Valuable Prognostic Biomarker In Patients Research Articles

FAR Ratio as Prognostic Biomarker in AMI.

Acute mesenteric ischemia (AMI) is a vascular emergency resulting from decreased blood flow caused by the occlusion of the mesenteric vessels, hypoperfusion, or vasospasm. This study aimed to investigate the prognostic value of the fibrinogen-to-albumin (FAR) ratio in patients with acute mesenteric ischemia. A total of 91 patients were enrolled in the study. Patients' demographics such as age and gender, pre- and postoperative hemoglobin, CRP, white blood cell (WBC), neutrophils, preoperative lymphocyte, alanine transaminase (ALT), aspartate transaminase (AST), thrombocytes, and postoperative D-dimer values were recorded. In addition, pre- and postoperative fibrinogen and albumin levels were recorded, and FAR was calculated. Patients were divided into two groups, survivors and non-survivors. The mean pre- and postoperative fibrinogen levels were statistically significantly higher in the non-survivor group than in the survivor group (p < 0.001). The mean pre- and postoperative albumin levels were significantly lower in the non-survivors than in the survivors (p = 0.059, p < 0.001; respectively). The mean pre- and postoperative FAR ratios were considerably higher in the non-survivor than in the survivor groups (p < 0.001). The change between pre- and postoperative fibrinogen, albumin, and FAR values was statistically significant between the non-survivors and the survivors (for all, p < 0.05). The preoperative and postoperative fibrinogen levels were significantly lower, and albumin levels were significantly higher in the survivor compared to the non-survivor patients with AMI. Furthermore, the preoperative and postoperative FAR ratio was significantly higher in the non-survivors. The FAR ratio may be a valuable prognostic biomarker for patients with AMI.

Comprehensive Analysis of Prognostic Value and Immune Infiltration of TFAP2 Family Members in Bladder Cancer from Database and FFPE Sample.

Background: Bladder cancer (BLCA) is one of the common malignant tumors worldwide. Recent studies have shown that Transcription factor activating protein-2(TFAP2) family proteins plays a bidirectional regulatory role in the process of tumorigenesis versus evolution by regulating the expression of tumor associated genes. However, little is known about the function of distinct TFAP2s proteins in patient with BLCA. Methods: Formalin-fixed paraffin-embedded (FFPE) sample tissues and clinical data of 240 patients with bladder cancer were collected for immunohistochemical analysis. The Human Protein Atlas, Gene Expression Profiling Interactive Analysis (GEPIA), Shiny Methylation Analysis Resource Tool (SMART), Kaplan-Meier plotter, cBioPortal, Metascape, LinkedOmics, TIMER and CIBERSORT were utilized to analyze differential expression, prognostic value, genetic alteration and immune cell infiltration of TFAP2 family in patients with BLCA. Results: Our study found that TFAP2 family proteins are generally expressed higher in BLCA tissues than in normal tissues. However, they show different trends in the growth, metastasis and survival prognosis of BLCA. TFAP2A and TFAP2C was associated with worse clinical stage and prognosis in BLCA patients, while TFAP2B, TFAP2D and TFAP2E showed the opposite trend. Importantly, the functions of the differentially expressed TFAP2s were primarily related to the developmental process, reproductive process, response to stimulus and immune system process, etc. Moreover, TFAP2 family was significantly correlated with the infiltration of six immune cell types and might regulate TAM polarization. Conclusion: TFAP2 family might be an important regulator of immune cell infiltration and a valuable prognostic biomarker in patients with BLCA.

M6A demethylase FTO renders radioresistance of nasopharyngeal carcinoma via promoting OTUB1-mediated anti-ferroptosis

Radiotherapy is a valid treatment for nasopharyngeal carcinoma (NPC), and radioresistance is the main cause of local NPC treatment failure. However, the underlying mechanisms and valuable markers of radioresistance for NPC remain have not been established. In this study, we observed that the m6A mRNA demethylase fat mass and obesity-associated protein (FTO) was significantly upregulated in radioresistant NPC tissues and cells relative to parental radiosensitive NPC tissues and cells. FTO enhances radioresistance by repressing radiation-induced ferroptosis in NPC. Mechanistically, FTO acts as an m6A demethylase to erase the m6A modification of the OTUB1 transcript and promote the expression of OTUB1, thereby inhibiting the ferroptosis of cells induced by radiation and finally triggering the radiotherapy resistance of NPC. Furthermore, our in vivo experiment results showed that the FTO inhibitor, FB23-2, and the ferroptosis activator, erastin, altered tumor responsiveness to radiotherapy in NPC cell lines and patient-derived xenografts. Our findings reveal, for the first time, that FTO enhances NPC radiotherapy resistance by withstanding radiation-induced ferroptosis, suggesting that FTO may serve as a potential therapeutic target and valuable prognostic biomarker in patients with NPC.

PACE4 Expression is a Novel Independent Prognostic Factor in Nasopharyngeal Carcinoma.

BackgroundPaired basic amino acid-cleaving enzyme 4 (PACE4) belongs to the family of proprotein convertase and is essential for tumor progression, whereas its role in cancer remains controversial and little is known about its role in nasopharyngeal carcinoma (NPC). The aim of this study was to examine if the expression of PACE4 is a prognostic biomarker for patients with NPC.MethodsImmunofluorescence (IF) and immunohistochemistry (IHC) were used to analyze PACE4 expression in NPC cell line CNE1 and 172 clinicopathologically characterized NPC tissues. The data were analyzed by Chi-square test, Kaplan–Meier plots, and Cox proportional hazards regression model.ResultsIF and IHC staining results showed that PACE4 was mainly located in the cytoplasm of NPC cell line (CNE1) and NPC tissues. Expression of PACE4 was observed in 46/172 (26.7%) of NPC tissues. Further analysis showed that expression of PACE4 was positively associated with late N stage, distant metastasis, and late clinical stage (P<0.05). High expression of PACE4 predicted shorter 5-year overall survival of patients with NPC, especially for the patients in advanced stage (32.7% vs 77.3%, P<0.001). Furthermore, multivariate analysis showed that PACE4 expression may serve as a potential prognostic factor for NPC.ConclusionOur results suggest that PACE4 may play a crucial role in tumor progression and may serve as a valuable prognostic biomarker for patients with NPC.

Retrospective study on the potential of albumin/globulin ratio as a prognostic biomarker for oral cavity cancer patients.

Although the serum albumin/globulin ratio (AGR) is recognized as a valuable prognostic biomarker in various cancers, its clinical value in oral cavity squamous cell carcinoma (OSCC) is still unclear. We aimed to probe the prognostic value of AGR in patients with OSCC undergoing curative surgery. This retrospective study analyzed 306 patients who were newly diagnosed as having OSCC and receiving curative surgery between 2008 and 2017. The correlation of AGR with survival outcomes was estimated using Cox proportional hazards models and Kaplan-Meier analysis. A nomogram based on AGR was established, and its accuracy was assessed according to the concordance index. The log rank test and Kaplan-Meier analysis indicated that patients who had low AGR had significantly shorter disease-free survival (DFS) as well as 5-year overall survival (OS) than those with high AGR. The multivariate Cox analysis revealed that low AGR was an independent predictor of poor OS and DFS (adjusted hazard ratio [aHR] = 2.812; 95% CI 1.729-4.573; p < 0.001, and aHR = 1.743; 95% CI 1.201-2.530; p = 0.003, respectively). The concordance index of the nomogram model based on TNM staging alone was 0.656 and could increase to 0.783 with the inclusion of AGR and other prognostic variables in the calculation. Preoperative AGR may represent an accessible, valuable prognostic biomarker in patients with OSCC. The nomogram model incorporating AGR and clinicopathological prognostic variables may improve the accuracy of prognostic predictions in these patients.

PBX1 is a valuable prognostic biomarker for patients with breast cancer.

Pre-B-cell leukemia transcription factor (PBX) proteins have important roles in the development of numerous organs. To date, four members of the PBX family have been identified to be involved in human cancer but little is known about their expression patterns and precise functions in breast cancer (BC) progression. The aim of the present study was to determine whether they have the potential to be prognostic biomarkers in patients with BC. The expression patterns of PBXs were evaluated using Oncomine, Cancer Cell Line Encyclopedia and Gene expression-based Outcome for Breast cancer Online algorithm analyses. The prognostic value of PBX1 was determined by Kaplan-Meier plotter analysis. It was observed that, among all PBX family members, only PBX1 was significantly upregulated in BC vs. normal tissues. Meta-analysis in the Oncomine database revealed that PBX1 was significantly upregulated in invasive breast carcinoma stroma, ductal breast carcinoma, invasive lobular breast carcinoma, invasive mixed breast carcinoma and male breast carcinoma compared with normal tissues. In addition, PBX1 was significantly correlated with forkhead box protein A1. Subtype analysis indicated that PBX1 overexpression was associated with luminal-like and hormone receptor-sensitive subtypes. In the survival analysis, a high expression level of PBX1 was associated with poor prognosis of patients with estrogen receptor (ER)-positive, luminal A and luminal B subtypes of BC. The results of the present study indicate that PBX1 may serve as a specific biomarker and essential prognostic factor for ER-positive, luminal A and luminal B subtypes of BC.

Usefulness of High-Sensitivity Troponin I to Predict Outcome in Patients With Newly Detected Atrial Fibrillation

The prognostic role of high-sensitivity cardiac troponin I (hs-TnI) in patients with newly detected atrial fibrillation (AF) is not well established. We investigate the association of elevated hs-TnI with clinical outcomes and explore the utility of hs-TnI for risk assessment in patients with newly detected AF. From August 2014 to December 2016, 2,361 consecutive patients with newly detected AF were enrolled in a retrospective, single-center registry. Of these, 957 patients were selected and classified into 4 groups according to hs-TnI quartiles. The primary outcome was all-cause death during follow-up. The hs-TnI level was 3.6 ng/L or less in the lowest quartile (Q1), more than 3.6 ng/L to 10.1 ng/L or less in the second quartile (Q2), more than 10.1 ng/L to 22.0 ng/L or less in the third quartile (Q3), and more than 22.0 ng/L in the highest quartile (Q4). The median follow-up period was 19.3 months. In multivariable Cox regression model, Q4 has a higher risk of all-cause death (adjusted hazard ratio [HR]: 3.49; 95% confidence interval [CI]: 1.21 to 10.00; p = 0.02), readmission for heart failure (adjusted HR: 1.75; 95% CI: 1.01-3.05; p = 0.04), and readmission for revascularization (adjusted HR: 3.90; 95% CI: 1.25 to 12.17; p = 0.02) compared with Q1. Independent predictors of all-cause death were renal insufficiency (adjusted HR: 1.96; 95% CI: 1.08 to 3.53; p = 0.02), highest hs-TnI quartile (adjusted HR: 3.30; 95% CI: 1.18 to 9.27; p = 0.02) and anticoagulation therapy (adjusted HR: 0.51; 95% CI: 0.27 to 0.93; p = 0.03). Elevated hs-TnI is independently associated with higher mortality in patients with AF and serves as a valuable prognostic biomarker in patients with newly detected AF.

MiR-421 expression independently predicts unfavorable overall survival in patients with esophageal adenocarcinoma.

This study aimed to examine the prognostic value of miR-421 in terms of overall survival (OS) and recurrence free survival (RFS) in ESAD and its potential regulatory network. An in-silico analysis was conducted using data from large databases, including The Cancer Genome Atlas-Esophageal Carcinoma (TCGA-ESCA), Starbase 3.0 and GeneMANIA. Both esophageal adenocarcinoma (ESAD) and esophageal squamous cell carcinoma (ESCC) tissues had significantly upregulate miR-421 expression, compared with adjacent normal tissues. Upregulated miR-421 expression was associated with shorter OS, but not RFS in ESAD. In patients with ESCC, no difference in miR-421 expression was observed regards to OS or RFS status. Univariate and multivariate analysis showed that high miR-421 expression was independently associated with shorter OS (HR: 2.77, 95%CI: 1.41-5.46, p<0.01), after adjustment of histological grade and pathological stages. The predicted regulatory network of miR-421 in ESAD includes both tumor suppressors and oncogenes, which makes the role of miR-421 quite mysterious in this cancer. MiR-421 expression might serve as a valuable prognostic biomarker in patients with ESAD. But future molecular studies are required to explore the exact regulatory effect of it.

Prognostic value of functional tumor burden on 68Ga-DOTATOC PET/CT in patients with pancreatic neuro-endocrine tumors.

Despite their relative quiescence, pancreatic neuro-endocrine tumors (pNET) can correspond to various presentations and outcomes. Several prognostic factors have been identified, including maximal standardized uptake value of the most intense focus (maxSUVmax) on Positron Emission Tomography (PET) with a somatostatin analogue. Herein, we investigate the prognostic value on progression free-survival of the total functional tumor volume (TFTV) measured by 68Ga-DOTATOC PET. From patients who underwent 68Ga-DOTATOC PET from 2008 to 2014, we selected consecutive patients with G1 or G2 pNET (2010 World Health Organization classification), at least one abnormal focus on PET and available follow-up data. TFTV was computed by summing the volumes of all pathological foci, delineated use of 41% of its SUVmax for each threshold focus. Fifty patients were included. During the follow-up period, 33 patients had stable or responsive disease (66%; median duration 28.5 months; range 6.3-77.7 months) and 17 patients experienced disease progression (34%; median progression time 21 months; range 6.7-44.7 months). Median PFS was 43.5 months. The best TFTV cut-off for predicting progression within 24 months was 13.8 cm3. Multivariate analysis determined that TFTV greater than 13.8 cm3 was the only criterion considered a significant risk factor for tumor progression (HR 2.9; p=0.0003). A significant difference in PFS was observed for TFTV (<13.8 vs. ≥ 13.8 cm3: median not reached vs. 25 months; p=0.0001). Our study suggests that 68Ga-DOTATOC TFTV measured on PET images is a valuable prognostic biomarker in patients with well-differentiated pNETs of all stages.

The prognostic value of high sensitive cardiac troponin I in patients receiving cardiac resynchronisation therapy

Background: Cardiac troponin I (cTnI) is a valuable prognostic biomarker in patients with chronic heart failure (CHF). However, the prognostic importance of cTnI in patients who received cardiac resynchronisation therapy (CRT) remains unknown. The aim of this prospective study was to determine the prognostic value of high-sensitive cTnI (hs-cTnI) in CHF patients receiving CRT.Methods: We performed measurements of baseline hs-cTnI levels in CRT patients with ischaemic as well as nonischaemic aetiology of CHF, and we investigated their possible association with response to CRT and survival of patients.Results: Ninety consecutive CRT patients (mean age 64 ± 9 years, 71 men) were included. According to the best cut-off value of hs-cTnI level to predict CRT response and all cause mortality, patients were divided into group 1 (hs-cTnI level ≥6.5 ng/l, n = 46) and group 2 (hs-cTnI level <6.5 ng/l, n = 44). During the follow-up period (1155 ± 406 days), 47% of patients were CRT responders (30% in group 1 and 64% in group 2, p = .002) and 31% of patients died from any cause (48% in group 1 and 14% in group 2, p = .001). Regression analysis showed that hs-cTnI level <6.5 ng/l was an independent predictor of CRT response (OR 3.49, p = .019) and that hs-cTnI level ≥6.5 ng/l was an independent predictor of all cause mortality (HR 3.01, p = .021).Conclusion: The hs-cTnI can be an useful biomarker with prognostic value in patients receiving CRT.

TRAF2 is a Valuable Prognostic Biomarker in Patients with Prostate Cancer.

BackgroundTRAF2 exerts important functions in regulating the development and progression of cancer. The aim of this study is to investigate whether TRAF2 is a valuable prognostic biomarker and to determine if it regulates TRAIL-induced apoptosis in prostate cancer.Material/MethodsMicroarray gene expression data from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were used to determine TRAF2 expression in prostate cancer. TRAF2 expression in prostate cancer was further investigated by immunohistochemistry assay. Kaplan–Meier curves and log-rank test were used to assess the recurrence-free rate. Cox regression was used to analyze prognostic factors. Effects of TRAF2 on regulating TRAIL-induced apoptosis in DU-145 cells were further investigated.ResultsWe found that TRAF2 was significantly upregulated in prostate cancer compared with normal prostate samples (P<0.001). In addition, compared with primary prostate cancer, TRAF2 was upregulated in metastatic prostate cancer (P=0.006). Furthermore, our results showed that high expression of TRAF2 was significantly associated with tumor stage of prostate cancer (P=0.035). TRAF2 high expression was associated with poorer recurrence-free survival in prostate cancer patients (P=0.013). TRAF2 was found to be a valuable independent prognostic factor for predicting recurrence-free survival (P=0.026). In addition, the present results indicate that TRAF2 affects TRAIL-induced apoptosis in prostate cancer DU-145 cells via regulating cleaved Caspase-8 and c-Flip expression.ConclusionsTRAF2 could be a novel prognostic biomarker for predicting recurrence-free survival in patients with prostate cancer, which might be associated with the effects of TRAF2 in regulating TRAIL-induced apoptosis in prostate cancer cells via c-Flip/Caspase-8 signalling.

Preoperative platelet-to-lymphocyte ratio is a valuable prognostic biomarker in patients with hepatocellular carcinoma undergoing curative liver resection.

The Platelet to lymphocyte ratio (PLR) has been reported to predict prognosis of patients with hepatocellular carcinoma (HCC). This study examined the prognostic potential of stratified PLR for HCC patients undergoing curative liver resection. Medical records were retrospectively analyzed for 778 HCC patients undergoing curative liver resection at the Affiliated Tumor Hospital of Guangxi Medical University and the First People's Hospital of Changde between April 2010 and October 2013. Patients were stratified based on quintile analysis of their preoperative PLR, and patients in different quintiles were analyzed for overall survival (OS) and disease-free survival (DFS) using Kaplan-Meier analysis. Independent predictors of death or recurrence were explored using multivariable Cox proportional hazard regression. Higher PLR quintiles were significantly associated with poorer overall survival (p < 0.001). Multivariate analysis showed PLR to be an independent risk factor for OS (p = 0.003). Patients in PLR quintile 5 had lower overall survival than in quintile 1 (hazard ratio (HR) = 2.780, 95% confidence interval (CI): 1.769-4.367, p < 0.001). Although patients in PLR quintile 5 had significantly lower disease-free survival (DFS) than in quintile 1 (HR = 1.534, 95% CI: 1.112-2.117, p = 0.009), this association was not significant after multivariable adjustment (p = 0.220). Subgroup analysis also showed that PLR quintiles were significantly associated with poor OS in patients positive for HBsAg or with cirrhosis (both p < 0.001). Similar results were obtained when PLR was analyzed as a dichotomous variable with cut-off values of 110 and 115. Elevated preoperative PLR may be independently associated with poor OS and DFS in HCC patients following curative resection.

Phosphorylation of gH2AX as a novel prognostic biomarker for laryngoesophageal dysfunction-free survival.

Current larynx preservation treatments have achieved an improvement of laryngoesophageal dysfunction-free survival (LDS) but lead to significant toxicities and recurrences. At present, there is no evidence to select the group of patients that may benefit from preservation approaches instead of surgery. Therefore, laryngeal biomarkers could facilitate pretreatment identification of patients who could respond to chemoradiation-based therapy. In this study, we evaluated retrospectively 53 patients with larynx cancer to determine whether gH2AX phosphorylation (pH2AX) alone or in combination with the membrane protein MAP17 (PDZK1IP1) could be used as prognostic biomarkers. We also evaluated whether the completion of cisplatin treatment and radiotherapy could predict survival in combination with pH2AX.We found that the dose of cisplatin received but not the length of the radiotherapy influenced LDS. High-pH2AX expression was associated with prolonged LDS (HR 0.26, p = 0.02) while MAP17 correlated with overall survival (OS) (HR 0.98, p = 0.05). High-MAP17 and high-pH2AX combined analysis showed improved LDS (with 61.35 months vs 32.2 months, p = 0.05) and OS (with 66.6 months vs 39.8 months, p = 0.01). Furthermore, the subgroup of high-pH2AX and optimal dose of cisplatin was also associated with OS (72 months vs 38.6 months, p = 0.03) and LDS (66.9 months vs 27 months, p = 0.017). These findings suggest that pH2AX alone or better in combination with MAP17 may become a novel and valuable prognostic biomarker for patients with laryngeal carcinoma treated with preservation approaches.

Preoperative platelet to lymphocyte ratio is a valuable prognostic biomarker in patients with colorectal cancer.

ObjectivesRecent studies suggest that an elevated preoperative platelet to lymphocyte ratio (PLR) may be considered a poor prognostic biomarker in patients with colorectal cancer (CRC). The aim of this study was to evaluate the prognostic impact of PLR in patients with CRC.MethodsWe enrolled 1314 patients who underwent surgery for CRC between 2005 and 2011. Preoperative PLR level was stratified into quintiles for Kaplan-Meier analysis and multivariable Cox proportional hazard regression models.ResultsHigher PLR quintiles were significantly associated with poorer overall survival (P = 0.002). Multivariate analysis showed that PLR was an independent risk factor for overall survival (OS) (P = 0.034). Patients in PLR quintile 5 had lower overall survival than in quintile 1 (hazard ratio (HR) = 1.701, 95% confidence interval (CI): 1.267–2.282, P < 0.001). Although patients in PLR quintile 5 had significantly lower disease-free survival (DFS) than in quintile 1 (HR = 1.522, 95% CI: 1.114–2.080, P = 0.008), this association was not significant after multivariable adjustment (P = 0.075). In the subgroup analysis, PLR remained an independent factor in terms of advanced tumor stage (III, IV), male sex, carcinoembryonic antigen (≤ 5 ng/ml), age (> 65 years) and body mass index (≤ 25) (P < 0.05 for all measurements). The results remained unchanged when the PLR was analyzed as a dichotomous variable by applying different cut-off values of 150, 185, 220.ConclusionsElevated preoperative PLR was independently associated with an increased risk of mortality in patients with CRC. The utility of PLR may help to improve prognostic predictors.

Pronecrotic Mixed Lineage Kinase Domain-Like (MLKL) Protein Expression Is a Prognostic Biomarker in Patients With Resected Pancreatic Adenocarcinoma

Mixed lineage kinase domain like protein (MLKL) is a necrosome component that mediates necrosis signaling and may play a role in cancer response to therapy. Our goal in this analysis was to evaluate MLKL as a novel prognostic factor in pancreatic adenocarcinoma (PAC) using immunohistochemistry (IHC) staining of resected PAC specimens. Eighty patients with tissue available for analysis were identified from a prospectively maintained database of patients undergoing resection for pancreas adenocarcinoma between January 2000 and October 2008. IHC analysis was performed for expression of MLKL in these resection specimens and scored using a previously established scoring system. Kaplan-Meier (KM) survival curves were generated for recurrence-free survival (RFS) and overall survival (OS) for all patients and for patients receiving adjuvant therapy. MLKL scores were correlated with RFS and OS using univariate (UV) and multivariate (MV) Cox regression analyses incorporating clinically relevant covariates. Median RFS and OS for all patients were 9.3 months (range, 0.6-110 months) and 15.4 months (range, 2.8-115 months), respectively. Twenty patients (24.5%) had positive margins and 48 (60%) had positive lymph nodes. Fifty-nine patients had adjuvant chemotherapy and only 2 patients had neoadjuvant chemotherapy. The most common chemotherapy agent utilized was gemcitabine (GEM) (n = 31 of 59; 52.5%) and most patients receiving adjuvant chemotherapy also received radiation therapy (39 of 59; 66.1%). On Kaplan-Meier analysis, low MLKL expression was associated with decreased OS (6 months vs 17 months; p = .006) in all patients. In the subset of patients receiving adjuvant chemotherapy, low MLKL expression was associated with decreased RFS (5 months vs 15 months; p = .006) in addition to decreased OS (6 months vs 19 months; p < .0001). On MV analysis after accounting for widely accepted adverse tumor characteristics, low MLKL expression remained a significant predictor of decreased OS in all patients (HR, 4.6; 95% CI, 1.6-13.8; p = .006) and of decreased RFS (HR, 6.4; 95% CI, 1.2-34.0; p = .03) and OS (HR, 3.9; 95% CI, 1.01-27.7; p = .048) in patients receiving adjuvant therapy (n = 59). In a subset of patients receiving GEM-based therapy (n = 31), low MLKL expression remained associated with decreased RFS (HR, 6.4; 95% CI, 1.2-34.0; p = .03) and OS (HR, 3.9; 95% CI, 1.01-27.7; p = .048). Low expression of MLKL is associated with significantly worse OS in all patients with early stage resected PAC. In patients receiving adjuvant therapy and in patients receiving gemcitabine-based adjuvant therapy, low MLKL expression is significantly associated with both decreased RFS and OS. MLKL may be a valuable prognostic biomarker in patients receiving adjuvant therapy may be helpful in personalizing pancreatic cancer therapy.