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Aim: To compare cancer-specific mortality (CSM) rates between radical prostatectomy (RP) vs. external beam radiotherapy (RT) in patients with ductal carcinoma (DC) of the prostate., Materials and Methods: Within the Surveillance, Epidemiology, and End Results (SEER) database (2004-2016), we identified 369 DC patients, of whom 303 (82%) vs. 66 (18%) were treated with RP vs. RT, respectively. Kaplan-Meier plots and uni- and stepwise multivariate Cox regression models addressed CSM in the unmatched population. After propensity score matching (PSM) and inverse probability of treatment weighting (IPTW), Kaplan-Meier curve and Cox regression models tested the effect of RP vs RT on CSM., Results: Overall, RT patients were older, harbored higher PSA values, higher clinical T and higher Gleason grade groups. 5-year CSM rates were respectively 4.2 vs. 10% for RP vs. RT (HR 0.40, 95% CI 0.16-0.99, p = 0.048, favoring RP). At step-by-step multivariate Cox regression, after adding possible confounders, the central tendency of the HR for RP vs. RT approached 1. PSM resulted into 124 vs. 53 patients treated respectively with RP vs. RT. After PSM, as well as after IPTW, the protective effect of RP was no longer present (HR 1.16, 95% CI 0.23-5.73, p = 0.9 and 0.97, 95% CI 0.35-2.66, p = 0.9, respectively)., Conclusions: Although CSM rate of ductal carcinoma RP patients is lower of that of RT patients, this apparent benefit disappears after statistical adjustment for population differences., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Ductal adenocarcinoma is an uncommon prostate cancer variant. Previous studies suggest that ductal variant histology may be associated with worse clinical outcomes, but these are difficult to interpret. To address this, we performed an international, multi-institutional study to describe the characteristics of ductal adenocarcinoma, particularly focussing on the effect of presence of ductal variant cancer on metastasis-free survival., Methods: Patients with ductal variant histology from two institutional databases who underwent radical prostatectomies were identified and compared with an independent acinar adenocarcinoma cohort. After propensity score matching, the effect of the presence of ductal adenocarcinoma on time to biochemical recurrence, initiation of salvage therapy and the development of metastatic disease was determined. Deep whole-exome sequencing was performed for selected cases (n = 8)., Results: A total of 202 ductal adenocarcinoma and 2037 acinar adenocarcinoma cases were analysed. Survival analysis after matching demonstrated that patients with ductal variant histology had shorter salvage-free survival (8.1 versus 22.0 months, p = 0.03) and metastasis-free survival (6.7 versus 78.6 months, p < 0.0001). Ductal variant histology was consistently associated with RB1 loss, as well as copy number gains in TAP1, SLC4A2 and EHHADH., Conclusions: The presence of any ductal variant adenocarcinoma at the time of prostatectomy portends a worse clinical outcome than pure acinar cancers, with significantly shorter times to initiation of salvage therapies and the onset of metastatic disease. These features appear to be driven by uncoupling of chromosomal duplication from cell division, resulting in widespread copy number aberration with specific gain of genes implicated in treatment resistance., Competing Interests: Conflict of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Importance: Although neoadjuvant endocrine therapy (NET) is an alternative to chemotherapy for strongly hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (ERBB2)-negative breast cancer, evidence is currently lacking regarding the probable survival outcomes of NET in comparison with those of neoadjuvant chemotherapy (NACT) for this cancer., Objective: To evaluate all-cause mortality among patients with strongly HR-positive and ERBB2-negative breast cancer treated with NET vs NACT., Design, Setting, and Participants: This cohort study included patients with a diagnosis of invasive ductal carcinoma (IDC) with strong HR positivity and ERBB2 negativity, treated between January 1, 2009, and December 31, 2016, with follow-up from the index date (ie, date of IDC diagnosis) to December 31, 2018. The data came from the Taiwan Cancer Registry Database. Data were analyzed from January to November 2020., Exposures: NET vs NACT for IDC with strong HR positivity and ERBB2 negativity., Main Outcomes and Measures: The primary end point was all-cause mortality. Propensity score matching was performed, and Cox proportional hazard models were used to analyze all-cause mortality among patients undergoing different neoadjuvant treatments., Results: A total of 640 patients (297 [46.4%] aged 20-49 years) undergoing NET (145 patients [22.7%]) or NACT (495 patients [77.3%]) were eligible for further analysis. In the multivariate Cox regression analyses, the adjusted hazard ratio (aHR) for all-cause mortality among the NET cohort compared with the NACT cohort was 2.67 (95% CI, 1.95-3.51; P < .001). The aHRs for age were 1.13 (95% CI, 1.03-2.24), 1.25 (95% CI, 1.13-2.45), and 1.37 (95% CI, 1.17-3.49) for all-cause mortality among patients aged 50 to 59, 60 to 69, and 70 years or older, respectively, compared with those aged 20 to 49 years (P = .002); the aHR for all-cause mortality among premenopausal women was 1.35 (95% CI, 1.13-1.56) compared with postmenopausal women (P < .001); and that of patients with a Charlson Comorbidity Index score of 2 or greater was 1.77 (1.37-2.26) compared with those with a score of 0 (P < .001). The aHRs of all-cause mortality for clinical tumor stage 2, 3, and 4 compared with 1 were 1.84 (95% CI, 1.07-3.40), 1.97 (95% CI, 1.03-3.77), and 2.49 (95% CI, 1.29-4.81), respectively (P = .009). The aHRs for all-cause mortality by clinical nodal (cN) stages were 1.49 (95% CI, 1.13-1.99) and 1.84 (95% CI, 1.31-2.61) for cN stage 1 and cN stages 2 or 3, respectively, compared with cN stage 0 (P = .005); those for differentiation were 1.77 (95% CI, 1.24-2.54) and 2.31 (95% CI, 1.61-3.34) for differentiation grade 2 and differentiation grade 3, respectively, compared with differentiation grade 1 (P < .001)., Conclusions and Relevance: The findings of this study suggest that for patients with strongly HR-positive and ERBB2-negative IDC, NACT may be considered the first choice for neoadjuvant treatment.

Abstract: Bone metastasis seriously affects the survival of breast cancer. Therefore, the study aimed to explore the independent prognostic factors in bone metastatic breast cancer (BMBC) and to construct a prognostic nomogram that can accurately predict the survival of BMBC and strictly divide the patients into different risk stratification.Four thousand three hundred seventy six patients with BMBC from the surveillance, epidemiology, and end results database in 2010 to 2015 were collected and randomly divided into training and validation cohort. Multivariate Cox regression identified the independent prognostic factors of BMBC. A nomogram for predicting cancer-specific survival (CSS) in BMBC was created using R software. The predictive performance of the nomogram was evaluated by plotting receiver operating characteristic (ROC) curves and calibration curves.Marital status, race, age, T stage, tumor grade, estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, brain metastasis, liver metastasis, lung metastasis, chemotherapy, and breast surgery were identified as independent prognostic factors for CSS of BMBC. The area under the ROC curve at 1-, 3-, and 5-year of the nomogram were 0.775, 0.756, and 0.717 in the internal validation and 0.785, 0.737, and 0.735 in the external validation, respectively. Calibration curves further confirmed the unbiased prediction of the model. Kaplan-Meier analysis verified the excellent risk stratification of our model.The first prognostic nomogram for BMBC constructed in our study can accurately predict the survival of BMBC, which may provide a practical tool to help clinicians evaluate prognosis and stratify the prognostic risk for BMBC, thereby determining which patients should be given intensive treatment and optimizing individual treatment strategies for BMBC., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Tumor-infiltrating lymphocytes (TILs) play an important role in mediating treatment response in pancreatic cancer. This meta-analysis investigated the prognostic significance of TIL subsets on overall survival (OS) and disease-free survival (DFS) of patients with pancreatic cancer. Studies were gathered via search of PubMed, Google Scholar, and Cochrane Library databases up to August 1, 2019. Using Review Manager version 5.3.5, pooled hazard ratios and 95% confidence intervals (CIs) were calculated using random or fixed-effects models, depending on the heterogeneity of studies. A total of 11 studies comprising 1760 patients were included in the meta-analysis. Pooled analysis revealed that high CD8 TILs were associated with improved OS [hazard ratio (HR)=0.59, 95% CI=0.51-0.69, P<0.00001] and DFS (HR=0.60, 95% CI=0.50-0.73, P<0.00001). Similarly, high CD3 TILs correlated with better OS (HR=0.64, 95% CI=0.54-0.75, P<0.00001) and DFS (HR=0.53, 95% CI=0.31-0.92, P<0.0001). In contrast, high FoxP3 TILs were associated with worse OS (HR=1.39, 95% CI=1.03-1.88, P=0.03). Finally, high CD4 TILs showed significant improvement in OS (HR=0.74, 95% CI=0.63-0.86, P=0.0001). TILs are a promising prognostic biomarker in pancreatic cancer. Prospective studies evaluating TILs are recommended as well as the establishment of standards in the assessment of TILs.

Background: The number of core needle biopsies in metastatic prostate cancer cases are sometimes reduced to avoid various complications. We analyzed whether core needle biopsy number influence IDC-P detection rate in patients with metastatic castration-sensitive prostate cancer (mHSPC)., Methods: We retrospectively evaluated data from 150 patients diagnosed with mHSPC. Subjects were allocated to three groups according to the number of core biopsies performed: ≤ 5, 6-9, and ≥ 10. The study endpoints were the cancer-specific survival (CSS) and overall survival (OS) rates., Results: For patients who underwent ≥ 10 core biopsies, a significant difference on CSS was detected between with or without IDC-P (P = 0.016). On the other hand, the difference decreased as the number of core biopsies became smaller (6-9; P = 0.322 and ≤ 5; P = 0.815). A similar trend was identified for the OS outcome. A significant difference on OS was also found between with or without IDC-P in patients who underwent ≥ 10 and 6-9 core needle biopsies (P = 0.0002 and 0.017, respectively), but not in those who underwent ≤ 5 core biopsies (P = 0.341). IDC-P served as a stronger prognostic marker for CSS and OS than did the other factors included in the multivariate analysis for patients had ≥ 10 core biopsies (P = 0.016, and P = 0.0014, respectively)., Conclusions: Given the IDC-P detection and its value as a prognostic marker, we propose the performance of ≥ 10 core biopsy procedures in patients diagnosed with mHSPC to minimize the sampling error of the IDC-P.

Background: The impact of length of time to surgery (TTS) on oncologic outcomes following neoadjuvant chemotherapy (NAC) in breast cancer patients is unclear. We investigated the relationship between TTS on residual cancer burden (RCB) score and oncologic outcomes., Methods: Patients with breast cancer receiving NAC from 2011 to 2017 were identified. The association of TTS with recurrence-free survival (RFS), overall and disease-specific survival (OS, DSS), and RCB score was examined with Kaplan-Meier and Cox proportional hazards analysis, adjusting for relevant clinicopathologic factors., Results: We identified 463 patients. Median TTS was 29 days (range 11-153). Median follow-up was 57 months (range, 2-93 months). Five-year local recurrence-free survival, locoregional RFS, OS, and DSS was 86%, 96%, 89%, and 91%, respectively. On multivariate analysis, TTS >6 weeks was independently associated with worse RFS (HR [hazard ratio] 3.45; p < .001) and DSS (HR 2.82; p < .05), while TTS >6 weeks was independently associated with a positive size of the effect on RCB score of 0.59 (p < .0001)., Conclusion: Prolonged TTS is a modifiable risk factor for adverse oncologic outcomes following NAC for breast cancer, possibly mediated by increasing RCB score overtime after NAC. In the absence of contraindications, surgery should be performed within 6 weeks following NAC for optimal oncologic outcomes., (© 2020 Wiley Periodicals LLC.)

Objectives: Salivary duct carcinoma (SDC) is a rare and aggressive subtype of salivary gland cancer. Androgen receptor (AR) (96%) and HER2 (29-46%) expression, and a high propensity for regional lymph node metastases are hallmarks of the disease. We hypothesized that c-MET, E-cadherin, PSMA tumor and PSMA neovascular expression may be prognostic factors in SDC., Materials and Methods: Expression levels of these proteins were established on tissue microarrays containing 165 primary SDC tumor specimens. Association with survival was studied with Kaplan-Meier curves, and univariable and multivariable Cox regression models. Furthermore, association with lymph node status, AR and HER2 expression, and gender was studied., Results: We found that patients with high PSMA tumor expression showed a significantly longer overall survival (OS) (median 83 vs. 43 months, P = 0.022), a trend towards a longer DFS (median 51 vs. 22 months, P = 0.094), and significantly reduced hazard ratio for death in the univariable Cox regression model (HR 0.46, P = 0.034). In the multivariable model only a high number of tumor-positive lymph nodes and high age (>80) at diagnosis were prognostic for poor OS. High PSMA tumor expression was also significantly associated with low N-stage (P = 0.001) and expression was higher in women versus men (P = 0.029). High PSMA tumor expression and E-cadherin loss were significantly associated with strong and weak AR-expression, respectively (P = 0.033 and P = 0.007). None of the factors were significantly associated with HER2 expression., Conclusion: c-MET, E-cadherin, and tumor and neovascular PSMA expression are no independent prognostic factors in SDC., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Although immune-checkpoint inhibitors (ICIs) are effective against various cancers, little is known regarding their role in salivary gland carcinoma (SGC) treatment. Therefore, we evaluated the efficacy and safety of nivolumab monotherapy in patients with recurrent and/or metastatic SGC. In this multicentre retrospective study, nivolumab (240 mg) was administered every 2 weeks. The overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety were examined; the correlation between treatment outcomes and clinicopathological factors was analysed. Twenty-four patients were enrolled; the most common histopathology was salivary duct carcinoma. Eleven tumours were PD-L1-positive; no tumour was microsatellite instability-high. The ORR was 4.2%, and the median PFS and OS were 1.6 and 10.7 months, respectively. One patient continued nivolumab for 28 months without disease progression. One patient showed grade 4 increase in creatine phosphokinase levels and grade 3 myositis. Biomarker analysis revealed significantly increased OS in patients with performance status of 0; modified Glasgow prognostic score of 0; low neutrophil-to-lymphocyte ratio, lactate dehydrogenase, and C-reactive protein; and high lymphocyte-to-monocyte ratio and in patients who received systemic therapy following nivolumab. Although nivolumab's efficacy against SGC was limited, some patients achieved long-term disease control. Further studies are warranted on ICI use for SGC.

This study is aimed at investigating tumoral and inflammatory cells and the significance of the prognostic factors of pancreatic ductal adenocarcinoma (PDAC); it is also aimed at determining the role of immunohistochemistry in the diagnosis and prognosis of this neoplasm. Materials and Methods . 230 cases of pancreatic ductal adenocarcinoma were included in the study group; these cases were selected from the archives of the Department of Pathology of the Fundeni Clinical Institute over a ten-year period. Immunohistochemistry was performed using the following antibodies: MUC 1, CD 34, Factor VIII, CD 68, MMP-7, CEA, p21, p53, and Ki 67. Results . There were 133 male (57.8%) and 97 female (42.2%) patients included in this study, with ages between 20 and 81 years old (mean age: 58.2 years) and with tumors located in the pancreatic head ( n = 196; 85.2%), pancreatic body ( n = 12; 5.2%), and pancreatic tail ( n = 20, 8.7%), as well as panpancreatic tumors ( n = 2; 0.9%). Patients presented with early stages (IA and IB), with low pathologic grade (G1), with small size tumors (less than 1-1.5 cm), with tumors located in the head of the pancreas, (p53: negative; p21: positive; and CD 68: positive in peritumoral tissue), with low nuclear index (Ki 67 < 10%), without metastases at the time of surgery (had a better prognosis), and with a survival rate of about 7 months. Conclusions . Immunohistochemistry is useful for an accurate diagnosis, differential diagnosis, and establishment of additional factors that might have a prognostic importance. It is recommended to study peritumoral tissue from the quantitative and qualitative points of view to increase the number of prognostic factors. This study represents a multidisciplinary approach, and it is a result of teamwork; it presents histopathological methods of examination of this severe illness and describes only a part of the scientific effort to determine the main pathological mechanisms of this neoplasm., Competing Interests: The authors declare no conflict of interest., (Copyright © 2020 Vlad Herlea et al.)

Purpose: The American Joint Committee on Cancer recognizes 6 rare histological variants of prostate adenocarcinoma. We describe the contemporary presentation and overall survival of these rare variants., Materials and Methods: We examined 1,345,618 patients who were diagnosed with prostate adenocarcinoma between 2004 and 2015 within the National Cancer Database. We focused on the variants mucinous, ductal, signet ring cell, adenosquamous, sarcomatoid and neuroendocrine. Characteristics at presentation for each variant were compared with nonvariant prostate adenocarcinoma. Cox regression was used to study the impact of histological variant on overall mortality., Results: Few (0.38%) patients presented with rare variant prostate adenocarcinoma. All variants had higher clinical tumor stage at presentation than nonvariant (all p <0.001). Metastatic disease was most common with neuroendocrine (62.9%), followed by sarcomatoid (33.3%), adenosquamous (31.1%), signet ring cell (10.3%) and ductal (9.8%), compared to 4.2% in nonvariant (all p <0.001). Metastatic disease in mucinous (3.3%) was similar to nonvariant (p=0.2). Estimated 10-year overall survival was highest in mucinous (78.0%), followed by nonvariant (71.1%), signet ring cell (56.8%), ductal (56.3%), adenosquamous (20.5%), sarcomatoid (14.6%) and neuroendocrine (9.1%). At multivariable analysis, mortality was higher in ductal (HR 1.38, p <0.001), signet ring cell (HR 1.53, p <0.01), neuroendocrine (HR 5.72, p <0.001), sarcomatoid (HR 5.81, p <0.001) and adenosquamous (HR 9.34, p <0.001) as compared to nonvariant., Conclusions: Neuroendocrine, adenosquamous, sarcomatoid, signet ring cell and ductal variants more commonly present with metastases. All variants present with higher local stage than nonvariant. Neuroendocrine is associated with the worst and mucinous with the best overall survival.

BACKGROUND The effects of marital status on infiltrating ductal carcinoma of breast cancer (IDC) have not been studied in detail. This study investigated the impact of marital status on IDC patients. MATERIAL AND METHODS SEER databases were searched from 2010 to 2015 for subjects who were married, divorced, single, and widowed. The influence of marital status on breast cancer-specific survival (BCSS) and overall survival (OS) of IDC patients was investigated through multivariate Cox regression analysis and Kaplan-Meier analysis. To prevent bias, propensity score matching (PSM) analysis was performed. RESULTS The 5-year OS was 89.6%in married patients, 84.9% in divorced patients, 83.5% in single patients, and 71.3% in widowed patients (p<0.001). The 5-year BCSS were 92.9%, 90.2%, 87.6%, and 86.4%, respectively (p<0.001). Multivariate Cox regression analysis revealed that marriage was a protective factor for patients with IDC in terms of OS (divorced: HR, 1.27; 95% CI, 1.21-1.32; p<0.001; single: HR, 1.36; 95% CI, 1.31-1.42; p<0.001; widowed: HR, 1.42; 95% CI, 1.36-1.48; p<0.001) and BCSS (divorced: HR, 1.15; 95% CI, 1.09-1.21; p<0.001; single: HR, 1.27; 95% CI, 1.21-1.33; p<0.001; widowed: HR, 1.32; 95% CI, 1.25-1.40; p<0.001). Following subgroup and PSM analysis, married patients were shown to have better OS and BCSS as opposed to divorced, single, or widowed patients. CONCLUSIONS We identify marital status as a predictor of survival in those with IDC. Widowed patients showed the highest mortality risk.

The study aimed to clarify the potential immune-related targets and mechanisms of Qingyihuaji Formula (QYHJ) against pancreatic cancer (PC) through network pharmacology and weighted gene co-expression network analysis (WGCNA). Active ingredients of herbs in QYHJ were identified by the TCMSP database. Then, the putative targets of active ingredients were predicted with SwissTargetPrediction and the STITCH databases. The expression profiles of GSE32676 were downloaded from the GEO database. WGCNA was used to identify the co-expression modules. Besides, the putative targets, immune-related targets, and the critical module genes were mapped with the specific disease to select the overlapped genes (OGEs). Functional enrichment analysis of putative targets and OGEs was conducted. The overall survival (OS) analysis of OGEs was investigated using the Kaplan-Meier plotter. The relative expression and methylation levels of OGEs were detected in UALCAN, human protein atlas (HPA), Oncomine, DiseaseMeth version 2.0 and, MEXPRESS database, respectively. Gene set enrichment analysis (GSEA) was conducted to elucidate the key pathways of highly-expressed OGEs further. OS analyses found that 12 up-regulated OGEs, including CDK1, PLD1, MET, F2RL1, XDH, NEK2, TOP2A, NQO1, CCND1, PTK6, CTSE, and ERBB2 that could be utilized as potential diagnostic indicators for PC. Further, methylation analyses suggested that the abnormal up-regulation of these OGEs probably resulted from hypomethylation, and GSEA revealed the genes markedly related to cell cycle and proliferation of PC. This study identified CDK1, PLD1, MET, F2RL1, XDH, NEK2, TOP2A, NQO1, CCND1, PTK6, CTSE, and ERBB2 might be used as reliable immune-related biomarkers for prognosis of PC, which may be essential immunotherapies targets of QYHJ., Competing Interests: The authors declare that they have no conflict of interest., (Copyright © 2020 Xiang Qian et al.)

Recent studies considered surgery as a treatment option for patients with pancreatic ductal adenocarcinoma (PDAC) and synchronous liver metastases. The aim of this study was to evaluate systematically the literature on the role of surgical resection in this setting as an upfront procedure or following primary chemotherapy. A systematic search was performed of PubMed, Embase and the Cochrane Library in accordance with PRISMA guidelines. Only studies that included patients with synchronous liver metastases published in the era of multiagent chemotherapy (after 2011) were considered, excluding those with lung/peritoneal metastases or metachronous liver metastases. Median overall survival (OS) was the primary outcome. Six studies with 204 patients were analyzed. 63% of patients underwent upfront pancreatic and liver resection, 35% had surgery after primary chemotherapy with strict selection criteria and 2% had an inverse approach (liver surgery first). 38 patients (18.5%) did not undergo any liver resection since metastases disappeared after chemotherapy. Postoperative mortality was low (< 2%). Median OS ranged from 7.6 to 14.5 months after upfront pancreatic/liver resection and from 34 to 56 months in those undergoing preoperative treatment. This systematic review suggests that surgical resection of pancreatic cancer with synchronous liver oligometastases is safe, and it can be associated with improved survival, providing a careful selection of patients after primary chemotherapy.

Background: To date, patients with metastasized pancreatic ductal adenocarcinoma (PDAC M1) are regarded as a uniform collective. We hypothesize the existence of oligometastatic disease (OMD): a state of PDAC M1 disease with better tumor biology, limited metastasis, and increased survival., Methods: Data of 128 PDAC M1 patients treated at the University of Cologne between 2008 and 2018 was reviewed. Interdependence between clinical parameter was calculated using the Mann-Whitney U-Test. Survival curves were generated using the Kaplan-Meier method and analyzed using the log-rank test., Results: Eighty-one (63%) patients had metastases confined to one organ (single organ metastasis, SOG) whereas the remaining 47 (37%) showed multiple metastatic sites (multi-organ metastasis, MOG). Survival analysis revealed a median overall survival (OS) of 12.2 months for SOG vs 4.5 months for MOG (95% CI 5.7-9.8; p < 0.001). We defined limited disease by the presence of ≤4 metastases in liver or lung. Limited disease together with CA 19-9 baseline < 1000 U/ml and response or stable disease after first-line chemotherapy defined OMD. We identified 8 patients with hepatic metastases and 2 with pulmonary metastases matching all OMD criteria. This group of 10 (7.8%) had a median overall survival of 19.4 vs 7.2 months compared to the remaining patients (95% CI 5.7-9.8; p = 0.009)., Conclusion: We propose a definition of oligometastatic disease in PDAC including anatomical criteria and biological criteria reflecting better tumor biology. The 10 OMD patients (7.8%) survived significantly longer and might even benefit from surgical resection in the future.

Background: According to the literature and our experience, patients with gastrointestinal metastases are relatively rare. Numerous case reports and literature reviews have been reported. We present one of the larger case series of gastrointestinal metastases., Objectives: To explore the clinical characteristics and prognosis of patients with gastrointestinal tract metastases, which are rare metastatic sites., Methods: Patients with gastrointestinal metastases in the setting of stage IV primary carcinomas treated at Beijing Ditan Hospital and Peking University International Hospital from November 1992 to August 2017 were included in this study. The diagnosis of gastrointestinal tract metastases was based on histopathology., Results: 30 patients (median age 56 years, 56.7% female) were included. The most common primary carcinomas associated with gastrointestinal metastases were breast (11 patients, 36.7%), stomach (9 patients, 30.0%), and lung (4 patients, 13.3%) cancer. The major pathological types were adenocarcinoma (16 patients, 53.3%) and ductal carcinoma (9 patients, 30.0%). Ten patients (33.3%) underwent local gastrointestinal treatment, and 20 patients (66.7%) underwent nonlocal treatment (involving chemotherapy alone or best supportive care). For breast cancer patients and gastric cancer patients who underwent local therapy, a significant survival advantage was observed ( p = 0.001 and p = 0.012, respectively). The presence of other common metastases was identified as an independent poor prognostic factor through multivariate analysis with a HR (hazard ratio) of survival of 0.182 (95% confidence interval (CI) 0.11-0.523, p = 0.031)., Conclusion: Gastrointestinal metastases are most frequently from breast invasive ductal carcinoma. The presentation of other common metastases with gastrointestinal metastasis indicates poor prognosis, and selected patients may benefit from surgical intervention., Competing Interests: There are no conflicts of interest., (Copyright © 2019 Li Lin et al.)

Programmed death-1 (PD-1), a key immune checkpoint molecule, has been developed as an oncotherapy target for various carcinomas. However, treatment with anti-PD-1 elicited only a minimal effect in pancreatic ductal adenocarcinoma (PDAC). Subsequent studies revealed the existence of a subset of PD-1 + T cells coexpressing CD38 and CD101, representing a fixed dysfunctional subpopulation that are not able to be rescued by anti-PD-1 immunotherapy. However, whether this subpopulation of PD-1 expressing CD8 + T cells could be useful in predicting PDAC stage or prognosing survival is unknown. In this study, we used flow cytometry and immunofluorescence assay to analyze the expression of CD38 and CD101 in 183 clinical PDAC samples, including 84 of peripheral blood and 99 of surgical tissues. High coexpression of CD38/CD101 on peripheral PD-1 + CD8 + T cells or tumor-infiltrating lymphocytes (TILs) was found to be most significantly correlated with Tumor/Node/Metastasis (T/N/M) classification and clinical stage, in contrast PD-1 + CD8 + T cells could not correlate with T classification. CD38/CD101 co-repression on TILs also correlated with the poor survival in these PDAC patient samples. Our data suggest that CD38/CD101 might represent a more helpful biomarker than PD-1 alone for diagnosis and prognosis of PDAC.

Background: We examined the expression of nonhomologous end-joining (NHEJ) proteins by breast cancer cells in patients with or without ipsilateral breast tumor recurrence (IBTR) after breast-conserving therapy. We also investigated whether there was a difference of NHEJ-related protein expression by tumor cells between two types of IBTR, i.e., true recurrence (TR) with regrowth from the tumor bed or development of a new primary tumor (NP)., Patients and Methods: The original cohort comprised 560 breast cancer patients who received breast-conserving therapy between February 1995 and March 2006, including 520 patients without IBTR and 40 patients with IBTR. Propensity score matching was employed to select 40 trios (120 patients) consisting of 1 patient with IBTR and 2 patients without IBTR. Immunohistochemical examination of proteins related to NHEJ was performed in surgical specimens., Results: The 40 patients with IBTR included 22 patients who developed TR and 18 who had NP. The 15-year overall survival rate was 85.9% for patients with NP and 95.5% for those with TR, while it was 96.5% for patients without IBTR. Patients with high XRCC4 expression in tumor cells had significantly higher IBTR rates than those with low XRCC4 expression (P < 0.001). The frequency of TR was significantly higher in patients with high expression of XRCC4 than in those with low XRCC4 expression (p < 0.001). XRCC4 expression by tumor cells was not significantly related to development of NP., Conclusion: IBTR due to TR may be related to low radiosensitivity of tumor cells, possibly related to high XRCC4 expression.

Introduction: To investigate whether the positive lymph node number (PLNN) and positive lymph node ratio (PLNR) could predict the prognosis of patients with major salivary gland cancer (MSGC) and to identify the optimal cutoff points for these variables that stratify patients according to their risk of survival., Methods: We used the Surveillance, Epidemiology, and End Results (SEER) database to identify all patients with MSGC between 1988 and 2014. A logistic regression analysis was carried out to evaluate the risk factors for lymph node metastasis (LNM) in MSGC. The X-tile program was used to identify the cutoff values for the PLNN and PLNR in MSGC patients with LNM. Cox proportional hazards regression models were performed to identify the predictors of cancer-specific survival (CSS)., Results: In the SEER database, 8668 eligible patients were identified and 3046 of them had LNM. The logistic regression analysis indicated that older age, male sex, larger tumor size, higher grade, tumor extension and high-risk pathology were associated with LNM. The X-tile program showed that a PLNN>4 and a PLNR>0.15 were prognostic indicators of CSS. A multivariable analysis indicated that, after the factors that might potentially affect the prognosis were adjusted for, the PLNN and PLNR were still associated with CSS., Conclusions: Our Results demonstrated that the PLNN and PLNR were independent prognostic indicators for MSGC patients with lymph node metastasis., (Copyright © 2018 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Purpose: To investigate clinicopathologic characteristics and cancer-specific mortality (CSM) rates of ductal carcinoma (DC) versus the common acinar adenocarcinoma in nonmetastatic and metastatic (M1) prostate cancer patients., Patients and Methods: Within the Surveillance, Epidemiology, and End Results database (2004-2015), we identified patients with histologically confirmed prostate adenocarcinoma who harbored either DC (n = 581) or acinar adenocarcinoma (n = 489,296). Kaplan-Meier and 4:1 propensity score-matched multivariable Cox regression models adjusted for clinical and pathologic parameters were used to test for CSM differences. Three separate analyses were performed on all patients with nonmetastatic disease, patients with nonmetastatic patients treated with radical prostatectomy only, and patients with metastatic disease., Results: DC was identified in 502 (0.10%) of 469,946 patients with nonmetastatic disease and 79 (0.39%) of 19,931 patients with metastatic disease. In patients with nonmetastatic disease, 253 (50.4%) DC patients underwent radical prostatectomy, 61 (12.2%) DC patients received external-beam radiotherapy, and 188 (37.4%) received other treatment modalities. In multivariable analyses, DC was associated with higher CSM in the overall nonmetastatic patient population (hazard ratio [HR] = 1.8; 95% confidence interval [CI], 1.3-2.6; P = .001), in the nonmetastatic radical prostatectomy population (HR = 2.8; 95% CI, 1.3-6.0; P < .01), and in the M1 population (HR = 1.6; 95% CI, 1.1-2.2; P < .01)., Conclusion: Prostate cancers of ductal origin represent a rare entity among patients with nonmetastatic disease as well as among patients with metastatic disease, and regardless of stage, DC behaves more aggressively., (Copyright © 2019 Elsevier Inc. All rights reserved.)

TP53 gene is mutated in approximately 80% of triple-negative breast cancer (TNBC). However, the prognostic significance of immunohistochemical (IHC)-detected p53 protein expression remains controversial in TNBC. In this study, we retrospectively analyzed the association between IHC-detected p53 expression and the prognosis in a cohort of 278 patients with stage I-III triple-negative breast invasive ductal carcinoma (IDC), who received surgery at the department of breast surgery in the Fourth Hospital of Hebei Medical University from 2010-01 to 2012-12. We found a positive expression ratio of IHC-detected p53 in triple-negative breast IDC of 58.6% (163/278). Furthermore, levels of expression were significantly associated with vessel tumor emboli and higher histologic grade (P = .038, P = .043, respectively), with the highest expression level observed in G3 breast cancer (64.7%). Additionally, Kaplan-Meier analysis showed that p53 expression indicated worse overall survival (OS) in the whole cohort (79.6% vs 89.6%, Log-rank test P = .025) as well as in stratified prognostic stage II patients (90.8% vs 100%, Log-rank test P = .027). The mortality risk of p53 expression patients was 2.22 times higher than that of p53 negative patients (HR: 2.222; 95%CI: 1.147-4.308). In addition, p53 expression was also associated with poor disease-free survival (DFS) (76.7% vs 86.8%, P = .020). Cox proportional hazard ratio model showed p53 expression was an independent risk factor for OS (P = .018) and DFS (P = .018) after controlling for tumor size, lymph node status, and vessel tumor emboli. Altogether, our data showed that IHC-detected p53 expression is a promising prognostic candidate for poor survival in triple-negative breast IDC patients. However, more studies are needed to determine if p53 may be applied to clinical practice as a biomarker and/or novel therapeutic target for TNBC.

Aim: To analyze the prognostic factors and the impact of postoperative radiotherapy (PORT) in parotid gland infiltrating ductal carcinoma (IDC)., Materials & Methods: 252 patients diagnosed with parotid gland IDC were identified from the SEER database. Kaplan-Meier and Cox regression analysis was performed to evaluate the prognostic factors. Propensity score matching was applied then., Results: Multivariate analysis showed old age and chemotherapy were independent risk factors in parotid gland IDC. Subgroup analysis demonstrated that overall survival (OS) rate of the PORT group was significantly superior to that of the no radiotherapy group in the T3-4 subgroup (p = 0.049), N1 subgroup (p = 0.019) and Tumor, Node, Metastasis (TNM) III subgroup (p = 0.025)., Conclusion: PORT improved survival of parotid gland IDC patients within T3-4, N1 and TNM III subgroups.

Background/objective: The definition of R0 resection for invasive pancreatic ductal carcinoma (IPDC) is important. However, there are different definitions among several countries in the world., Methods: From 2001 to 2015, 100 consecutive patients with IPDC who underwent pancreatic resection in our hospital were enrolled. We compared survival and recurrence patterns between the R0 group and R1 group based on the UICC (Union for International Cancer Control) classification (current-R0 vs. current-R1) and based on our revised classification, which defines R0 as a surgical margin of >1 mm (revised-R0 vs. revised-R1)., Results: The 100 patients comprised 58 males and 42 females, and their median age was 70 [32-87]. There were 84 patients in the current-R0 group and 43 in the revised-R0 group. There was no difference in overall survival (OS) or recurrence-free survival (RFS) between the current-R0 group and current-R1 group. However, there was a tendency toward a higher OS rate in the revised-R0 than revised-R1 group (log-rank p = 0.065), and RFS was significantly better in the revised-R0 than revised-R1 group (log-rank p = 0.002). There was no significant difference in the recurrence patterns between the current-R0 and current-R1 groups. In contrast, the local recurrence rate was significantly lower in the revised-R0 than revised-R1 group (21% vs. 42%, respectively; p = 0.026)., Conclusion: The revised classification of surgical resection may be more useful than the current UICC classification for prediction of prognosis and local recurrence of IPDC., (Copyright © 2017. Published by Elsevier Taiwan LLC.)

Background: Approximately 80% of patients with pancreatic ductal adenocarcinoma (PDAC) have metastatic disease with poor prognosis, but clinically available biomarkers for the diagnosis, prediction of prognosis, and target therapy have not yet been identified., Objective: To investigate the expression of aquaporin-1 (AQP1) and AQP3 protein and their clinicopathological significances in PDACs., Materials and Method: AQP1 and AQP3 protein expression in 106 PDAC, 35 peritumoral tissues, 55 benign pancreatic lesions, and 13 normal pancreatic tissues was measured by immunohistochemistry., Results: Western blot showed that AQP1 and AQP3 protein expression was significantly higher in PDAC tissues than that in benign pancreatic tissues (P<0.01). Immunohistochemistry showed that the percentages of positive AQP1 and AQP3 expressions were significantly higher in PDAC tumors than that in peritumoral tissues, benign, and normal pancreatic tissues (P<0.01). Benign pancreatic lesions with positive AQP1 and AQP3 expression exhibited a dysplasia or intraepithelial neoplasia. The percentage of cases with positive AQP1 and AQP3 expression was significantly lower in PDAC patients without lymph node metastasis and invasion, and having low Tumor, Node and Metastasis (TNM) stage disease than in patients with lymph node metastasis, invasion, and high TNM stage disease (P<0.05 or <0.01). Kaplan-Meier survival analysis showed that positive AQP1 and AQP3 expression were significantly associated with survival in PDAC patients (P<0.001). Cox multivariate analysis revealed that positive AQP1 and AQP3 expression was independent poor prognosis factors in PDAC patients. The area under the curve of receiver operating characteristic curve was 0.669 for AQP1 and 0.707 for AQP3, respectively., Conclusions: Positive AQP1 and AQP3 expressions are associated with the tumorigenesis and progression of PDAC. Both AQP1 and AQP3 are a diagnostic marker of PDAC and a predictive marker of poor prognosis in PDAC patients.

This study aimed to elucidate the genetic landscape of biliary papillary neoplasms. Of 28 cases examined, 7 underwent whole exome sequencing, while the remaining 21 were used for validation studies with targeted sequencing. In the whole exome sequencing study, 4/7 cases had mutations in either APC or CTNNB1, both of which belong to the Wnt/β-catenin pathway. Somatic mutations were also identified in genes involved in RAS signaling (KRAS, BRAF), a cell cycle regulator (CDC27), histone methyltransferase (KMT2C, KMT2D), and DNA mismatch repair (MSH3, MSH6, PMS1). Combined with discovery and validation cohorts, mutations in APC or CTNNB1 were observed in 6/28 subjects (21%) and were mutually exclusive. When the cases were classified into intraductal papillary neoplasms of the bile duct (IPNBs, n=14) and papillary cholangiocarcinomas (n=14) based on the recently proposed classification criteria, mutations in APC and CTNNB1 appeared to be entirely restricted to IPNBs with 6/14 cases (43%) harboring mutations in either gene. These genetic alterations were detected across the 3 nonintestinal histologic types. In immunohistochemistry, the aberrant cytoplasmic and/or nuclear expression of β-catenin was found in not only 5/6 IPNBs with APC or CTNNB1 mutations, but also 6/8 cases with wild-type APC and CTNNB1 (total 79%). In addition, APC and CTNNB1 alterations were exceptional in nonpapillary cholangiocarcinomas (n=29) with a single case harboring CTNNB1 mutation (3%). This study demonstrated recurrent mutations in APC and CTNNB1 in nonintestinal-type IPNBs, suggesting that activation of the Wnt/β-catenin signaling pathway is relevant to the development and progression of IPNBs.

Objective Intraductal papillary neoplasm of the bile duct (IPNB) has been increasingly recognized and reported. However, its clinical features are still controversial because of its low incidence. In the present study, we investigated the characteristics of IPNB. Methods In total, 28 patients with IPNB were treated at our institution from January 2000 to December 2016. Clinical data were collected and a retrospective accurate database was constructed. Demographic characteristics, perioperative management, and prognosis were retrospectively analyzed. Results Abdominal discomfort was the most common symptom. Preoperative imaging revealed biliary tract dilatation in 23 patients. Left lateral or left hepatic lobectomy was the most frequently performed surgical procedure. Histological analysis revealed malignancy in 17 patients. Eighty-eight lymph nodes were swept from the patients with malignant disease, but only three were metastatic. Twenty-one patients were followed up for 3 to 60 months (mean, 29.4 ± 18.2 months). Seven patients died during the follow-up period. Patients with benign tumors had significantly greater disease-free survival. Conclusions IPNB is a rare biliary disease that occurs mainly in patients of advanced age. The most common symptom is abdominal discomfort. Lymphatic metastasis is uncommon. Patients with benign tumors may have a better prognosis than those with malignant tumors.

Pseudoprogression has been observed in patients with various tumor types treated with immunotherapy. However, the frequency of pseudoprogression is unknown in gastrointestinal malignancies. Metastatic colorectal cancer (mCRC) and advanced pancreatic ductal adenocarcinoma (PDAC) patients who progressed on treatment with immunotherapy beyond RECIST version 1.1 criteria were analyzed. Degree of progression, tumor markers, time to progression, overall survival, Eastern Cooperative Oncology Group Performance Status (ECOG PS), and costs were analyzed for patients treated beyond progression (TBP) and not treated beyond progression. Fifty-nine of 159 (37%) patients with mCRC or PDAC were TBP (31 mCRC, 28 PDAC). Fifty-four of 59 (92%) patients were microsatellite stable. Zero of these 59 patients with initial treatment beyond progression demonstrated subsequent radiographic tumor shrinkage at a median 42 days from first scan documenting progression. A pseudoprogression rate of >6% could be excluded with 95% confidence. Compared with baseline, median growth on the first and second scan that showed progression was 29.8% and 43%, respectively. In those not treated beyond progression, median growth at first restaging was 31.2%. The trend in change in tumor size positively correlated with the trend in tumor markers in all patients TBP. Fifteen patients (25%) experienced grade 3/4 adverse events by continuing treatment beyond progression, whereas 19 (32%) experienced deterioration in ECOG PS. Pseudoprogression was not seen in microsatellite stable patients with mCRC or PDAC treated with immunotherapy. Changes in tumor markers correlated with changes in tumor volume. This data may help inform future treatment decisions and/or trial design in patients with mCRC or advanced PDAC treated with immunotherapy.

Background: This study aimed to investigate the efficacy of docetaxel in castration-resistant prostate cancer (CRPC) patients with intraductal carcinoma of the prostate (IDC-P)., Patients and Methods: We retrospectively identified 79 CRPC patients with distant metastasis at initial diagnosis from June 2002 to January 2014. All patients received initial androgen deprivation therapy and 46 received docetaxel chemotherapy after progressing to CRPC. The primary outcome of interest was cancer-specific survival (CSS) from the time of CRPC diagnosis. The Cox regression model was used to confirm whether IDC-P and docetaxel would act as independent factors for prognosis., Results: IDC-P was found in 62 of 79 patients. The median CSS in the IDC-P-present group was 18.2 versus 45.6 months in the IDC-P-absent group (HR 2.67; 95% CI 1.18 to 6.06; P = 0.019). Docetaxel was administered to 36 patients with IDC-P and 10 patients without IDC-P, with a median CSS of 20.5 versus 53.2 months, respectively (HR 2.98; 95% CI 1.02 to 8.64; P = 0.044). Multivariate analysis demonstrated that the presence of IDC-P and docetaxel were independent prognostic factors for CSS (P = 0.026 and 0.005, respectively) and overall survival (OS) (P = 0.029 and 0.001, respectively)., Conclusion: The presence of IDC-P is an independent prognostic factor in CRPC patients with distant metastases and IDC-P in needle biopsies at the time of initial diagnosis. Docetaxel may prolong CSS and OS in CRPC patients with distant metastases and IDC-P in needle biopsies at the time of initial diagnosis.

Objective: To identify risk factors of biochemical recurrence after radical prostatectomy in high-risk patients., Methods: A total of 191 high-risk prostate cancer patients according to the D'Amico classification treated with radical prostatectomy at a single institution between April 2000 and December 2013 were enrolled. The pathological evaluation including intraductal carcinoma of prostate was reassessed, and the clinical and pathological risk factors of biochemical recurrence were analyzed., Results: The median follow up after radical prostatectomy was 49 months. The 5-year biochemical recurrence-free survival rate after radical prostatectomy in high-risk prostate cancer patients was 41.6%. Initial prostate-specific antigen, pathological Gleason score, seminal vesicle invasion, extraprostatic extension and intraductal carcinoma of the prostate were significantly associated with biochemical recurrence-free survival. The 5-year biochemical recurrence-free survival rates in patients with zero, one, two and three of these risk factors were 92.9%, 70.7%, 38.3% and 28.8%, respectively. In patients with four or more factors, the biochemical recurrence-free survival rate was 6.1% after 18 months., Conclusions: In D'Amico high-risk patients treated with radical prostatectomy, risk factors for biochemical recurrence can be identified. Patients with fewer risk factors have longer biochemical recurrence-free survival, even among these high-risk cases., (© 2018 The Japanese Urological Association.)

Relative increase of grade 4 and presence of invasive cribriform and/or intraductal carcinoma have individually been associated with adverse outcome of Gleason score 7 (GS 7) prostate cancer. The objective of this study was to investigate the relation of Gleason grade 4 tumor percentage (%GG4) and invasive cribriform and/or intraductal carcinoma in GS 3+4=7 prostate cancer biopsies. We reviewed 1031 prostate cancer biopsies from the European Randomized Study of Screening for Prostate Cancer. In total 370 men had G3+4=7. The relation of invasive cribriform and/or intraductal carcinoma and %GG4 with biochemical recurrence-free survival (BCRFS) after radical prostatectomy (n=146) and radiation therapy (n=195) was analyzed using Cox regression. Invasive cribriform and/or intraductal carcinoma occurred in 7/121 (6%) patients with 1-10% GG4, 29/131 (22%) with 10-25%, and 52/118 (44%) with 25-50% GG4 (P<0.001). In crude analysis, both invasive cribriform and/or intraductal carcinoma (HR 2.72; 95% CI: 1.33-5.95; P=0.006) and 10-50% GG4 (HR 2.43; 95% CI: 1.10-5.37; P=0.03) were associated with BCRFS after prostatectomy. In adjusted analysis, invasive cribriform and/or intraductal carcinoma was an independent predictor for BCRFS (HR 2.40; 95% CI: 1.03-5.60; P=0.04) after prostatectomy, whereas percentage %GG4 (HR 1.00; 95% CI: 0.97-1.03; P=0.80) was not. While invasive cribriform and/or intraductal carcinoma (HR 2.58; 95% CI: 1.59-4.21; P<0.001) performed better than 10-50% GG4 (HR 1.24; 95% CI: 0.67-2.29; P=0.49) for prediction of BCRFS after radiation therapy, both parameters were insignificant in analysis adjusted for prostate-specific antigen (P=0.001), positive biopsies (P<0.001) and tumor volume (P=0.05). In conclusion, increased %GG4 is associated with invasive cribriform and/or intraductal carcinoma in GS 3+4=7 prostate cancer biopsies. Invasive cribriform and/or intraductal carcinoma is an independent parameter for BCR after prostatectomy, whereas %GG4 is not. The presence of invasive cribriform and/or intraductal carcinoma has to be included in pathology reports and should act as exclusion criterion for active surveillance.

Infiltrating ductal carcinoma (IDC) is a rare histologic subtype of prostate cancer. We investigated the clinicopathological features and prognosis of IDC compared with acinar cell carcinoma (ACC). We identified 3814 men diagnosed with prostate cancer between 2004 to and 2013 in the Surveillance, Epidemiology, and End Results database, including 511 IDC and 3303 ACC cases. Prostate cancer-specific survival (PCSS) was compared using univariate and multivariate Cox proportional hazards models. Generally, IDC occurred in older men (≥ 65 years old) and presented with larger sizes, and higher grades, American Joint Committee on Cancer (AJCC) stages, AJCC T stages, lymph node positive rates and metastasis rates. Men with IDC were less likely to undergo radical prostatectomy, but more likely to be treated with adjuvant radiation than men with ACC. Five-year PCSS rates were significantly worse in IDC. In the multivariate analysis, patients with ACC had a better PCSS than patients with IDC. In conclusion, IDC has unique clinicopathological characteristics and has worse prognosis than ACC. Multivariable Cox regression analysis showed that age over 85 years, higher grade and T stage, and metastasis at diagnosis were independent prognostic factors of worse survival outcomes, whereas radical prostatectomy was an independent prognostic factor of better survival outcomes.

Strong evidence exists indicating that the risk of breast cancer (BC) occurrence is influenced by complex internal environmental factors, including blood lipid and lipoprotein components. However, the roles of these components in BC development and progression remain controversial. This study examined whether serial serum lipid and lipoprotein measurements were associated with breast cancer risk and whether lipoproteins had BC prognostic properties. We compared the plasma-related parameter levels, including lipid and lipoprotein levels between 299 patients with invasive ductal breast cancer, also known as invasive ductal carcinoma (IDC), and 200 healthy donors. We performed univariate and multivariate logistic regression analyses to assess overall survival (OS) and disease-free survival (DFS). We found that the serum glucose, triacylglycerol, and low-density lipoprotein levels were significantly higher in patients with IDC than in healthy donors. However, high-density lipoprotein and apolipoprotein A1 (apoA1) levels were lower in patients with IDC than in healthy donors. Multivariate regression analysis demonstrated that elevated apoA1 levels were associated with a reduced risk of IDC, and univariate analysis showed that patients with IDC with lower apoA1 levels at diagnosis had larger tumors than patients with high apoA1 levels. Moreover, patients with IDC with lower apoA1 levels were more likely to have positive axillary lymph nodes, and were diagnosed at more advanced disease stages than patients with high apoA1 levels. We used a Cox regression model to assess the relationships between the above parameters and DFS and OS, after adjusting for tumor T and N stages, which were determined using the TNM classification system, and immunohistochemical subtypes. We found that lower apoA1 levels at diagnosis were associated with poor DFS and OS. At 60 months of follow-up, the DFS rate is 74.5% in the apoA1 L1 group, 89.9% in apoA1 L2 group, and 93.1% in apoA1 L3 group (p=0.0002). Similarly, the OS rate is 78.2% in apoA1 L1 group, 91.3% in apoA1 L2 group, and 93.7% in apoA1 L3 group (p=0.0012). In conclusion, our data indicate that low apoA1 levels are an independent predictor of the poor clinical outcomes in IDC patients.

Objectives: A total of 15 men who died of prostate cancer had cT1/2 biopsy Gleason score ≤6 prostate cancer at prevalence screening in the European Randomized study of Screening for Prostate Cancer Rotterdam. Our objective was to explain (part of) these prostate cancer deaths by undergrading with the classical Gleason score., Methods: Biopsy specimens of 98 men with classical Gleason score ≤6 or 3 + 4 = 7 at prevalence screening in the European Randomized study of Screening for Prostate Cancer Rotterdam were retrospectively reviewed by two pathologists using the International Society of Urological Pathology 2014 modified Gleason score. These 98 men included 15 men with cT1/2 classical Gleason score ≤6 who died of prostate cancer (cases) and 83 randomly selected men with classical Gleason score ≤6 or 3 + 4 = 7 (controls). The primary outcome was the reclassification rate from classical Gleason score ≤6 to modified classical Gleason score 3 + 4 = 7 (grade group 2) stratified for prostate cancer death. The secondary outcome was the rate of cribriform/intraductal carcinoma in Gleason score-reclassified men stratified for prostate cancer death., Results: A total of 79 out of 98 men had classical Gleason score ≤6 prostate cancer. A total of eight out of 15 (53%) prostate cancer deaths with classical Gleason score ≤6 were reclassified to modified Gleason score 3 + 4 = 7, compared with 16 out of 64 (25%) men with non-fatal prostate cancer (P = 0.017). A total of five out of eight (63%) Gleason score-reclassified men with fatal prostate cancer had cribriform/intraductal carcinoma, compared with two out of 16 (13%) Gleason score-reclassified men with non-fatal prostate cancer (P = 0.011)., Conclusions: Part of the prostate cancer deaths with Gleason score ≤6 at prevalence screening in the European Randomized study of Screening for Prostate Cancer Rotterdam could be explained by biopsy undergrading. The present study confirms that the International Society of Urological Pathology 2014 modified Gleason score is more accurate for prognostic assessment based on prostate biopsy than the classical Gleason score., (© 2017 The Japanese Urological Association.)

Background: Breast cancer is the most frequent malignancy among women in Eastern Morocco. In this paper, we provide the first report on molecular breast cancer subtypes in this region. This is the largest population-based study on breast cancer among Moroccan women., Methods: We analyzed 2260 breast cancer cases diagnosed at the Hassan II Regional Oncology Center between October 2005 and December 2012. Clinico-pathological and therapeutic features were studied. Molecular subtypes were determined and their associations with the clinico-pathological characteristics of the tumors were examined., Results: The mean age at diagnosis was 48.7 years ±11.4. Invasive ductal carcinoma was the predominant histological type (77.1%), followed by lobular invasive carcinoma (15.3%). The mean size of breast tumors was 3.5 cm ± 1.96, and 84% of our patients are diagnosed with tumors of more than 2 cm. Histological grade II tumors were the most frequent (70.4%), followed by advanced histological grade (18%). Lymph node positive tumors were observed in 64.8% of cases and 29.3% of patients had distant metastasis. Most tumors were hormone receptor-positive (73%) and 28.6% were HER2 positive. 86.1% of patients with hormone receptor-positive breast cancer were given hormone therapy, while 68.9% of patients with HER2+ breast cancer received targeted therapy with Herceptin. Luminal A was the commonest molecular subtype, followed by Luminal B, Triple Negative and HER2. The highest prevalence of premenopausal patients was observed in Triple Negative subtype (72.2%), followed by HER2 (64.1%), Luminal B (62.2%), and Luminal A (55.1%). Luminal B subtype had a poorer prognosis than Luminal A. Compared with Triple Negative, HER2 subtype tend to spread more aggressively and is associated with poorer prognosis., Conclusions: Unlike Western countries, breast cancer occurs at an earlier age and is diagnosed at a more advanced stage in Eastern Morocco. In this region, hormone receptor-positive tumors are predominant and so the majority of breast cancer patients should benefit from hormone therapy. HER2 subtype presents an aggressive tendency, suggesting the importance of anti-HER2 therapy. This study will contribute in developing appropriate screening and cancer management strategies in Eastern Morocco.

Precision oncology entails making treatment decisions based on a tumor's molecular characteristics. For prostate cancer, identifying clinically relevant molecular subgroups is challenging, as molecular profiling is not routine outside of academic centers. Since histologic variants of other cancers correlates with specific genomic alterations, we sought to determine if ductal adenocarcinoma of the prostate (dPC) - a rare and aggressive histopathologic variant - was associated with any recurrent actionable mutations. Tumors from 10 consecutive patients with known dPC were sequenced on a targeted next-generation DNA sequencing panel. The median age at diagnosis was 59 years (range, 40-73). Four (40%) patients had metastases upon presentation. Archival tissue from formalin-fixed paraffin-embedded prostate tissue samples from nine patients and a biopsy of a metastasis from one patient with castration-resistant prostate cancer were available for analysis. Nine of 10 samples had sufficient material for tumor sequencing. Four (40%) patients' tumors had a mismatch repair (MMR) gene alteration (N = 2, MSH2; N = 1, MSH6; and N = 1, MLH1), of which 3 (75%) had evidence of hypermutation. Sections of the primary carcinomas of three additional patients with known MMR gene alterations/hypermutation were histologically evaluated; two of these tumors had dPC. MMR mutations associated with hypermutation were common in our cohort of dPC patients. Since hypermutation may predict for response to immune checkpoint blockade, the presence of dPC may be a rapid means to enrich populations for further screening. Given our small sample size, these findings require replication.

Background: Although adjuvant chemotherapy with gemcitabine is standard care for resected pancreatic cancer, S-1 has shown non-inferiority to gemcitabine for advanced disease. We aimed to investigate the non-inferiority of S-1 to gemcitabine as adjuvant chemotherapy for pancreatic cancer in terms of overall survival., Methods: We did a randomised, open-label, multicentre, non-inferiority phase 3 trial undertaken at 33 hospitals in Japan. Patients who had histologically proven invasive ductal carcinoma of the pancreas, pathologically documented stage I-III, and no local residual or microscopic residual tumour, and were aged 20 years or older were eligible. Patients with resected pancreatic cancer were randomly assigned (in a 1:1 ratio) to receive gemcitabine (1000 mg/m(2), intravenously administered on days 1, 8, and 15, every 4 weeks [one cycle], for up to six cycles) or S-1 (40 mg, 50 mg, or 60 mg according to body-surface area, orally administered twice a day for 28 days followed by a 14 day rest, every 6 weeks [one cycle], for up to four cycles) at the data centre by a modified minimisation method, balancing residual tumour status, nodal status, and institutions. The primary outcome was overall survival in the two treatment groups, assessed in the per-protocol population, excluding ineligible patients and those not receiving the allocated treatment. The protocol prespecified that the superiority of S-1 with respect to overall survival was also to be assessed in the per-protocol population by a log-rank test, if the non-inferiority of S-1 was verified. We estimated overall and relapse-free survival using the Kaplan-Meier methods, and assessed non-inferiority of S-1 to gemcitabine using the Cox proportional hazard model. The expected hazard ratio (HR) for mortality was 0.87 with a non-inferiority margin of 1.25 (power 80%; one-sided type I error 2.5%). This trial is registered at UMIN CTR (UMIN000000655)., Findings: 385 patients were randomly assigned to treatment between April 11, 2007, and June 29, 2010 (193 to the gemcitabine group and 192 to the S-1 group). Of these, three were exlcuded because of ineligibility and five did not receive chemotherapy. The per-protocol population therefore consisted of 190 patients in the gemcitabine group and 187 patients in the S-1 group. On Sept 15, 2012, following the recommendation from the independent data and safety monitoring committee, this study was discontinued because the prespecified criteria for early discontinuation were met at the interim analysis for efficacy, when all the protocol treatments had been finished. Analysis with the follow-up data on Jan 15, 2016, showed HR of mortality was 0.57 (95% CI 0.44-0.72, pnon-inferiority<0.0001, p<0.0001 for superiority), associated with 5-year overall survival of 24.4% (18.6-30.8) in the gemcitabine group and 44.1% (36.9-51.1) in the S-1 group. Grade 3 or 4 leucopenia, neutropenia, aspartate aminotransferase, and alanine aminotransferase were observed more frequently in the gemcitabine group, whereas stomatitis and diarrhoea were more frequently experienced in the S-1 group., Interpretation: Adjuvant chemotherapy with S-1 can be a new standard care for resected pancreatic cancer in Japanese patients. These results should be assessed in non-Asian patients., Funding: Pharma Valley Center, Shizuoka Industrial Foundation, Taiho Pharmaceutical., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Introduction: Triple-negative breast cancer (TNBC) is a heterogeneous disease with no definitive prognostic markers. As a major component of tight junctions, claudins (CLDNs) presumably play an important role in carcinogenesis and progression of breast cancer. This study was aimed at determining the relationship between the expression of CLDNs and the clinical outcomes of TNBCs., Materials and Methods: The surgical specimens of primary breast tumors from a consecutive cohort of 173 TNBC patients were retrospectively collected. The membranous expression of CLDN1, CLDN2, CLDN4, and CLDN7 was measured by immunohistochemistry. Then, the associations between CLDN expression, clinicopathological features, and clinical outcomes were assessed., Results: Positive CLDN1, CLDN2, CLDN4, and CLDN7 membrane expression was detected in 44.5%, 54.9%, 76.9%, and 73.4% of the cohort specimens, respectively. A lack of CLDN1 expression was related to only lymph node metastasis (P = 0.014). The rate of CLDN4-positive tumors was significantly increased in tumors of a higher grade (P = 0.003). Importantly, negative CLDN1 expression was associated with worse relapse-free survival (RFS) in both lymph node positive (LN+) and negative (LN-) cases (both P<0.001). Similarly it was also associated with shorter overall survival (OS)(P = 0.003 in LN+ cases; P = 0.018 in LN- cases). In the LN+ subgroup, CLDN2-negative cases had a significantly higher risk of recurrence (P = 0.008). Multivariate analysis revealed that negative CLDN1 expression was an independent prognostic factor for high risk of both recurrence and death (HR 5.529, 95% CI 2.664-11.475, P<0.001; HR 3.459, 95% CI 1.555-7.696, P = 0.002). However, neither CLDN4 nor CLDN7 expression was associated with survival., Conclusion: In TNBC, the CLDN1-negative phenotype predicts a high risk of recurrence and death. The absence of CLDN1 expression is strongly suggested to be an independent adverse prognostic factor in this heterogeneous subtype of breast cancer.

Adamts17 is a member of a family of secreted metalloproteinases. In this report, we show that knockdown of Adamts17 expression induces apoptosis and inhibits breast cancer cell growth. Adamts17 expression can rapidly be induced by estrogens. siRNA knockdown of Sp1 or Myc demonstrated that Sp1 is required to induce Adamts17 gene expression in response to estrogen. Moreover, reporter assays showed that the proximal promoter and the upstream sequences were not capable of conferring estrogen responsiveness, suggesting that Sp1 elements may be located in the downstream intronic region. We further demonstrated that Sp1 and Myc binding in the proximal promoter region contributed to the Adamts17 basal expression. Furthermore, histone deacetylase (HDAC) and methylase inhibitors also induced Adamts17 expression, indicating that epigenetic alterations, such as aberrant HDAC and/or methylation are associated with dysregulated Adamts17 expression. By meta-analysis using Oncomine microarray data, we found that higher Adamts17 expression is found in several human cancer cell subtypes, especially in breast ductal carcinoma. Moreover, we found that there is an inverse correlation between higher Adamts17 expression and patients' survival. Our study suggests that Adamts17 may support breast cancer cell growth and survival., (© 2014 Wiley Periodicals, Inc.)

Background: Intraductal carcinoma (IDC) of prostate is a distinct entity associated with higher Gleason score and poor prognosis. The prognostic significance of large cribriform Gleason pattern 4 (LC) in conjunction with IDC has not been previously investigated. The aim of our study was to determine the impact of IDC and LC on biochemical recurrence-free rate (bRFR) in a contemporary prostatectomy cohort., Methods: Prostate cancers of 246 prostatectomies, median follow-up 130.6 months, were graded with the International Society of Urological Pathology (ISUP) 2005 modified Gleason score (GS) and assessed for the presence of LC and/or IDC. In 57 cases with LC and/or IDC, immunostaining was performed to distinguish LC and IDC. The Kaplan-Meier (KM) method was used to estimate 5-year bRFR probabilities. Cox proportional hazards models were used to generate hazard ratios (HRs) and 95% confidence intervals (CIs)., Results: Multivariable analysis showed that the presence of any amount of LC or IDC had a highly significant prognostic effect on bRFR (HR 2.98, 95% CI: 1.68-5.28, p=0.0002) after adjusting for GS, surgical margin status and pathological stage. Although IDC alone tended to be associated with a worse prognosis, LC and IDC did not appear to be associated with a difference in bRFR when analysed separately., Conclusion: We demonstrate that the presence of any amount of LC/IDC is a significant prognostic factor after adjusting for Gleason score and T stage in determining patient outcome and we advocate including the presence of either in routine pathology reporting., (Crown Copyright © 2014. Published by Elsevier Ltd. All rights reserved.)

Intraductal carcinoma of the prostate (IDC-P) has been described as a lesion associated with intraductal spread of invasive carcinoma and consequently aggressive disease. However, there are a few reported cases of pure IDC-P without an associated invasive component, strongly suggesting that this subset of IDC-P may represent a precursor lesion. We compared the clinicopathological features between the morphologically "regular type" IDC-P and "precursor-like" IDC-P. IDC-P was defined as follows; 1) solid/dense cribriform lesions or 2) loose cribriform/micropapillary lesions with prominent nuclear pleomorphism and/or non-focal comedonecrosis. We defined precursor-like IDC-P as follows; 1) IDC-P without adjoining invasive adenocarcinoma but carcinoma present distant from the IDC-P or 2) IDC-P having adjoining invasive microcarcinoma (less than 0.05 ml) and showing a morphologic transition from high-grade prostatic intraepithelial neoplasia (HGPIN) to the IDC-P. IDC-P lacking the features of precursor-like IDC-P was categorized as regular type IDC-P. Of 901 radical prostatectomies performed at our hospital, 141 and 14 showed regular type IDC-P and precursor-like IDC-P in whole-mounted specimens, respectively. Regular type IDC-P cases had significantly higher Gleason score, more frequent extraprostatic extension and seminal vesicle invasion, more advanced pathological T stage, and lower 5-year biochemical recurrence-free rate than precursor-like IDC-P cases. Multivariate analysis revealed nodal metastasis and the presence of regular type IDC-P as independent predictors for biochemical recurrence. Our data suggest that IDC-P may be heterogeneous with variable clinicopathological features. We also suggest that not all IDC-P cases represent intraductal spread of pre-existing invasive cancer, and a subset of IDC-P may be a precursor lesion.

Cell cycle regulators cdc27 and securin participate in control of the mitotic checkpoint and survey the mitotic spindle to maintain chromosomal integrity. This is achieved by their functions in metaphase-anaphase transition, DNA damage repair, enhancement of mitotic arrest and apoptosis. We report on the roles of cdc27 and securin in aneuploidy and prognosis of breast cancer. The study comprises 429 breast cancer patients with up to 22 years of follow-up. DNA content was determined by image cytometry, and immunopositivity for cdc27 and securin was based on tissue microarrays. An inverse association between cdc27 and securin expression was observed in both image cytometric and immunohistochemical analyses. Low cdc27 and high securin expression identified patients with significant difference in disease outcome. Cdc27 and securin immunoexpression identified patients at risk of early cancer death within five years from diagnosis. In multivariate analysis, the combination of cdc27 and securin immunohistochemistry was the strongest predictor of cancer death after lymph node status. We demonstrate, for the first time in human breast cancer, the prognostic value of cdc27 and securin immunohistochemistry. Cdc27 and securin appear promising biomarkers for applications in predicting disease progression, prognostication of individual patients and potential in anti-mitotic drug development., (© 2013 APMIS. Published by John Wiley & Sons Ltd.)

Background: Because of its low incidence, the clinical characteristics of the salivary duct carcinoma (SDC) based on a statistical analysis with a large number of patients remain to be elucidated, and thus it has been impossible to standardize the optimal treatments of SDC including adjuvant systemic therapy., Aims: The present study aimed to determine the prognostic factors along with the clinical outcomes of patients with SDC and to evaluate the expression of several receptor molecules as treatment targets., Methods: We performed a statistical analysis and immunohistochemical examination of 16 patients with SDC who had undergone initial treatment in the Department of Otorhinolaryngology, Head and Neck Surgery, Keio University School of Medicine from 1996 to 2010., Results: The 3-year disease-free survival (DFS) and cause-specific survival (CSS) rates were 29.2% and 72.7%, respectively. At the time of the analysis, 6 patients are alive without the disease, 2 patients are alive with distant metastasis, whereas 7 patients had died of distant metastasis, and 1 patient had died of another cause (pulmonary embolism). We examined the prognostic value of the clinico-pathological factors such as age, sex, T classification, N classification, clinical stage, primary site, histological pre-existence of pleomorphic adenoma. A univariate analysis revealed that DFS was significantly correlated with age (p = 0.049), T classification (p = 0.018), and clinical stage (p = 0.029), whereas no factor was found to be correlated with CSS. A multivariate analysis demonstrated that age (> or = 61 vs. < or = 60, risk ratio (RR) = 5.423, p = 0.042) and T classification (3, 4 vs. 1, 2, RR = 1.087, p = 0.020) were the independent prognostic factors for DFS. Positive expressions of HER2, ER (estrogen receptor), PR (progesterone receptor), AR (androgen receptor), and MIB-1 (index > 20%) were found in 50%, 6%, 13%, 100%, and 69%, respectively. However, none of them showed significant correlation with survival., Conclusion: Frequent expressions of HER-2 and AR in SDC suggest that these receptors can be suitable molecular targets of systemic therapy for patients with SDC in which distant metastasis seems to be the largest obstacle to improving survival. In order to assess the efficacy of anti-HER-2 therapy and anti-androgen therapy for each receptor-positive SDC, a multi-institutional joint research system should be organized.

Background: A primary ductal adenocarcinoma of the lacrimal gland is a rare epithelial malignant tumor, and its clinicopathological and immunohistochemical features have not been well determined. The purpose of this study was to determine the clinicopathological characteristics of lacrimal duct carcinomas and to determine their long-term prognosis., Methods: We performed immunohistochemical studies of biological and proliferative markers of primary ductal adenocarcinomas of the lacrimal gland in five patients, and followed their long term prognosis. We also reviewed nine published cases of primary ductal adenocarcinomas of the lacrimal gland., Results: All specimens were positive for the androgen receptor, and three of five specimens overexpressed the HER-2/neu protein. Nuclear immunostaining for p53 ranged from 10% to 95% and that of Ki-67 from 20% to 70% in the tumor cells. Four of five patients had distant metastases and three patients died from the disease during the 5-year follow-up., Conclusions: Our findings indicate that primary ductal adenocarcinomas of the lacrimal gland express androgen receptors and a wide range of proliferative markers. Their long-term prognosis is poor.

Ductal adenocarcinoma (DAC) of the prostate is thought to have worse prognosis than prostatic acinar carcinoma (PAC). We aimed to evaluate the prognostic significance of histopathological patterns of DAC. A series of 1,051 radical prostatectomy specimens from Karolinska University Hospital 1998-2005 was reviewed. A ductal component was classified as classical DAC (DACC) if it had columnar, pseudostratified epithelium, elongated nuclei, and papillary, glandular, or cribriform architecture; borderline DAC (DACB) if it lacked elongated nuclei or classical architecture; and prostatic adenocarcinoma with ductal features (PCDF) if stratified high-grade nuclei were found. DACC, DACB, and PCDF were seen in 2.6, 4.0, and 1.6 % of the cases. DAC was usually mixed with PAC and constituted 10-100 % (mean 40 %) of the main tumor. Location was periurethral, peripheral, or both in 69.8, 3.5, and 26.7 %. Necrosis was seen in 31.3 %, stromal invasion of DAC in 52.3 %, and intraductal spread in 91.9 %. In DACC/DACB and PAC, extraprostatic extension was seen in 66.7 and 42.4 % (p < 0.001) and seminal vesicle invasion in 13.0 and 5.0 % (p = 0.0045). DACC, DACB, and PCDF had a hazard ratio for biochemical recurrence of 1.5 (0.7-2.8), 1.4 (0.8-2.6) and 1.2 (0.5-2.7). When PCDF was excluded from DAC, hazard ratio was 1.4 (95 % CI 0.9-2.3, p = 0.12). Location, % DAC, necrosis, stromal invasion, or Gleason score were not predictive of recurrence. This suggests that DACC and DACB are more aggressive than average PAC, while cancers with acinar architecture and pseudostratified high-grade nuclei should not be included in DAC.

To identify biologically relevant groupings or clusters of nuclear receptors (NR) that are associated with breast neoplasia, with potentially diagnostic, discriminant or prognostic value, we quantitated mRNA expression levels of all 48 members of the human NR superfamily by TaqMan low-density array analysis in 116 curated breast tissue samples, including pre- and postmenopausal normal breast and both ERα(+) and ERα(-) tumor tissue. In addition, we have determined NR levels in independent cohorts of tamoxifen-treated ERα(+) and ERα(-) tissue samples. There were differences in relative NR mRNA expression between neoplastic and normal breast, and between ER(+) and ER(-) tumors. First, there is overexpression of the NUR77 subgroup and EAR2 in neoplastic breast. Second, we identify a signature of five NR (ERα, EAR2, NUR77, TRα, and RARγ) that classifies breast samples with more than 97% cross-validated accuracy into normal or cancer classes. Third, we find a novel negative association between five NR (TRβ, NUR77, RORγ, COUP-TFII, and LRH1) and histological grade. Finally, four NR (COUP-TFII, TRβ, PPARγ, and MR) are significant predictors of metastasis-free survival in tamoxifen-treated breast cancers, independent of ER expression. The present study highlights the discriminant and prognostic value of NR in breast cancer; identifies novel, clinically relevant, NR signatures; and highlights NR signaling pathways with potential roles in breast cancer pathophysiology and as new therapeutic targets.

Purpose: Salivary duct carcinomas (SDC) are a rare and aggressive subtype of salivary gland cancers for which cytotoxic chemotherapy has limited efficacy. We investigated whether genotyping analysis could detect novel tumor-specific mutations that would help direct SDC patient treatment using targeted agents., Experimental Design: We genotyped 27 SDC archival specimens from patients followed at Massachusetts General Hospital and Massachusetts Eye and Ear Infirmary (Boston, MA) between 2000 and 2011. These included the tumors of 8 patients who were tested prospectively. Targeted mutational analysis of 13 clinically relevant cancer genes was conducted using SNaPshot multiplexed genotyping. FISH was conducted to detect HER2 gene amplification. Patient medical records and tumor histopathologic features were retrospectively reviewed., Results: Mutually exclusive genetic aberrations were detected in 15 of 27 (56%) tumors, including 2 (7%) mutations in BRAF, 5 (19%) mutations in PIK3CA, and 8 (30%) cases of HER2 gene amplification. To our knowledge, this is the first time that BRAF and PIK3CA mutations have been reported in this tumor type. Prospective clinical testing of 8 patients with SDC identified actionable genetic alterations in 6 tumors and influenced therapeutic decisions for all 6 patients., Conclusion: SNaPshot molecular profiling identified novel genetic changes in SDCs, expanded the therapeutic options for patients with this rare tumor, and is changing SDC management at our institution. These findings highlight the importance of using broad-based genetic profiling to expedite the identification of effective-targeted therapies for patients with rare malignancies., (©2012 AACR.)

Salivary duct carcinoma is an aggressive malignancy with a high mortality rate, which phenotypically resembles high-grade breast ductal carcinoma. The parotid gland is the most common location. Standard treatment is surgery to the primary tumour together with post-operative radiotherapy. Despite this, there is a high rate of local recurrence, cervical nodal involvement and distant metastasis. Chemotherapy is currently considered only for end-stage, disseminated disease; however, current evidence indicates that chemotherapy used with radiotherapy may result in improved disease control and survival.Human epidermal growth factor receptor-2 is a proto-oncogene which is over-expressed in both breast ductal carcinoma and salivary duct carcinoma. Clinical studies of patients with metastatic breast cancer, using trastuzumab, a monoclonal antibody directed against human epidermal growth factor receptor-2, have shown significant efficacy in tumour response, resulting in improved survival. Such advances in immunohistochemistry, and in targeted immunotherapy for breast ductal carcinoma, should be applied to the treatment of salivary duct carcinoma.

Gene and protein expression changes observed with tumorigenesis are often interpreted independently of each other and out of context of biological networks. To address these limitations, this study examined several approaches to integrate transcriptomic and proteomic data with known protein-protein and signaling interactions in estrogen receptor positive (ER+) breast cancer tumors. An approach that built networks from differentially expressed proteins and identified among them networks enriched in differentially expressed genes yielded the greatest success. This method identified a set of genes and proteins linking pathways of cellular stress response, cancer metabolism, and tumor microenvironment. The proposed network underscores several biologically intriguing events not previously studied in the context of ER+ breast cancer, including the overexpression of p38 mitogen-activated protein kinase and the overexpression of poly(ADP-ribose) polymerase 1. A gene-based expression signature biomarker built from this network was significantly predictive of clinical relapse in multiple independent cohorts of ER+ breast cancer patients, even after correcting for standard clinicopathological variables. The results of this study demonstrate the utility and power of an integrated quantitative proteomic, transcriptomic, and network analysis approach to discover robust and clinically meaningful molecular changes in tumors.

Ductal carcinoma in situ (DCIS) is a precursor lesion that can gives rise to invasive breast cancer (IBC). It has been proposed that both the nature of the lesion and the tumor microenvironment play key roles in progression to IBC. Here, laser capture microdissected tissue from pure DCIS and pure IBC were employed to define key gene expression profiles in either the epithelial or stromal compartment associated with disease progression. Each tissue had distinct gene expression profiles, and a DCIS/IBC classifier accurately distinguished DCIS versus IBC in multiple independent data sets. However, contrary to other studies that profiled DCIS associated with invasive disease, we found that the most significant alterations in gene expression were observed in the epithelial compartment rather than in the stroma. In particular, genes associated with epithelial-to-mesenchymal transition and myoepithelial cell-specific genes were enriched in invasive cancer relative to pure DCIS. Such alterations in transcript levels were associated with all subtypes of breast cancer, but were particularly indicative of poor outcome in ER-negative breast cancer. Together, these studies indicate that lesion-specific differences in gene expression associated with invasive phenotype are particularly relevant in the progression of DCIS to invasive breast cancer.