Risk Of Poor Overall Survival Research Articles

Identification of gemcitabine resistance-related AHNAK2 gene associated with prognosis and immune infiltration in pancreatic cancer

PurposeGemcitabine is a basic chemotherapy drug for pancreatic cancer (PC), but resistance is common and causes tumor recurrence and metastasis. Therefore, it is significant to explore gemcitabine resistance-related molecules for individualized treatment and prognosis assessment of PC. MethodsIn this study, transcriptome sequencing and TCGA database analysis were performed, and a differentiated gene AHNAK2 was screened. MEXPRESS database, tissue microarray analysis, and CIBERSORT and TIMER databases were used to correlate AHNAK2 expression with clinicopathological features and prognosis and immune infiltration of PC. Enrichment analysis was used to investigate the significant biological processes associated with AHNAK2. ResultsAHNAK2 was highly expressed in gemcitabine-resistant cells. High expression of AHNAK2 increased the risk of poor overall survival (OS) and progression-free survival (PFS) in PC. Clinicopathologic analysis revealed that AHNAK2 correlated with KRAS, TP53 mutations, histologic type, short OS, N stage, and elevated CA199 levels in PC. Knockdown of AHNAK2 inhibited the ability of cell proliferation and colony formation and enhanced the toxic effect of gemcitabine in PC. Meanwhile, the knockdown of AHNAK2 expression enhanced cell-ECM adhesion, inhibited cell-cell adhesion, and downregulated the KRAS/p53 signaling pathway in PC. Furthermore, AHNAK2 was correlated with immune infiltration, especially B cells and macrophages. ConclusionsOur study unveils for the first time the pivotal role of AHNAK2 in PC, particularly its association with gemcitabine resistance, clinical prognosis, and immune infiltration. AHNAK2 not only drives the proliferation and drug resistance of PC cells by potentially activating the KRAS/p53 pathway but also significantly impacts cell-cell and cell- ECM adhesion. Additionally, AHNAK2 plays a crucial role in modulating the tumor immune microenvironment. These insights underscore AHNAK2's unique potential as a novel therapeutic target for overcoming gemcitabine resistance, offering new perspectives for PC treatment strategies.

Clinical significance of preoperative albumin and alkaline phosphatase in colorectal cancer: a systematic review and meta-analysis.

To investigate the association between preoperative serum levels of albumin (ALB) and alkaline phosphatase (ALP) with postoperative outcome in colorectal cancer (CRC) patients. A thorough literature search was conducted across Embase, PubMed, and Cochrane Library databases, identifying 20 eligible studies encompassing 61,296 participants. Studies were primarily observational and case-control in nature, with some randomized controlled trials also included. The random effects model was utilized to synthesize the effect sizes, while study quality was appraised using the Newcastle-Ottawa Scale and the Cochrane Risk of Bias Assessment Tool. Findings revealed that CRC patients with preoperative ALB levels below 3.5 g/dl were at an elevated risk for postoperative complications (OR = 2.56, 95% CI: 2.12-3.08), increased mortality (OR = 4.54, 95% CI: 2.02-10.20), and a poorer prognostic survival risk (HR = 2.09, 95% CI: 1.58-2.77). Additionally, elevated ALP levels were associated with a higher risk of poor overall survival (HR = 1.67, 95% CI: 1.44-1.94). However, publication bias was noted in some studies. Preoperative hypoalbuminemia and elevated ALP levels are significantly linked to adverse postoperative events and reduced survival in CRC patients, suggesting their potential as prognostic biomarkers.

Identification of ONECUT3 as a stemness-related transcription factor regulating NK cell-mediated immune evasion in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) has a dismal response to the current T cell-based immunotherapies, which is attributed to intratumoral heterogeneity caused by PDAC stem cells and lack of major histocompatibility complex class I required for neoantigen presentation. Although this scenario makes natural killer (NK) cells attractive candidates for immunotherapeutic agents targeting MHC-I-deficient cancer stem cells in heterogeneous PDACs, little is known about PDAC stem cell immunology. In our study, PDAC-specific datasets from public databases were collected for in-depth bioinformatic analysis. We found that the abundance of PDAC stemness negatively influenced the infiltration of NK cells and identified the transcription factor ONECUT3 enriched in PDACs with high stemness index scores and Pan-cancer Stemness Signature levels. A series of NK cell-targeted inhibitory immune checkpoints were highly expressed in ONECUT3high PDACs. The patient group with high levels of ONECUT3 expression had a high risk of poor overall survival, even if accompanied by high infiltration of NK cells. Furthermore, the prostanoid metabolic process was enriched in ONECUT3high PDACs with high levels of NK cell-targeted inhibitory immune checkpoints. ONECUT3 enriched in high-stemness PDACs possessed the potential to transcriptionally regulate the prostanoid metabolism-related genes. Our study reveals ONECUT3 as a candidate stemness-related transcription factor regulating NK cell-targeted inhibitory immune checkpoints in PDAC. ONECUT3-mediated prostanoid metabolism may regulate cancer stemness and immune evasion in PDAC. Synergistic inhibition of prostanoid metabolism may improve the efficacy of NK cell-based immunotherapies targeting intratumoral heterogeneity caused by PDAC stem cells.

Novel Machine Learning Algorithm Can Stratify Risk of Poor Overall Survival after Curative Resection of Colorectal Liver Metastases

Novel Machine Learning Algorithm Can Stratify Risk of Poor Overall Survival after Curative Resection of Colorectal Liver Metastases

Identification of CEACAM5 as a stemness-related inhibitory immune checkpoint in pancreatic cancer

Immunotherapy has emerged as a new cancer treatment modality. However, tumour heterogeneity can diminish checkpoint blockade response and shorten patient survival. As a source of tumour heterogeneity, cancer stem cells act as an indispensable reservoir for local recurrence and distant metastasis. Thus, precision immunotherapy targeting tumour heterogeneity requires a comprehensive understanding of cancer stem cell immunology. Our study aimed to identify stemness-related inhibitory immune checkpoints and relevant regulatory pathways in pancreatic cancer. Pancreatic cancer-specific datasets in The Cancer Genome Atlas and the Cancer Therapeutics Response Portal were collected for in-depth bioinformatic analysis. Differentially expressed genes between pancreatic cancers with high and low stemness index (mRNAsi) scores were compared to screen out inhibitory immune checkpoints. Survival analysis was used to predict the prognostic value of immune checkpoint plus immune infiltrate in patients with pancreatic cancer. The expression of stemness-related immune checkpoint across immune subtypes of pancreatic cancer was detected and gene set enrichment analysis was performed to figure out the relevant regulatory signallings. The abundance of cancer stemness predicted a low immunotherapy response to pancreatic cancer. The inhibitory immune checkpoint CEACAM5 that was enriched in pancreatic cancers with high mRNAsi scores also exhibited a strong correlation with invasive cell-enriched signature and Msi+ tumour-initiating cell-enriched signature. Levels of CEACAM5 expression were higher in the interferon-γ dominant immune subtype of pancreatic cancers that are characterized by high M1 macrophage infiltration. The patient group with high levels of CEACAM5 expression had a high risk of poor overall survival, even if accompanied by high infiltration of M1 macrophages. Furthermore, prostanoid and long-chain unsaturated fatty acid metabolic processes showed a significant association with cancer stemness and CEACAM5 expression. Our findings suggest that CEACAM5 is a candidate stemness-related innate immune checkpoint in pancreatic cancer, and is potentially regulated by prostanoid and long-chain unsaturated fatty acid metabolic processes. Immune checkpoint blockade of CEACAM5, which synergizes with inhibition of those regulatory pathways, may improve the efficacy of precision immunotherapy targeting tumour heterogeneity caused by cancer stem cells.

Clinical Implication of Preoperative Renal Function on Oncological Outcomes in Patients with Upper Tract Urothelial Carcinoma after Radical Nephroureterectomy.

This study aims to evaluate the impact of preoperative renal function on oncological outcomes in patients with upper tract urothelial carcinoma (UTUC) who underwent radical nephroureterectomy (RNU). We performed a retrospective analysis of patients who underwent RNU between 2000 and 2012 at six academic centers. The patients were stratified into two groups based on preoperative renal function: eGFR < 60 mL/min/1.73 m2 (chronic kidney disease; CKD) and eGFR ≥ 60 mL/min/1.73 m2 (non-CKD). We investigated oncological outcomes, including overall survival, cancer-specific survival, and progression-free survival dichotomized by preoperative renal function. Multivariable Cox proportional hazards regression was used to determine if preoperative CKD was associated with oncological outcomes. In total, 1733 patients were eligible for the present study (CKD = 707 and non-CKD = 1026). Significant differences were noted in the clinical and pathologic features among the two groups, including age, sex, tumor localization, pathological T stage, tumor grade, and number of patients who received adjuvant chemotherapy. The estimated five-year overall survival (79.4 vs. 67.5%, log-rank p < 0.001), cancer-specific survival (83.5 vs. 73.6%, log-rank p < 0.001), and progression-free survival (74.6 vs. 61.5%, log-rank p < 0.001) were significantly different between the two groups, longer in the non-CKD group. Upon multivariable analysis, preoperative CKD status was associated with increased risk of overall mortality, cancer-specific mortality, and progression (p = 0.010, p = 0.016, and p = 0.008, respectively). UTUC patients with preoperative CKD had a higher risk of poor overall survival, cancer-specific survival, and progression-free survival after RNU than those without CKD.

Correlation between RASSF1A Methylation in Cell-Free DNA and the Prognosis of Cancer Patients: A Systematic Review and Meta-Analysis.

Background Although the effects of methylation of the Ras association domain-containing protein 1 isoform A (RASSF1A) gene in cell-free DNA on the outcomes of patients with different types of cancer have been reported, the results are inconsistent. Objective: To explore the relationships between RASSF1A methylation in cell-free DNA and the outcomes of cancer patients. Methods The PubMed, Embase, and Web of Science databases were searched for papers related to this topic on December 8, 2021. The retrieved articles were screened by two independent researchers, following which the methodological quality of the selected studies was evaluated using the Newcastle-Ottawa Scale. Additionally, hazard ratios were calculated, and publication bias of the studies was determined using Egger's test. Results Nine relevant publications involving a combined total of 1254 patients with different types of cancer were included in this study. The combined results of the random effects models yielded a hazard ratio of 1.73 (95% confidence interval: 1.31, 2.29; P < 0.001), which suggested there was a significant association between RASSF1A methylation and overall survival, and patients with an RASSF1A methylation status had a significantly increased risk of total death. Moreover, the Egger test result suggested there was no significant publication bias among the included studies. Conclusions The methylation of RASSF1A in cell-free DNA in cancer patients was observably associated with an increased risk of poor overall survival.

Prognosis and clinicopathological characteristics of renal cell carcinoma: does bilateral occurrence influence overall and cancer-specific survival?

BackgroundTo compare clinicopathological characteristics and prognosis of bilateral and unilateral renal cell carcinoma.MethodsData from patients who had been diagnosed with renal cell carcinoma (RCC) and undergone radical nephrectomy (RN) from 2004 to 2014 were extracted from the Surveillance, Epidemiology, and End Results (SEER) registry. The χ2 test was used to compare relevant characteristics between patients with bilateral and unilateral RCC. Survival curves were generated by the Kaplan-Meier method and the log-rank test was used to compare overall survival (OS) and cancer-specific survival (CSS). Cox proportional hazards regression analysis was used to determine the risk factors for OS and CSS.ResultsThe study cohort comprised 41,573 patients. A nonlinear relationship between age and OS and CSS was identified with and without adjusting for potential factors. Threshold effect analysis revealed that ages 54 and age 74 were the turning points associated with changes in OS and CSS, respectively. Multivariate Cox regression analysis demonstrated that age category, race, grade, and T, N, and M stage were prognostic factors for OS and CSS of patients with RCC. Additionally, sex and pathology were significantly associated with OS.ConclusionsBilateral occurrence does not influence OS and CSS in patients with RCC who have undergone RN. The risk of poor OS and CSS was higher with greater age category, tumor grade, and T stage. Patients in different age categories (<54, ≥54 and <74, ≥74 years) may benefit from individualized attention and therapeutic strategies.

Deregulation of cell adhesion molecules is associated with progression and poor outcomes in endometrial cancer: Analysis of The Cancer Genome Atlas data.

Cell adhesion molecules (CAMs) determine the behavior of cancer cells during metastasis. Although some CAMs are dysregulated in certain types of cancer and are associated with cancer progression, to the best of our knowledge, a comprehensive study of CAMs has not been undertaken, particularly in endometrial cancer (EC). In the present study the expression of 225 CAMs in EC patients with various clinicopathological phenotypes were evaluated by statistical analysis using publicly available data from The Cancer Genome Atlas database. The Kaplan-Meier method, and univariate and multivariate Cox proportional hazards regression models were used for survival analyses. Among the differentially expressed CAMs that were associated with aggressive clinicopathological phenotypes, 10 CAM genes were independent prognostic factors compared with other clinicopathological prognostic factors, including stage, grade, age, lymph node status, peritoneal cytology and histological subtype. A total of six genes (L1 cell adhesion molecule, mucin 15, cell surface associated, cell adhesion associated, oncogene regulated, immunoglobulin superfamily member 9B, protocadherin 9 and protocadherin β1) were selected for integrative analysis. The six-gene signature was demonstrated to be an independent prognostic factor and could effectively stratify patients with different risks. Patients with more high-expression CAMs had a higher risk of poor overall survival (OS) rate. The mortality risk for patients with elevation of >4 CAMs was 11 times of that in those without elevation of these 6 CAMs. Similar results were obtained when relapse-free survival (RFS) time was used during the analysis. Prognostic reliability of the six-gene model was validated using data of an independent cohort from the International Cancer Genome Consortium. In conclusion, a combination of CAM alterations contributed to progression and aggressiveness of EC. The six-gene signature was effective for predicting worse OS and RFS in patients with EC and could be complementary to the present clinical prognostic criteria.

Weight Adjusted Urinary Creatinine Excretion Predicts Transplant Outcomes in Adult Patients with Acute Myeloid Leukemia in Complete Remission

Background: Sarcopenia, the loss of muscle mass, has been recognized as a prognostic factor for cancer patients. For example, low body mass index (BMI) was reported to be a risk of poor overall survival (OS) among allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. However, low BMI was not associated with high non-relapse mortality (NRM) rate, and BMI may not directly reflect the physical condition. (Bone Marrow Transplant. 2014;49:1505-12). To evaluate the clinical impact of the muscle volume on the prognosis of allo-HSCT recipients, other biomarkers that directly reflect muscle mass may be warranted. Urinary creatinine excretion (UCE) has been reported to estimate muscle mass and have prognostic value for kidney transplant patients (Transplantation. 2008;86:391-8.). There is no report to evaluate clinical impact of UCE on the prognosis of allo-HSCT recipients. Therefore, we retrospectively analyzed the association between pre-transplant UCE and the transplant outcomes. Methods: We included 173 adult patients with acute myeloid leukemia (AML) in complete remission (CR) who underwent first allo-HSCT from 2006 to 2017 at our institute and measured UCE before allo-HSCT. Concerned the possibility of urine storage failure, two patients with low total daily urine volume (&lt;0.5L/day) were excluded from this analysis. Therefore, we investigated the remaining 171 patients. In order to correct the physical disparities of individual patients, we evaluated the clinical impact of weight adjusted UCE (WA-UCE) ,i.e UCE / body weight [μmol/kg/day] (Intensive Care Med. 2018;44:1699-708.). We used receiver operating characteristics curve in order to determine the cutoff value of the WA-UCE and classified the patients into the high and low WA-UCE group. We evaluated transplant outcomes such as OS, progression-free survival (PFS), NRM, and cumulative incidence of relapse (CIR) between two groups. Results: The median age at allo-HSCT was 52 (range, 18-73) and there were more male patients (n=111) than female patients (n=60). Regarding cytogenetic risk, 15 (9.1%), 112 (65.8%), and 38 (23.0%) were categorized as favorable, intermediate, and poor risk, respectively (There were five patients without cytogenetic data). The median follow-up period of survivors was 704 (range, 9 to 3,857) days. We defined the cutoff value of the weight adjusted UCE as 148 μmol/kg/day in male and 128 μmol/kg/day in female. Among 171 patients, 90 patients (male = 59, female = 31) were in the high WA-UCE group and 81 patients (male = 52, female = 29) were in the low WA-UCE group. We found no significant differences between two groups in terms of the number of relapse before allo-HSCT, cytogenetic risks, conditioning regimens, hematopoietic cell transplantation comorbidity index, donor-recipient HLA matching, donor source, or estimated glomerular filtration rate. On the other hand, patient's age at allo-HSCT was significantly younger (low vs. high WA-UCE group: median, 53 [range, 18 - 73] vs. 48 [range, 19 - 68] years, P = 0.02) and BMI was lower (low vs. high WA-UCE group: median, 22.3 [range, 15.4 - 38.8] vs. 21.9 [range, 15.4 - 29.3] kg/m2, P = 0.003) in high WA-UCE group. In univariate analysis, we observed a significant difference in OS, PFS, and NRM between two groups (low vs. high WA-UCE group: 1-year OS, 60.1% vs. 80.9%, P &lt; 0.01; 1-year PFS, 54.1% vs. 70.9%, P = 0.02; 1-year NRM, 24.8% vs. 12.3%, P = 0.02) (Figure1). On the other hand, there was no significant difference in 1-year CIR between two groups (low vs. high WA-UCE group: 21.1% vs. 16.8%, P = 0.63). In our cohort, the low BMI (&lt; 18.5 kg/m2) was not significantly associated with OS, PFS, CIR, and NRM (low vs. high BMI group: 1-year OS, 77.6% vs. 69.9%, P = 0.51; 1-year PFS, 74.1% vs. 60.9%, P = 0.45; 1-year CIR, 14.8% vs. 19.5%, P = 0.02, 1-year NRM, 11.1% vs. 19.5%, P = 0.70) In multivariate analysis, the low WA-UCE was an independent risk factor for OS (Hazard ratio (HR) [95% confidence interval (CI)]; 2.29 [1.38 - 3.80], P &lt; 0.01), PFS (HR [95% CI]; 1.76 [1.11 - 2.79], P = 0.02), and NRM (HR [95% CI]; 2.22 [1.13 - 4.36], P = 0.02) (table1). Conclusion: In allo-HSCT adult recipients with AML in CR, low WA-UCE before transplantation was associated with poor prognosis, which related to high NRM within 1 year. WA-UCE can be an independent, objective, simple, and reliable biomarker for evaluating muscle mass and predicting transplant outcome. Disclosures No relevant conflicts of interest to declare.

Abstract 1564: Polymorphisms in nucleotide excision repair genes were associated with the survival of post-operative oral squamous cell carcinoma patients treated with adjuvant concurrent chemoradiotherapy

Abstract Background: The nucleotide excision repair (NER) pathway plays a major role in the repair of DNA damaged by exogenous agents including chemo-and radiotherapeutic agents. Thus, we investigate the association between key potentially functional single nucleotide polymorphisms (SNPs) in the NER pathway and clinical outcomes in oral squamous cell carcinoma (OSCC) patients treated with concurrent chemoradiotherapy (CCRT). Methods: Thirteen SNPs in five key NER genes were genotypes in 319 OSCC patients using iPLEX MassARRAY. Multivariate Cox proportional hazards models and Kaplan-Meier survival curves were used to estimate risk of death or recurrence. Results: Carriers of the XPC rs2228000 TT genotype showed a borderline significant increased risk for poor overall survival under the recessive model (hazard ratio [HR]=1.81, 95% confidence interval [CI]=0.99–3.29). The CC genotypes of ERCC5 rs17655 (HR=1.54, 95% CI=1.03–2.29) and ERCC1 rs735482 (HR=1.65, 95% CI=1.06–2.58) were associated with an increased risk for worse disease-free survival under the recessive model. In addition, participants carrying both CC genotype of ERCC5 rs17655 and ERCC1 rs735482 exhibited an enhanced susceptibility for recurrence (HR=2.60, 95% CI=1.11–6.09). However, no statistically significant interaction was observed between them. Conclusion: Our findings show that the ERCC5 rs17655 CC and ERCC1 rs735482 CC genotypes were associated with an increased risk for recurrence in OSCC patients treated with CCRT. Therefore, CCRT may not be beneficial and alternative treatments are required for them. Citation Format: Chih-Ching Yeh, Thomas Senghore, Huei-Tzu Chien, Wen-Chang Wang, You-Xin Chen, Chi-Kuan Young, Shiang-Fu Huang. Polymorphisms in nucleotide excision repair genes were associated with the survival of post-operative oral squamous cell carcinoma patients treated with adjuvant concurrent chemoradiotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1564.

&lt;p&gt;Clinicopathological impacts of c-Met overexpression in bladder cancer: evidence from 1,336 cases&lt;/p&gt;

Background: The clinicopathological impacts of c-Met overexpression in bladder cancer have been investigated in several studies with conflicting results. We performed this systematic review and meta-analysis to assess the pathologic and prognostic roles of c-Met status in bladder cancer patients.Methods: Eligible studies were searched and identified from the PubMed and China National Knowledge Infrastructure (CNKI) databases (up until October 4, 2018). The DerSimonian-Laird random-effects model was used to calculate the pooled risk estimates.Results: Eight studies including 1,336 bladder cancer cases were eventually included in this meta-analysis. We detected a significantly increased risk of poor overall survival (OS) associated with the high expression of c-Met (HR=2.42, 95% CI 1.36–4.32). There was no association between c-Met status and nuclear grade (OR=0.82, 95% CI 0.29–2.31) or tumor stage (OR=1.42, 95% CI 0.41–4.89).Conclusion: This study shows that the overexpression of c-Met in primary cancer tissues is associated with a worse OS in human bladder cancer. However, larger studies using standardized methods and criteria are warranted to verify these findings.

Polymorphisms in ERCC5 rs17655 and ERCC1 rs735482 Genes Associated with the Survival of Male Patients with Postoperative Oral Squamous Cell Carcinoma Treated with Adjuvant Concurrent Chemoradiotherapy.

The nucleotide excision repair (NER) pathway plays a major role in the repair of DNA damaged by exogenous agents, such as chemotherapeutic and radiotherapeutic agents. Thus, we investigated the association between key potentially functional single nucleotide polymorphisms (SNPs) in the NER pathway and clinical outcomes in oral squamous cell carcinoma (OSCC) patients treated with concurrent chemoradiotherapy (CCRT). Thirteen SNPs in five key NER genes were genotyped in 319 male OSCC patients using iPLEX MassARRAY. Cox proportional hazards models and Kaplan–Meier survival curves were used to estimate the risk of death or recurrence. Carriers of the XPC rs2228000 TT genotype showed a borderline significant increased risk of poor overall survival under the recessive model (hazard ratio (HR) = 1.81, 95% confidence interval (CI) = 0.99–3.29). The CC genotypes of ERCC5 rs17655 (HR = 1.54, 95% CI = 1.03–2.29) and ERCC1 rs735482 (HR = 1.65, 95% CI = 1.06–2.58) were associated with an increased risk of worse disease-free survival under the recessive model. In addition, participants carrying both the CC genotypes of ERCC5 rs17655 and ERCC1 rs735482 exhibited an enhanced susceptibility for recurrence (HR = 2.60, 95% CI = 1.11–6.09). However, no statistically significant interaction was observed between them. Our findings reveal that the ERCC5 rs17655 CC and ERCC1 rs735482 CC genotypes were associated with an increased risk of recurrence in male patients with OSCC treated with CCRT. Therefore, CCRT may not be beneficial, and alternative treatments are required for such patients.

Patterns of Ibrutinib Use, Discontinuation, and Hospitalization Among Patients with Chronic Lymphocytic Leukemia (CLL) in a US Healthcare Claims Database

Introduction:Current treatment options for CLL or small lymphocytic leukemia (SLL) include novel oral therapies that are taken until disease progression. Ibrutinib is approved in frontline and relapsed/refractory CLL and is the most common oral treatment since Food and Drug Administration approval in 2014. Despite favorable responses with ibrutinib, treatment discontinuation occurs (41-50%) (Mato et al. Haematologica 2018; Sharman et al. Blood 2017) and increases the risk of poor overall survival (Follows GA and UK CLL Forum. Poster Presentation 14th International Conference on Malignant Lymphoma Palazzo dei Congressi, Lugano Switzerland, 2017). Previous studies have reported that in addition to disease progression, intolerance and toxicity were primary reasons for discontinuation. However, hospitalizations have not been explored to date. This study used a large US claims database to evaluate ibrutinib treatment patterns and toxicity-related hospitalizations among patients with CLL.Methods:A retrospective analysis of Truven Health MarketScan® Commercial Claims Database was conducted. Patients were included if they initiated ibrutinib treatment (index) between 2/12/2014 and 3/31/2017 and were diagnosed with CLL or CLL along with SLL. Patients were excluded if they had other cancers, did not have at least 180 days of continuous enrollment pre-index (baseline), were treated with ibrutinib within this baseline period, or had less than 180 days of observation after ibrutinib initiation.Patients were categorized into 1 of 3 treatment cohorts: (1) those who had continuous ibrutinib claims without any gap (Users), (2) those who had a treatment gap, but had at least 1 ibrutinib claim after the gap (Retreated), and (3) those who completely discontinued ibrutinib treatment or switched to another treatment (Discontinued/Switched). A gap in treatment was defined as a period of ≥60 days after the end of treatment exposure (Mato et al. Cancer Biology & Therapy 2018). Patient demographics, time to first treatment discontinuation, and frequency of hospital-related adverse events (AEs) were determined for each cohort. AEs were obtained in the 60 days prior to the last ibrutinib claim (pre-discontinuation) and in the exposure period for the last claim plus 60 days after (post-discontinuation). AEs were assessed for the User cohort based on a proxy derived from a median time from initial treatment to discontinuation in the Retreated and Discontinued groups and using the +/- 60-day time window.Results:There were 714 patients included in the analyses. Most patients were male (69%) and the average age at CLL diagnosis was 55.8 years. There were 451 (63%) in the User cohort, 96 (13%) in the Retreated cohort, and 167 (24%) in the Discontinued/Switched cohort.The median time from ibrutinib initiation to end of study observation was 16.8 (6.0-44.2) months. The median time to ibrutinib discontinuation was 4.9 (1.0-40.4) and 6.0 (1.0-34.1) months for the Retreated and Discontinued/Switched cohorts, respectively. For the Retreated cohort, patients were off ibrutinib treatment for a median of 3.2 (2.0-32.0) months before restarting ibrutinib again. Among the Discontinued/Switched cohort, 61% discontinued ibrutinib treatment without receiving any further treatment and 39% switched to another treatment.Retreated and Discontinued/Switched cohorts had higher hospitalization rates compared to the User cohort. The 5 most common inpatient diagnoses were pneumonia, pancytopenia/neutropenia, fever, sepsis, and atrial fibrillation across both the Retreated and Discontinued/Switched cohorts (Table 1). Discontinued/Switched cohort were more likely to have any hemorrhage diagnosis for hospitalization (6%).Conclusion:Consistent with other studies (median follow-up of 17-20 months) (Mato et al. Haematologica 2018; Sharman et al. Blood 2017), the overall treatment discontinuation with ibrutinib in our study was approximately 37% with a median follow-up of 16.8 months. A limitation is that exact reasons for stopping treatment cannot be ascertained from claims data. However, patients who paused or stopped ibrutinib were more likely to have higher rates of hospital-related AEs than those who continued treatment. As treatment discontinuation is likely to occur during a long treatment exposure, oral agents with a finite duration of treatment and with better tolerability are needed for patients with CLL. DisclosuresTo:Genentech, Inc.: Employment, Other: May own stocks/stock options at Roche. Yeh:Genentech, Inc.: Employment, Other: May own stock/stock options at Roche. Biondo:Roche: Equity Ownership; Genentech, Inc.: Employment, Other: May own stocks/stock options at Roche. Masaquel:Genentech, Inc.: Employment, Other: May own stocks/stock options at Roche.

Hematopoietic lineage cell-specific protein 1 immunoreactivity indicates an increased risk of poor overall survival in patients with ovarian carcinoma.

Hematopoietic lineage cell-specific protein 1 (HS1) is a 75-kDa intracellular protein that is expressed primarily in hematopoietic cells. Several previous studies have demonstrated the association between HS1 expression and a poor prognosis in hematopoietic malignancies; however, in solid tumors, no studies not been reported. The present study examined the distribution and expression of HS1 in human epithelial ovarian carcinoma (EOC) to determine its clinical significance. Paraffin sections were obtained from EOC tissues and immunostained with HS1 antibody, and then the staining intensities were evaluated. Overall survival (OS) was determined using the Kaplan-Meier estimator method, and multivariate analysis was performed using the Cox proportional hazards analysis. In total, 195 patients with EOC (median age, 56 years) were enrolled into the present study. HS1 immunoreactivity was categorized based on expression levels: Low (89/195; 45.6%) and high (106/195; 54.4%). Results demonstrated no association between expression level(s) and any clinicopathological parameter including age, International Federation of Gynecology and Obstetrics (FIGO) staging, type of chemotherapy or type of surgery received. The 5-year OS rates of patients who demonstrated low (n=89) and high (n=106) HS1 expression were 90.4 and 66.7%, respectively. The OS times for patients with high HS1 expression were significantly shorter compared with those for patients exhibiting low HS1 expression (P=0.0065). Results obtained from the multivariate analysis demonstrated that the FIGO stage and the amount of HS1 expressed were significant independent prognostic markers for poorer OS (hazard ratio, 3.539; 95% confidence interval, 1.221-12.811; P=0.0187). High HS1 expression levels may serve as a useful biomarker in patients with EOC who are likely to exhibit an unfavorable clinical outcome.

Clinical and demographic characteristics among patients with urothelial carcinomas of the upper urinary tract and bladder in Taiwan

BackgroundUrothelial carcinoma (UC) is derived from the urothelium of the urinary tract, and includes cancers of the bladder, renal pelvis and ureter. The aim of this study was to investigate the clinical and demographic features among patients with bladder cancer and urothelial carcinoma of the upper urinary tract (UTUC) in Taiwan. MethodsThe present study recruited a total of 736 histopathologically confirmed UC cases, which consisted of 470 bladder cancer and 266 UTUC between September 1998 and December 2009. Clinical and demographic features were collected by an interview utilizing a structured questionnaire, and supplemented by medical chart review. This study was approved by institutional review boards of the collaborating hospitals. The multivariate Cox proportional hazards model was performed to investigate prognostic factors for disease-free survival (DFS) and overall survival (OS). All statistical analyses were performed using the Statistical Analysis Software for Windows, version 9.1 (SAS Institute, Cary, NC, USA). ResultsUTUC patients had higher proportions of advanced clinical stage (T2–4) and poor cell differentiation (G3). Bladder cancer patients with advanced clinical stages (T2–3 and T4) had increased risks of poorer OS (hazard ratio, HR = 1.7 and 3.9, respectively). UTUC patients with the advanced clinical stage (T4) had a significantly greater risk of poorer OS (HR = 8.7). Bladder cancer patients with a high grade (G2–3) had a significantly increased risk of poorer OS (HR = 3.8). ConclusionBased on the limited parameters and heterogeneous data, the present study merely observed that bladder cancer and UTUC patients with the higher tumor stage have a significant increased risk of poor overall survival. Therefore, the causal mechanisms of UC prognosis remained to be further explored in a larger population.

Programmed cell death-ligand 1 expression in surgically resected stage I pulmonary adenocarcinoma and its correlation with driver mutations and clinical outcomes

BackgroundProgrammed cell death-ligand 1 (PD-L1) is expressed in a group of cancers that may be suitable targets for specific immunotherapy. This study investigated the expression of PD-L1 in surgically resected stage I adenocarcinomas and correlated this with known major driver mutations and clinical outcomes. Materials and methodsOne hundred and sixty-three patients with surgically resected stage I adenocarcinomas were explored. Paraffin-embedded tumour sections were stained with PD-L1 antibody. Tumours with moderate-to-strong membrane staining in ⩾5% of tumour cells were scored as positive for PD-L1 overexpression. The driver mutation epidermal growth factor receptor (EGFR), Kirsten rat sarcoma viral oncogene homolog (KRAS), and v-raf murine sarcoma viral oncogene homolog B (BRAF) were examined by direct sequencing and anaplastic lymphoma kinsase (ALK) by immunohistochemistry. The correlations of PD-L1 expression with major driver mutations and clinicopathologic parameters were analysed. ResultsThe overall frequency of PD-L1 overexpression was 39.9% (65/163). PD-L1 had higher positive results in tumours with higher grade differentiation and vascular invasion and PD-L1 expression was not associated with the expressions of EGFR, KRAS, BRAF and ALK. Multivariate analysis revealed that abnormal carcinoembryonic antigen (CEA) and higher grade of differentiation were risk factors for poor relapse-free survival (RFS) and PD-L1 expression correlated with better RFS. Advanced pathologic stage was the independent risk for poor overall survival (OS). ConclusionsThe PD-L1 expression can be used as a prognostic indicator predictive of RFS in patients with surgically resected stage I lung adenocarcinomas. There may be a possibility for immunotherapy targeting the PD-L1 pathway in patients with lung adenocarcinoma in the future.

Rationale for using pathologic tumor dimensions and nodal status to subclassify surgically treated stage IB cervical cancer patients

Between 1969 and 1988, 401 patients were treated by radical hysterectomy and pelvic lymphadenectomy for Stage IB cervical carcinoma at the University of Alabama at Birmingham. In multivariate analysis, pathological tumor diameter ( P < 0.0001) and the presence of lymph node metastasis ( P = 0.0005) proved to be the dominant two histopathologic features that significantly correlated with overall survival. Although 5-year survival for the overall group was 85%, 5-year survival in patients with lesions >3.0 cm in diameter and with regional nodal metastasis was less than 30%. This discrepancy in survival in surgically treated early-stage cervical cancer patients supports a need for subcategorization by risk factors such as pathologic tumor dimensions and nodal status and for further investigation of alternative neoadjuvant and adjuvant therapies in those early-stage cervical cancer patients deemed at high risk for poor overall survival.