Survival In Node-negative Patients Research Articles

Choice of Treatment for Patients With Non-small-cell Lung Cancer >5 cm Between Surgery Alone and Surgery Plus Adjuvant Radiotherapy.

Background: According to the lung cancer staging project, T2b (>5–7 cm) and T3 (>7 cm) non-small cell lung cancers (NSCLC) should be reclassified into T3 and T4 groups. The objective of this study was to evaluate the effect of surgery alone or surgery plus adjuvant radiation (SART) on survival of node-negative patients with NSCLC >5 cm.Methods: We identified 4557 N0 patients with NSCLC >5 cm in the Surveillance, Epidemiology, and End Results database from 2004 to 2014. Overall survival (OS) and cancer–specific survival (CSS) were compared among patients who underwent surgery alone and SART. The proportional hazards model was applied to evaluate multiple prognostic factors.Results: 1,042 and 525 patients who underwent surgery alone and SART, respectively were enrolled after propensity-score matching. OS and CSS favored surgery alone rather than SART. Multivariate analysis showed that the number of lymph nodes examined more than six was associated with better OS and CSS for NSCLC >5 cm, especially in patients treated with surgery alone. Lobectomy should be recommended as the primary option for NSCLC >5 to 7 cm, whereas its superiority was not significant over sublobectomy for NSCLC >7 cm.Conclusion: Surgery alone should be recommended as the first choice for patients with NSCLC >5 cm. The number of examined lymph nodes should be more than six in patients with NSCLC >5 cm, especially for those who undergo surgery alone. For patients with NSCLC >7 cm who could not tolerate lobectomy, sublobectomy might be an alternative surgical procedure.

Use of Nodal Staging Score in Evaluating the Accuracy of Pathologic Nodal Status in Node-Negative Ampullary Carcinoma

BackgroundThe minimum number of lymph nodes (LNs) that should be resected for accurate nodal staging in patients with ampullary carcinoma (AC) remains controversial. This study aimed to establish a nodal staging score (NSS) to evaluate whether a pathological node-negative AC patient is indeed free of a nodal disease. MethodsA total of 2539 AC patients with stages I–III were retrieved from the Surveillance, Epidemiology and End Result database (design cohort [DC], n = 2382) and First Affiliated Hospital of Sun Yat-sen University (validation cohort [VC], n = 157). NSS was developed to represent the probability that a node-negative patient was correctly staged as a function of the number of examined LNs (ELNs) and pathologic T stage with a beta-binomial model. Its prognostic value in node-negative patients was assessed by survival analysis. ResultsThe probability of missing a metastatic LN decreased as the number of the ELNs increased. NSS was escalated as the number of ELNs increased. For patients with early-stage (T1–T2) and late-stage (T3–T4) tumors, examining 7 and 33 lymph nodes could ensure an NSS of 80.0%, respectively. Multivariate analysis showed that higher NSS was an independent favorable prognostic factor for overall survival in node-negative patients with AC (DC, p < 0.001; VC, p = 0.001). ConclusionsNSS model could be used to evaluate the accuracy of nodal staging and predict the prognosis of node-negative AC patients. It could assist in making clinical strategies in node-negative AC patients.

Stereotactic body radiation therapy with higher biologically effective dose is associated with improved survival in stage II non-small cell lung cancer

ObjectivesThe role of stereotactic body radiation therapy (SBRT) in treating stage II non-small cell lung cancer (NSCLC) remains unclear. This study evaluates SBRT dose prescription patterns and survival outcomes in Stage II NSCLC using the National Cancer Database (NCDB). Materials and methodsPatients diagnosed with Stage II NSCLC and treated with SBRT between 2004–2013 were identified in NCDB. The biologically effective dose with α/β = 10 Gy (BED10) was calculated. Overall survival (OS) was analyzed using the Kaplan-Meier method and Cox regression models. ResultsOf 56,543 patients with Stage II NSCLC, 451 (0.8%) received SBRT. There were 360 patients (79.8%) with node-negative and 91 patients (20.2%) with node-positive disease. The most common prescriptions were 10 Gy x 5 (35.9%) and 12 Gy x 4 (19.3%). The mean and median BED10 were 114.9 Gy and 105.6 Gy, respectively. With median follow-up of 19.3 months, overall median survival was 23.7 months. Median survival was 22.4 months for those treated with BED10 < 114.9 Gy versus 31.5 months for BED10 ≥ 114.9 Gy (p = 0.036). On multivariate analysis, BED10 as a continuous variable (hazard ratio [HR] 0.991, p = 0.009) and ≥ 114.9 Gy (HR 0.63, p = 0.015) were associated with improved survival in node-negative patients. BED10 as a continuous variable (HR 0.997, p = 0.465) and ≥ 114.9 Gy (HR 0.81, p = 0.546) were not significant factors for predicting survival in node-positive patients. ConclusionSBRT is infrequently utilized to treat Stage II NSCLC in the United States. Treatment with higher BED10 was associated with improved survival, and the benefit was limited to patients with node-negative disease.

The Prognostic Impact of the Aryl Hydrocarbon Receptor (AhR) in Primary Breast Cancer Depends on the Lymph Node Status.

Increasing evidence implicates the aryl hydrocarbon receptor (AhR) as a possible regulator of mammary carcinogenesis. This study aims to clarify its prognostic impact in breast cancer (BC). Meta-analyses performed at the mRNA level demonstrated that the predictive value of AhR expression in BC depends on the lymph node (LN) status. AhR expression and sub-cellular location were then analyzed by immunohistochemistry in 302 primary BC samples. AhR was expressed in almost 90% of cases with a predominant nuclear location. Nuclear and cytoplasmic AhR levels were significantly correlated and associated with the expression of RIP140 (receptor-interacting protein of 140 kDa), an AhR transcriptional coregulator and target gene. Interestingly, total and nuclear AhR levels were only significantly correlated with short overall survival in node-negative patients. In this sub-group, total and nuclear AhR expression had an even stronger prognostic impact in patients with low RIP140-expressing tumors. Very interestingly, the total AhR prognostic value was also significant in luminal-like BCs and was an independent prognostic marker for LN-negative patients. Altogether, this study suggests that AhR is a marker of poor prognosis for patients with LN-negative luminal-like BCs, which warrants further evaluation.

Challenging the conventional treatment of colon cancer by sentinel lymph node mapping and its role of detecting micrometastases for adjuvant chemotherapy.

All colon cancer patients with lymph node (LN) positive disease are treated with chemotherapy. Patients with node negative disease are usually cured by surgery alone. Yet about 20% of patients develop recurrence within 5years despite node negative status. This may often be the result of missed micrometastases by conventional examination. Sentinel lymph node (SLN) mapping was developed to find those nodes detected by blue dye which was ultrastaged to detect micrometastases. Consecutive patients, underwent SLN mapping with the blue dye with success rate of 99.2%. Average number of LN was 18.3, average number of SLN was 3/patient and overall nodal positivity was 45%. Ten patients had skip metastases. Overall survival of 235 patients was 84months with survival of node negative patients 97months versus 68months for node positive patients. For stage I-IV patients, overall survival was as follows: stage I-115 months, stage II-90 months, stage III-84months and stage IV-24months respectively. Patients with micrometastases after chemotherapy had average survival of 108months versus those without chemotherapy was 50months. Thus, SLN mapping techniques is highly successful, easily reproducible and finds micrmoetastases in over 15% of patients which could have been missed by conventional pathological examination. These patients when treated with adjuvant chemotherapy have similar survival as those of node negative disease. Similarly, patients without any nodal metastases after SLN mapping and ultrastaging, may be considered as true node negative disease and may avoid further adjuvant chemotherapy.

Adjuvant Chemotherapy Is Associated With Improved Survival in Locally Invasive Node Negative Non-Small Cell Lung Cancer

The objectives of this study are to explore factors that are associated with use of adjuvant chemotherapy and to evaluate its impact on overall survival in node-negative patients who undergo lung and chest wall resection for non-small cell lung cancer (NSCLC). Patients who underwent concomitant lung and chest wall resection for NSCLC were abstracted from the National Cancer Database. Clinical, pathologic, treatment, and follow-up data were obtained. Patients with pathologic nodal metastases or patients who received any radiation treatment were excluded, and the cohort was dichotomized based on administration of adjuvant postoperative chemotherapy. Between 1998 and 2010, 824 patients met the inclusion criteria. This cohort exclusively consisted of pT3 N0 patients who did not receive any induction treatment or adjuvant radiation treatment. Adjuvant chemotherapy was administered to 255 patients (31%). Patients in the chemotherapy group were younger and had shorter inpatient length of stay. Both groups had similar comorbidities, tumor size, unplanned readmission rate, and incomplete resection rate. In multivariable analysis, younger age and shorter length of stay were associated with a greater likelihood of receiving adjuvant chemotherapy. Adjuvant chemotherapy was associated with improved survival (hazard ratio 0.74, 95% CI: 0.6 to 0.9), whereas increasing age, white race, length of inpatient stay, tumor size, and residual tumor were independently associated with greater risk of death. Patients who undergo lobectomy with chest wall resection for locally advanced NSCLC should be strongly considered for postoperative adjuvant chemotherapy even in the absence of nodal disease. Actual selection of patients for adjuvant chemotherapy is affected by perioperative factors.

Indications for Adjuvant Mediastinal Radiotherapy in Surgically Resected Small Cell Lung Cancer

Adjuvant mediastinal radiotherapy (AMR) is used after surgical resection for patients with small cell lung cancer (SCLC), but data guiding its use are scant. We sought to examine whether AMR was associated with an improvement in survival for resected SCLC patients and to define subpopulations who should be selected for AMR. Patients undergoing lobectomy, pneumonectomy, and sublobar resection for SCLC were identified in the National Cancer Database (2004 to 2013). Kaplan-Meier survival curves and Cox proportional hazards were used to evaluate associations between AMR and survival. Hazard ratios were adjusted for patient comorbidity, demographics, tumor characteristics, such as stage, grade, histology, and margin status, and receipt of adjuvant chemotherapy. We identified 3,101 patients. Those receiving AMR were younger, more likely to have greater pathologic T and N stage, to undergo sublobar resection, and to have a positive margin. Kaplan-Meier curves showed better median survival for patients with pN1 or pN2 disease who received AMR. After adjustment, Cox models showed AMR was associated with a lower risk of death for pN1 (hazard ratio, 0.79; 95% confidence interval, 0.63 to 1.00; p= 0.05) and pN2 (hazard ratio, 0.60; 95% confidence interval, 0.48 to 0.75; p < 0.0001). In the overall cohort, AMR was not associated with better survival in node-negative patients. AMR was, however, associated with improved survival for patients receiving sublobar resection (hazard ratio, 0.72; 95% confidence interval, 0.57 to 0.90; p= 0.004). AMR is associated with longer survival for node-positive patients after resection for SCLC, especially those with pN2. AMR may also be associated with longer survival in patients undergoing sublobar resections.

P1.07-017 Indications for Adjuvant Mediastinal Radiation in Surgically Resected Small Cell Lung Cancer

Adjuvant mediastinal radiation (AMR) is an adjunctive therapy for patients with surgically resected small cell lung cancer (SCLC). However, little data guides its use. We sought to examine whether there was a survival benefit associated with AMR for resected SCLC patients and to define sub-populations who should be selected for AMR. Patients undergoing resection (lobectomy, pneumonectomy and sublobar resection) for SCLC were identified in the National Cancer Database, 2004 – 2013. Kaplan-Meier survival curves and Cox proportional hazards were used to evaluate the impact of receipt of AMR on survival. Hazard ratios were adjusted for patient comorbidity and demographic information, as well as tumor stage, grade, histology, margin status and receipt of adjuvant chemotherapy. 3,113 patients were identified. Those receiving AMR were younger, more likely to have greater pathologic T- and N- stage, more likely to undergo sublobar resection and have a positive margin. Kaplan-Meier curves showed better median survival for patients with N1-3 disease who received AMR. After adjustment, Cox models showed lower risk of death for N1, N2/3 and sublobar resection with AMR (HR0.79 CI0.65 – 0.96, p=0.02; HR 0.60 CI0.48 – 0.75, p<0.0001). In the overall cohort, AMR was not associated with better survival in node-negative patients. AMR was, however, associated with improved survival for patients receiving sublobar resection (HR0.72 CI0.58 – 0.92, p=0.006). AMR has significant benefit for node-positive patients after resection for SCLC, especially those with pN2 or pN3. Patients undergoing sublobar resection may benefit from AMR.

Outcome After Sentinel Lymph Node Dissection in Vulvar Cancer: A Subgroup Analysis of the AGO-CaRE-1 Study.

Analyzing the large patient cohort of the multicenter AGO-CaRE-1 study, we compared isolated sentinel lymph node dissection (SLND) with radical lymph node dissection (LND) of the groin in relation to recurrence rates and survival. The AGO-CaRE-1 study retrospectively collected data on treatment patterns and follow-up of vulvar cancer patients [International Federation of Gynecology and Obstetrics (FIGO) stage ≥1B] treated at 29 gynecologic cancer centers between 1998 and 2008. This subgroup analysis evaluated the influence of SLND alone on progression-free survival (PFS) and overall survival (OS). In 487 (63.1%) of 772 included patients with tumors smaller than 4cm, an LND was performed and no metastatic lymph nodes were detected (LN0). Another 69/772 (8.9%) women underwent SLND alone, showing a negative SLN (SLN0). Tumors in the LN0 group were larger and showed a deeper invasion (LN0 vs. SLN0 tumor diameter: 20.0 vs. 13.0mm, p<0.001; depth of invasion: 4.0 vs. 3.0mm, p=0.002). After a median follow-up of 33months (0-156), no significant differences in relation to isolated groin recurrence rates (SLN0 3.0% vs. LN0 3.4%, p=0.845) were detected. Similarly, univariate 3-year PFS analysis showed no significant differences between both groups (SLN0 82.7% vs. LN0 77.6%, p=0.230). A multivariate Cox regression analysis, including tumor diameter, depth of invasion, age, grading, and lymphovascular space invasion was performed: PFS [hazard ratio (HR) 0.970, 95% confidence interval (CI) 0.517-1.821] and OS (HR 0.695, 95% CI 0.261-1.849) did not differ significantly between both cohorts. This subgroup analysis of the large AGO-CaRE-1 study showed similar results for groin LND and SLND alone with regard to recurrence rates and survival in node-negative patients with tumors <4cm.

Prognostic impact of the combination of glucose transporter 1 and ATP citrate lyase in node-negative patients with non-small lung cancer.

Metabolic alternations are deemed a hallmark of cancer cells. Among many metabolic pathways, glycolysis and lipogenesis are essential metabolic processes in cancer cells. In this study, we examined the prognostic impact of the combined expression of glycolysis-related glucose transporter 1 (GLUT1) and ATP-citrate lyase (ACLY), which are important molecules in lipogenesis, in patients with non-small cell lung cancer (NSCLC). GLUT1 and ACLY expression in 134 NSCLC specimens were determined by immunohistochemistry using a tissue microarray (TMA). We examined the overall survival of patients with GLUT1-, ACLY- or GLUT+ACLY-positive expression using Kaplan-Meier analysis. We analyzed the prognostic impact of combined GLUT1 and ACLY expression according to lymph node status using multivariate Cox analysis. Patients with GLUT1- or ACLY-positive expression exhibited poorer overall survival compared with GLUT1- or ACLY-negative patients. GLUT1-positive/ACLY-positive expression status was associated with the worst overall survival, in contrast with GLUT1 negative/ACLY-negative expression status, which was correlated with the best overall survival (P=0.003). GLUT1-positive/ACLY-positive expression was significantly correlated with poor prognosis in node-negative but not in node-positive patients. Multivariate Cox analysis indicated combined expression of GLUT1 and ACLY was an independent prognostic factor for overall survival in node-negative patients with NSCLC (P=0.049). These results suggest that the combined expression of GLUT1 and ACLY could be a more valuable prognostic factor than their individual expression in node-negative patients with NSCLC.

The Prognostic Significance of Nodal Ratio on Breast Cancer Recurrence and its Potential for Incorporation in a New Prognostic Index

Axillary nodal status is an inherent part of prognostic tools such as the Nottingham Prognostic Index (NPI). Literature suggests that nodal ratio is a stronger predictive parameter than the total number of positive nodes sampled. Studies also note improved survival in node-negative patients with a larger proportion of nodes excised. The aim of this study was to assess disease-free survival (DFS) comparing the number of negative and positive nodes excised and nodal ratio as the predictive parameters. Consecutive axillary lymph node dissections (ALND) were analyzed over a 25-year period. Data were analyzed using Cox Regression and Kaplan-Meier survival curves. Eight hundred and forty-nine ALNDs were identified, with 327 positive ALNDs and 268 node negative ALNDs incorporated in the study following exclusions. A prognostic index based on nodal ratio was devised and applied retrospectively to 327 positive ALNDs prior to 2002. This index was then prospectively validated in 116 consecutive positive ALNDs from 2002 to 2005. In node negative ALNDs, no significant difference in DFS was noted in patients having </≥ 10 nodes, or having </≥ 14 nodes removed. In node-positive patients, nodal ratio was a stronger predictor of DFS than total positive nodes excised. A prognostic index incorporating nodal ratio more accurately predicts survival than the NPI in node-positive patients as assessed in both a retrospective and a prospective patient cohort. Prognostic indices incorporating nodal ratio may prove more accurate than the current NPI. The extent of ALND did not impact survival in node-negative patients.

183 Pelvic lymph-nodal irradiation improves biochemical relapse-free survival of node-negative patients treated with high-dose salvage radiotherapy after radical prostatectomy. A single-institute analysis of 206 patients

183 Pelvic lymph-nodal irradiation improves biochemical relapse-free survival of node-negative patients treated with high-dose salvage radiotherapy after radical prostatectomy. A single-institute analysis of 206 patients

Perigastric Tumor Deposits in Primary Gastric Cancer: Implications for Patient Prognosis and Staging

Metastatic nodules in perigastric adipose tissue without evidence of lymph node tissue have been reported in gastric cancers. However, the morphological features and clinical significance of perigastric tumor deposits (TD) have not been clarified in gastric cancers. To demonstrate the clinical implication of perigastric TD, 653 consecutive gastric cancer patients were enrolled and all of their slides were reviewed. Separate tumor nodules in the perigastric fat were classified as perigastric TD and correlated with clinicopathologic features and patient survival. Perigastric TD were observed in 156 (23.9 %) of 653 patients. Perigastric TD were associated with synchronous distant metastasis (p < 0.001), independently of depth and venous invasion. There was a significant difference between the overall survival of those with and without TD by univariate (p < 0.001) and multivariate (p = 0.001) survival analyses. However, distant metastasis or patient prognosis could not be predicted by the morphologic patterns of the TD (p > 0.05). When TD without lymph node tissue and lymph node metastasis were recorded separately, TD were observed in 13 node-negative patients. The overall survival of node-negative patients with TD was significantly worse than that of node-negative patients without TD (p < 0.001). Perigastric TD significantly correlated with distant metastasis and satisfactorily predicted patient outcomes independently of invasion depth, lymph node metastasis, and other clinicopathologic factors. Our findings suggest that perigastric TD should be included in the staging of patients with gastric cancer.

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We appreciate this editorial comment and agree with the issues raised. Although the benefits of pelvic lymphadenectomy have been demonstrated time and again, an evidence-based determination of the extent of dissection remains elusive. The question of surgical dissection limits is inherent to oncological surgery, and it would be difficult to identify a malignancy in which the tug-and-pull of more versus less surgery has not been widely debated to define the minimal extent of surgery with best possible outcomes. Over a century ago, William Halsted commented on the extent of node dissection at the time of radical mastectomy: “I fail to see why the neck involvement in itself is more serious than the axilla area. The neck can be cleaned out as thoroughly as the axilla.” 1 Halsted W.S. A clinical and histological study of certain adenocarcinomata of the breast: and a brief consideration of the supraclavicular operation and of the results of operation for cancer of the breast from 1889 to 1898 at the Johns Hopkins Hospital. Ann Surg. 1898; 28: 557-576 PubMed Google Scholar Yet, the question is not what is feasible but what is beneficial. Editorial CommentUrologyVol. 80Issue 3PreviewThe relationship between lymph node (LN) count and survival in patients undergoing radical cystectomy for bladder cancer continues to be a point of discussion. Several studies have shown that LN count correlates with recurrence and survival. Intuitively this makes sense—removal of micrometastatic disease should improve survival in patients with clinically LN-negative disease and presumably from removal of disease in patients with low volume nodal metastases. The authors examined this relationship by identifying and controlling for key confounding variables in a large population-based cohort and found that nodal count indeed correlates with survival in node-negative patients but not in node-positive patients. Full-Text PDF

Number of retrieved lymph nodes and survival in node-negative patients undergoing laparoscopic colorectal surgery for cancer

The number of retrieved lymph nodes in colorectal cancer resection may have an impact on staging and survival. Examination of at least 12 nodes has become a quality measure for adequate surgical practice. To evaluate the impact of the number of retrieved lymph nodes in laparoscopic colorectal surgery for cancer on node-negative patients' survival. Evaluation of our prospective in-hospital collected data of patients that underwent laparoscopic surgery for curable colorectal cancer over a 5-year period. Long-term data were collected from our outpatient's clinic data and personal contact when necessary. During a 5-year period since September 2003,173 patients were operated laparoscopically for curable colorectal cancer. Of the 117 patients who were node negative, 85 node-negative patients (72%) had 12 or more evaluated lymph nodes (mean, 18.3 + 2.4), while 32 node-negative patients had less than 12 (mean, 8.3 + 6.2). Patients with fewer than 12 nodes evaluated had significantly more left-sided tumors, while patients with 12 nodes or more had more right-sided tumors. A comparison of 5-year disease free and overall Kaplan-Meier survival curves revealed no statistically significant difference between the two groups. Evaluation of less than 12 nodes may not necessarily impact patients' survival in node-negative patients undergoing laparoscopic resection for curable colorectal cancer. A lower number of nodes may be sufficient.

Does the Mechanism of Lymph Node Invasion Affect Survival in Patients with Pancreatic Ductal Adenocarcinoma?

BackgroundLymph node metastases are prognostically significant in pancreatic ductal adenocarcinoma. Little is known about the significance of direct lymph node invasion. AimThe aim of this study is to find out whether direct lymph node invasion has the same prognostic significance as regional nodal metastases. MethodsRetrospective review of patients resected between 1/1/1993 and 7/31/2008. “Direct” was defined as tumor extension into adjacent nodes, and “regional” was defined as metastases to peripancreatic nodes. ResultsOverall, 517 patients underwent pancreatic resection for adenocarcinoma, of whom 89 had one positive node (direct 26, regional 63), and 79 had two positive nodes (direct 6, regional 68, both 5). Overall, survival of node-negative patients was improved compared to patients with positive nodes (N0 30.8 months vs. N1 16.4 months; p < 0.001). There was no survival difference for patients with direct vs. regional lymph node invasion (p = 0.67). Patients with one positive node had a better overall survival compared to patients with ≥2 positive nodes (22.3 and 15 months, respectively; p < 0.001). The lymph node ratio (+LN/total LN) was prognostically significant after Cox regression (p < 0.001). ConclusionsIsolated direct invasion occurs in 20% of patients with one to two positive nodes. Node involvement by metastasis or by direct invasion are equally significant predictors of reduced survival. Both the number of positive nodes and the lymph node ratio are significant prognostic factors.

Small Beginnings: Do They Matter? The Importance of Lymphovascular Invasion in Early Breast Cancer

Small Beginnings: Do They Matter? The Importance of Lymphovascular Invasion in Early Breast Cancer

Overexpression of E2F-5 correlates with a pathological basal phenotype and a worse clinical outcome

The purpose of the present study is to identify genes that contribute to cell proliferation or differentiation of breast cancers independent of signalling through the oestrogen receptor (ER) or human epidermal growth factor receptor 2 (HER2). An oligonucleotide microarray assayed 40 tumour samples from ER(+)/HER2(−), ER(+)/HER2(+), ER(−)/HER2(+), and ER(−)/HER2(−) breast cancer tissues. Quantitative reverse transcriptase PCR detected overexpression of a cell cycle-related transcription factor, E2F-5, in ER-negative breast cancers, and fluorescence in situ hybridisation detected gene amplification of E2F-5 in 5 out of 57 (8.8%) breast cancer samples. No point mutations were found in the DNA-binding or DNA-dimerisation domain of E2F-5. Immunohistochemically, E2F-5-positive cancers correlated with a higher Ki-67 labelling index (59.5%, P=0.001) and higher histological grades (P=0.049). E2F-5-positive cancers were found more frequently in ER(−)/progesterone receptor (PgR)(−)/HER2(−) cancer samples (51.9%, P=0.0049) and in breast cancer samples exhibiting a basal phenotype (56.0%, P=0.0012). Disease-free survival in node-negative patients with E2F-5-positive cancers was shorter than for patients with E2F-5-negative cancers. In conclusion, we identify, for the first time, a population of breast cancer cells that overexpress the cell cycle-related transcription factor, E2F-5. This E2F-5-positive breast cancer subtype was associated with an ER(−)/PgR(−)/HER2(−) status, a basal phenotype, and a worse clinical outcome.

Prognostic influence of immunohistochemically detected lymph node micrometastasis and histological subtype in pN0 oesophageal cancer

Introduction Differences in frequency and clinical impact of lymph node micrometastasis between histological subtypes of oesophageal cancer have not been determined. Methods 1204 lymph nodes from 32 squamous cell carcinomas and 54 adenocarcinomas with complete resection and pN0 status were re-evaluated using a serial sectioning protocol including immunohistochemistry. Intra-nodal tumour cells were classified as micrometastases (0.2–2 mm) or isolated tumour cells (<0.2 mm). Results There was no significant difference in the frequency of micrometastases between adenocarcinoma and squamous cell carcinoma (11.3% vs. 3.1%, p = n.s.). In the squamous cell carcinoma group, Kaplan–Meier curves showed a significantly prolonged 5-year survival ( p = 0.02) and disease free interval ( p < 0.01) for immunohistochemically node negative versus node positive patients. In patients with adenocarcinoma, no such difference ( p = n.s. and p = n.s., respectively) was seen. In patients who did not undergo pre-treatment, those with adenocarcinoma had a significant 5-year survival (65% vs. 53%; p = 0.03) and disease free interval (83% vs. 58%; p < 0.05) advantage over those with squamous cell carcinoma. After pre-treatment, no difference between the histological subtypes was detected. Regression analysis did not reveal any factors that significantly affected overall survival in node negative patients. However, four factors did significantly influence disease free interval: pre-treatment (HR 3.3 [95% CI 1.2–9.1], p = 0.02); micrometastasis (HR 5.3 [95% CI 1.4–19.7], p = 0.01); UICC stage II vs. 0/I (HR 2.2 [95% CI 1.1–4.4], p = 0.03); and adenocarcinoma (HR 0.3 [95% CI 0.1–0.9], p = 0.03). Conclusion The difference in frequency and clinical impact of immunohistochemically detected micrometastasis may indicate that adenocarcinoma and squamous cell carcinoma should not be treated as one entity.

Distinct Functions of Natural ADAM-15 Cytoplasmic Domain Variants in Human Mammary Carcinoma

Adamalysins [a disintegrin and metalloproteinase (ADAM)] are a family of cell surface transmembrane proteins that have broad biological functions encompassing proteolysis, adhesion, and cell signal regulation. We previously showed that the cytoplasmic domain of ADAM-15 interacts with Src family protein tyrosine kinases and the adaptor protein growth factor receptor binding protein 2 (Grb2). In the present study, we have cloned and characterized four alternatively spliced forms of ADAM-15, which differ only in their cytoplasmic domains. We show that the four ADAM-15 variants were differentially expressed in human mammary carcinoma tissues compared with normal breast. The expression of the individual isoforms did not correlate with age, menopausal status, tumor size or grade, nodal status, Nottingham Prognostic Index, or steroid hormone receptor status. However, higher levels of two isoforms (ADAM-15A and ADAM-5B) were associated with poorer relapse-free survival in node-negative patients, whereas elevated ADAM-15C correlated with better relapse-free survival in node-positive, but not in node-negative, patients. The expression of ADAM-15A and ADAM-15B variants in MDA-MB-435 cells had differential effects on cell morphology, with adhesion, migration, and invasion enhanced by expression of ADAM-15A, whereas ADAM-15B led to reduced adhesion. Using glutathione S-transferase pull-down assays, we showed that the cytoplasmic domains of ADAM-15A, ADAM-15B, and ADAM-15C show equivalent abilities to interact with extracellular signal-regulated kinase and the adaptor molecules Grb2 and Tks5/Fish, but associate in an isoform-specific fashion with Nck and the Src and Brk tyrosine kinases. These data indicate that selective expression of ADAM-15 variants in breast cancers could play an important role in determining tumor aggressiveness by interplay with intracellular signaling pathways.