Higher Nodal Stage Research Articles

Expression of aldehyde dehydrogenase 1A1 in oral squamous cell carcinoma and its correlation with clinicopathological parameters.

Background:Aldehyde dehydrogenase 1A1 (ALDH1A1) is a key aldehyde dehydrogenase (ALDH) isozyme, related to the cancer stem cells which are responsible for initiating tumor growth, progression, and recurrence. High expression of ALDH1A1 has been reported in several tumor types in humans and its expression is associated with poor prognosis. The aim of this study was to assess the expression of the ALDH1A1 in oral squamous cell carcinoma (SCC) and its correlation with various clinicopathological parameters.Materials and Methods:ALDH1A1 expression was analyzed by using immunohistochemistry on paraffin blocks of 112 cases of primary oral SCC and their corresponding 68 lymph nodes with metastatic deposits. ALDH1A1 expression was also correlated with various clinicopathological parameters. Statistical analysis was done with statistical analysis software, the Statistical Package for the Social Sciences version 21.0.Results:High ALDH1A1 expression was observed in 31.2% of cases of primary oral SCC as compared to 73.5% in lymph node metastasis. A statistically significant difference (P = 0.04) was observed in high TNM stages (68.6%) of the tumor as compared to low TNM stages (31.4%). However, histopathological grades of tumor showed nonsignificant correlation with ALDH1A1 expression (P = 0.093). 40.2% of patients were expired at the end of the study, and the rate of mortality was significantly higher (P = 0.01) in patients with high ALDH1A1 expression as compared to low expression (60.0% vs. 31.2%).Conclusion:High ALDH1A1 expression was associated with higher TNM tumor stage and high nodal stage. It was also associated with high mortality rate which validates it as a marker of invasiveness and poor prognosis in oral SCC.

Predictive factors for distant recurrence of colorectal cancer in patients after curative resection for stage I-III colorectal cancer in Australia.

Distant recurrence is a devastating occurrence after colorectal cancer resection. This study aimed to identify the risk factors for distant recurrence following surgery. All consecutive colorectal cancer resections with curative intent were included from a prospectively maintained colorectal cancer database. The primary outcome was to identify predictive factors for distant recurrence of colorectal cancer. A total of 670 eligible cases were identified with 88 (13.1%) developing distant recurrence during the follow-up period. The median time to distant recurrence was 1.2years with the most common sites of distant recurrence being the lung (44.3%) and liver (44.3%). Predictive factors for distant recurrence in colon cancer included a high tumor, nodal, and overall stage of the primary cancer (p < 0.001 for all). Surgical complications (p = 0.007), including anastomotic leak (p = 0.023), were associated with a higher risk of developing distant recurrence in rectal cancer patients. Independent variables associated with distant recurrence included tumor stage (OR 1.61, p = 0.011), nodal stage (OR 2.18, p < 0.001), and both KRAS (OR 11.04, p < 0.001) and MLH/PMS2 (OR 0.20, p = 0.035) genetic mutations. Among patients with distant recurrence, treatment with surgery conferred the best survival, with patients < 50years of age having the best overall 5-year survival. Predictive factors for distant recurrence include advanced tumor and nodal stages, and the presence of KRAS and MLH/PSM2 mutations. Clinicians should be cognizant of these risk factors, and instate close surveillance plans for patients exhibiting these features.

Abstract 627: Molecular validation of the 8th edition AJCC cancer staging system for resectable pancreatic cancer: Proposal of integrative translational staging system

Abstract Introduction: Even though the 8th edition AJCC cancer staging system for pancreatic cancer has validated major clinicopathologic factors in multiple clinical cohorts, there is still an unmet need for integrative consideration using multi-omics data to stratify the patients with pancreatic cancer elaborately. Methods: We performed a comprehensive analysis and profiling using genomic, transcriptomic, and proteomic data from TCGA-PAAD and other translational cohorts (4 cohorts, n=340). Molecular features and major subtypes were analyzed mutually with clinical and pathologic factors, especially the 8th AJCC staging system. Results: Aggressive molecular subtypes, basal-like and squamous subtype, were significantly associated with a higher nodal stage, but tumor size didn't show a clear association with molecular features. The activated stroma of the pancreatic cancer microenvironment was significantly correlated with poor differentiation and large tumor size. The mutational pattern of KRAS and several transcriptomic pathways, such as epithelial-mesenchymal transition and DNA repair, were differently presented in each clinical stage from the 8th AJCC TNM staging system. The optimal algorithm was identified to show significantly higher performance for the prediction for cancer relapse and cancer-specific survival in discovery and validation cohorts. The in-silico prediction for molecular target agents and immunotherapy was performed for final clusters from the optimal stratification system revealed from the integrative analysis. Conclusions: Our comprehensive multi-omics analysis reveals clear needs for the combination of clinical staging and molecular profiling and provides crucial evidence for precision strategy in patients with resectable pancreatic cancer. Citation Format: Sung Hwan Lee, Sunyoung Lee, Ju-Seog Lee. Molecular validation of the 8th edition AJCC cancer staging system for resectable pancreatic cancer: Proposal of integrative translational staging system [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 627.

Can we predict the need of nutritional support following pancreatoduodenectomy?

Poor nutritional status predisposes to complications after pancreatoduodenectomy (PD) and the development of complications adversely affects the nutritional status. The initially prevalent practise of a routine enteral feeding access at the time of surgery has been challenged in favour of a more selective approach. We hypothesised that if need of nutritional support (NS) could be predicted, a tube jejunostomy (TJ) could be added to the surgical procedure. A retrospective study of 562 consecutive patients who underwent PD from March 2013 to December 2020 using selective TJ placement. Need of NS was defined as use of TJ beyond POD 4, initiation of parenteral nutrition (PN) and need of nasojejunal (NJ) tube. Preoperative and intraoperative parameters were analysed to identify factors predicting the need of SN. Of 562 patients, 105 (18.7%) needed NS. TJ was performed for 46 (8.2%) patients, PN used in 83 (14.8%) and NJ placed for 28 (4.9%). TJ was most useful in patients with psychiatric disorders. PN was most commonly initiated for delayed gastric emptying (DGE) (70/83, 84.3%). Male sex and a higher operative blood loss were associated with the need of NS. Since PN was most commonly initiated for DGE and patients with major complications almost always need NS, factors predicting DGE and major complications were assessed. Preoperative gastrointestinal bleed and high creatinine levels were associated with DGE. High creatinine and nodal stage were associated with major complications. TJ can be selectively added in patients with psychiatric disorders, preoperative gastrointestinal bleed, high creatinine and high operative blood loss.

Medullary breast carcinoma: a pathogenic review and immunohistochemical study using tissue microarray.

Introduction:Medullary breast carcinomas (MBCs) are distinguished by circumscribed, high-grade morphology with dense chronic inflammation; they are associated with the basal phenotype but have a relatively good prognosis.Methods:This study aimed to review the clinicopathological features of MBCs diagnosed at the Department of Pathology, Singapore General Hospital and correlate them with immunohistochemical expression of hormonal markers and c-erbB-2, the basal markers p53, cytokeratin (CK) 14, epidermal growth factor receptor (EGFR) and 34BE12, and the follow-up outcome.Results:Using Ridolfi's criteria for histologic reviews, 62 patients previously diagnosed as having ‘typical MBC’ (n = 26), ‘atypical MBC’ (n = 32) and ‘invasive carcinoma with focal medullary-like features’ (n = 4) were re-classified as follows: ‘typical MBC’ (n = 6; 9.7%), ‘atypical MBC’ (n = 46; 74.2%), and ‘non-medullary infiltrating carcinoma’ (n = 10; 16.1%). Clinicopathological parameters, including ethnicity, age, tumour size and concurrent ductal carcinoma in situ (DCIS), showed no statistically significant correlation with review diagnoses and immunohistochemical findings. Presence of lymphovascular invasion and nodal stage were significantly correlated with recurrence and breast cancer-related deaths, respectively. ER negativity was significantly correlated with triple positivity for basal markers CK14, EGFR and 34BE12, which comprised patients who showed a significantly decreased disease-free survival rate within a 10–15-year follow-up period.Conclusions:Lymphovascular invasion and high nodal stage as well as triple negativity among typical and atypical MBCs that have basal-like phenotype represent a portion of invasive carcinomas with medullary features that may have poor outcomes in this otherwise relatively good prognostic group.

Factors Associated with Overall Survival in Pancreatic Cancer Treated with Neoadjuvant Therapy and Surgery

Introduction: Median survival following surgical resection of pancreatic cancer (PC) has increased due to advances in chemotherapy, radiotherapy, and surgical technique. We examined clinical factors associated with overall survival (OS) in patients with PC who received neoadjuvant therapy and surgery. Method: We conducted a retrospective review of a prospectively maintained PC database at high-volume referral center. Patients with non-metastatic PC who received neoadjuvant therapy and underwent surgical resection between 2009 and 2019 were included. Demographic, clinical, and pathologic variables were examined with Cox proportional hazards models to identify prognostic factors on OS. Results: Neoadjuvant therapy and surgery was completed in 460 consecutive patients; 227 (49.4%) patients were female. The median age was 64 (IQR[58, 71]) years. Median OS was 40.2 (IQR[23.4, 87.3]) months. On bivariate analysis, elevated CA19-9 prior to surgery (HR 1.8 [1.4,2.3]), vein resection (HR 1.6 [1.2, 2.1]), lymphovascular invasion (HR 1.5 [1.1, 2.0]), positive superior mesenteric artery margin (HR 1.8 [1.2, 2.7]) and higher nodal stage were associated with worse OS. On multivariate analysis, shorter OS was associated with increased CA19-9 (HR 1.6 [1.2,2.2]), higher nodal stage (HR 1.5 [1.0, 2.1] for N1; HR 1.9 [1.2, 3.0] for N2), and liver as the first site of disease recurrence. Preoperative clinical stage was not a significance predictor of OS. Conclusions: We report OS outcomes from one of the largest cohorts of resected PC in the era of neoadjuvant therapy. Preoperative CA19-9 after neoadjuvant therapy was associated with OS, emphasizing the impact of treatment response on OS.

Extracapsular Extension Does Not Decrease Overall Survival in Rectal Cancer Patients with Lymph Node Metastasis Following Neoadjuvant Chemoradiotherapy

Background. The Tumor-Node-Metastasis system does not include additional prognostic factors present in the Lymph Node Metastasis (LNM) such as extra-capsular extension (ECE), which is associated with decreased survival. There are not studies addressing this topic in rectal cancer patients with preoperative chemoradiotherapy (nCRT) and total mesorectal excision (TME). Aim. We aimed to examine the survival influence of ECE in patients with stage III rectal cancer who received nCRT followed by surgery. Methods. A retrospective study of 126 patients prospectively collected with rectal cancer in clinical stage III rated with nCRT and TME from 2010 to 2015 was performed. Results. In total, 71.6% of cases had 1 to 3 lymph node metastases, most tumors were grade 2 (52.4%), 25.4% had good pathologic response, 77.8% had a good quality TME, and the median tumor budding count was 4/0.785 mm2. Forty-four (34.9%) patients had ECE+, which was associated with a higher nodal stage (pN2), perineural invasion and a higher lymph node retrieval. The factors associated with the survival were a higher pathologic T stage, higher pathological N stage, high-grade tumors, and perineural invasion. The ECE did not decrease the 5–year survival with a similar median survival (86.5 months for the ECE+ group vs. 84.1 for the ECE–). Conclusion. Our results demonstrate that ECE has no impact on overall survival in rectal cancer patients who received nCRT and this was independent of nodal stage or number of lymph nodes examined.

Molecular validation of the 8th edition AJCC cancer staging system in patients with resected pancreatic cancer: Proposal of integrative translational staging system.

e16765 Background: Even though the 8th edition AJCC cancer staging system for pancreatic cancer has validated with major clinicopathologic factors in multiple clinical cohorts, there is still an unmet need for integrative consideration using multi-omics data to stratify the patients with pancreatic cancer elaborately. Methods: We performed a comprehensive analysis and profiling using genomic, transcriptomic, and proteomic data from TCGA-PAAD and other translational cohorts (4 cohorts, n = 340). Molecular features and major subtypes were analyzed mutually with clinical and pathologic factors, especially the 8th AJCC staging system. Results: Aggressive molecular subtypes, basal-like and squamous subtype, were significantly associated with a higher nodal stage, but tumor size didn't show a clear association with molecular features. The activated stroma of pancreatic cancer microenvironment was significantly correlated with poor differentiation and large tumor size. The mutational pattern of KRAS and several transcriptomic pathways such as eptihelial-mesenchymal transition and DNA repair were differently presented in each clinical stage from the 8th AJCC TNM staging system. The optimal algorithm was identified to show significantly higher performance for the prediction for cancer relapse and cancer-specific survival in discovery and validation cohorts. The in silico prediction for molecular target agents and immunotherapy were performed for final clusters from optimal stratification system revealed from the integrative analysis. Conclusions: Our comprehensive multi-omics analysis reveals clear needs for the combination of clinical staging and molecular profiling and provides crucial evidence for precision strategy in patients with resectable pancreatic cancer.

Abstract P4-02-11: Can preoperative axillary staging replace sentinel node biopsy? Comparison of preoperative axillary and final histologic nodal findings in 2108 patients with primary breast cancer

Abstract Background Axillary staging is an integral part of the preoperative work-up in patients with breast cancer. Given the increasing number of patients treated with neoadjuvant chemotherapy (NC) and current guidelines to perform sentinel-node biopsy after the completion of neoadjuvant chemotherapy, axillary staging has gained more importance. Beside the prediction of nodal involvement, correct prediction of nodal stage is crucial in order to select respective treatment for the patients. Materials and Methods Patients treated for primary breast cancer from 01/2013 to 01/2018 and received preoperative sonografic axillary staging and surgery were identified from the breast databases of two large volume hospitals. In case of sonografic suspicion of nodal involvement an axillary biopsy was performed. Accuracy of axillary staging was examined regarding the concordance between prediction of nodal involvement and nodal (N) stage with final pathology. A multivariate model was used to identify factors associated with a high accuracy of axillary sonografic staging. Results Among 2220 patients, 112 were excluded due to incomplete clinical data or axillary surgery after completion of neoadjuvant chemotherapy leaving 2108 patients for final analysis. 1535 (73 %) showed a N0 stage on final pathology. Accuracy of axillary staging regarding prediction of nodal involvement was 92 % (1929/2108) with a sensitivity of 80 % and a specificity of 96 %, a positive predictive value of 88 % and a negative predictive of 93 %. Prediction of nodal stage was correct in 1894 of 2018 cases (90 %). Concordance between sonografic prediction of N stage and final pathology decreased with higher nodal stages (N0 - 91 %, N1 84 %, N2 81 %, N3 68 %) and was higher in node negative patients (91 %) compared to node positive patients (86 %; p ≤ 0.05). On multivariate analysis the presence of nodal involvement was the only factor associated with concordance of axillary staging and pathologic nodal stage (OR 0.11 (95 %CI 0.08 - 0.16) p ≤ 0.01). Conclusion In this large population of patients with primary breast cancer, we showed a high accuracy of preoperative axillary staging with respect to nodal involvement and prediction of respective N stage. With a negative predictive value of 93 % regarding node negativity, axillary staging showed accurate outcomes but improvements in sensitivity are necessary in oder to compete with sentinel node biopsy. Citation Format: Julia Caroline Radosa, Martin Deeken, Lisa Stotz, Sarah Huwer, Carolin Müller, Rosemarie Weinmann, Christoph G Radosa, Marc P Radosa, Stefan Wagenpfeil, Erich-Franz Solomayer. Can preoperative axillary staging replace sentinel node biopsy? Comparison of preoperative axillary and final histologic nodal findings in 2108 patients with primary breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-02-11.

Abstract PD1-08: Frequency, characteristics and prognostic factors of PD-L1+ triple negative breast cancer using the PD-L1 SP142 companion assay

Abstract Background: TNBC is the most aggressive sub-type of breast cancer and has limited targeted therapies. Atezolizumab was recently FDA-approved for patients with advanced PD-L1+ TNBC. In a well-characterized cohort of patients with early-stage TNBC, we used the FDA-approved PD-L1 SP142 companion assay for atezolizumab to score whole tumor sections for PD-L1 expression. We determined the frequency and scoring distribution of PD-L1 in these tumors and evaluated PD-L1 status for associations with clinicopathologic variables and outcomes. Methods: Whole tumor sections from 498 women with surgically-treated, non-(distant) metastatic TNBC (ER/PR &amp;lt;1% &amp; HER2-negative by central review) were semi-quantitatively scored for % of PD-L1-staining tumor cells (TC) or tumor-associated immune cells (IC) (PD-L1 SP142, Ventana, performed in CAP/CLIA-certified clinical laboratory). Per FDA assay guidelines, PD-L1+ tumors were defined as ≥1% of tumor-associated immune cells (IC) staining per tumor area. Baseline clinical characteristics, histopathologic features, Ki-67 proliferative indices (PI), and stromal tumor infiltrating lymphocytes (TILs) were correlated with PD-L1 status. The impact of tumoral PD-L1 status on invasive disease-free survival (IDFS) and overall survival (OS) was assessed using Cox proportional hazards models. Results: The majority of tumors were pT1-T2 (95%), pN0-1 (85%), and grade 3 (90%) with Ki-67 &amp;gt;15% (80%). 228/498 (46%) tumors were PD-L1+, distributed as IC score 1-5%: 21%, 6-10%: 13%, 11-20%: 5% and &amp;gt;20%: 7%. 270/498 (54%) were PD-L1-. 43 (8.6%) of tumors had PD-L1 staining in TC (all but 1 were also IC+). PD-L1 IC expression was associated with larger tumor size (p = 0.005), higher nodal stage (≥pN1: 43% vs. 31%, p &amp;lt; 0.001), higher grade (grade 3: 95% vs. 86%, p&amp;lt; 0.001), higher Ki-67 PI (&amp;gt;15%: 88% vs. 69%, p &amp;lt;0.001), and stromal TILs (median score: 40% vs. 10%; p &amp;lt; 0.001). PD-L1 IC status was not associated with patient age. Among histologic subtypes, PD-L1+ tumors were more frequently medullary type (31% vs. 6%) and less frequently metaplastic type (4% vs 10%). At time of this analysis, median follow-up for IDFS and OS were 11 years and 7.2 years, respectively. By univariable analysis, absence of PD-L1 IC expression was associated with poorer IDFS (median: 15.5 vs. 20 years, p = 0.04) and OS (9.5 vs. 17.5 years, p &amp;lt; 0.05).By multivariable analysis, tumor size, stromal TILs, nodal status, and adjuvant chemotherapy (CTX) were significantly associated with IDFS. Age, stromal TILs, nodal status, and receipt of adjuvant CTX were associated with OS. PD-L1+ tumors trended toward improved IDFS (statistical significance not reached), HR: 0.68 (95% CI: 0.45-1.03, p= 0.068) but not OS: 0.90 (95% CI: 0.52-1.57, p= 0.32). Conclusion: Using the PD-L1 SP142 companion assay, almost half of early-stage TNBC were PD-L1+ (IC). However, PD-L1 expression correlated with increasing tumor size and nodal burden, as well as histologic grade, Ki-67 PI, stromal TILs and lymphocyte-enriched subtypes. PD-L1 was associated with improved IDFS and OS in univariable analysis but not multivariable analysis. The majority of the PD-L1+ tumors (73%) had IC scores ≤10%, with heterogeneous tumoral staining. Given the low (1%) assay threshold for positivity, these data emphasize the utility of evaluating PD-L1 in whole tumor sections rather than tissue cores. Citation Format: Jodi M Carter, Mei-Yin C Polley, Jason P Sinnwell, Roberto A Leon-Ferre, Fergus J Couch, Krishna R Kalari, Judy C Boughey, Minetta C Liu, Daniel W Visscher, Matthew P Goetz. Frequency, characteristics and prognostic factors of PD-L1+ triple negative breast cancer using the PD-L1 SP142 companion assay [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD1-08.

Abstract P1-18-02: Outcomes of patients with ER+/HER2+ non-metastatic breast cancer treated with trastuzumab without chemotherapy

Abstract Purpose: The development of trastuzumab has significantly improved prognosis and treatment of Her2 positive breast cancer. The efficacy of trastuzumab monotherapy is limited and thus standard of care is to combine trastuzumab with chemotherapy. Yet for those who cannot tolerate chemotherapy, there is no randomized data comparing no trastuzumab with trastuzumab monotherapy in the non-metastatic setting. We therefore examined the outcomes of non-metastatic patients treated with trastuzumab without chemotherapy in the National Cancer Database (NCDB). Methods: We included female patients from 2013-2016 with clinical stage I-III breast cancer who received surgery with ER+/HER+ disease. Patients treated with Her2 therapy after 2013 had their treatment classified under immunotherapy, whereas those treated before 2013 had Her2 therapy classified under chemotherapy. Exclusion criteria included male sex, prior cancer history, and clinical stage IV disease. We also excluded patients with pathologic stage 0 (DCIS), stage IV, or unknown pathologic stage. Treatments compared included chemotherapy (CT), adjuvant hormone therapy alone (HT), combination HT + trastuzumab (HT+T), and no adjuvant treatment (NT). Pearson chi square analysis, one-way ANOVA, and the Kaplan Meier method was used to evaluate the differences in clinical characteristics for the treatment groups and effects of treatment on overall survival. Results: We identified 46,025 patients who met eligibility criteria. The median follow-up was 31 months (SD 13.16) for CT, 30 months (SD 14.07) for HT, 30 months (SD 12.87) for HT + T, and 27 months (SD 14.61) for NT. Most patients received standard of care with CT (78%, n=36008), 12% (n=5632) received adjuvant HT without T (HT), 3% (n=1157) were treated with HT+T, and 12% (n=2669) with NT. There was a higher representation of elderly patients &amp;gt;70 years old in the HT (41%) and HT +T (51%) and NT arm (38%) compared to the CT arm (13%). There was a higher representation of lobular histology specifically in the HT + T arm (52%) compared to CT (11%), HT (11%), or NT arm (11%). There was a higher representation of patients with Charlson Deyo Comorbidity Scores of 1-2 (vs. 0) in the HT (21%) and HT +T arms (21%) compared to the CT (15%) or NT (18%) arms. There was a higher representation of node positive patients (N1-3 vs. N0) in the CT (38%) and HT+T (27%) groups vs. the HT (13%) and NT (16%) arms. Similarly, there were more patients with high grade disease (G3) and lymphovascular invasion (+LVI) in the CT (48% G3, 25% +LVI) and HT+T (45% G3, 20% +LVI) arms vs. in the HT (30% G3, 12% +LVI) and NT (39% G3, 15% +LVI) arms. Medicare patients were more likely to be treated with HT +T (58%) or HT (50%) than CT (24%) or NT (45%) which likely reflects the overlap of Medicare and older age. As compared to the standard of care CT arm, the patients treated without CT, had significantly worse overall survival. There was no improvement in OS for HT+T vs. HT without T. Hazard ratios for treatment regimens without CT were significantly worse with a HR 2.26 (95% CI 0.4-1.9) for HT without T, 3.01 (95% CI 0.3-2.3) for HT + T, and 4.37 (95% CI 3.7-5.1) for NT (p&amp;lt;0.0001). Conclusions: This is the largest retrospective analysis of US patients with ER+/HER2+ non-metastatic breast cancer. Those treated with HT + T (vs. CT, HT, and NT) are more likely to have lobular histology. Patients treated with HT+T (vs. HT) are more likely to have more aggressive disease including higher nodal stage, higher grade, and the presence of LVI. Those treated with HT+T (vs. CT) are more likely to be older. We fail to identify an OS benefit with HT + T compared to HT alone though further analysis including a multivariate analysis and propensity score matching will further elucidate the outcome of this group. Citation Format: Susanna Nguy, S. Peter Wu, Cheongeun Oh, Naamit K Gerber. Outcomes of patients with ER+/HER2+ non-metastatic breast cancer treated with trastuzumab without chemotherapy [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-18-02.

Expression of CD133 is associated with poor prognosis in stage II colorectal carcinoma.

CD133 is currently believed to be one of the best colorectal cancer stem cell markers. This study aimed to evaluate prognostic significance of CD133 expression in colorectal cancer patients.A total of 303 patients with stage I to III colorectal cancer who underwent curative surgical resection from 2003 to 2008 at a single institution were included. CD133 expression was evaluated using immunohistochemical staining, and clinicopathological data were retrospectively reviewed. The patients were dichotomized after scoring CD133 expression (0 to 2+: low CD133 expression vs 3+ to 4+: high CD133 expression) according to the extent of area of CD133 positive tumor cells (<50% vs ≥50%) and pattern of staining (membranous staining of the luminal surface and/or staining of cellular debris in the tumor glands and cytoplasm).The 5-year overall survival (OS) (61.9% vs 80.2%, P = .001) and disease-free survival (64.8% vs 75.8%, P = .026) were poorer in the high CD133 expression group than the low CD133 expression group. In the multivariate analysis for risk factors of OS in the whole population, higher nodal stage (N2 compared to N0: hazard ratio [HR] 3.141; 95% confidence interval [CI] 1.718–5.744, P < .001), perineural invasion (HR 2.262; 95% CI 1.347–3.798, P = .002) and high CD133 expression (HR 1.929; 95% CI 1.221–3.048, P = .005) were independent poor prognostic factors of OS. Subgroup analyses according to each TNM stage revealed that CD133 expression was associated with OS only within the stage II patients (HR 3.167 95% CI 1.221–8.216, P = .018). Furthermore, the stage II patients demonstrating the high CD133 expression showed survival benefit of adjuvant chemotherapy, regardless of high-risk feature positivity (HR 0.201 95% CI 0.054–0.750, P = .017).High CD133 expression is correlated with poor prognosis in colorectal cancer patients after radical resection. The CD133 expression may serve as a more potent and informative biomarker for prognosis than conventional high-risk features in the stage II colorectal cancer patients.

Clinical Predictors of Laryngeal Preservation Rate in Stage III-IV Laryngeal Cancer and Hypopharyngeal Cancer Patients Treated with Organ Preservation

Purpose:To determine factors affecting laryngeal preservation rate in laryngeal and hypopharyngeal cancer patients treated with organ preservation.Material and Methods:Retrospective study examining stage III to IV laryngeal and hypopharyngeal cancer patients who have been treated with organ preservation. Conventional radiation must be applied in all patients with minimum dose of 45 Gray. Weekly or triweekly chemotherapy can be adding during radiation. Salvage surgery should be considered in residual disease or local recurrence. Kaplan-Meier was used for survival analysis and, Log rank test and Cox proportional hazard test were used for uni and multivariate analysis.Results:From January 2010 to October 2014, there were 69 patients treated with laryngeal preservation and 53 patients received radiation dose 61-70 Gray. After completing radiation, we found that 44 patients have no residual tumor within 6 months and 33 patients can preserve their functional larynx later with complete response (median follow up 6 mo, range 0-46.3 mo). The 1-year, 2-year and 3-year laryngeal preservation rate was 49%, 36 % and 32 % respectively. On univariate analysis, lower nodal stage (p = 0.008), stage III disease (p = 0.046), tumor volume <10 ml (p = 0.005), no true vocal cord involvement (p = 0.016), dose 61-70 Gray (p < 0.001) and no interruption of treatment (p = 0.017) have better laryngeal preservation rates. ECOG performance status 2, higher nodal stage, stage IV, presence of true vocal cord involvement, upper airway obstruction before/during radiation and radiation dose below 61-70 Gray had an effect on worse overall survival when evaluated with univariate analysis statistical significance. Conclusion:For factors that affected laryngeal preservation in our study were nodal stage, group stage, tumor volume, true vocal cord involvement, radiation dose and treatment break time more than one week with statistical significance.

Prognostic importance of 18F-fluorodeoxyglucose uptake by positron emission tomography for stage III non-small cell lung cancer treated with definitive chemoradiotherapy

ObjectivesSurvival heterogeneity exists among patients with non-small cell lung cancer (NSCLC), even within the same stage. We aimed to evaluate the prognostic role of pre-treatment maximum standardized uptake value (SUVmax) in patients treated with definitive concurrent chemoradiotherapy for stage III NSCLC. Materials and methodsBetween 2010 and 2017, 103 patients with stage III NSCLC who underwent 18F-FDG PET/CT at the time of diagnosis were included in the study. ResultsHigher tumor stages were correlated with higher pre-treatment SUVmax of lymph nodes (LNs) (p=0.005) but were not correlated with higher SUVmax of primary tumor (PT) (p=0.2). The median SUVmax of LNs was 2.84, 8.06, and 11.11 in stage IIIa, IIIb and IIIc, respectively. Higher nodal stage was also correlated with higher SUVmax of LNs (p=0.01). According to ROC analysis, there was no significant cut-off value of SUVmax observed for PT, therefore continuous variables were used for survival analyses. The best SUVmax cut-off was ‘3.5’ for the LNs, therefore the SUVmax of LNs was evaluated as both a dichotomous and a continuous variable. Pre-treatment SUVmax of PT did not predict survival outcomes but both the continuous and dichotomous variables of SUVmax of LNs predicted RFS and OS. Nodal stage (N0–2 vs N3) and AJCC stage (IIIa vs IIIb vs IIIc) were the other prognostic factors. ConclusionsPre-treatment SUVmax of LNs had prognostic value in patients treated with definitive concurrent chemoradiotherapy for stage III NSCLC. In future trials, pre-treatment SUVmax of the LNs would serve as a guide for patients who might benefit from more aggressive treatments.

Immunohistochemical Expression of MMR Proteins with Clinicopathological Correlation in Colorectal Cancer in Egypt.

BACKGROUND:Microsatellite instability (MSI) is the genetic pathway underlying 15% of sporadic colorectal carcinoma (CRC) and hereditary non-polyposis CRC. MSI-H CRC has a distinct clinicopathological characteristic including excess mucin and signet ring component, proximal colon, Crohn’s like reaction, lymphocytic infiltration, and better survival.AIM:This research aims to screen Egyptian CRC patients for MSI status by IHC testing of expression of the MMR proteins in correlation to its clinicopathological features.MATERIAL AND METHODS:Immunohistochemistry study for mismatch repair proteins (MMR) was done on 115 cases of CRC. Their expressions were assessed and correlated to clinicopathological parameters in an attempt to obtain the most significant predictors of MSI.RESULTS:MSI (low and high) represents 67% of the study cases. The most frequent expression pattern was combined loss of MLH, and PMS2 (38% of MSI) followed by a combined loss of MSH2, and MSH6 (29% of MSI). There was significant correlation of expression pattern of MMR proteins with the laterality, lymphovascular emboli, perineural invasion, grade, T stage, N stage, signet ring component, tumor infiltrating lymphocyte, and peritumoral lesion (0.014, 0.035, 0.012, 0.033, 0.013, 0.000, 0.041, 0.012, and 0.009 respectively). Proximal location (right sided) and lower grade, higher nodal stage, and marked TIL were selected as predictors of MS-H CRC (0.005, 0.031, 0.025, and 0.000 respectively).CONCLUSION:All clinicopathological and histological parameters should be assessed in CRC for the sake of predicting MSI. The optimal approach to MSI evaluation is (IHC) assessment of MMR proteins.

Opportunities for use of radiation therapy in penile cancer based on patterns of care in the United States from 2007 to 2013.

Background:Radiation therapy (RT) is an effective modality for the treatment of squamous cell carcinomas of the penis. The National Comprehensive Cancer Network recommends consideration of primary radiation for penile preservation, in surgically unresectable tumors, and as adjuvant therapy for positive margins, bulky groin nodes or pelvic nodes. We performed a population-based analysis to evaluate the usage of RT in penile cancer from 2007 to 2013.Methods:We used the Surveillance, Epidemiology and End Results (SEER) database to identify men diagnosed with squamous cell carcinoma of the penis from 2007 to 2013. Patients were grouped as early stage (T1–T2N0), locally advanced (T3–T4N0), node-positive (T1xN1–3) and metastatic. We used linear regression model to test for factors associated with adjuvant radiation in node-positive patients.Results:We identified 2200 men diagnosed with penile cancer between 2007 and 2013. Of these, 66.4% had early stage, 10.7% had locally advanced, 15.5% had node-positive, 3.2% had metastatic cancer. Among patient with early stage cancer, RT was used in 14 patients (1.0%) and postoperative radiation in an additional 45 patients (3.1%). Among 340 patients with node-positive cancer, 62.1% received surgery alone, 5.6% radiation alone, 21.8% surgery with adjuvant radiation, and 10.6% neither surgery nor radiation. Of patients who had surgery, 26.0% had adjuvant radiation. On univariate analysis, higher nodal stage (N2–3 versus N1) was associated with adjuvant radiation (p = 0.02), while there was a trend for higher T-stage (T3/T4 versus T1/T2) (p = 0.08) and history of prior malignancy (p = 0.06). On multivariate analysis, only higher nodal stage (N2–3 versus N1) was associated with use of adjuvant radiation [hazard ratio (HR) 1.94, p = 0.03].Conclusions:A small percentage of patient who are eligible for primary or adjuvant RT in the United States receive this treatment. Further work should be done to assess barriers to use of radiation in patients with penile cancer.

Differential prognostic relevance of patho-anatomical factors among different tumor-biological subsets of breast cancer: Results from the adjuvant SUCCESS A study

ObjectivesIn breast cancer, large tumor size, positive nodal stage and a triple-negative tumor subtype are associated with reduced survival, but the interactions between these prognostic factors are not well understood. Material and methodsHere we re-evaluated the impact of tumor size, nodal stage and tumor subtype on disease-free survival (DFS), overall survival (OS), distant disease-free survival (DDFS) and breast cancer specific survival (BCSS) in a retrospective analysis using data from the adjuvant SUCCESS A trial. Subgroup analyses were conducted to assess whether the effect of tumor size and nodal stage on survival depended on tumor subtype. ResultsIncreasing tumor size, higher nodal stage and triple negative breast cancer (TNBC) were associated with unfavorable prognosis (all p < 0.001). There was no significant interaction between tumor subtype and tumor size (p > 0.5 for all four survival endpoints), but we found significant interactions between tumor subtype and nodal stage (p < 0.05 for all four survival endpoints), with no differences in survival among tumor subtypes for patients with pN0 tumors (all p > 0.05) and pronounced differences in survival among tumor subtypes for patients with positive nodal stage (all p < 0.001). ConclusionsThis analysis confirms tumor size, nodal stage and tumor subtype as independent prognostic factors in high-risk early breast cancer. Nodal-positive patients with TNBC had a considerably worse outcome compared to nodal-positive patients with another tumor subtype. This underlines the importance for early detection particularly for patients with TNBC. Trial registrationEudraCT 2005-000490-21; ClinicalTrials.gov Identifier: NCT02181101.

Prognostic significance of p16 & p53 immunohistochemical expression in triple negative breast cancer

Backgroundp16 and p53 genes are frequently mutated in triple negative breast cancer & prognostic value of these mutations have been shown; however, their role as immunohistochemical overexpression has not been fully validated. Therefore we aimed to evaluate the association of p16 and p53 overexpression in triple negative breast cancer with various prognostic parameters.MethodsTotal 150 cases of triple negative breast cancers were selected from records of pathology department archives that underwent surgeries at Liaquat National hospital, Karachi from January 2008 till December 2013. ER, PR and Her2neu immunohistochemistry were re-performed to confirm triple negative status. p16 & p53 immunohistochemistry was performed on all cases and association with various clinicopathologic parameters was determined.ResultsMean age of the patients involved in the study was 48.9 years. Most of the patients presented at stage T2 with a high mean ki67 index i.e. 46.9%. 42.7% of cases had nodal metastasis. Although 84% cases were of invasive ductal carcinoma; however a significant proportion of cases were of metaplastic histology (9.3%). Fifty-one percent (76 cases) of cases showed positive p53 expression while 49% (74 cases) were negative. Higher percentage of p53 expression was found to correlate with higher T stage, high ki67 index and higher nodal stage. On the other hand, strong intensity of p53 expression was positively correlated with higher tumor grade and ki67 index. Seventy-one percent (98 cases) of cases showed positive p16 expression, whereas 24.8% (34 cases) were negative and 3.6% (5 cases) showed focal positive p16 expression. However, no significant association was found between p16 expression and various clinical and pathologic parameters. Similarly, no significant association of either p16 or p53 over-expression was noted with recurrence status of patients.ConclusionOn the basis of significant association of p53 over-expression with worse prognostic factors in triple negative breast cancer, therefore we suggest that more large scale studies are needed to validate this finding in loco-regional population. Moreover, high expression of p16 in triple negative breast cancer suggests a potential role of this biomarker in triple negative breast cancer pathogenesis which should be investigated with molecular based research in our population.

Increased expression of immediate early response gene 3 protein promotes aggressive progression and predicts poor prognosis in human bladder cancer

BackgroundImmediate early response gene 3 (IER3) is a stress-inducible gene, which exerts diverse effects in regulating cell apoptosis and cell cycle. Growing evidence shows that IER3 functions either as an oncogene or a tumor suppressor in various human cancers with a cancer type-dependent manner. However, the involvement of IER3 in human bladder cancer (BCa) has not been elucidated. In the current study, we aimed to investigate the expression pattern and the clinical significance of IER3 in BCa.MethodsWe performed immunohistochemistry analysis to examine the subcellular localization and the expression levels of IER3 protein in 88 BCa specimens obtained from Department of Pathology in Massachusetts General Hospital. The associations of IER3 protein expression with various clinicopathological features and patients’ overall survival were statistically evaluated.ResultsIER3 protein was mainly expressed in the cytoplasm in bladder cancer cell. Of 88 BCa tissue specimens, 39 (44.3%) showed high expression of IER3 protein and 49 (55.7%) showed low expression. High IER3 protein expression was significantly associated with high pathologic nodal stage (p = 0.018). Kaplan-Meier analysis revealed that the overall survival of BCa patients with overexpression of IER3 protein was shorter than that with low expression (p < 0.01). Multivariate analysis by Cox regression further identified IER3 as an independent prognostic factor of BCa patients (p = 0.010).ConclusionsOur findings suggest for the first time that the increased expression of IER3 protein may promote the aggressive progression of BCa. Importantly, IER3 may be a potential prognostic marker for BCa patients.

Is there a benefit to adjuvant radiation in stage III penile cancer after lymph node dissection? Findings from the National Cancer Database

ObjectiveThe role of adjuvant radiation in advanced penile cancer (PC) is unknown. We used the National Cancer Database (NCDB) to determine factors associated with receiving adjuvant radiation (aXRT) and their influence on prognosis in men who underwent inguinal lymph node dissection (ILND) for stage III disease. Materials and methodsWe queried the NCDB from 1998–2012 for all men with PC who had pathologic nodal status and aXRT data available. Clinical and pathologic variables associated with aXRT were examined using chi-square testing. Logistic regression evaluated the odds of receiving aXRT while multivariate Cox regression analysis evaluated the influence of aXRT on overall survival (OS). ResultsA total of 589 patients underwent ILND for stage III PC with 23% (N = 136) receiving aXRT. Mean age was 61.8 ±13.7 years. Factors associated with receiving aXRT included higher pathologic nodal stage (MV OR 1.85, 95% CI: 1.13–3.05), while greater distance of travel (MV OR 0.48, 95% CI: 0.25–0.92), and treatment in an academic setting (MV OR 0.53, 95% CI: 0.35–0.81) were inversely associated with receiving aXRT. On Cox regression analysis, aXRT improved OS (combined HR 0.58, 95% CI: 0.39–0.86), which appeared to have been driven by higher nodal burden (N2: HR 0.53, 95% CI: 0.32–0.88; N1: HR 1.36, 95% CI: 0.60–3.09). ConclusionsDeterminants of aXRT delivery in stage III PC appear to be related to the proximity to community cancer centers and greater nodal burden. We find evidence of a survival benefit with the use of aXRT, particularly in those with higher nodal stage. Multi-institutional studies are needed to confirm these findings and improve treatment algorithms for high-stage PC.