Longer Cancer-specific Survival Research Articles

Comparison of patients with renal cell carcinoma in adjuvant therapy trials to a real-world population.

To compare characteristics and outcomes of patients included versus those not in adjuvant therapy trials post complete resection of renal cell carcinoma (RCC). Adult patients following complete resection for clear cell RCC between January 1, 2011, and March 31, 2021, were included. Patients had intermediate high, high risk nonmetastatic disease (modified UCLA Integrated Staging System) or fully resected metastatic (M1) disease as per the inclusion criteria of adjuvant studies. Demographic, clinical, and outcomes between trial and nontrial patients were compared. Of 1,459 eligible patients, 63 (4.3%) participated in an adjuvant trial. Disease characteristics were similar between groups. Trial patients were younger (mean age 58.1 vs. 63.6 years; P < 0.0001) and had lower Charlson Comorbidity Index scores (mean 4.2 vs. 4.9; P = 0.009). Unadjusted disease-free survival (DFS) at 5 years for trial patients was 48.6% and 39.2% for nontrial patients (HR 0.71, 0.48-1.05, P = 0.08). Median DFS was higher for trial patients in comparison to nontrial patients (4.4 years, IQR 1.7- not reached; vs. 3.0 years, IQR 0.8-8.6; P = 0.08). Cancer specific survival (CSS) at 5 years for trial patients was 85.2% in comparison to 78.6% for nontrial patients (HR 0.45, 0.22-0.92, P = 0.03). Unadjusted estimated overall survival (OS) at 5 years was 80.8% for trial patients and 74.8% (HR 0.42, 0.18-0.94; P = 0.04) for nontrial patients. Patients in adjuvant trials were younger and healthier with longer CSS and OS in comparison to those not included in adjuvant trials. These findings may have implications when we generalize trial results to real world patients.

Spatially resolved multimarker evaluation of CD274 (PD-L1)/PDCD1 (PD-1) immune checkpoint expression and macrophage polarisation in colorectal cancer

BackgroundThe CD274 (PD-L1)/PDCD1 (PD-1) immune checkpoint interaction may promote cancer progression, but the expression patterns and prognostic significance of PD-L1 and PD-1 in the colorectal cancer microenvironment are inadequately characterised.MethodsWe used a custom 9-plex immunohistochemistry assay to quantify the expression patterns of PD-L1 and PD-1 in macrophages, T cells, and tumour cells in 910 colorectal cancer patients. We evaluated cancer-specific mortality according to immune cell subset densities using multivariable Cox regression models.ResultsCompared to PD-L1– macrophages, PD-L1+ macrophages were more likely M1-polarised than M2-polarised and located closer to tumour cells. PD-L1+ macrophage density in the invasive margin associated with longer cancer-specific survival [Ptrend = 0.0004, HR for the highest vs. lowest quartile, 0.52; 95% CI: 0.34–0.78]. T cell densities associated with longer cancer-specific survival regardless of PD-1 expression (Ptrend < 0.005 for both PD-1+ and PD-1– subsets). Higher densities of PD-1+ T cell/PD-L1+ macrophage clusters associated with longer cancer-specific survival (Ptrend < 0.005).ConclusionsPD-L1+ macrophages show distinct polarisation profiles (more M1-like), spatial features (greater co-localisation with tumour cells and PD-1+ T cells), and associations with favourable clinical outcome. Our comprehensive multimarker assessment could enhance the understanding of immune checkpoints in the tumour microenvironment and promote the development of improved immunotherapies.

A prognostic score based on B cell and plasma cell densities compared to T cell densities in colorectal cancer

PurposeThe purpose of this study was to compare a B cell/plasma cell–based scoring system to T cell score and evaluate their prognostic value in colorectal cancer.MethodsWe used immunohistochemistry to analyze the expression of CD20, CD138, CD3, and CD8 in 221 colorectal cancer patients. CD20+ B cell and CD138+ plasma cell densities in the tumor center and invasive margin were calculated and converted into a B cell/plasma cell score. T cell score was defined similarly, using CD3+ and CD8+ T cell densities. Their associations with tumor and patient characteristics and survival were analyzed.ResultsKaplan–Meier analysis showed a high B cell/plasma cell score was associated with a tendency towards longer survival (p = 0.089), but no statistically significant association was found. High T cell score associated with longer cancer-specific survival in Kaplan–Meier analysis and multivariable Cox regression analysis (p < 0.001). Additionally, high T cell score associated with lower disease stage (p < 0.001) and lesser lymphovascular invasion (p = 0.020).ConclusionsHigh T cell score is associated with longer survival and clinicopathological factors typical to less aggressive tumors. This study did not support the additional prognostic value of B cell/plasma cell quantification.

Impact of Metastasectomy on Cancer Specific and Overall Survival in Metastatic Renal Cell Carcinoma: Analysis of the REMARCC Registry.

Treatment paradigms for management of metastatic renal cell carcinoma (mRCC) are evolving. We examined impact of surgical metastasectomy on survival across in mRCC stratified by risk-group. Multicenter retrospective analysis from the Registry of Metastatic RCC database. The cohort was subdivided utilizing Motzer criteria (favorable-, intermediate-, high-risk). Primary outcome was all-cause mortality (ACM)/overall survival (OS); secondary outcome was cancer-specific mortality (CSM)/cancer-specific survival (CSS). Impact of metastasectomy was analyzed via Cox-Regression analysis adjusting for potential prognostic variables and Kaplan-Meier analysis (KMA) within each risk-group. Four hundred thirty-one patients (59 favorable-risk, 274 intermediate-risk, 98 high-risk; median follow-up 27.2 months) were analyzed. Metastasectomy was performed in 22 (37%), 66 (24%), and 32 (16%) of favorable-, intermediate- and high-risk groups (P=.012). Median number of metastases at diagnosis differed significantly (favorable-risk 2, intermediate-risk 3.4, high-risk 5.1, P < .001). On Cox-regression, high-risk (HR=1.72, P=.002) was associated with worsened ACM, while metastasectomy was associated with improved ACM (HR=0.56, P=.005). On KMA, median OS (months) was longer with metastasectomy in favorable- (92.7 vs. 25.8, P=.003) and intermediate-risk (26.3 vs. 20.1, P=.038), but not high-risk (P=.911) groups. Metastasectomy was associated with longer CSS in favorable- (76.1 vs. 32.8, P=.004) but not intermediate- (P=.06) and high-risk (P=.595) groups. Metastasectomy was independently associated with improved ACM and CSM, as well as improved CSS and OS in favorable- and intermediate-risk mRCC patients. Metastasectomy may be considered as component of multimodal management strategy in favorable and intermediate-risk subgroups. In high-risk patients, metastasectomy should be deferred except in select circumstances.

Oncological outcomes from surgical vs. non-surgical treatments for advanced hypopharyngeal squamous cell carcinoma: a surveillance, epidemiology, and end results-based study.

Patients with advanced hypopharyngeal squamous cell carcinomas (HSCCs) have poor prognoses. The use of surgical or non-surgical treatments for these patients remains a topic of debate. This study compared survival following surgical and non-surgical treatments of patients with advanced HSCC based on the Surveillance, Epidemiology and End Results (SEER) database. Patients diagnosed with hypopharyngeal cancer from 2004 to 2018 were identified from the SEER database. Patients were divided into non-surgical group and surgical group, and patients in the surgical group were further divided into three groups: surgery-only, surgery with adjuvant radiation therapy and surgery with adjuvant chemoradiation therapy. The primary endpoint was overall survival (OS), and the secondary outcome was cancer-specific survival (CSS). Outcomes were analyzed using Kaplan-Meier analysis. A multivariate Cox regression analysis was also used to identify independent prognostic factors. The records of 1568 eligible patients with stage III or IV HSCC were examined. Receipt of surgery was associated with a longer OS [hazard ratio (HR) = 0.47, 95% confidence interval (CI): 0.4-0.56] and a longer CSS (HR = 0.47, 95% CI: 0.38-0.57) after adjusting for age, sex, race, tumor site, tumor size, tumor grade, TNM stage, AJCC stage, number of carcinomas, prior cancer, receipt of radiotherapy, and receipt of chemotherapy. The results for OS were similar in an exploratory analysis of different patient subgroups. Among patients with advanced HSCC in the SEER database, treatment with surgery was associated with longer OS and CSS than treatment with a non-surgical modality.

Cancer immunohistogram representing cancer-immunity cycle by immunohistochemistry predicts the efficacy of immune checkpoint inhibitors in urological cancer patients

We developed an immunohistogram representing an individual cancer-immunity cycle based on immunohistochemical analyses. We evaluated its ability to predict the efficacy of immune checkpoint inhibitors (ICI) in 11 patients with urothelial carcinoma and 7 patients with renal cell carcinoma who underwent surgery and received ICIs for disease recurrence. Immunohistochemical analyses for CD8, TIA-1, HLA class I, HLA-DR, and PD-L1 were performed and scored 0–3. T-cell infiltration pattern was classified into desert, excluded, partially inflamed, and inflamed. Tumors with an inflamed or partially inflamed pattern and positive scores (score ≥ 1) for all five immune markers were classified as “immune-hot” and others as “immune-cold.” Association between the immunohistogram and ICI treatment efficacy was evaluated with objective response rate, disease control rate (DCR), progression-free survival (PFS), and cancer-specific survival (CSS). Eight (44%) and 10 (56%) patients had immune-hot and immune-cold tumors, respectively. Immune-hot tumors showed a higher DCR (100% vs. 40%, p < 0.01), longer PFS (median unreached for hot, 1.3 months for cold, p < 0.01), and longer CSS (median unreached for hot, 3.3 months for cold, p < 0.01) than immune-cold tumors. The immunohistogram could be clinically useful as an accessible biomarker for precision cancer immunotherapy in urological cancer.

Prognostic significance of spatial and density analysis of T lymphocytes in colorectal cancer

BackgroundAlthough high T cell density is a strong favourable prognostic factor in colorectal cancer, the significance of the spatial distribution of T cells is incompletely understood. We aimed to evaluate the prognostic significance of tumour cell-T cell co-localisation and T cell densities.MethodsWe analysed CD3 and CD8 immunohistochemistry in a study cohort of 983 colorectal cancer patients and a validation cohort (N = 246). Individual immune and tumour cells were identified to calculate T cell densities (to derive T cell density score) and G-cross function values, estimating the likelihood of tumour cells being co-located with T cells within 20 µm radius (to derive T cell proximity score).ResultsHigh T cell proximity score associated with longer cancer-specific survival in both the study cohort [adjusted HR for high (vs. low) 0.33, 95% CI 0.20–0.52, Ptrend < 0.0001] and the validation cohort [adjusted HR for high (vs. low) 0.15, 95% CI 0.05–0.45, Ptrend < 0.0001] and its prognostic value was independent of T cell density score.ConclusionsThe spatial point pattern analysis of tumour cell-T cell co-localisation could provide detailed information on colorectal cancer prognosis, supporting the value of spatial measurement of T cell infiltrates as a novel, robust tumour-immune biomarker.

Spatial Organization and Prognostic Significance of NK and NKT-like Cells via Multimarker Analysis of the Colorectal Cancer Microenvironment.

Although tumor-infiltrating T cells hold a beneficial prognostic role in colorectal cancer, other lymphocytic populations are less characterized. We developed a multiplexed immunofluorescence assay coupled with digital image analysis and machine learning to identify natural killer (NK) cells (NCAM1+CD3-), natural killer T-like (NKT-like) cells (NCAM1+CD3+), and T cells (NCAM1-CD3+) within the PTPRC+ (CD45+) cell population and to measure their granzyme B (GZMB; cytotoxicity marker) and FCGR3A (CD16a; NK-cell maturity marker) expression. We evaluated immune cell densities and spatial configuration in 907 incident colorectal carcinoma cases within two prospective cohort studies. We found that T cells were approximately 100 times more abundant than NK and NKT-like cells. Overall, NK cells showed high GZMB expression and were located closer to tumor cells than T and NKT-like cells. In T and NKT-like cells, GZMB expression was enriched in cells in closer proximity to tumor cells. Higher densities of both T and NKT-like cells associated with longer cancer-specific survival, independent of potential confounders (P trend < 0.0007). Higher stromal GZMB+ and FCGR3A+ NK-cell densities associated with longer cancer-specific survival (P trend < 0.003). For T and NKT-like cells, greater proximity to tumor cells associated with longer cancer-specific survival (P trend < 0.0001). These findings indicate that cytotoxic NCAM1+CD3-GZMB+ NK cells and NCAM1+CD3+ NKT-like cells are relatively rare lymphocytic populations within the colorectal cancer microenvironment and show distinct spatial configuration and associations with patient outcome. The results highlight the utility of a quantitative multimarker assay for in situ, single-cell immune biomarker evaluation and underscore the importance of spatial context for tumor microenvironment characterization.

Distinguishing optimal esophagectomy candidates in elderly patients: A nomogram based on propensity score matching

BackgroundA survival benefit from esophagectomy was observed in elderly patients. But it's unclear how to identify specific patients who can benefit. Thus, we aimed to establish a predictive model to identify optimal candidates for esophagectomy. MethodsPatients (age ≥75 years) with esophageal cancer in Surveillance, Epidemiology and End Results (SEER) database were used to establish the predictive model. Propensity-score matching (PSM) was applied to eliminate the imbalance between esophagectomy group and non-esophagectomy group. We hypothesized that elderly patients could benefit from esophagectomy with longer cancer specific survival (CSS) time than those who did not receive esophagectomy. Patients received surgery were divided into beneficial group and non-beneficial group according to the median CSS time of non-esophagectomy group. Prognostic factors affecting patients’ long-term survival were identified. Among esophagectomy group, a logistic regression model based on these factors was established to build a nomogram. ResultsA total of 7,025 eligible patients were extracted from the SEER database, with 831 patients received esophagectomy. Surgery was independently associated with better long-term survival (median CSS time in the matched population: 35 vs. 8 months, p < 0.001). As a result, 361 (68.6%) patients were divided into beneficial group (CSS >8 months). Factors including age, tumor site, histology, differentiation grade, TNM stage, and tumor size were used to formulate the nomogram, which was named as esophagectomy candidates screening score (ECSS). The validation from two aspects showed the model a useful and stable one. ConclusionA predictive model was established to distinguish optimal candidates for esophagectomy among elderly patients with EC.

The platelet to lymphocyte ratio is a potential inflammatory marker predicting the effects of adjuvant chemotherapy in patients with stage II colorectal cancer

BackgroundThe effects of adjuvant chemotherapy in patients with stage II colorectal cancer (CRC) has been in controversy for a long time. Our study aimed to find an effective inflammatory marker to predict the effects of chemotherapy.MethodsSeven hundred eight stage II CRC patients in our institution were included. The subpopulation treatment effect pattern plot (STEPP) analysis was used to determine the optimal inflammatory marker and cut-off value. Propensity score matching (PSM) was performed to balance discrepancy between the chemotherapy and non-chemotherapy group. Survival analyses based on overall survival (OS) and cancer-specific survival (CSS) were performed with Kaplan-Meier methods with log-rank test and Cox proportional hazards regression. The restricted mean survival time (RMST) was used to measure treatment effect.ResultsThe platelet to lymphocyte ratio (PLR) was chosen as the optimal marker with a cut-off value of 130 according to STEPP. In OS analysis, PLR was significantly associated with the effects of chemotherapy (interaction p = 0.027). In the low-PLR subgroup, the chemotherapy patients did not have a longer OS than the non-chemotherapy patients (HR: 0.983, 95% CI: 0.528–1.829). In the high-PLR subgroup, the chemotherapy patients had a significantly longer OS than the non-chemotherapy patients (HR: 0.371, 95% CI: 0.212–0.649). After PSM, PLR was still associated with the effects of chemotherapy. In CSS analysis, PLR was not significantly associated with the effects of chemotherapy (interaction p = 0.116). In the low-PLR subgroup, the chemotherapy patients did not have a longer CSS than the non-chemotherapy patients (HR: 1.016, 95% CI: 0.494–2.087). In the high-PLR subgroup, the chemotherapy patients had a longer CSS than the non-chemotherapy patients (HR: 0.371, 95% CI: 0.212–0.649). After PSM, PLR was not associated with the effects of chemotherapy.ConclusionsPLR is an effective marker to predict the effects of chemotherapy in patients with stage II CRC.

Distinct effect of body mass index by sex as a prognostic factor in localized renal cell carcinoma treated with nephrectomy ~ data from a multi-institutional study in Japan ~

BackgroundWe assessed the prognostic value of body mass index (BMI) in Asian patients with localized RCC who underwent nephrectomy.MethodsA total of 665 patients who underwent nephrectomy for localized RCC were enrolled in the present study and divided into the two BMI groups: i.e., BMI < 25 in 463 (69.6%) and BMI > 25 in 202 (30.4%) patients.ResultsIn total, there were 482 (72.5%) males and 183 (27.5%) females. Five-year cancer-specific survival (CSS) rates were significantly higher in increased BMI than the lower BMI group (97.1 and 92.5%: P = 0.007). When stratified by sex, significantly longer CSS in higher BMI was confirmed in males (5-year CSS of 92.7% in BMI < 25 and 98.1% in BMI > 25, p = 0.005), while there was no difference in CSS between BMI groups for female patients. Multivariable analysis exhibited that higher BMI was an independent predictor for favorable CSS in male (cox model: p = 0.041, Fine & Gray regression model: p = 0.014), but not in the female. Subgroup analysis for CSS revealed that favorable CSS with higher BMI was observed in patient subgroups of age < 65 (p = 0.019), clear cell histology (p = 0.018), and tumor size > 4 cm, p = 0.020) as well as male (p = 0.020).ConclusionOur findings collected from the multi-institutional Japanese dataset demonstrated longer survival in patients with higher BMI than lower BMI for non-metastatic RCC treated with nephrectomy. Intriguingly, this finding was restricted to males, but not to females.

Disease course of lung oligometastatic colorectal cancer treated with stereotactic body radiotherapy.

Stereotactic body radiotherapy (SBRT) or stereotactic ablative radiotherapy (SABR) has been shown to increase survival rates in oligometastatic disease (OMD), but local control of colorectal metastases remains poor. We aimed to explore the natural course of oligometastatic colorectal cancer and to investigate how SBRT of lung metastases can delay the progression to polymetastatic disease (PMD). 107 lung oligometastases in 38patients were treated with SBRT at asingle institution. The median number of treated lesions was 2 (range1-5). Time to PMD (ttPMD) was defined as the time from SBRT to the occurrence of >5new metastases. Genetic biomarkers such as EGFR, KRAS, NRAS, BRAF, and microsatellite instability were investigated as predictive factors for response rates. Median follow-up was 28months. At median follow-up, 7patients were free from disease and 31had progression: 18patients had sequential oligometastatic disease (SOMD) and 13polymetastatic progression. All SOMD cases received asecond SBRT course. Median progression-free survival (PFS) was 7months (range 4-9months); median ttPMD was 25.8months (range 12-39months) with 1‑ and 2‑year PFS rates of 62.5% and 53.4%, respectively. 1‑ and 2‑year local PFS (LPFS) rates were 91.5% and 80%, respectively. At univariate analysis, BRAF wildtype correlated with better LPFS (p = 0.003), SOMD after primary SBRT was associated with longer cancer-specific survival (p = 0.031). Median overall survival (OS) was 39.5months (range 26-64months) and 2‑year OS was 71.1%. The present results support local ablative treatment of lung metastases using SBRT in oligometastatic colorectal cancer patients, as it can delay the transition to PMD. Patients who progressed as SOMD maintained asurvival advantage compared to those who developed PMD.

Effects of insurance status on long-term survival among non-small cell lung cancer (NSCLC) patients in Beijing, China: A population-based study.

ObjectiveTo evaluate the effects of health insurance status on long-term cancer-specific survival of non-small cell lung cancer (NSCLC) in Beijing, China, using a population-based cancer registry data.MethodsInformation on NSCLC patients diagnosed in 2008 was derived from the Beijing Cancer Registry. The medical records of 1,134 cases were sampled and re-surveyed to obtain information on potential risk factors. Poorly-insured status was defined as Uninsured and New Rural Cooperative Medical Insurance Scheme (NRCMS), while well-insured included Urban Employees Basic Medical Insurance (UEBMI) and Free Medical Care (FMC). To estimate survival outcomes, individuals were followed-up until December 31, 2018. Cancer-specific survival probabilities at 5 and 10 years after diagnosis were estimated using the Kaplan-Meier method. Log-rank test was used to compare long-term survival with different characteristics. Multivariable Cox proportional hazard regression model was used to examine the relative effect of insurance status on cancer-specific mortality.ResultsWell-insured NSCLC patients have longer cancer-specific survival than poorly-insured individuals [hazard ratio (HR)=0.81; 95% confidence interval (95% CI): 0.67−0.97), even after adjusting for age, gender, cancer stage, smoking status, family history and residential area. Older age and rural residence were associated with a higher risk of cancer-specific mortality (HR=1.03; 95% CI: 1.02−1.03 and HR=1.25; 95% CI: 1.07−1.46, respectively). Smoking individuals had a 41% higher long-term cancer-specific mortality risk than non-smoking ones (HR=1.41; 95% CI: 1.20−1.66).ConclusionsNSCLC patients with good insurance status had better survival rates than those with poor insurance. An association was significant even after 10 years. Large population-based studies are needed to validate that high reimbursement insurance status can lead to the improvement of long-term cancer prognosis in China.

Multispectral immunofluorescence and computational imaging analysis define the prognostic role of T-cell infiltrates in gastric cancer

Abstract Background Gastric cancer (GC) is the 3rd commonest cause of cancer mortality. T cells infiltrates are prognostic in other cancer types (Pages 2018) but most studies in GC have used manual counting, lacked a validation cohort and were performed in Asian patients with often better outcomes than Western patients. The prognostic role of T cells hence remains poorly established in Western GCs. Methods Tissue microarrays from 474 therapy naive GCs resected in Leeds, UK, were split into discovery and validation cohorts and stained using multispectral immunofluorescence for CD8 (cytotoxic-), CD45RO (memory-), FOXP3 (regulatory-T cells), cytokeratin and DAPI. T cell densities were measured by computational image analysis. GCs were assigned to 5 equal sized density classes (C1 low to C5 high) for each marker and cancer specific survival (CSS) was assessed. Results CD45RO (p = 0.000) and FOXP3 (p = 0.001) densities were significantly associated with CSS in the discovery cohort (n = 327). For both markers, C1 (low) and C5 (high) were associated with the shortest and longest CSS, respectively, C2 to C4 all showed similar CSS and were consolidated into an intermediate group. Reanalysis using low, intermediate and high groups showed significant associations of CD45RO (p = 0.024) and FOXP3 (p = 0.003) densities with CSS in the validation cohort (n = 147). TNM stage, CD45RO and FOXP3 densities were independent predictors of CSS in multivariate analysis of both cohorts. EBV positive (EBV+) and MMR deficient (dMMR) GCs are considered highly immunogenic GC subtypes. 20/475 GCs were EBV+ and 70% of these showed high CD45RO or FOXP3 densities. 51/488 were dMMR but only 38% were CD45RO or FOXP3 high, perhaps indicating the frequent acquisition of immune evasion mechanisms by dMMR GCs (von Loga 2019). Conclusion This study identified and validated CD45RO and FOXP3 T cell infiltrates as independent prognostic markers in Western GC patients. This may enable personalized follow up or (neo)adjuvant treatment strategies. Whether high infiltrates are predictive of immunotherapy benefit should be assessed. Unexpectedly, high FOXP3 densities were associated with longer CSS, warranting studies into the role regulatory T cells in GC. Legal entity responsible for the study Marco Gerlinger. Funding National Institute for Health Research and Biomedical Research Council - Royal Marsden Hospital, Cancer Research UK, Schottlander Foundation. Disclosure All authors have declared no conflicts of interest.

PI3K/AKT Signaling in Breast Cancer Molecular Subtyping and Lymph Node Involvement.

Lymph node metastatic involvement persists to be among the most important predictors of recurrence and survival in breast carcinoma (BC). This study is aimed at investigating possible gene expression differences in primary BC between patients with or without lymph node involvement at the time of diagnosis. In a retrospective study, we investigated the potential prognostic role of 9 candidate biomarkers at the mRNA level in a cohort of 305 breast cancer patients, 151 lymph node-negative (LN-) and 154 lymph node-positive (LN+) individuals. The analyzed genes belonged to the RAS pathway (RAF1, ERBB2, PIK3CB, AKT1, AKT2, and AKT3), RB pathway (RB1 and CDK2), and cellular differentiation (KRT8). Their expression profiles were investigated by RT-qPCR and were correlated to immunohistochemically based molecular subtypes and BC clinical and pathological features. The differential expression of several genes in the primary tumor tissue was related to the LN involvement. Some of those genes, including PIK3CB, RB1, and AKT3, were more expressed in LN- BC patients, while some others, notably ERBB2 and AKT1, in LN+ ones. Among the candidate biomarkers, the expression levels of AKT isoforms influenced also patients' survival rates. In detail, higher expression levels of AKT1 and AKT2 negatively influenced overall patients' survival, and in particular, AKT2 expression levels defined a group of luminal B BC patients with shorter cancer-specific survival. On the contrary, longer cancer-specific survival was recorded in luminal A BC patients with higher expression levels of AKT3. That finding was also confirmed by Cox multivariate analysis. The same AKT3 resulted to be a possible candidate predictive biomarker for Tamoxifen response. In conclusion, our study highlighted the complex regulation of the PI3K/AKT pathway in BC and its differences in BC patients with and without lymph node involvement.

Partial penectomy or total penectomy for T1 and T2 squamous cell carcinoma of the penis

Background: To assess prognostic factors and survival outcomes for partial penectomy (PP) and total penectomy (TP) patients with T1 and T2 squamous cell carcinoma of the penis. Methods: The Surveillance, Epidemiology, and End Results (SEER) database was used to identify 708 penile cancer patients. Among these, 607 underwent PP and 101 underwent TP. Kaplan-Meier analysis was used to compare survival outcomes between PP and TP patients. Univariate and multivariate Cox proportional hazards regression models were used to determine prognostic factors. Results: There were significant differences in marital status and regional lymph node removal between patients of the PP and TP groups. Multivariate regression analysis demonstrated that age [odds ratio (OR) =1.045; 95% confidence interval (CI): 1.034–1.057; P<0.0001], T2 carcinoma (OR =1.388; 95% CI: 1.077–1.788; P=0.0114), node stage N1–3 (OR =3.351; 95% CI: 2.317–4.847; P<0.0001), and ≥4 regional lymph nodes removed (OR =0.498; 95% CI: 0.255–0.972; P=0.0411) were independent predictors of overall survival (OS). Age (OR =1.019; 95% CI: 1.005–1.033; P=0.0065), stage N1–3 (OR =5.127; 95% CI: 3.213–8.181; P<0.0001), and ≥4 regional lymph nodes removed (OR =0.452; 95% CI: 0.219–0.932; P=0.0315) were independent predictors of cancer specific survival (CSS). However, there was no significant difference between PP and TP in terms of OS and CSS. Conclusions: There was no significant difference in terms of OS and CSS between patients treated by PP or TP. T2 was associated with shorter OS, while age and N1–3 were associated with shorter OS and CSS. Removal of ≥4 regional lymph nodes was associated with longer OS and CSS.

Clinicopathological and prognostic significance of MKK4 and MKK7 in resectable pancreatic ductal adenocarcinoma

Mitogen-activated protein kinase kinase 4 (MKK4) and mitogen-activated protein kinase kinase 7 (MKK7) were shown to regulate biological behavior in many malignancies. In pancreatic ductal adenocarcinoma (PDAC), it remains controversial whether MKK4 and MKK7 have pro-oncogenic or tumor-suppressive activities. Furthermore, their clinicopathological and prognostic implications are unknown. In the present study, we detected MKK4 and MKK7 expressions in the nucleus and cytoplasm of resected PDAC tissues from 321 patients by tissue microarray-based immunohistochemistry. Cytoplasmic MKK4 and MKK7 expressions were significantly downregulated, whereas nuclear MKK4 expression was significantly upregulated in tumor tissues compared with nontumor tissues. Tumor cytoplasmic MKK4 and MKK7 expressions were significantly negatively associated with histologic grade. Cytoplasmic MKK4 expression was also negatively correlated with CA19-9 level. By univariate analysis, high cytoplasmic MKK4 expression was significantly associated with longer cancer-specific survival (hazard ratio [HR], 0.705; 95% confidence interval, 0.510-0.974), with a similar trend observed for MKK7 expression. High MKK4 and MKK7 messenger RNA expressions were significantly associated with longer overall survival in The Cancer Genome Atlas database. Although MKK4 expression was not significant in a multivariate Cox regression analysis, combination of MKK4/MKK7 and pN stage was identified as an independent prognostic indicator and had the lowest HR (HR, 0.308; 95% confidence interval, 0.126-0.752). Furthermore, combined analysis of MKK4 and MKK7 greatly increased the prognostic predictive power. In addition, downregulation of MKK4 or MKK7 increased proliferation of pancreatic cancer cells in vitro. In conclusion, high MKK4 expression and its combination with high MKK7 expression both predicted favorable prognosis in resectable PDAC.

High CD169 expression in lymph node macrophages predicts a favorable clinical course in patients with esophageal cancer.

Recent findings indicate CD169-positive lymph node sinus macrophages (LySMs) in the regional lymph nodes (RLNs) play an important role in anti-cancer immunity. In the present study, we investigated the correlation between CD169 expression in RLNs and clinicopathologic factors. Higher CD169 expression in LySMs was significantly associated with longer cancer-specific survival (CSS). The density of tumor-infiltrating lymphocytes (TILs) in the cancer nest and CD169 expression on LySMs were positively associated in patients who underwent pretreatment. As CD169 expression is thought to reflect a high interferon signature in RLNs, we tried to identify immunity-related genes that are up-regulated by interferon in macrophages as well as CD169. Indoleamine 2,3-dioxygenase (IDO1) was found to be elevated by interferon, and expression of IDO1 was tested using immunohistochemistry. IDO1 expression on LySMs was positively correlated with CD169 expression; however, there was no significant correlation between IDO1 and clinicopathologic factors. These results suggest that high expression of CD169 in LySMs reflects a high potential for anti-cancer immune responses in esophageal cancer patients and that monitoring CD169 expression would be useful for evaluating the potential of anti-cancer immune reactions.

Total iron-binding capacity is a novel prognostic marker after curative gastrectomy for gastric cancer.

Patients with gastric cancer (GC) are affected by changes in iron status. Before surgery, GC patients are likely to have iron-deficiency anemia; and after gastrectomy, patients suffer from low nutritional status and low iron. This study investigated preoperative iron status associated with prognosis after curative gastrectomy for gastric cancer. We evaluated preoperative serum hemoglobin (Hgb), Fe and total iron-binding capacity (TIBC) in 298 patients who underwent curative gastrectomy for GC without preoperative chemotherapy, and analyzed these factors' associations with prognosis after surgery. Of the 298 patients, 129 (43.2%) had low Hgb levels, and 33 (11.1%) had low TIBC (< 260µg/dl) that was not associated with Hgb or Fe level. Patients with low TIBC were significantly associated with older age (≥ 65years old; P = 0.0085), low albumin (< 3.9g/dl; P = 0.0388) and high CRP (≥ 0.15mg/dl; P = 0.0018) in multivariate analysis. Low Fe (< 60µg/dl) was not associated with disease-free survival (DFS) or overall survival (OS); however, low Fe was associated with longer cancer-specific survival in Stage III GC patients (P = 0.0333). Both low Hgb and low TIBC were significantly associated with shorter DFS (Hgb: P = 0.0433; TIBC: P < 0.0001) and shorter OS (Hgb: P = 0.0352; TIBC: P < 0.0001). Low TIBC were significantly associated with shorter DFS (HR 2.167, 95% CI 1.231-3.639, P = 0.0086) and shorter OS (HR 2.065, 95% CI 1.144-3.570, P = 0.0173) in multivariate Cox hazard regression analysis. Preoperative serum TIBC level of GC patients who undergo curative gastrectomy is a novel prognostic marker in univariate and multivariate analyses.

Differential expression of the sirtuin family in renal cell carcinoma: Aspects of carcinogenesis and prognostic significance

ObjectivesSirtuins (1–7) are evolutionarily conserved NAD-dependent deacetylases that play an important role in carcinogenesis. However, their role in renal cell carcinoma (RCC) remains unclear. The objective of the present study was to examine the role of SIRTs in RCC carcinogenesis and prognosis. Materials and methodsParaffin-embedded specimens from 102 patients who underwent extirpative renal surgeries for renal masses between January 2004 and December 2010 were examined. SIRT expression was compared between RCC and adjacent normal kidney tissues by immunohistochemical staining. Survival differences and cancer-specific survival were analyzed with the Kaplan-Meier log-rank test and univariate and multivariate Cox regression analyses, respectively. ResultsSIRT1, SIRT3, and SIRT6 expression was significantly lower in RCC than in normal tissues (P = 0.001, P = 0.006, and P = 0.033, respectively), whereas the expression of other SIRT proteins did not differ significantly between the 2 tissues. SIRT3 expression was significantly associated with longer cancer-specific survival (HR = 0.133, P = 0.047), after adjusting for age, T stage, Fuhrman grade, Karnofsky performance status, and distant metastases. Kaplan-Meier analysis showed that patients with high-SIRT3 expression had relatively better survival than those with low-SIRT3 expression (P = 0.046, log-rank test). ConclusionsOur results provide preliminary evidence suggesting that SIRT1, SIRT3, and SIRT6 function as tumor suppressors in RCC. In particular, SIRT3 seems to have a favorable influence on the survival of patients with clear cell RCC.