Including Node Status Research Articles

Novel Histopathological Biomarkers in Prostate Cancer: Implications and Perspectives.

Prostate cancer (PCa) is the second most frequently diagnosed cancer in men. Despite the significant progress in cancer diagnosis and treatment over the last few years, the approach to disease detection and therapy still does not include histopathological biomarkers. The dissemination of PCa is strictly related to the creation of a premetastatic niche, which can be detected by altered levels of specific biomarkers. To date, the risk factors for biochemical recurrence include lymph node status, prostate-specific antigen (PSA), PSA density (PSAD), body mass index (BMI), pathological Gleason score, seminal vesicle invasion, extraprostatic extension, and intraductal carcinoma. In the future, biomarkers might represent another prognostic factor, as discussed in many studies. In this review, we focus on histopathological biomarkers (particularly CD169 macrophages, neuropilin-1, cofilin-1, interleukin-17, signal transducer and activator of transcription protein 3 (STAT3), LIM domain kinase 1 (LIMK1), CD15, AMACR, prostate-specific membrane antigen (PSMA), Appl1, Sortilin, Syndecan-1, and p63) and their potential application in decision making regarding the prognosis and treatment of PCa patients. We refer to studies that found a correlation between the levels of biomarkers and tumor characteristics as well as clinical outcomes. We also hypothesize about the potential use of histopathological markers as a target for novel immunotherapeutic drugs or targeted radionuclide therapy, which may be used as adjuvant therapy in the future.

Screening of the novel immune-suppressive biomarkers of TMED family and whether knockdown of TMED2/3/4/9 inhibits cell migration and invasion in breast cancer

Transmembrane p24 trafficking protein (TMED) family members are implicated in several solid tumors, but their clinical relevance for breast cancer (BC) remains unclear. This study aimed to probe their prognostic values and relations with tumor immunity in BC. TMED family mRNA expression was assessed in five microarray datasets (GSE65212, GSE42568, GSE5364, GSE22820 and GSE45827) from Gene Expression Omnibus (GEO) database and invasive breast cancer (BRCA) cohort from The Cancer Genome Atlas (TCGA). Receiver operating characteristic (ROC) curve was performed to determine the predictive values of filtered members of the TMED family. The protein expressions of screen genes were validated by Clinical Proteomic Tumor Analysis Consortium (CPTAC) data from University of ALabama at Birmingham CANcer data analysis portal (UALCAN) and detected in the clinical specimens by western blot assay. Clinicopathologic variables were analyzed with bc-GenExMiner, and patient prognostic data were obtained with Kaplan-Meier Plotter. In vitro wound healing and invasion assays were performed on siRNA-transfected BC cell lines. TIMER 2.0, SangerBox, and ImmPort were used to evaluate tumor immune infiltration, immune checkpoints, and other immune-related genes. CbioPortal, Metascape, Expression2kinases, and LinkedOmics were used to explore gene regulatory network. BC tissues expressed TMED2/3/4/9 at a higher level than normal tissues, providing diagnostic potential. All the areas under the ROC curve for TMED2/3/4/9 were more than 0.7. TMED2/3/4/9 correlated with numerous clinical variables, including lymph node status, Scarff-Bloom-Richardson score (SBR), Nottingham Prognostic Index (NPI), estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER-2), and triple-negative breast cancer (TNBC) status, and their high expression predicted the poor prognosis of BC patients. TMED2/3/4/9 knockdown drastically inhibited the migratory and invasive capacities of MDA-MB-231 and HCC1937 cells. TMED2/3/4/9 expressions correlated negatively with the infiltration of tumor-suppressive immune cells such as CD8+ T cells, dendritic cells, and natural killer cells, and was inversely related to a variety of immune checkpoint genes, including programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte associated protein 4 (CTLA4). A set of kinases, transcription factors, and microRNAs (miRNAs) may regulate TMED2/3/4/9 abnormalities at the genome level. TMED2/3/4/9 may serve as diagnostic, prognostic, and immune-suppressive biomarkers in BC.

A Prospective Study to Assess the Toxicity and Response of Preoperative Chemoradiotherapy in Oesophageal or Oesophagogastric Junction Cancer

Background: Carcinoma of the esophagus is an aggressive disease. Neoadjuvant chemoradiotherapy achieves the highest complete pathologic response rates, R0 resection rates, and improves 3-5 years survival rates. Methods: Patients with resectable carcinoma oesophagus were included in this prospective study. 22 patients were enrolled. All eligible patients were given radiation for a total radiation dose of 41.4Gy in 23 fractions of 1.8Gy each with five fraction administered per week. Weekly chemotherapy given with carboplatin (AUC 2mg/mm/mt) and paclitaxel (50mg/m2 of BSA). The patients were monitored weekly during the treatment for toxicities. These patients were evaluated with CECT after four to six weeks, and sent for surgery. Histopathological reports of these patients which included lymph node status, pathological response and resection margins were noted. Results: A total of 22 patients were enrolled. Neutropenia was the most common hematological toxicity and 4.5% had grade 2 neutropenia.There was no Grade 3 or 4 hematological toxicity. Most common GI toxicity seen was esophagitis and anorexia. 1 patient developed grade 3 esophagitis. 22% patients had grade 2 anorexia.17 patients underwent surgery and all of them had negative resected margins, 5 out of these 17 patients had pathological complete response. Conclusion: Preoperative chemoradiotherapy with weekly paclitaxel and carboplatin have good clinical response in terms of negative resection margin and pathological complete response with accepted level of toxicity. Prospective trials in larger series of patients are needed with long follow up.

Prosigna® breast cancer assay: histopathologic correlation, development, and assessment of size, nodal status, Ki-67 (SiNK™) index for breast cancer prognosis

The Prosigna® assay is a United States Food and Drug Administration (US-FDA) cleared molecular test for prognostic use in hormone receptor-positive stage I/II breast cancer in postmenopausal women. We analyzed histopathologic features of 79 cases with Prosigna® assay results and found a significant correlation between tumor size, grade, and Ki-67 labeling index with Prosigna® score (0–40, 41–60, and 61–100) and Prosigna® risk categories. Since the Prosigna® risk stratification is influenced by lymph node status, we designed an index that included lymph node status and the two most correlated variables (size and Ki-67 labeling index). This was termed the size, nodal, and Ki-67 (SiNK™) index and is calculated as follows: (size in mm) + (pN × 10) + (Ki-67 labeling index). The SiNK™ index was divided into ≤40 and >40 to test its prognostic significance in a well-characterized dataset of 106 ER+/HER2-negative stage I–II invasive breast cancers treated with standard multi-modality therapy with long term follow-up (average 101 months follow-up). Patients with SiNK™ ≤40 showed significantly improved distant recurrence-free survival (96% distant recurrence-free survival in SiNK™ ≤40 compared to 81% in SiNK™ >40; log-rank test p value: 0.0027). SiNK™ provides strong prognostic information in ERo+/HER2-negative breast cancers. SiNK™ index is simple to calculate using data from routine pathology reports. This should be further evaluated in larger datasets.

The prognostic role of the androgen receptor in patients with triple-negative early breast cancers and primary surgery.

e12042 Background: The prognostic value of androgen receptor (AR) expression in triple-negative breast cancer (TNBC) is debated and might be partially masked by the use of adjuvant chemotherapy, which might benefit AR-negative TNBC more than AR-positive cases. We compared the prognostic value of AR in a case control study of consecutive women with TNBC treated or not with adjuvant chemotherapy (ACT). Methods: We retrospectively studied AR expression by immunohistochemistry in all consecutive patients with a secondary metastatic TNBC treated in UZ-Leuven between 2000 and 2009. The control group were cases of TNBC never developing secondary metastatic disease during a long follow-up period matched 1:1 for age and tumor grade. Relations between demographics and clinical pathological features and AR protein expression were studied, including stromal tumor infiltrating lymphocytes (sTILs). Secondary metastatic disease connections with AR protein expression was assessed using the Akaike information criterion; time-to metastasis (TTM) was studied using a linear model with and without ACT correcting for lymph node involvement. We explored whether results differed by AR protein expression levels (0%, 1-34%, ≥34% of tumor cells) and body-mass index (BMI) comparing normal ( < 25kg/m2) with overweight/obese patients BMI. Results: We included 139 patients (69 metastatic and 70 non-metastatic; median age 51.0 years); median follow-up for both groups was 8 years. AR protein expression level ≥ 1% was observed in 25% (n = 34) and ACT was given in 73% (n = 101). AR-positive as compared to AR-negative TNBC patients were older (p = 0.04). Results based on multivariable models including lymph node status and ACT as confounders showed that AR-negative cases have a higher metastasis risk compared to AR-positive patients (3.015 odds ratio (95% CI 1.199-7.582), p = 0.02); this difference was more significant in ACT-naive patients (10.823 odds ratio (95% CI 1.897-61.740), p = 0.007). ACT-treated patients had the best outcome if AR was low (1≤ and < 34%) followed by those with a normal weight and an AR-negative high sTIL TNBC. Conclusions: The AR is prognostic in TNBC and this is clearer in non-ACT treated patients with a TNBC. Our results might suggest that if ACT is given, only the AR-positive TNBC with low AR-expression do well.

Effect of functional genetic variants in chemokine decoy receptors on the recurrence risk of breast cancer.

Duffy antigen receptor for chemokine (DARC) and CCBP2, the two members of chemokine decoy receptor family, restrain cell proliferation and invasion through sequestrating cytotoxic chemokines. Our previous research clarified two functional nonsynonymous single nucleotide polymorphisms (SNPs): rs12075 in DARC and rs2228468 in CCBP2 were significantly correlated with lymph node metastasis. However, the role of their genetic variations on survival of breast cancer remains unclear. In the present study, rs12075 in DARC and rs2228468 in CCBP2 were genotyped in 806 patients with primary breast cancer. The endpoint was recurrence‐free survival (RFS). Cox regression model was used to explore the association between SNPs and patients’ survival. The results revealed that participants with GG genotype in rs12075 appeared a higher recurrence risk compared with AG/AA genotype after adjustment with clinical parameters including lymph node status (AG+AA vs GG: hazard ratio [HR] = 0.54, 95% confidence interval [CI], 0.31‐0.93, P = 0.027). Furthermore, subgroup analysis revealed that GG genotype frequency of rs12075 had a positive correlation with RFS compared with AG/AA genotype (AG+AA vs GG: HR = 0.22, 95% CI, 0.05‐0.91, P = 0.021) in triple‐negative breast cancer (TNBC) subtype but not in other subtypes. No significant association between the genotypic variants and relapse risk was found in rs2228468 (AC+AA vs CC: HR = 0.80, 95% CI, 0.56‐1.14, P = 0.222). There was also no significant difference in survival among rs2228468 polymorphism in any subtypes. Our study suggested that rs12075 could be served as a key predictive factor of recurrence risk in breast cancer, especially for TNBC subtype. Further researches to monitor SNPs will provide further opportunities to determine clinical prognosis.

P53 as a predictor of clinical outcome in localized prostate cancer.

57 Background: p53 is one of the most common genetic aberrations in human cancer and is associated with poor outcomes with hormone therapy in advanced prostate cancer (PCa). p53 is a well-established predictor of biochemical relapse in PCa, however, increasing evidence from ICECaP has demonstrated that metastatic relapse (MR) not biochemical relapse (BCR) is a surrogate for prostate-cancer specific mortality (PCSM). Furthermore, there are now a range of novel therapeutic strategies targeting p53 mutations and their downstream effector pathways. This study aimed to assess the association between p53 expression and MR/PCSM in men with localized PCa. Methods: The study consisted of 271 men with localized PCa treated with radical prostatectomy. Surgical cancer specimens were stained for p53 by immunohistochemistry (IHC) and scored as a) percentage of p53-positive tumor nuclei in all major foci of cancer within the prostate; and (b) clustering, where the presence of 12 or more p53-positive cells within a x200 power field was deemed “cluster positive”. Results: At a median follow-up of 15.8 years (range 4 months - 24.3 years), 57.5% (156/271) had a biochemical relapse, 18% (49/271) had suffered a metastatic relapse, and 9.5% (25/271) had died of prostate cancer. Increasing percentage of p53 positive nuclei was significantly associated with shorter time to BCR (p < 0.001), MR (p < 0.001) and PCSM (p < 0.001). Half of patients were p53 cluster positive. P53 cluster positivity was significantly associated with all clinical endpoints (BCR: HR 2.0, 95% CI 1.51-2.65, p < 0.001; MR: HR 4.1, 95%CI 2.02-8.14, p < 0.001; PCSM: HR 12.2, 95%CI 1.6-93; p = 0.016). These associations were independent of other established prognostic variables including lymph node status, baseline PSA, Gleason and ISUP grade on multivariable analysis. Conclusions: This study has confirmed the association of p53 in radical prostatectomy tissue with clinically relevant endpoints of metastatic relapse and prostate cancer specific mortality. p53 is a potential stratification factor and may be useful for identifying those who will most benefit from adjuvant therapy. Incorporation of p53 status into ongoing clinical trials is now warranted.

Carbon-ion radiotherapy for patients with advanced stage non-small-cell lung cancer at multicenters.

ABSTRACTCarbon-ion radiation therapy (CIRT) for advanced non–small-cell lung cancer (NSCLC) has not been well studied to date. This paper aimed to analyze a retrospective multicenter survey for detecting problems with the use of CIRT for Stage II and III NSCLC (7th UICC TNM Staging System). Inclusion was restricted to patients with Stage II and III NSCLC who received CIRT from November 2003 to December 2014. We gathered the data from three CIRT operating centers on July 2015. Patients with radiotherapy history, patients with cancers other than lung cancer, and those receiving palliative therapies were excluded. The patient characteristics, prescribed dose/fraction, survival rates, and adverse effects were analyzed. The total number of patients was 64 (male: 49, female: 15). Of these, 53 patients were medically inoperable. The median age was 76 years (range 46–91), and the median follow-up period was 18.5 months (range 3.2–121.5). The clinical staging consisted of 10 Stage IIA, 30 Stage IIB, 23 Stage IIIA and 1 Stage IIIB. The median prescribed dose was 72.0 Gy (RBE) (range 52.8–72.0) in 16 fractions (range 4–16). The 2-year overall survival, progression-free survival, and local control rates were 62.2% [confidence interval (CI): 47.5–76.9], 42.3% (CI: 28.8–55.8) and 81.8% (CI: 69.9–94.0), respectively. There were no higher than Grade 2 adverse effects observed. CIRT for inoperable Stage II and III NSCLC could be implemented without severe adverse effects, but the clinical staging (including lymph node status) was inhomogeneous. In addition, the prescribed dose and fractionation were not standardized. Further data accumulation and a multiple centers prospective trial for evaluating clinical stage–based results are required.

A different prognostic value of BRAFV600E mutation positivity in various age groups of patients with papillary thyroid cancer.

The aim of the retrospective single-center study was to assess the prognostic value of BRAFV600E mutation positivity (BRAFV600E+) on disease persistence/recurrence in patients with papillary thyroid cancer (PTC). A total of 199 patients having had initial surgery with neck dissection in our hospital between 6/2009-6/2012 were included in the cohort. Excluded were patients with unifocal microcarcinoma ≤1cm. BRAFV600E mutation was tested from formalin-fixed paraffin-embedded surgicaly removed tumors. All included patients were postoperatively treated with radioiodine. The median duration of follow-up was 43 months, quartiles range 30 - 58 months. Variables included in the final model: BRAFV600E+, categorised age, sex, and high-risk status, or alternatively lymph node status. Based on differences in persistence/recurrence rates, patients were divided into three age categories (<35, 35-60, ≥60). Multiple regression analysis showed a significant interaction between BRAFV600E+ and age, modifying the effect of BRAFV600E+ on persistence/recurrence. BRAFV600E+ in low-risk patients of any age and in high-risk middle-aged patients did not confer additional hazard compared with BRAFV600E mutation negative (BRAFV600E-) low-risk and BRAFV600E- high-risk patients, respectively. However, younger (<35 years) and older (≥60 years) high-risk BRAFV600E+ patients had 17.28 and 33.49-fold increased hazard of persistence/recurrence, respectively, compared with low-risk BRAFV600E- patients. The alternative model including lymph node status yielded similar results for the prognostic significance of BRAFV600E+ in younger and older patients. In conclusion, the prognostic value of BRAFV600E+ depends on high-risk status and likely on age-associated factors. Such additional knowledge could change clinical decision-making in treatment modality.

Abstract P2-08-10: Validation of prediction of local recurrence (LR) by Prosigna® (PAM50) in a Danish breast cancer cooperative group (DBCG) cohort of hormone receptor positive (HR+), postmenopausal early breast cancer (EBC) patients allocated to 5yr of endocrine therapy (ET)

Abstract Background: HR+EBC patients are routinely treated with both adjuvant radiation therapy (RT) and ET. RT is considered an important tool for achieving local control of disease. A limited number of biomarkers have been demonstrated to predict LR. In a previously performed retrospective analysis of a randomized trial, Prosigna (PAM50) risk of recurrence (ROR) score identified low risk patients with a local recurrence rate of 1.6% at 9.5yr median follow-up. In this study, we seek to validate the ability of ROR to predict LR in a comprehensive nationwide cohort from Denmark. Methods: Using the population based DBCG database primary FFPE tumor blocks and follow-up data were collected from all postmenopausal Danish women diagnosed from 2000-2003 with HR+EBC (N=2,722). Prosigna (PAM50) on the NanoString nCounter® Dx Analysis System assigned each patient an ROR score and associated risk group based on pre-specified cutoffs. Patients are also assigned an intrinsic subtype (Luminal A, Luminal B, Her2-Enriched, Basal-Like) based on gene expression. Univariate and multivariate analyses were performed to assess the ability of Prosigna (PAM50) to predict LR. Results: 48 local recurrences were observed with median follow-up of 9.25 yr. Continuous ROR was significantly associated with LR in univariate and multivariate models including node status (0, 1, 2, or 3 positive nodes), tumor size (≤2 vs.&amp;gt;2cm), grade (I, II, III, or unknown), age (≤65 vs.&amp;gt;65yr), and local treatment (mastectomy (MX), lumpectomy+RT, or MX+RT) (p=0.036 and p=0.049, respectively). Clinicopathologic variables were not significant in the multivariate model alone or in combination (p=0.85 for full model excluding ROR). Utilization of a pre-specified LR cutoff, hazard ratio (HR) and [95%CI, p-value] for high risk vs. low risk patients in a univariate analysis was 1.96 [1.11-3.46, p=0.0205] and 2.04 [1.08-3.83, p=0.0275] in the multivariate analysis. 10-year cumulative incidence of LR for low risk patients was 1.7% [1.1%-2.6%]. Similarly, 10-year cumulative incidence of LR for Luminal A patients was 1.7% [1.1%-2.6%]. 10-year cumulative incidence for high risk patients was 2.3% [1.3%-3.2%]. Conclusions: In a large population-based study of n=2,722 patients, Prosigna (PAM50) predicted LR over standard variables. These data validate a pre-specified cutoff separating patients at high and low risk of LR. Additional studies of Prosigna (PAM50) in RT-untreated populations are ongoing. Citation Format: Ole Eriksen J, Jensen M-B, Laenkholm A-V, Kibøll T, Bruun Rasmussen B, Knoop AS, Ferree S, Haffner T, Buckingham W, Schaper C, Ejlertsen B. Validation of prediction of local recurrence (LR) by Prosigna® (PAM50) in a Danish breast cancer cooperative group (DBCG) cohort of hormone receptor positive (HR+), postmenopausal early breast cancer (EBC) patients allocated to 5yr of endocrine therapy (ET). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-08-10.

Tumor-infiltrating lymphocytes predict cutaneous melanoma survival

Understanding differences in survival across distinct subgroups of melanoma patients may help with the choice of types of therapy. Tumor-infiltrating lymphocytes (TILs) are considered a manifestation of the host immune response to tumor, but the role of TILs in melanoma mortality is controversial. The aim of this study was to investigate independent prognostic factors for melanoma mortality. We carried out a 10-year cohort study on 4133 melanoma patients from the same geographic area (Lazio) with primary cutaneous melanoma diagnosed between January 1998 and December 2008. The probability of survival was estimated using Kaplan-Meier methods and prognostic factors were evaluated by multivariate analysis (Cox proportional hazards model). The 10-year survival rate for melanoma decreased with increasing Breslow thickness (Pfor trend<0.0001) and with age (Pfor trend<0.0001) whereas survival increased with increasing levels of TILs (Pfor trend=0.0001). The 10-year survival rate for melanoma divided into TILs intensity as scanty, moderate, and marked was 88.0, 92.2, and 97.0%, respectively. In the multivariate Cox model, the presence of high levels of TILs in primary invasive melanomas was associated with a lower risk of melanoma death (hazard ratio 0.32; 95% confidence interval 0.13-0.82) after controlling for sex, age, Breslow thickness, histological type, mitotic rate, and ulceration. After including lymph node status in the multivariate analysis, the protective effect of marked TILs on melanoma mortality remained (hazard ratio 0.37; 95% confidence interval 0.15-0.94). The results of this study suggest that the immune microenvironment affects melanoma survival.

Abstract 4312: A novel miRNA-based predictive model for biochemical failure following post-prostatectomy salvage radiation therapy

Abstract Prostate cancer (PCa) is the second most common cancer among men worldwide. Radical prostatectomy (RP) is a standard treatment for PCa, yet 30-40% of these men experience biochemical failure (BF) and must undergo additional treatment such as radiation therapy (RT). Unfortunately, a subset of these patients develop resistance to RT and have disease progression. It is important to stratify men based on risk of recurrence as well as identify the most suitable treatment approach to take in PCa to reduce non-necessary patient burden. Currently used methods that include clinical and histopathological factors lack disease specificity and sensitivity. A more informative classification system is needed and molecular biomarkers may serve to bridge the gap of the inadequacies of current prognostic and predictive methods. There were two major objectives for this study. The first was to identify microRNA (miRNA) signatures that predict time to BF post-RP. Secondly, and most novel to the field of RT, we sought to determine miRNAs that could predict BF following post-RP salvage RT as well as develop a new model using both miRNAs and clinical factors. Using the NanoString Human v2 array, we profiled 800 miRNAs in forty-three PCa patients that all experienced BF post-RP and subsequently underwent salvage RT. We identified an 88-miRNA signature that could predict time to BF post-RP using multivariate Cox regression analysis. We observed that these 88 miRNAs could classify patients into two groups (early vs late BF) and that the probabilities to the time to first BF were significantly different between the groups. To identify miRNAs that could independently predict BF post-salvage RT, we performed a multivariate Cox regression analysis with lymph node status and Gleason score which lead to the discovery of nine miRNAs. We wanted to not only identify miRNAs that could independently predict BF post-salvage RT, but also develop a model using these miRNAs in combination with currently used clinical factors to improve upon existing methods. We performed a Cox regression analysis including lymph node status, Gleason score, and the 9 independently identified miRNAs and applied a step-wise model selection strategy to determine the best predictive miRNAs. Two miRNAs with Gleason score and lymph node status had the best predictability. Further specificity and sensitivity analysis indicated that the addition of these miRNAs greatly improved the predictive ability of lymph node status and Gleason score alone (AUC = 0.83 vs 0.66). To the best of our knowledge, this is the first report correlating molecular biomarkers with response to salvage RT. This research has the potential to greatly impact future treatment strategies by using molecular biomarker profiles alone or in combination with other clinical factors to assign the most suitable therapy to individuals the first time and thus avoid over or under treatment. Citation Format: Erica Hlavin Bell, Simon Kirste, Jessica L. Fleming, Petra Stegmaier, Vaness Drendel, Xiaokui Mo, Stella Ling, Denise Fabian, Isabel Manring, Cordula A. Jilg, Wolfgang Schultze-Seemann, Maureen McNulty, Debra L. Zynger, Douglas Martin, Julia White, Martin Werner, Anca L. Grosu, Arnab Chakravarti. A novel miRNA-based predictive model for biochemical failure following post-prostatectomy salvage radiation therapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4312. doi:10.1158/1538-7445.AM2015-4312

The role of lymph nodes in predicting the prognosis of ampullary carcinoma after curative resection.

BackgroundLymph node involvement is one of the well-demonstrated prognostic factors in ampullary carcinoma. The aim of this study is to clarify the role of lymph nodes in predicting the survival outcome of ampullary carcinoma.MethodsA cohort of consecutive curative pancreaticoduodenectomies for ampullary carcinoma from 1999 to 2014 was retrospectively analyzed. The effect of node-associated variables, including lymph node status, positive lymph node number, total harvested lymph node (THLN) number, and lymph node ratio (LNR) was examined using univariate and multivariate analyses for survival outcome prediction.ResultsIn 194 evaluable patients, univariate analysis demonstrated that stage, cell differentiation, perineural invasion, and nodal status were significant conventional prognostic factors. Concerning the node-associated variables, positive nodal status, positive lymph node number ≥2, THLN number <14, and LNR ≥0.15 were significantly associated with poorer survival outcomes, with a 5-year survival rate of 20.3, 38.9, 25.4, and 18 %, respectively. By multivariate analysis, nodal status and THLN number were two independent predictors of survival. The most favorable 5-year survival rate was 84.4 % in patients with negative nodal involvement and THLN number ≥14, compared with the poorest 5-year survival rate of 16.1 % in those with positive nodal status and THLN number <14.ConclusionsTumor biology reflected by lymph node status is the most important independent prognostic factor; nevertheless, surgical radicality based on THLN number also plays a significant role in the survival outcome for patients with ampullary carcinoma after curative pancreaticoduodenectomy.

Lymph node status did not significantly improve the predictability of survival in patients with clinically early-stage endometrial cancer.

The aim of this study was to determine whether knowledge of lymph node status improves survival prediction in clinically early-stage endometrial cancer. The records of 661 patients with apparently uterine-confined disease were reviewed. The performance in predicting overall survival and cause-specific survival was compared between a multivariate prognostic model with nodal status and a model without nodal status by calculating Harrell concordance index. Among 661 patients with clinically early-stage endometrial cancer, the lymph node metastasis rate was 8.3% (55/661). Lymph node metastasis independently associated with cause-specific survival only when no stratification according to adjuvant treatment was applied (P = 0.035). After stratification according to adjuvant radiotherapy, lymph node status marginally associated with cause-specific survival (P = 0.073), whereas myometrial invasion retained its strong association with cause-specific survival (P < 0.001). However, there was no significant difference in the performance of the survival model using only uterine factors and the model using lymph node status and uterine factors (concordance index, 0.77 vs 0.77, respectively; P = 0.798). Knowledge of lymph node status did not significantly improve the performance of survival prediction in apparently uterine-confined endometrial cancer, although it was independently associated with survival. In the patients with clinically early-stage endometrial cancer, the accuracy of the prediction of survival was comparable between risk grouping without lymph node status and that including lymph node status.

Cytoreduction and heated intraperitoneal chemotherapy for colorectal cancer: Are we excluding patients who may benefit?

Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are increasingly used to treat peritoneal carcinomatosis from colorectal cancer. It is still relatively unknown which poor prognostic factors to avoid in order to optimize patient selection for CRS + HIPEC. Between February 2003 and October 2011, 68 consecutive colorectal cancer patients who underwent CRS + HIPEC with a complete cytoreduction were identified from a prospective database. Survival analysis was performed using the Kaplan-Meier method, with log rank testing of differences between groups. Multivariate analysis was conducted using Cox proportional hazard regression. Median follow-up was 30.3 (range, 2-88) months amongst survivors. Patients with a peritoneal cancer index (PCI) of 10 or less showed improved survival over those with a PCI of 11 or higher (P = 0.03). No difference in survival was seen for the other potentially poor prognostic variables including lymph node status, synchronous peritoneal disease, peri-operative systemic chemotherapy, and rectal cancer primary. A low PCI was associated with improved survival. Complete CRS + HIPEC appears to result in similar survival outcomes regardless of delivery of peri-operative systemic chemotherapy. Rectal origin, lymph node status, and synchronous peritoneal disease should not be used as an absolute exclusion criteria for CRS + HIPEC based on current data.

The role of sentinel lymph node biopsy in cervical cancer: an overview of the literature

Cervical cancer is the second most common cancer in southern African women. Although the FIGO staging does not include lymph node status, lymph node metastasis is an important risk factor for recurrence and death in patients with early cervical cancer. Accurate information about lymph node metastasis is crucial to decide on optimal individualised treatment. Complete pelvic lymphadenectomy is the current standard used to obtain accurate information on lymph node status. Because of the low incidence of nodal metastasis in patients with early cervical cancer, identifying women in whom lymphadenectomy can be safely avoided would result in less morbidity associated with pelvic lymphadenectomy, without compromising overall and disease-free survival. Over the past 15 years, the role of sentinel lymph node (SLN) biopsy has been studied extensively in patients with early-stage cervical cancer. Assessment of the SLN in women with early-stage disease may potentially offer an alternative to complete lymphadenectomy. Data are limited with regard to the role of SLN assessment in patients with cervical cancer in low-resource settings where the prevalence of HIV and other gynaecological infections is high.

Aldehyde Dehydrogenase 1 Expression in Inflammatory Breast Cancer as Measured by Immunohistochemical Staining

BackgroundInflammatory breast cancer (IBC) is a rare but aggressive type of breast carcinoma. Despite multimodality approaches, the clinical outcome of patients with IBC remains poor. Tumors arising from cancer stem cells (CSCs) are associated with drug resistance, tumor recurrence, and poor prognosis. This study aimed to evaluate expression of aldehyde dehydrogenase 1 (ALDH1), a putative stem cell marker, in IBC tumors. Materials and MethodsTissue microarrays of 74 surgically resected IBC tumors were immunohistochemically stained for ALDH1. The results were correlated with clinicopathologic parameters and survival data and were compared with findings published in the literature. ResultsThe median follow-up time of the cohort was 42.1 months, and the 5-year overall survival (OS) rate was 46%. Twenty-four tumors (32%) were positive for ALDH1 staining. However, ALDH1 expression was not significantly associated with clinicopathologic variables, including lymph node status, tumor grade, and the status of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. Log-rank testing found that ALDH1 expression was not significantly associated with the OS rate, although there was a trend toward an association with lower OS rate (P = .07). The findings were consistent with some of the published data, but substantial inconsistency among reports was noted. ConclusionIn this IBC cohort, no significant correlation between ALDH1 expression and prognosis or other clinicopathologic variables was found. Although sample size and selection criteria may be contributory factors, inconsistent results reported in the literature raise concern regarding the reliability of immunohistochemically identified ALDH1 as a sole marker of breast CSCs. Further study is required to elucidate the significance of CSCs in IBC biology.

A dual-centre, cohort comparison of open, laparoscopic and robotic-assisted radical cystectomy

The role of minimally invasive radical cystectomy as opposed to open surgery for bladder cancer is not yet established. We present comparative outcomes of open, laparoscopic and robotic-assisted radical cystectomy Prospective cohort comparison of 158 patients from 2003-2008 undergoing open radical cystectomy (ORC) (n = 52), laparoscopic radical cystectomy (LRC) (n =58) or robotic-assisted radical cystectomy (RARC) (n = 48) performed by a team of three surgeons at two hospitals. Peri-operative data, complication rates, length of hospital stay, oncological outcome (including lymph node status) and survival were recorded. Statistical analyses were adjusted to account for potential confounding factors such as ASA grade, gender, age, diversion type and final histology. RARC took longer than LRC and ORC. Patients were about 30 times more likely to have a transfusion if they had ORC than if they had RARC (p < 0.0001) and about eight times more likely to have a transfusion if they had LRC compared with RARC (p < 0.006). Patients were four times more likely to have a transfusion if they had ORC as compared with LRC (p < 0.007). Patients were four times more likely to have complications if they had ORC than RARC (p = 0.006) and about three times more likely to have complications with LRC than with RARC (p = 0.02). Hospital stay was mean 19 days after ORC, 16 days after LRC and 10 days after RARC. Despite study limitations, RARC had the lowest transfusion and complication rates and the shortest length of stay, although taking the longest to perform.

Clinicopathological study of invasive extramammary Paget’s disease: subgroup comparison according to invasion depth

Extramammary Paget's disease (EMPD) is a distinct form of malignant skin neoplasm. Invasive EMPD is relatively rare and its detailed histopathological features have not been investigated to date. Surgical specimens were obtained from 51 patients with primary invasive EMPD. Clinical data including lymph node status were retrieved from the patients' medical records. Cases were divided into subgroups according to invasion depth: dermal invasion ≤ 1 mm (minimal invasion) and dermal invasion > 1 mm in depth. Histological patterns (nodular/glandular pattern or micronodular pattern), lymphatic/venous invasion, mitosis and lymph node status were compared between the two groups. The invasive EMPDs included 26 cases (51.0%) with dermal invasion ≤ 1 mm (minimal invasion) and 25 cases (49.0%) with dermal invasion > 1 mm in depth. Lymph node metastasis was detected in 2/26 (7.7%) patients with minimally invasive EMPD. Nodular/glandular pattern (72.0%), lymphatic/venous invasion (52.0%), mitosis (88.0%) and nodal metastasis (88.0%) were all significantly more frequent in cases with dermal invasion > 1 mm, compared to EMPDs with dermal invasion ≤ 1 mm (minimal invasion) (P < 0.001). These results suggest that invasive EMPD can be divided according to invasion depth, with a cut-off depth of 1 mm. This might represent the basis for a useful, EMPD-specific staging system.

Stathmin Overexpression Identifies High-Risk Patients and Lymph Node Metastasis in Endometrial Cancer

Overexpression of the oncogen Stathmin has been linked to aggressive endometrial carcinoma and a potential for PI3Kinase inhibitors in this disease. We wanted to validate the prognostic value of Stathmin expression in a large prospective multicenter setting. As lymph node sampling is part of current surgical staging, we also aimed to test if Stathmin expression in endometrial curettage specimens could predict lymph node metastasis. A total of 1,076 endometrial cancer patients have been recruited from 10 centers to investigate the biological tumor marker Stathmin in relation to clinicopathologic variables, including lymph node status and survival. Stathmin immunohistochemical staining was carried out in 477 hysterectomy and 818 curettage specimens. Seventy-one percent of the patients (n = 763) were subjected to lymph node sampling, of which 12% had metastatic nodes (n = 94). Overexpression of Stathmin was detected in 37% (302 of 818) of the curettage and in 18% (84 of 477) of the hysterectomy specimens investigated. Stathmin overexpression in curettage and hysterectomy specimens were highly correlated and significantly associated with nonendometrioid histology, high grade, and aneuploidy. Stathmin analysis in preoperative curettage samples significantly correlated with, and was an independent predictor of, lymph node metastases. High Stathmin expression was associated with poor disease-specific survival (P ≤ 0.002) both in curettage and hysterectomy specimens. Stathmin immunohistochemical staining identifies endometrial carcinomas with lymph node metastases and poor survival. The value, as a predictive marker for response to PI3Kinase inhibition and as a tool to stratify patients for lymph node sampling in endometrial carcinomas, remains to be determined.