Kaplan-Meier Log-rank Survival Analysis Research Articles

SAMHD1 expression contributes to doxorubicin resistance and predicts survival outcomes in diffuse large B-cell lymphoma patients.

Diffuse large B-cell lymphoma (DLBCL) is a commonly diagnosed, aggressive non-Hodgkin's lymphoma. While R-CHOP chemoimmunotherapy is potentially curative, about 40% of DLBCL patients will fail, highlighting the need to identify biomarkers to optimize management. SAMHD1 has a dNTPase-independent role in promoting resection to facilitate DNA double-strand break (DSB) repair by homologous recombination. We evaluated the relationship of SAMHD1 levels with sensitivity to DSB-sensitizing agents in DLBCL cells and the association of SAMHD1 expression with clinical outcomes in 79 DLBCL patients treated with definitive therapy and an independent cohort dataset of 234 DLBCL patients. Low SAMHD1 expression, Vpx-mediated, or siRNA-mediated degradation/depletion in DLBCL cells was associated with greater sensitivity to doxorubicin and PARP inhibitors. On Kaplan-Meier log-rank survival analysis, low SAMHD1 expression was associated with improved overall survival (OS), which on subset analysis remained significant only in patients with advanced stage (III-IV) and moderate to high risk (2-5 International Prognostic Index (IPI)). The association of low SAMHD1 expression with improved OS remained significant on multivariate analysis independent of other adverse factors, including IPI, and was validated in an independent cohort. Our findings suggest that SAMHD1 expression mediates doxorubicin resistance and may be an important prognostic biomarker in advanced, higher-risk DLBCL patients.

Failed shrimp vaccination attempt with yellow head virus (YHV) attenuated in an immortal insect cell line

This short paper on yellow head virus Type-1 (YHV-1) of shrimp describes preliminary research on the potential for using YHV-1 attenuated in insect cells to protect shrimp against yellow head disease (YHD). YHV-1 can cause severe mortality in the cultivated shrimp Penaeus (Penaeus) monodon and Penaeus (Litopenaeus) vannamei. No practical vaccination has been reported. The C6/36 mosquito cell cultures inoculated with YHV-1 become positive by PCR and by immunocytochemistry (immunopositive) for up to 30 split-cell passages. Shrimp injected with homogenates from low-passage cultures die from typical YHV-1 disease while shrimp injected with homogenates from high passage cultures do not, even though they become PCR positive and immunopositive for YHV-1. This suggested that viral attenuation had occurred during insect-cell passaging, and it opened the possibility of using homogenates from high-passage insect cultures as a vaccine against YHV-1. To test this hypothesis, homogenates from 30th-passage, YHV-positive cultures were injected into shrimp followed by challenge with virulent YHV-1. Controls were injected with homogenate from 30th-passage, naive (normal stock) insect-cell cultures. No shrimp mortality occurred following injection of either homogenate, but shrimp injected with the YHV-1 homogenate became both RT-PCR positive and immunopositive. Upon challenge 10 days later with YHV-1, mortality in shrimp injected with naive insect-cell homogenate was 100% within 7 days post-challenge while 100% mortality in the YHV-1 homogenate group did not occur until day 9 post-challenge. Kaplan-Meier log-rank survival analysis revealed that survival curves for the two groups were significantly different (p < 0.001). The cause of delay in mortality may be worthy of further investigation.

The Number of Positive Tumor Markers (NPTM) Achieves Higher Value in the Prognosis Prediction of Gastric Cancer.

The clinical application of combined tumor markers is still limited. We aim to explore the value of the combination of multiple tumor markers in gastric cancer (GC) prognosis. The prognostic significance was evaluated using Kaplan-Meier log-rank survival analysis and multivariable Cox regression analysis. The estimated area under the curve (AUC) was compared to evaluate the discriminatory ability of different indicators. A nomogram was constructed based on the results of multivariable cox regression, and its performance was evaluated by Harrell's concordance index and calibration curve. NPTM (number of positive tumor markers) displayed independent prognostic significance whether in the whole cohort or in patients with different stages. Patients with the all-negative tumor markers had a worse prognosis after postoperative chemotherapy in all cohort (P = 0.023) or in age ≤60 subgroup (P = 0.012), while patients with positive tumor markers had a better prognosis after postoperative chemotherapy in stage III (P = 0.012). The AUC value of NPTM is higher than any individual tumor marker. The 1-, 3-, and 5-year AUC values of the CTNM (combination of NPTM and pTNM) increased by 5%, 4.8%, and 3.6%, respectively, compared with TNM staging system. The nomogram constructed including NPTM showed its high accuracy (C - index = 0.706) versus TNM staging system (C - index = 0.646) and CTNM (C - index = 0.681). NPTM was an independent predictor of gastric cancer prognosis, showing more accurate prognostic performance than individual tumor markers. Especially its significance in guiding postoperative adjuvant chemotherapy regimens and predicting prognosis by combination with TNM staging system may have a better clinical application value.

Postoperative Respiratory Failure Following Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy is Associated with Volume of Intraoperative Crystalloid Administration and Worse Survival.

Postoperative respiratory failure (PRF) is associated with increased morbidity after surgery. This retrospective study explores preoperative and perioperative risk factors associated with PRF in patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) and the resultant impact on survival. We identified all patients who underwent CRS/HIPEC at our institution between 2007 and 2017. PRF was defined as mechanical ventilation for more than 48h after surgery or reintubation not related to an additional procedure within the first 30 days postoperatively. The relationship between clinicopathologic variables and PRF was examined using Kaplan-Meier log-rank survival analysis and multivariable Cox regression models with 90-day, 1-year and 5-year overall survival (OS). Overall, 314 patients underwent CRS/HIPEC, of whom 24 patients (7.6%) developed PRF. On univariable analysis, chronic obstructive pulmonary disease (COPD) was the only preoperative risk factor associated with PRF (p=0.049). Of the intraoperative risk factors, diaphragmatic resection (p=0.008), Peritoneal Cancer Index (PCI) > 20 (p<0.001), and volume of intraoperative crystalloid (p<0.001) were all associated with PRF. On multivariable Cox regression, only intraoperative crystalloid was significantly associated with PRF (p<0.001), with a volume above 5.3L (area under the curve [AUC] 0.77) having a high predictive accuracy for PRF.Five-year OS was significantly decreased in patients with PRF (30.2% vs. 52.6%, hazard ratio 2.6, 95% confidence interval 1.5-4.4; p<0.001). Liberal intraoperative crystalloid volume resuscitation is a potential independent, modifiable intraoperative risk factor for PRF following CRS/HIPEC that may contribute to decreased long-term OS.

Prognostic significance of serum tumor marker normalization in the perioperative period for patients with advanced gastric cancer.

BackgroundNeoadjuvant chemotherapy (NCT) was developed to improve the prognosis of patients with advanced gastric cancer (AGC). Some studies have confirmed the diagnostic and prognostic value of various serum tumor markers in gastric cancer. However, most of these studies were focused on the value of preoperative and postoperative tumor markers in patients undergoing surgery with or without adjuvant therapy, and only a few studies focused on AGC patients undergoing NCT.MethodsWe retrospectively analyzed the data of consecutive patients with histologically confirmed AGC who received NCT prior to surgical resection at Zhejiang Cancer Hospital from January 2010 to September 2018. The prognostic impact of tumor markers before and after NCT, including Carcinoembryonic antigen (CEA), Carbohydrate antigen199 (CA199), Carbohydrate antigen125 (CA125), Alpha-FetoProtein (AFP), Carbohydrate antigen242 (CA242), and Carbohydrate antigen724 (CA724), were evaluated using Kaplan-Meier log-rank survival analysis. The association between tumor marker normalization during preoperative chemotherapy and clinicopathological characteristics was also investigated.ResultsFour hundred and seventy-two patients were included in the study. The levels of CEA, CA199, CA125, CA242, and CA724 before NCT could predict prognosis, and the levels of CA199, CA125, CA242, and CA724 after NCT were correlated with prognosis. The overall survival (OS) rate decreased with an increasing number of positive tumor markers before and after preoperative chemotherapy. Tumor marker abnormalization after NCT was not related to chemotherapy, whereas patients with tumor marker normalization after NCT obtained survival benefits.ConclusionsTumor markers before and after NCT, such as CA199, CA125, CA242, and CA724, have a discriminatory ability for patients with GC. The normalization of tumor markers after NCT was associated with better survival.

Prognostic significance of pre- and post-operative tumour markers for patients with gastric cancer

BackgroundIn clinical practice, carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9 are the most common markers measured before and after surgery for gastric cancer (GC). However, which pre- or post-operative combined tumour markers (CEA and CA19-9) have more prognostic value remains unclear.MethodsConsecutive patients undergoing a resection for GC at the Fujian Medical University Union Hospital were included as a discovery database between January 2011 and December 2014. The prognostic impact of pre- and post-operative tumour markers was evaluated using Kaplan–Meier log-rank survival analysis and multivariable Cox regression analysis. The results were then externally validated.ResultsA total of 735 and 400 patients were identified in the discovery cohort and in the validation cohort, respectively. Overall survival rates decreased in a stepwise manner in association with the number of pre- and post-operative positive tumour markers (both P < 0.001). Multivariable analysis revealed that the number of pre-operative positive tumour markers was an independent prognostic factor (P < 0.05). For patients with abnormal pre-operative tumour markers, normalisation of tumour markers after surgery is an independent prognostic protective factor (hazard ratio (HR) = 0.618; 95% confidence interval (CI) = 0.414–0.921), and patients with both positive post-operative tumour markers had double the risk of overall death (HR = 2.338; 95% CI = 1.071–5.101). Similar results were observed in the internal validation and external validation cohorts.ConclusionPre-operative tumour markers have a better discriminatory ability for post-operative survival in GC patients than post-operative tumour markers, and the normalisation of tumour markers after surgery was associated with better survival.

Prognostic significance of combined Lymphocyte-monocyte Ratio and Tumor-associated Macrophages in Gastric Cancer Patients after Radical Resection

Background: Immune function is recognized as an important prognostic indicator in gastric cancer (GC). The relationship between the lymphocyte-monocyte ratio (LMR) and tumor-associated macrophage (TAM) has received far less attention.Methods: A total of 401 patients from a prospective trial (NCT02327481) were enrolled in this study. The relationships between the LMR, TAM, and clinicopathologic variables were analyzed using a Kaplan-Meier log-rank survival analysis, and multivariate Cox regression models were used to identify associations with recurrence-free survival (RFS) and overall survival (OS). The discriminatory power of the prognostic models for both RFS and OS were compared. The decision curve analysis was performed to compare the clinical utility of the prognostic models.Results: High LMR was observed in 81.5% of the 401 GC patients, and high TAM infiltration was observed in 45.9% of the patients. In a multivariate Cox analysis of all patients, LMR and TAM were both independent prognostic factors for RFS and OS. Patients with high TAM expression had similar mean LMR levels than patients with low TAM expression. Moreover, LMR appeared to lose its prognostic significance in patients with high TAM expression levels. Finally, the model that included the TAM had better predictive capability and clinical utility for both RFS and OS.Conclusions: Although LMR and TAM are both independent predictors of RFS and OS in resectable GC patients, LMR seem to attenuate its prognostic significance in patients with high TAM expression. This information may be helpful in the clinical management of patients with GC. Further external studies are warranted to confirm this hypothesis.

Expression of Prox1 in Medullary Thyroid Carcinoma Is Associated with Chromogranin A and Calcitonin Expression and with Ki67 Proliferative Index, but Not with Prognosis.

Medullary thyroid carcinoma (MTC) has been shown to express Prospero homeobox protein 1 (Prox1), a transcription factor whose expression is altered in a variety of human cancers. We conducted a retrospective study on a series of 32 patients with MTC to test the correlation of Prox1 expression in MTC with clinicopathological features and to evaluate its prognostic significance. Correlation of Prox1 immunohistochemical expression with tumor size, proliferative index (Ki67), and calcitonin and CEA serum levels prior to surgery was tested for significant correlations. The difference in Prox1 and Ki67 immunohistochemical expression according to the immunohistochemical staining intensity of CEA, chromogranin A, and calcitonin was tested using the Kruskal-Wallis H test and linear regression analysis. The prognostic value of Prox1 and Ki67 for our patient cohort was assessed by Kaplan-Meier log rank survival analysis. We demonstrated a positive correlation between Prox1 expression and Ki67 index. Prox1 also showed significant difference in expression according to chromogranin A and calcitonin immunohistochemical expression, with higher Prox1 expression in tumors with stronger chromogranin A or calcitonin staining. Prox1 expression did not correlate with PFS or OS based on Kaplan-Meier log rank survival analysis. In conclusion, Prox1 expression in MTC is positively correlated with Ki67 and with the immunohistochemical expression of chromogranin A and calcitonin. However, the present study does not support a role for Prox1 in MTC prognosis.

Preoperative Leucocyte-Based Inflammatory Scores in Patients with Colorectal Liver Metastases: Can We Count on Them?

Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and lymphocyte-to-monocyte ratio (LMR) have been identified as potential prognostic factors for overall survival (OS) in primary colorectal cancer, and there is a growing interest in their use in colorectal liver metastases (CLMs). However, optimal cut-off values for these ratios have not been defined by making comparison between series difficult. This study aimed to confirm the prognostic value of inflammatory scores in patients undergoing resection for CLM. We retrospectively analysed data from 376 consecutive patients who underwent liver surgery for CLM between June 2010 and August 2015. We assessed the reproducibility of previously published ratios and determined new cut-off values using the Cut-off Finder web-based tool. Relations between cut-off values and OS were analysed with Kaplan-Meier log-rank survival analysis and multivariate Cox models. Three hundred and forty-three patients had full preoperative blood tests for calculation of NLR, PLR and LMR. The number of cut-off values which showed a significant discrimination for OS was 49/249 (19.7%) for NLR, 28/316 (8.9%) for PLR and 22/214 (10.3%) for LMR, all with a scattered nonlinear distribution. This study showed that inflammatory scores expressed as ratios do not seem to be consistently reliable prognostic markers in patients with resectable CLM.

The lymphocyte-to-monocyte ratio is a superior predictor of overall survival compared to established biomarkers in HCC patients undergoing liver resection

The aim of this study was to investigate the prognostic value of the lymphocyte-to-monocyte ratio (LMR) in patients undergoing hepatectomy and to compare it to established biomarkers including the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR). Medical records were retrospectively analyzed for 652 HCC patients undergoing hepatectomy at the Affiliated Tumor Hospital of Guangxi Medical University and the First People’s Hospital of Changde between April 2004 to April 2012. The correlation between the LMR and clinical variables were analyzed in Kaplan-Meier log-rank survival analysis and then multivariate Cox regression models trying to find relation with disease-free survival (DFS) and overall survival (OS). The area under the ROC curve (AUC) of the LMR(AUC:0.627) for predicting long-term survival was greater than that of the NLR(AUC:0.600) and the PLR(AUC:0.520).Multivariate analysis showed LMR to be an independent risk factor for OS (P = 0.002), and the NLR and PLR were not independently significant. Subgroup analysis also showed that LMR was significantly associated with poor DFS and OS in patients positive for HBsAg or with cirrhosis (both P < 0.001).Elevated preoperative LMR is an independently associated with poor OS and DFS in HCC patients following curative resection and appears to be superior to NLR and PLR.

Lymphocyte/Monocyte Ratio is a Novel Predictor for Early Stage Extranodal Natural Killer/T-cell Lymphoma, Nasal Type.

Objective: Great heterogeneity exists in clinical behavior and survival outcome in patients with stage IE/IIE extranodal natural killer/T-cell lymphoma, nasal type (ENKTL). In this study, we proposed lymphocyte/monocyte ratio (LMR) as a new prognostic factor for these early stage ENKTL.Methods: We retrospectively examined the LMR as a prognostic variable in a cohort of 379 patients with newly diagnosed stage IE/IIE ENKTL. The relationship between the LMR and clinicopathologic variables were analyzed in Kaplan-Meier log-rank survival analysis, and the Cox proportional hazards model was used to determine the survival significance of the LMR for both progression-free survival (PFS) and overall survival (OS).Results: Patients were categorized into two different groups based on the LMR using cut-off value of 2.0. The 5-year PFS rates in the low and high LMR group were 43.9% and 62.7%, respectively, and the 5-year OS rates in the two groups were 59.1% and 77.7%, respectively. In multivariate analysis, low LMR at diagnosis was associated with worse PFS (hazard ratio 1.611, 95% confidence interval: 1.027-2.525, P =0.038) independent of age (P=0.033) and treatment stratagem (P<0.001), and indicated worse OS (hazard ratio 2.003, 95% confidence interval: 1.124-3.569, P =0.018) independent of age (P=0.007), LDH level (P=0.042), local tumor invasiveness (P=0.008), and treatment stratagem (P<0.001).Conclusion: The LMR is an independent prognostic factor for both DFS and OS in patients with stage IE/IIE ENKTL, and provides additional prognostic value beyond standard clinicopathological parameters.

Colorectal Cancer, Systemic Inflammation, and Outcome: Staging the Tumor and Staging the Host.

This study aims to examine the clinical utility of the combination of TNM stage and modified Glasgow Prognostic Score (mGPS) in patients undergoing potentially curative resection of colorectal cancer (CRC). Of measures of the systemic inflammatory response, the mGPS has been most extensively validated in patients with cancer. Data from 1000 consecutive patients undergoing potentially curative CRC resection from a single institution (January 1997-May 2013) were included. The relationship between mGPS [0-C-reactive protein (CRP) ≤ 10 mg/L, 1-CRP > 10 mg/L and albumin ≥35 g/L, 2-CRP > 10 mg/L and albumin < 35 g/L], TNM stage, and cancer-specific survival (CSS) and overall survival (OS) was examined using Kaplan-Meier log-rank survival analysis and multivariate Cox regression analysis. An mGPS of 0, 1, and 2 was observed in 63%, 21%, and 16% of patients, respectively. Median follow-up was 56 months (interquartile range: 28-107 months). TNM and mGPS were independently associated with CSS and OS (all P < 0.001). In all patients, TNM and mGPS stratified 5-year CSS and OS from 97% and 87% (stage I, mGPS = 0) to 32% and 26% (stage III, mGPS = 2), respectively. In patients undergoing elective resection of colon cancer (n = 575), 5-year CSS and OS ranged from 100% and 87% (stage I, mGPS = 0) to 37% and 30% (stage III, mGPS = 2), respectively. This study shows how the combination of TNM and mGPS effectively stratifies outcome in patients undergoing potentially curative resection of CRC. These data support routine staging of both the tumor and the host in patients with CRC.

Radiation Therapy Patterns of Care in Gastric Adenocarcinoma: A Single-Institution Experience

Gastric adenocarcinoma (GAC) is one of the most commonly diagnosed cancers worldwide. The two standard approaches for treatment of resectable advanced gastric cancer are postoperative adjuvant 5-fluorouracil-based (5-FU) chemoradiation based on the Intergroup 0116 trial (INT-0116) or perioperative epirubicin, cisplatin, and 5-FU (ECF) chemotherapy based on the MAGIC (MRC Adjuvant Gastric Infusional Chemotherapy) trial. The most appropriate treatment strategy to decrease recurrence rates and improve survival remains controversial. The purpose of this study was to analyze the change in patterns of care in GAC patients treated at one institution after the 2006 Cunningham/MAGIC trial and secondarily describe recurrence patterns and survival outcomes. One hundred fifty patients were analyzed from a prospectively maintained database of patients who underwent resection for GAC between December 2000 and June 2013. The cohort was divided into patients treated between 2000-2006 (Early) and 2007-2013 (Late). Survival outcomes were calculated from the date of surgery to the date of last follow-up or the date of death from any cause. Clinicopathologic features of the two cohorts were analyzed by chi-square test for categorical variables and student’s t-test for continuous variables. Kaplan-Meier log-rank survival analysis was performed to evaluate association of the two cohorts with patient survival. The median follow-up for the entire cohort was 23.2 mos and the median OS was 40.9 mos. Patients receiving adjuvant radiation therapy was equivalent between the two cohorts (n = 23 vs n = 35, p = 0.21). Neoadjuvant chemotherapy alone increased from 2 patients in the Early cohort to 32 patients in the Late cohort (p<0.001). 86 patients in the Late cohort had D2 lymphadenectomy compared to 40 patients in the Early cohort (p = 0.002). Overall 3-year survival was 68.8% for the Late cohort and 43.6% for the Early cohort (p = 0.010). Overall recurrence rate was 25.3% with no difference in rates of recurrence between the two cohorts (30.4% vs 22.3%, p = 0.37). The number of patients who receive adjuvant chemoradiation has not changed significantly from pre-MAGIC to post-MAGIC; however, neoadjuvant chemotherapy has become more prevalent. In turn, overall 3-year survival in this GAC cohort has increased. The results of the study describe the benefits of neoadjuvant chemotherapy and D2 lymphadenectomy on GAC patient overall survival but demonstrate no effects on recurrence-free survival. New treatment approaches are prolonging survival but may be failing to target the subset of patients who are more likely to recur. As we begin to redefine treatment for GAC patients and integrate different treatment modalities, we hope to continue to improve the overall survival of our patients and lower recurrence rates.

Low CHD5 expression activates the DNA damage response and predicts poor outcome in patients undergoing adjuvant therapy for resected pancreatic cancer

The DNA damage response (DDR) promotes genome integrity and serves as a cancer barrier in precancerous lesions but paradoxically may promote cancer survival. Genes that activate the DDR when dysregulated could function as useful biomarkers for outcome in cancer patients. Using a siRNA screen in human pancreatic cancer cells, we identified the CHD5 tumor suppressor as a gene, which, when silenced, activates the DDR. We evaluated the relationship of CHD5 expression with DDR activation in human pancreatic cancer cells and the association of CHD5 expression in 80 patients with resected pancreatic adenocarcinoma (PAC) by immunohistochemical analysis with clinical outcome. CHD5 depletion and low CHD5 expression in human pancreatic cancer cells lead to increased H2AX-Ser139 and CHK2-Thr68 phosphorylation and accumulation into nuclear foci. On Kaplan-Meier log-rank survival analysis, patients with low CHD5 expression had a median recurrence-free survival (RFS) of 5.3 vs 15.4 months for patients with high CHD5 expression (P=0.03). In 59 patients receiving adjuvant chemotherapy, low CHD5 expression was associated with decreased RFS (4.5 vs 16.3 months; P=0.001) and overall survival (OS) (7.2 vs 21.6 months; P=0.003). On multivariate Cox regression analysis, low CHD5 expression remained associated with worse OS (HR: 3.187 (95% CI: 1.49-6.81); P=0.003) in patients undergoing adjuvant chemotherapy. Thus, low CHD5 expression activates the DDR and predicts for worse OS in patients with resected PAC receiving adjuvant chemotherapy. Our findings support a model in which dysregulated expression of tumor suppressor genes that induce DDR activation can be utilized as biomarkers for poor outcome.