remains a clinical challenge, particularly for retroperitoneal, deep truncal, or advanced extremity disease. 2′,2′-Difluoro-2′-deoxycytidine (gemcitabine) is a potent radiosensitizer in many tumor types, but it has not been studied in human STS. The purpose of this study was to determine the radiosensitizing potential of gemcitabine in preclinical models of human STS.

Materials and Methods

The in vitro radiosensitizing activity of gemcitabine was assessed with clonogenic survival assay on three human STS cell lines: SK-LMS-1 (leiomyosarcoma), SW-872 (liposarcoma), and HT-1080 (fibrosarcoma). Cell cycle distribution was determined using dual-channel flow cytometry. The in vivo radiosensitizing activity of gemcitabine was assessed with subcutaneous SK-LMS-1 nude mice xenografts. Tumor-bearing mice were treated with concurrent weekly gemcitabine and fractionated daily radiotherapy (RT) (2 Gy daily) for 3 weeks (a total dose of 30 Gy).

Results

The 50% inhibitory concentration (IC₅₀) of gemcitabine for the human STS cell lines ranged from 10 to 1000 nM. Significant in vitro radiosensitization was demonstrated in all three human STS cell lines using gemcitabine concentrations at and below the IC₅₀. Maximal radiosensitization was associated with accumulation of cells in early S-phase. SK-LMS-1 xenografts displayed significant tumor growth delay with combined gemcitabine and RT compared to either treatment alone. Treatment related toxicity was greatest in the gemcitabine plus RT arm, but remained at an acceptable level.

Conclusions

Gemcitabine is a potent radiosensitizer in preclinical models of human STS. Clinical trials combining gemcitabine and RT in human STS are warranted.     

Pre-treatment neutrophil to lymphocyte ratio is elevated in epithelial ovarian cancer and predicts survival after treatment

Purpose  Inflammatory cells can both suppress and stimulate tumor growth, and the influence of inflammatory cells on clinical outcome has been the focus of many studies. The purpose of this study was to evaluate the effectiveness of the neutrophil to lymphocyte ratio (NLR), a measure of the systemic inflammatory response, as an additional discriminative biomarker in epithelial ovarian cancer and to determine whether it predicts survival and recurrence. Methods  We studied 192 patients with epithelial ovarian cancer, 173 with benign ovarian tumors, 229 with benign gynecologic disease, and 405 healthy controls. Serum CA125 levels and leukocyte counts according to subtypes were recorded prior to treatment in all study subjects. In epithelial ovarian cancer, the diagnostic usefulness of NLR, in combination with CA125, was evaluated. The correlation between NLR and overall and disease-free survival was analyzed using both univariate and multivariate analyses adjusting for the known prognostic factors (age, stage, cell type, and grade). Results  Preoperative NLR in ovarian cancer subjects (mean 6.02) was significantly higher than that in benign ovarian tumor subjects (mean 2.57), benign gynecologic disease subjects (mean 2.55), and healthy controls (mean 1.98) (P < 0.001). The sensitivity and specificity of NLR in detecting ovarian cancer was 66.1% (95% CI, 59.52–72.68%) and 82.7% (95% CI, 79.02–86.38%), respectively (cutoff value: 2.60). In early stage ovarian cancer, CA125 was not elevated in 19 out of 49 patients. Seven (36.8%) of these 19 patients were NLR positive. On Cox multivariate analysis, NLR positive, stage III/IV, and older age were independent poor prognostic factors, and being NLR positive was the most powerful predictive variable (Hazard Ratio = 8.42 [95% CI: 1.09–64.84], P = 0.041). Conclusions  Our findings provide evidence for the association between NLR and epithelial ovarian cancer. Preoperative NLR, in combination with CA125, may represent a simple and cost-effective method of identifying ovarian cancers, and an elevated NLR may predict an adverse outcome in ovarian cancer.     

软组织透明细胞肉瘤临床进展

透明细胞肉瘤是一种罕见的高度恶性软组织肉瘤.多发于青少年及中年,以四肢远端的深部软组织多见,常与肌腱和腱膜相毗邻,易复发和转移.组织来源尚未明确,限制了有效的预后因素分析及治疗原则的确立.早期诊断和首次广泛切除是改善透明细胞肉瘤预后的关键.肿瘤大小与是否发生转移关系密切,是影响预后的重要因素.本文就透明细胞肉瘤的临床病理特点、鉴别诊断、临床治疗及预后分析的进展进行综述.     

Circulating cell-free DNA,peripheral lymphocyte subsets alterations and neutrophil lymphocyte ratio in assessment of COVID-19 severity

Cell destruction results in plasma accumulation of cell-free DNA (cfDNA). Dynamic changes in circulating lymphocytes are features of COVID-19. We aimed to investigate if cfDNA level can serve in stratification of COVID-19 patients, and if cfDNA level is associated with alterations in lymphocyte subsets and neutrophil-to-lymphocyte ratio (NLR). This cross-sectional comparative study enrolled 64 SARS-CoV-2-positive patients. Patients were subdivided to severe and non-severe groups. Plasma cfDNA concentration was determined by real-time quantitative PCR. Lymphocyte subsets were assessed by flow cytometry. There was significant increase in cfDNA among severe cases when compared with non-severe cases. cfDNA showed positive correlation with NLR and inverse correlation with T cell percentage. cfDNA positively correlated with ferritin and C-reactive protein. The output data of performed ROC curves to differentiate severe from non-severe cases revealed that cfDNA at cut-off ≥17.31 ng/µl and AUC of 0.96 yielded (93%) sensitivity and (73%) specificity. In summary, excessive release of cfDNA can serve as sensitive COVID-19 severity predictor. There is an association between cfDNA up-regulation and NLR up-regulation and T cell percentage down-regulation. cfDNA level can be used in stratification and personalized monitoring strategies in COVID-19 patients.     

Cytopathological diagnosis of alveolar soft part sarcoma,a rare soft tissue neoplasm

S. Agarwal, R. Gupta, V. K. Iyer, S. R. Mathur and R. Ray Cytopathological diagnosis of alveolar soft part sarcoma, a rare soft tissue neoplasm Objective: Alveolar soft part sarcoma (ASPS) is a rare soft tissue neoplasm, having various morphological mimics, especially on fine needle aspiration cytology (FNAC). Because no definite immunohistochemical markers are available to aid a correct diagnosis, knowledge of the cytomorphological features is essential for correct patient management. Cytological features of five cases of ASPS are discussed, along with the ultrastructural findings available in one of them. Methods: Cytology records from 1997 to 2009 were reviewed for cases with a diagnosis of ASPS on cytology. The histology slides of the cases were also assessed for confirmation of the diagnosis. All the slides were reviewed by three pathologists. Results: There were five cases of ASPS diagnosed on FNAC. Their cytological features were noted in detail. The diagnoses in all the cases were confirmed on histology, and ultrastructural findings available in one of them were also assessed. Conclusions: The knowledge of cytological features may aid in diagnosing this rare tumour correctly on FNA smears, thus enabling correct patient management.     

Prognostic significance of peripheral blood-derived neutrophil/lymphocyte ratio in patients with digestive cancer

Accumulating studies reported the clinical value of derived neutrophil/lymphocyte ratio (dNLR) regarding the prediction of survival outcomes in digestive cancers, however, the prognostic significances of dNLR in these cancers were inconsistent. This study was carried out to clarify the relationship between circulating dNLR and prognosis in gastrointestinal (GI) cancers. Eligible publications were collected and extracted by searching Pubmed, Embase, Web of Science, and Google Scholar up to November 21, 2018. The prognostic impact of dNLR in subjects with GI cancers was assessed with the overall hazard ratios (HRs). A total of 26 studies with up to 13,945 participants were recruited. Our findings showed that peripheral blood dNLR before treatment could be a useful prognostic predictor in digestive cancers, an elevated dNLR indicated a shorter overall survival (OS) in GI tumors (HR, 1.44; 95% confidence interval [CI], 1.36–1.51). Furthermore, its significant prognostic value for OS was also confirmed in subgroup analyses stratified by disease type, publication year, type of research, detection method, geographic location, cut-off value, treatment, analysis type, follow-up time and disease stage. In addition, high dNLR was significantly associated with worse cancer-specific survival (HR, 1.25; 95% CI, 1.04–1.47) and inferior event-free survival (HR, 1.22; 95% CI, 1.11–1.33) in patients with digestive cancers. Our study showed elevated peripheral blood dNLR may indicate unfavorable outcomes in digestive cancer.     

Adaptive radiotherapy in patients receiving neoadjuvant radiation for soft tissue sarcoma

AimThe aim of this study is to evaluate tumor volume changes during preoperative radiotherapy and to assess the role of adaptive radiation.BackgroundContemporary neoadjuvant radiotherapy utilizes image guidance for precise treatment delivery. Moreover, it may depict changes in tumor size and shape.Materials and methodsBetween 2016 and 2018, 23 patients aged ≥18 years with soft tissue sarcoma were treated with neoadjuvant radiation followed by surgical resection. The tumor volumes (cc) were measured using the Pinnacle planning system prior to starting radiotherapy and during treatment, the changes in volume and absolute differences were estimated. Moreover, patient's position on the machine was evaluated to assess setup offsets. The triggers for plan adaptation were >1 cm expansion or unacceptable setup offsets.ResultsThe mean tumors volume at presentation was 810 cc (range, 55–4000). At last cone beam CT the tumor volume had changed in 14 patients (61%); it was stable in nine patients (39%). Disease regression was documented in eight patients (35%), with median shrinkage of −20.5% (range, −2 to −29%), while tumor progression was observed in six cases (26%), the median change was 12.5% (range, +10 to +25%).Adaptive radiation was required in four patients (17%). For the remaining 19 cases (83%), the dose distribution was adequate to cover target volumes.ConclusionsChange in soft tissue sarcoma volume during radiation is not uncommon. Image guidance should be used to reduce setup errors and to detect differences in tumor volume. Image guidance and adaptive radiation are paramount to ensure optimal radiation delivery.     

Role of neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR) and mean platelet volume (MPV) in assessing disease control in Asian patients with axial spondyloarthritis

Introduction: C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) which are used for assessment of axial spondyloarthritis (AxSpA) related disease activity have poor specificity and sensitivity. Neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR) and mean platelet volume (MPV) have not been investigated as disease activity markers among Asian AxSpA patients.

Methodology: A retrospective, cross-sectional study was conducted in Singapore General Hospital from January 2013 to December 2015 to investigate the role of NLR, PLR and MPV as disease activity markers in AxSpA patients.

Results: The mean age of patients (n?=?122) was 37.0?±?12.5 years old and majority of them were male (n?=?93, 76.2%). No significant differences were found between patients with disease with regards to age, gender, ethnicity, HLAB-27 status, age at onset of diagnosis of AxSpA, duration of disease and comorbidities such as cardiac disease (p?>?0.05).

There were no significant differences in the ESR, NLR, PLR and MPV between the four disease activity groups (p?>?0.05). However, patients with very high disease activity had higher ESR and CRP compared to patients with inactive disease and moderate disease activity (p?Conclusion: NLR, PLR and MPV were not associated with disease activity in Asian AxSpA patients.     

Evaluation of a xenogeneic VEGF vaccine in dogs with soft tissue sarcoma

Active immunization against pro-angiogenic growth factors or their receptors is an emerging strategy for controlling tumor growth and angiogenesis. Previous studies in rodent tumor models have indicated that immunization against xenogeneic growth factors is more likely to induce effective anti-tumor responses than immunization against the autologous growth factor. However, the effectiveness or safety of the xenogeneic vaccination approach has not been previously assessed in a clinically relevant outbred, spontaneous tumor model. Therefore, we investigated the safety and anti-tumor and anti-angiogenic effects of a xenogeneic vascular endothelial cell growth factor (VEGF) vaccine in pet dogs with spontaneous cancer. Nine dogs with soft tissue sarcoma were immunized with a recombinant human VEGF vaccine over a 16-week period. The effects of immunization on antibodies to human and canine VEGF, circulating VEGF concentrations, tumor microvessel density (MVD), and tumor growth were assessed. The xenogeneic VEGF vaccine was well-tolerated by all dogs and resulted in induction of humoral responses against both human and canine VEGF in animals that remained in the study long enough to receive multiple immunizations. Three of five multiply immunized dogs also experienced sustained decreases in circulating plasma VEGF concentrations and two dogs had a significant decrease in tumor MVD. The overall tumor response rate was 30% for all treated dogs in the study. We conclude therefore that a xenogeneic VEGF vaccine may be a safe and effective alternative means of controlling tumor growth and angiogenesis.     

Maffucci syndrome and soft tissue sarcoma: a case report

Background

Maffucci syndrome, a congenital mesodermal dysplasia characterized by multiple enchondromas and hemangiomas, was first described in 1881, and 200 cases have been reported in the literature since then. Its etiology is unknown, there is no predilection for race or sex, and the development of lesions usually occurs in puberty. The risk of sarcomatous transformation is about 25%.

Case presentation

The initial investigation of the case reported here focused on the diagnosis and treatment of malignancy, and the first diagnostic hypothesis was thrombosed hemangioma. After histopathologic confirmation of soft tissue sarcoma, examinations were performed to stage the tumor and enchondromas were found in ribs. The final diagnosis was Maffucci syndrome with malignant transformation.

Conclusion

Treatment should aim at symptom relief and early detection of malignancies; no therapy is indicated for asymptomatic patients. As in the case reported here, bone or soft tissue lesions that grow or become painful should be biopsied.

     

大肠埃希菌感染小鼠外周血中性粒细胞与 淋巴细胞比值的动态变化

目的通过观察大肠埃希菌感染小鼠模型不同时间段外周血中,中性粒细胞与淋巴细胞比值的动态变化,分析外周血中中性粒细胞/淋巴细胞比值与大肠埃希菌感染炎症程度的关系,以及中性粒细胞与淋巴细胞在大肠埃希菌感染时的可能作用机制。方法将麦氏浊度为2.73约为1×109CFU/m L大肠埃希菌通过尾静脉注射建立ICR小鼠感染模型44只、空白对照4只及阴性对照4只。实验组按1、3、6、12、24、48、72、96、120、144和168 h,共11个时间段,每次取4只小鼠,抽取外周血800μL,利用SYSMEX2100检查白细胞总数、中性粒细胞计数、淋巴细胞计数、中性粒细胞/淋巴细胞比值变化情况。结果大肠埃希菌ICR小鼠感染组1~24 h白细胞总数比对照组降低(0.01P0.05),第2天时与对照组比较差异无统计学意义,第3天至第7天白细胞总数比对照组高且差异有统计学意义(P0.01),并在第7天时略有回落;感染组中性粒细胞计数值在感染12 h到第7天比对照组高,差异有统计学意义;中性粒细胞/淋巴细胞比值对照组为0.06±0.03,感染1 h为0.07±0.04,与对照组比较差异无统计学意义(P0.05),3 h、6 h两组与对照组比较差异有统计学意义(0.01P0.05),12 h开始到第7天感染组与对照组比较差异有统计学意义,且第7天时为最高值(1.52±0.38)。结论中性粒细胞/淋巴细胞比值,比白细胞总数计数、中性粒细胞计数在大肠埃希ICR小鼠感染模型组中判断小鼠感染状况敏感,中性粒细胞/淋巴细胞比值结合白细胞总数计数、中性粒细胞计数能为临床大肠埃希菌感染的状况提供更灵敏的诊断参考数据,且易在临床推广。     

A scoring model based on neutrophil to lymphocyte ratio predicts recurrence of HBV-associated hepatocellular carcinoma after liver transplantation

Background

Neutrophil to lymphocyte ratio (NLR) has been proposed to predict prognosis of hepatocellular carcinoma (HCC). However, the cut-off values are empirical. We determined the optimal cut-off value to predict HCC recurrence after liver transplantation (LT) and further established a scoring model based on NLR.

Methodology/Principal Findings

We analyzed the outcome of 101 HBV-associated HCC patients undergoing LT. Preoperative risk factors for tumor recurrence were evaluated by univariate analysis. By using ROC analysis, NLR≥3 was considered elevated. The disease-free survival (DFS) and overall survival (OS) for patients with high NLR was significantly worse than that for patients with normal NLR (the 5-year DFS and OS of 28.5% and 19.5% vs. 64.9% and 61.8%, respectively; P<0.001). Univariate analysis revealed that tumor size >5 cm, tumor number >3, macrovascular invasion, AFP≥400 µg/L, NLR≥3, and HBV-DNA level >5 log10 copies/mL were preoperative predictors of DFS. Cox regression analysis showed macrovascular invasion, tumor number, and high NLR were independent prognostic factors. We then established a preoperative prognostic score based on multivariate analysis. Each factor was given a score of 1. Area under the ROC curve of the score was 0.781. All nine patients with score 3 developed recurrence within 6 months after LT. Of 71 patients without vascular invasion, three patients with both tumor number >3 and NLR≥3 developed recurrence within 14 months after LT while the 5-year DFS and OS for patients with a score of 0 or 1 were 68.1% and 62.8%, respectively.

Conclusions/Significance

Preoperative elevated NLR significantly increases the risk of recurrence in patients underwent LT for HCC. Patients with both NLR≥3 and tumor number >3 are not a good indication for LT. Our score model may aid in the selection of patients that would most benefit from transplantation for HCC.     

A spatially and temporally restricted mouse model of soft tissue sarcoma

Soft tissue sarcomas are mesenchymal tumors that are fatal in approximately one-third of patients. To explore mechanisms of sarcoma pathogenesis, we have generated a mouse model of soft tissue sarcoma. Intramuscular delivery of an adenovirus expressing Cre recombinase in mice with conditional mutations in Kras and Trp53 was sufficient to initiate high-grade sarcomas with myofibroblastic differentiation. Like human sarcomas, these tumors show a predilection for lung rather than lymph node metastasis. Using this model, we showed that a prototype handheld imaging device can identify residual tumor during intraoperative molecular imaging. Deletion of the Ink4a-Arf locus (Cdkn2a), but not Bak1 and Bax, could substitute for mutation of Trp53 in this model. Deletion of Bak1 and Bax, however, was able to substitute for mutation of Trp53 in the development of sinonasal adenocarcinoma. Therefore, the intrinsic pathway of apoptosis seems sufficient to mediate p53 tumor suppression in an epithelial cancer, but not in this model of soft tissue sarcoma.     

Suppression of soft tissue sarcoma growth by a host defense-like lytic peptide

Background

Soft tissue sarcoma (STS) is an anatomically and histologically heterogeneous neoplasia that shares a putative mesenchymal cell origin. The treatment with common chemotherapeutics is still unsatisfying because of association with poor response rates. Although evidence is accumulating for potent oncolytic activity of host defense peptides (HDPs), their potential therapeutic use is often limited by poor bioavailability and inactivation in serum. Therefore, we tested the designer host defense-like lytic D,L-amino acid peptide [D]-K₃H₃L₉ on two STS cell lines in vitro and also in an athymic and syngeneic mouse model. In recent studies the peptide could show selectivity against prostate carcinoma cells and also an active state in serum.

Methods

In vitro the human synovial sarcoma cell line SW982, the murine fibrosarcoma cell line BFS-1 and primary human fibroblasts as a control were exposed to [D]-K₃H₃L₉, a 15mer D,L-amino acid designer HDP. Cell vitality in physiological and acidic conditions (MTT-assay), cell growth (BrdU) and DNA-fragmentation (TUNEL) were investigated. Membrane damage at different time points could be analyzed with LDH assay. An antibody against the tested peptide and recordings using scanning electron microscopy could give an inside in the mode of action. In vivo [D]-K₃H₃L₉ was administered intratumorally in an athymic and syngeneic (immunocompetent) mouse model with SW982 and BFS-1 cells, respectively. After three weeks tumor sections were histologically analyzed.

Results

The peptide exerts rapid and high significant cytotoxicity and antiproliferating activity against the malignant cell lines, apparently via a membrane disrupting mode of action. The local intratumoral administration of [D]-K₃H₃L₉ in the athymic and syngeneic mice models significantly inhibited tumor progression. The histological analyses of the tumor sections revealed a significant antiproliferative, antiangiogenic activity of the treatment group.

Conclusion

These findings demonstrate the in vitro and in vivo oncolytic activity of [D]-K₃H₃L₉ in athymic and syngeneic mouse models.