Decreased Disease Specific Survival Research Articles

Regulator of G protein signaling 16 restrains apoptosis in colorectal cancer through disrupting TRAF6-TAB2-TAK1-JNK/p38 MAPK signaling

Colorectal cancer (CRC) remains a major global cause of cancer-related mortality, lacking effective biomarkers and therapeutic targets. Revealing the critical pathogenic factors of CRC and the underlying mechanisms would offer potential therapeutic strategies for clinical application. G protein signaling (RGS) protein family modulators play essential role within regulating downstream signaling of GPCR receptors, with function in cancers unclear. Our study focused on the expression patterns of RGS proteins in CRC, identifying Regulator of G protein signaling 16 (RGS16) as a prospective diagnostic and therapeutic target. Analyzing 899 CRC tissues revealed elevated RGS16 levels, correlating with clinicopathological features and CRC prognosis by immunohistochemistry (IHC) combined with microarray. We confirmed the elevated RGS16 protein level in CRC, and found that patients with RGS16-high tumors exhibited decreased disease-specific survival (DSS) and disease-free survival (DFS) compared to those with low RGS16 expression. Functional assays demonstrated that RGS16 promoted the CRC progression, knockdown of RGS16 led to significantly increased apoptosis rates of CRC in vitro and in vivo. Notably, we also confirmed these phenotypes of RGS16 in organoids originated from resected primary human CRC tissues. Mechanistically, RGS16 restrained JNK/P38-mediated apoptosis in CRC cells through disrupting the recruitment of TAB2/TAK1 to TRAF6. This study provides insights into addressing the challenges posed by CRC, offering avenues for clinical translation.

Prognostic capacity of PIV (pan-immune-inflammation value) in patients with head and neck squamous cell carcinoma

IntroductionThe pan-immune-inflammation value (PIV), an index that results from the following ratio: (neutrophils × monocytes × platelets)/lymphocytes, has been proposed as a prognostic biomarker in different tumour models. The aim of this study is to analyse the prognostic capacity of PIV in patients with head and neck squamous cell carcinoma (HNSCC). Patients and methodsRetrospective study of 1187 patients with HNSCC treated at our centre between 2000−2017. PIV value was obtained from an analysis performed within 3 weeks prior to the start of treatment. ResultsPIV value was significantly associated with toxic consumption (0.001), tumour location (0.0001), tumour extension (0.0001), and histological grade (0.016). Four categories were defined based on PIV value using a recursive partitioning analysis: category I: PIV < 136.3 (n = 118, 9.9%), category II: PIV 136.3–451.1 (n = 594, 50.0%), category III: PIV 451.1−1,141.2 (n = 357, 30.1%), and category IV: PIV > 1141.2 (n = 118, 9.9%). A significant and ordered decrease in disease-specific survival was observed as the PIV category increased. This decrease in survival was independent of the type of treatment, tumour extension, or location of the primary tumour. The PIV category was and independent prognostic factor of disease-specific survival in a multivariable study. ConclusionsPIV is a prognostic biomarker in patients with HNSCC.

Capacidad pronóstica del PIV (pan-immune-inflammation value) en pacientes con carcinoma escamoso de cabeza y cuello

IntroductionThe pan-immune-inflammation value (PIV), an index that results from the following ratio: (neutrophils×monocytes×platelets) / lymphocytes, has been proposed as a prognostic biomarker in different tumor models. The aim of this study is to analyze the prognostic capacity of PIV in patients with head and neck squamous cell carcinoma. Patients and methodsRetrospective study of 1,187 patients with head and neck squamous cell carcinoma treated at our center between 2000-2017. PIV value was obtained from an analysis performed within 3 weeks prior to the start of treatment. ResultsPIV value was significantly associated with toxic consumption (0.001), tumor location (0.0001), tumor extension (0.0001), and histological grade (0.016). Four categories were defined based on PIV value using a recursive partitioning analysis: category i: PIV<136.3 (n=118, 9.9%), category ii: PIV 136.3-451.1 (n=594, 50.0%), category iii: PIV 451.1-1,141.2 (n=357, 30.1%), and category iv: PIV>1,141.2 (n=118, 9.9%). A significant and ordered decrease in disease-specific survival was observed as the PIV category increased. This decrease in survival was independent of the type of treatment, tumor extension, or location of the primary tumor. The PIV category was an independent prognostic factor of disease-specific survival in a multivariable study. ConclusionsPIV is a prognostic biomarker in patients with head and neck squamous cell carcinoma.

Cancer cell genotype associated tumor immune microenvironment exhibits differential response to therapeutic STING pathway activation in high-grade serous ovarian cancer

BackgroundHigh-grade serous ovarian carcinoma (HGSC) is the most lethal gynecologic malignancy characterized by resistance to chemotherapy and high rates of recurrence. HGSC tumors display a high prevalence of tumor suppressor...

Prognostic value of transcriptional expression of fibronectin type III domain-containing 4 (FNDC4) in head and neck carcinoma patients treated with chemoradiotherapy

PurposeFNDC4 gene encodes the fibronectin type III domain-containing 4 protein. Elevated expression of FNDC4 has been associated with poor prognosis in several types of cancer. There are no studies that have evaluated the prognostic capacity of FNDC4 in patients with head and neck cancer (HNSCC). The aim of our study was to analyze the relationship between the transcriptional expression of FNDC4 and prognosis in HNSCC patients.MethodsWe determined the transcriptional expression of FNDC4 in 67 patients with advanced-stage HNSCC (III–IV) treated with chemoradiotherapy. The FNDC4 expression was categorized according to the disease-specific survival with a recursive partitioning analysis.ResultsThere were significant differences in disease-specific survival as a function of the level of FNDC4 transcriptional expression. The 5-year disease-specific survival for patients with high FNDC4 expression (n = 44, 65.7%) was 32.9% (95% CI: 16.5–49.3%), and for patients with low expression (n = 23, 34.3%) it was 85.4% (95% CI: 70.2–100%) (P = 0.0001). Patients with a high FNDC4 expression had poorer local (P = 0.097), regional (P = 0.008), and distant (0.034) recurrence-free survival. The results of a multivariate analysis showed that patients with a high FNDC4 expression had a 6.15-fold increased risk of death as a consequence of the HNSCC (95% CI: 1.71–22.06).ConclusionFNCF4 transcriptional expression was significantly related to the disease-specific survival of HNSCC patients treated with chemoradiotherapy. Patients with elevated FNDC4 expression had a significant decrease in disease-specific survival.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12094-022-02870-3.

Expanding Criteria for Prognostic Stage IA in Hormone Receptor-Positive Breast Cancer.

The prognostic significance of patients with low-risk recurrence score (RS) results in the context of the American Joint Committee on Cancer (AJCC) eighth edition pathologic prognostic staging has not been investigated. We evaluated if expanded RS criteria can be considered for downstaging in AJCC pathologic prognostic staging. Using Surveillance, Epidemiology, and End Results data, we identified patients with T1-3N0-3M0 hormone receptor-positive, HER2-negative breast cancer treated from 2010 to 2015 with follow-up data through 2016. We evaluated TNM categories, grade, and RS result. The primary outcome measured was 5-year disease-specific survival (DSS) of patients with low-risk RS results not already pathologic prognostic stage IA, determined by T and N categories per AJCC eighth edition. All statistical tests were 2-sided. Of 154 050 patients with median follow-up of 49 months (range = 0-83), RS results were obtained in 60 886 (39.5%): RS was less than 11 in 13 570 (22.3%); 11-17 in 22 719 (37.3%); 18-25 in 16 521 (27.1%); and 26 or higher in 8076 (13.3%). Five-year DSS for pathologic prognostic stage IA patients (n = 114 910, 74.6%) was 98.8%. Among N0-1 patients with a RS less than 18 not staged as pathologic prognostic stage IA by current criteria, 5-year DSS was excellent and not statistically significantly different than for pathologic prognostic stage IA patients (97.2%-99.7%; P > .05). For those with a RS of 18-25, there was a small decrease in DSS for T2N0 (2.3%) and modest decrease for T1-2N1 (4.2%-6.4%) compared with pathologic prognostic stage IA patients (P < .001). Patients with a RS less than 18 have excellent 5-year DSS regardless of T category for N0-1 disease suggesting further modification of the AJCC staging system using this cutoff.

SMAD4 Expression in Renal Cell Carcinomas Correlates With a Stem-Cell Phenotype and Poor Clinical Outcomes.

Renal cell carcinoma (RCC) is the most lethal neoplasm of common urologic cancers with poor prognoses. SMAD4 has a principal role in TGF-β (Transformis growth factorβ)-induced epithelial to mesenchymal transition (EMT) as a key factor in gaining cancer stem cell (CSC) features and tumor aggressiveness. This study aimed to evaluate the expression patterns and clinical significance of SMAD4 in RCC and the impact of its targeting on stem cell/mesenchymal cells and EMT characteristics in renal spheroid derived cells (SDCs) compared to parental cells (PCs) in RCC. The expression pattern and clinical significance of SMAD4 was evaluated in RCC. SDCs were enriched using a sphere culture system. Then SDCs and their PCs were compared with respect to their sphere and colony formation, expression of putative CSC markers, invasiveness as well as expression of genes, including stemness/mesenchymal, SMAD4 and TGFβ1genes. Finally, the effect of SMAD4 knockdown on SDCs was analyzed. We demonstrated that SMAD4 is positively correlated with decreased disease specific survival (DSS) in RCC patients and clear cell RCC (ccRCC) subtype and associates with poor DSS in patients with RCC, especially in ccRCC as the most metastatic RCC subtype. SDCs exhibited higher stem cell/mesenchymal properties. Inhibition of SMAD4 in PCs accelerated the dissociation of SDCs and decreased their clonogenicity, invasiveness, expression of mesenchymal markers and expression of SMAD4 and TGFβ1 genes compared to SDCs before transfection. We suggest that targeting SMAD4 may be useful against renal CSCs and may improve RCC prognosis.

Mortalité et facteurs pronostiques du myxofibrosarcome — analyse rétrospective de 109 patients

BackgroundMyxofibrosarcoma (MFS) is one of the most common sarcoma subtype in elderly patients. They are reported to recur locally independently of the tumour grade in 30–40% of cases and metastases are reported to develop in high-grade tumours in 20–35% cases. As MFS is a rare diagnosis, data investigating specific survival and independent risk factors are lacking and have mostly been limited to single orthopaedic oncology centre studies so far. Thus we set up a pathology-based retrospective study and analyzed all MFS diagnosed in our institution with the following aims: (1) analysis of independent risk factors for overall survival, disease specific survival, local recurrence-free survival and distant metastasis free survival following resection of MFS and (2) analysis of resection margin status. HypothesisHigh-grade MFS have a low survival distant metastasis free survival and local recurrence-free survival is dependent on surgical margin status. Patients and methodsWe retrospectively analysed 109 patients (median 66 years [range, 21–96]) diagnosed with MFS and a median follow-up of 42 months at one centre between 1990 and 2014. Tumor-associated survival, including competing risk analysis, and prognostic factors for local recurrence, metastatic disease and death from disease were investigated and included in a multivariate analysis. ResultsOverall survival was 79% [95% CI: 71.9–87.5] at 3 years and 76% [95% CI: 67.4–84.6] at 5 years. Disease specific survival was 85% [95% CI: 78.4–92.2] at 3 years and 80% [95% CI: 72.2–88.2] at 5 years. There were local recurrences in 11/109 patients (10%). Local recurrence-free survival (LRFS) was 95% [95% CI: 92.0–99.8] at 3 and 88% [95% CI: 84.3–96.4] at 5 years. Metastatic disease (n=25; 23%) occurred after a median follow-up of 10 months. Distant metastasis free survival was 78% [95% CI: 69.9–85.9] at 3 and 77% [95% CI: 68.4–84.8] at 5 years. R1 status at primary resection was an independent risk factor for decreased local recurrence-free survival (OR: 8.5, 95% CI: 1.59–49.79 [p=0.01]). Grading was an independent risk factor for decreased disease specific survival (OR 13.4, 95% CI: 1.65–1734.84 [p=0.01]) and distant metastasis free survival (OR 16.2, 95% CI: 2.0–2110.5 [p=0.004]). Primary resection achieved R0 margins in 63 (58%) of 109 patients. Margins were adequate significantly more often (p<0.001) in patients treated primarily at a sarcoma centre (R0=58/68, 85%) than in those treated primarily at non-sarcoma centres (R0=5/41, 12%), whereby the latter significantly more often treated superficial tumours (p=0.001) with a size of less than 5cm (p<0.001). DiscussionPatients with high-grade MFS had a poorer prognosis with respect to Disease specific survival/Distant metastasis free survival than low-grade MFS. Local recurrence did not significantly affect disease specific survival. Level of evidenceIV.

Tumor-associated mortality and prognostic factors in myxofibrosarcoma – A retrospective review of 109 patients

BackgroundMyxofibrosarcoma (MFS) is one of the most common sarcoma subtype in elderly patients. They are reported to recur locally independently of the tumour grade in 30-40% of cases and metastases are reported to develop in high-grade tumours in 20-35% cases. As MFS is a rare diagnosis, data investigating specific survival and independent risk factors are lacking and have mostly been limited to single orthopaedic oncology centre studies so far. Thus we set up a pathology-based retrospective study and analyzed all MFS diagnosed in our institution with the following aims: (1) analysis of independent risk factors for overall survival, disease specific survival, local recurrence-free survival and distant metastasis free survival following resection of MFS; (2) analysis of resection margin status. HypothesisHigh-grade MFS have a low survival distant metastasis free survival and local recurrence free survival is dependent on surgical margin status. Patients and MethodsWe retrospectively analysed 109 patients (median 66 years [range, 21–96]) diagnosed with MFS and a median follow-up of 42 months at one centre between 1990 and 2014. Tumor-associated survival, including competing risk analysis, and prognostic factors for local recurrence, metastatic disease and death from disease were investigated and included in a multivariate analysis. ResultsOverall survival was 79% [95%CI: 71.9–87.5] at 3 years and 76% [95%CI: 67.4–84.6] at 5 years. Disease specific survival was 85% [95%CI: 78.4–92.2] at 3 years and 80% [95%CI: 72.2–88.2] at 5 years. There were local recurrences in 11/109 patients (10%). Local recurrence free survival (LRFS) was 95% [95%CI: 92.0–99.8] at 3 and 88% [95%CI: 84.3–96.4] at 5 years. Metastatic disease (n=25; 23%) occurred after a median follow-up of 10 months. Distant metastasis free survival was 78% [95%CI: 69.9–85.9] at 3 and 77% [95%CI: 68.4–84.8] at 5 years. R1 status at primary resection was an independent risk factor for decreased Local Recurrence-free survival (OR: 8.5, 95%CI: 1.59–49.79 [p=0.01]). Grading was an independent risk factor for decreased Disease specific survival (OR 13.4, 95%CI: 1.65–1734.84 [p=0.01]) and Distant metastasis free survival (OR 16.2, 95%CI: 2.0–2110.5 [p=0.004]). Primary resection achieved R0 margins in 63 (58%) of 109 patients. Margins were adequate significantly more often (p<0.001) in patients treated primarily at a sarcoma centre (R0=58/68, 85%) than in those treated primarily at non-sarcoma centres (R0= 5/41, 12%), whereby the latter significantly more often treated superficial tumours (p=0.001) with a size of less than 5cm (p<0.001). DiscussionPatients with high-grade MFS had a poorer prognosis with respect to Disease specific survival/Distant metastasis free survival than low-grade MFS. Local recurrence did not significantly affect disease specific survival. Level of EvidenceIV.

Number of sentinel lymph nodes (SLN) removed in breast cancer (BC) patients undergoing sentinel lymph node biopsy (SLNB) in the province of Saskatchewan, Canada: Real-world experience.

e19240 Background: SLNB is considered standard of care for BC patient's undergoing surgery. This standard of care is based on several randomized, prospective clinical trials showing non inferiority of this procedure compared to full axillary lymph node dissection (FALND). Retrieval of less than 3 lymph nodes at the time of SLN biopsy has been shown to be associated with decrease in disease specific survival. In the NSABP B-32 study, removal of two SLN rather than one almost halved the false negative rate. SK has an area of 651,900 square kilometer, with a small population of 1,098,352. This population is widely distributed throughout the province with variable access to health care. This study provides us with a unique opportunity to see if data obtained in clinical trials can be replicated in community settings. Methods: After approval from SK Cancer Agency and research ethics board of University of SK. Female Patient’s with BC who underwent SLNB from Jan 2010 to Dec 2014, were identified using cancer registry. 529 charts were reviewed retrospectively. Exclusion criteria’s were Male BC, pathology other than invasive ductal or lobular, locally advanced or metastatic disease, T4 tumors, patients who received neo adjuvant therapy, patients who had declined or were unable to receive post-operative recommended adjuvant systemic or radiation therapy, patients with full axillary lymph node dissection. Data was analyzed using SAS 9.4 software. Results: Rate of 1, 2 and 3 or more SLN was 21, 35 and 44% respectively. The median number of lymph nodes retrieved were 2. 14% of patients had positive lymph nodes. 259/529 (48.9 %) of patients used both vital blue dye and radiotracer method for detection of SLN. In 510/529 (96.4%) radiotracer method was used to detect lymph nodes. Blue dye was used in 264/529 (49.9%). Median number of SLN retrieved using both methods were 2. No change in median number of SNL retrieved in different quadrants and central part of the breast were noted, the number remained 2. Conclusions: Our review showed that rate of single lymph node retrieval was lower than what is reported in US SEER data base study of 37%, however the number of median lymph node retrieval was 2 which is considered less than optimal with reported higher rate of false negative rate. We did not attempt to look at disease-specific survival as our sample size is small. Continued data evaluation of established practice is required to improve quality of care and replication of advances established in clinical trials.

Abstract P5-06-09: Comparative analysis of proposed strategies for incorporating biologic factors into breast cancer staging

Abstract Background: Tumor biology is an important prognostic factor in breast cancer. The 8th edition AJCC pathologic prognostic stage incorporates biologic factors (grade, ER, PR, and HER2 status) along with anatomic staging to improve risk stratification. Additional staging models have been proposed including Bioscore and Risk Score. The Bioscore assigns a score of 0-7 based on anatomic stage, ER, HER2, and grade. The Risk Score assigns a score of 0-3 to each anatomic stage group, with 1 point assigned for ER-negative, HER2-negative, or grade 3 status. The objective of this study was to compare the performance of these models in a large, population-based cohort of breast cancer patients. Methods: The Surveillance, Epidemiology and End Results Program (SEER) database was used to identify primary stage I-IV breast cancer patients diagnosed in 2010. Patients were excluded for inflammatory carcinoma, neoadjuvant therapy, and missing data on receptors or tumor grade. 5-year disease specific survival (DSS) estimates were calculated using Cox regression for each staging model: AJCC anatomic stage, AJCC pathologic prognostic stage, Bioscore and Risk Score. Harrell concordance index (C-index) and Akaike Information Criterion (AIC) were used to compare each model in predicting DSS, with higher C-index and lower AIC indicating better predictive value and model fit. Results: 21,901 patients were included with a median age was 60 years. Median follow up was 52 months. All four staging models stratified DSS survival, with stepwise increases in hazard ratios and decrease in DSS for each increase in risk category (Table). The C-index of each model with biologic factors was higher than for anatomic stage, with the Risk Score having the highest C-index (0.832 for the anatomic stage; 0.856 for pathologic prognostic stage; 0.855 for Bioscore; and 0.864 for Risk Score). AIC was lowest for Risk Score (27315 for anatomic stage; 26874 for prognostic stage; 27120 for Bioscore; and 26753 for Risk Score), suggesting the best model fit for staging. Discussion: Staging models incorporating biologic factors perform better than anatomic staging alone. The Risk Score has the lowest AIC and may be the easiest to use as it simply assigns 1 point each for ER-negative, HER2-negative, and grade 3 tumors to each anatomic stage. In addition, the Risk Score has the added benefit of being the only staging system to stratify stage IV disease. We advocate for consideration of the Risk Score as an alternative to the pathologic prognostic stage for ease of use, optimal communication with patients and providers, and to standardize future clinical trials. Table. 5-yr estimates of DSS in 21,464 breast cancer patients in 4 models of breast cancer stagingAnatomic Stage5-yr DSSPrognostic Stage5-yr DSSBioscore5-yr DSSRisk Score5-yr DSSIA98.6IA98.7098.9IA098.9IB96.3IB93.7199.1199.2IIA94.5IIA90.1297.5297.1IIB92IIB84.2393.2392.8IIIA83.3IIIA80.5488.3IIA096.7IIIB73.2IIIB72.3570.2197.7IIIC68.6IIIC53.3656.2291.0IV38.8IV38.8732.2386.8IIB096.6194.7290.4380.4IIIA092.8190.0274.9365.2IIIB096.0180.3269.6353.9IIIC063.3178.0268.2339.7IV061.7147.5230.3310.8 Citation Format: Olga Kantor, Jiangong Niu, Hui Zhao, Sharon H Giordano, Kelly K Hunt, Tari A King, Elizabeth A Mittendorf, Mariana Chavez-MacGregor. Comparative analysis of proposed strategies for incorporating biologic factors into breast cancer staging [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 P5-06-09.

Comparative Analysis of Proposed Strategies for Incorporating Biologic Factors into Breast Cancer Staging

Tumor biology is an important prognostic factor in breast cancer. This study aimed to compare three staging systems incorporating both biologic factors and anatomic staging (AJCC 8th-edition pathologic prognostic staging, Bioscore, and Risk Score) in a large population-based cohort. The Surveillance, Epidemiology and End Results program was used to select patients with primary stages 1-4 breast cancer diagnosed in 2010. Patients with inflammatory carcinoma, those with missing data for biologic factors, and those with stages 1-3 disease not treated with surgery were excluded from the study. Estimates of 5-year disease-specific survival (DSS) were calculated using the Kaplan-Meier method. The Harrel concordance index (C-index) and the Akaike Information Criterion were used to compare each model in terms of predicting DSS. The study included 21,901 patients with a median age of 60years. The median follow-up period was 52months. All the staging models stratified DSS, with a stepwise decrease in DSS for each increase in risk category or score. The C-index of each model incorporating biologic factors was higher than the C-index for anatomic staging alone (C-index: 0.832 vs. 0.856 for AJCC pathologic prognostic staging, 0.856 for Bioscore, and 0.864 for Risk Score, all p < 0.001). The staging systems incorporating biologic factors did not differ significantly in terms of model fit. Staging systems incorporating biologic factors perform better than anatomic staging alone. Implementation of the AJCC 8th-edition pathologic prognostic staging was an important initial step in the inclusion of tumor biology in staging. Given its simplicity and ease of use, the Risk Score should be given consideration as an alternative staging system.

Prognostic capacity of Systemic Inflammation Response Index (SIRI) in patients with head and neck squamous cell carcinoma.

Inflammation and immune evasion are associated with carcinogenesis. Systemic Inflammation Response Index (SIRI) has been proposed as a pretreatment peripheral blood biomarker. The aim of this study is to analyze its prognostic capacity in head and neck squamous cell carcinomas (HNSCC). We performed a retrospective study in 824 patients with HNSCC. SIRI was calculated by neutrophils*monocytes/lymphocytes. Using a recursive-partitioning analysis considering disease-specific survival (DSS) as dependent variable, three categories were defined according to SIRI value. Males, patients with history of toxic consumption, oropharyngeal or hypopharyngeal tumors, and advanced tumors had a significantly higher SIRI value. As SIRI increased, a significant decrease in DSS was observed. In a multivariable analysis, SIRI was an independent predictor of DSS. Moreover, SIRI was a significant predictor of local, regional, and distant recurrence-free survival. SIRI has independent prognostic capacity in HNSCC. Patients with higher SIRI have a significant decrease in DSS.

Comparison of preoperative myometrial invasion on MRI with intraoperative frozen section in predicting adverse prognostic factors and survival in endometrioid endometrial cancer

Aim: There are no studies that have evaluated the accuracy of the finding of myometrial invasion in each modality in predicting adverse prognostic factors and survival. We compared the association of myometrial invasion on MRI and frozen section with presence of adverse prognostic factors and decreased disease-specific survival (DSS) in endometrioid endometrial cance. Material and Methods: A total of 149 patients diagnosed and treated surgically for endometrioid endometrial cancer at a single institution between 2010 and 2017 were included in the study. Accuracies of radiological myometrial invasion and frozen section myometrial invasion in predicting the histopathological myometrial invasion, other adverse prognostic factors and DSS were compared.Results: Frozen section had an accuracy, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of 89.2%, 100.0%, 84.7%, 72.8% and 100.0%, respectively in diagnosing histopathological deep (≥50%) myometrial invasion with a kappa value of 0.876 (p<0.001). MRI had an accuracy, sensitivity, specificity, PPV and NPV of 71.3%, 55.8%, 80.6%, 63.2%, 75.3%, respectively with a kappa value of 0.392 (p<0.001) in predicting deep myometrial invasion. The accuracy of the finding of deep myometrial invasion on frozen section was higher than the finding of deep myometrial invasion on MRI in predicting the presence of adverse prognostic factors. However, the specificities and NPV’s were higher than their respective sensitivity and PPV values overall for both modalitiesd.Conclusion: Although MRI is frequently used in the preoperative evaluation of patients with endometrial cancer, the finding of deep myometrial invasion on MRI was not as accurate as that of frozen section in predicting the presence of adverse prognostic factors and poor survival. However, both test modalities demonstrated high specificity and NPV. As such both tests may provide higher efficacy in identifying patients without advanced disease who may not require complete lymph node dissection.

The pathologist's role in the detection of rare variants of bladder cancer and analysis of the impact on incidence and type detection.

Histology is one of the most important factors determining the prognosis of bladder cancers and rare variants are generally associated with decreased disease specific survival compared to pure transitional cell carcinomas. We believe that rare bladder cancer variants are likely underdiagnosed in the absence of a dedicated uro-pathologist in many centers. The objective of this study is to evaluate the contribution of a dedicated uro-pathologist on the identification of rare bladder cancer variants. We retrospectively analyzed the clinical and histological records of all patients which underwent a radical cystectomy and lymph node dissection between January 2000 and September 2015. The sample was divided in two groups: Group A, consists of patients who underwent radical cystectomy in the absence of a dedicated uro-pathologist at our institution, whereas the Group B consists of patients who underwent surgery when a dedicated uro-pathology service was available. We then evaluated the impact of a dedicated uro-pathologist on rare variants detection. One hundred thirty-seven out of 551 (24.9%) of patients who underwent RC had at least one rare variant. In Group A 38/238 (16%) of patients showed a rare variant, while 99/313 (31.6%; P<0.001) in group B. Furthermore, the diagnosis of sarcomatoid variant was statistically significantly less common in group A (P=0.0026). The concordance between final radical cystectomy histology and previous transurethral resection of bladder tumor (TURBT) histology was poor in both groups (overall 50.4%). The presence of a dedicated urological anatomical pathologist is of paramount importance and significantly increases the detection rate of non-transitional cell carcinoma bladder cancer types, but it does not increase the concordance rate between histological diagnoses in TURBT and radical cystectomy specimens.

Impact of Delayed Adjuvant Radiotherapy in the Survival of Women with Breast Cancer.

ObjectiveOur objective was to determine whether a delay in adjuvant radiotherapy is related to a decrease in relapse-free survival and disease-specific survival of women with operable breast cancer.MethodsData on 1000 patients diagnosed with breast cancer were recorded. The cohort was divided into five groups according to the timing of radiotherapy: ≤30 days, 31 to 60 days, 61 to 90 days, 91 to 120 days, and >120 days. The relapse-free survival and disease-specific survival were also calculated in relation to the number of patients.ResultsThis study found no statistical difference for delays in adjuvant radiotherapy in patients with early breast cancer, but we noted a statistical decrease in disease-specific survival in patients with locally advanced breast cancer receiving radiotherapy after a delay of at least 60 days.ConclusionWaiting times for radiotherapy should be as short as reasonably achievable, given the specific risk factors in the individual patient.

HLA-E expression and its clinical relevance in human renal cell carcinoma.

The non-classical human leukocyte antigen E (HLA-E) expression is frequently overexpressed in tumor diseases, transplants and virus-infected cells and represents an immunomodulatory molecule by binding to the receptors CD94/NKG2A, -B and –C on NK and T cells. Due to its immune suppressive features HLA-E expression might represent an important mechanism of tumors to escape immune surveillance.While an aberrant expression of the non-classical HLA-G antigen in human renal cell carcinoma (RCC) has been demonstrated to be associated with a worse outcome of patients and reduced sensitivity to immune effector cell-mediated cytotoxicity, the expression and function of HLA-E has not yet been analyzed in this tumor entity.Higher levels of HLA-E transcripts were detected in all RCC cell lines and tumor lesions, which were tested in comparison to normal kidney epithelium. Immunohistochemical staining of a tissue microarray (TMA) using the HLA-E-specific monoclonal antibody TFL-033 recognizing the cytoplasmic HLA-E α-chain as monomer revealed a heterogeneous HLA-E expression in RCC lesions with the highest frequency in chromophobe RCC when compared to other RCC subtypes. HLA-E expression did not correlate with the frequency of CD3+, CD4+, CD8+ and FoxP3+ immune cell infiltrations, but showed an inverse correlation with infiltrating CD56+ cells. In contrast to HLA-G, HLA-E expression in RCCs was not statistically significant associated with a decreased disease specific survival. These data suggest that HLA-E overexpression frequently occurs in RCC and correlates with reduced immunogenicity.

Pretreatment count of peripheral neutrophils, monocytes, and lymphocytes as independent prognostic factor in patients with head and neck cancer.

The purpose of this study was to analyze the prognostic value of pretreatment count of peripheral neutrophils, lymphocytes, monocytes, and neutrophil-to-lymphocyte ratio (NLR) in patients with head and neck squamous cell carcinoma (HNSCC). Local, regional, and distant recurrence-free survival and disease-specific survival were analyzed according to the count of neutrophils, lymphocytes, monocytes, and NLR. We observed a decrease in disease-specific survival as the quartile category of neutrophils, monocytes, and NLR increased. In the case of lymphocytes, patients in the lower quartile had lower disease-specific survival. Considering the disease-specific survival as the dependent variable, a recursive partitioning analysis classified the patients according to the neutrophil and monocyte counts. High pretreatment count of peripheral neutrophils and/or monocytes was independently related with worse prognosis in patients with HNSCC. Classification based on pretreatment neutrophil and monocyte counts enabled the identification of different prognostic profiles. © 2016 Wiley Periodicals, Inc. Head Neck 39: 219-226, 2017.

Missense mutations in the TP53 DNA-binding domain predict outcomes in patients with advanced oral cavity squamous cell carcinoma.

TP53 mutations have been linked to reduced survival in patients with oral cavity squamous cell carcinoma (OSCC). However, the impact of different types of TP53 mutations remains unclear. Here, we demonstrate that the carriage of missense mutations in the TP53 DNA binding domain (DBD missense mutations) is associated with decreased disease-specific survival (DSS) compared with wild-type TP53 (P=0.002) in a cohort of 345 OSCC patients. In contrast, DSS of patients bearing all of the remaining TP53 mutations did not differ from that observed in wild-type TP53 patients (P=0.955). Our classification method for TP53 mutations was superior to previously reported approaches (disruptive, truncating, Evolutionary Action score, mutations in L2/L3/LSH) for distinguishing between low- and high-risk patients. When analyzed in combination with traditional clinicopathological factors, TP53 DBD missense mutations were an independent prognostic factor for shorter DSS (P=0.014) alongside with advanced AJCC T- and N-classifications and the presence of extracapsular spread. A scoring system that included the four independent prognostic factors allowed a reliable patient stratification into distinct risk groups (high-risk patients, 16.2%). Our results demonstrate the usefulness of TP53 DBD missense mutations combined with clinicopathological factors for improving the prognostic stratification of OSCC patients.

10 - Correlating Copy Number Alterations in Dedifferentiated Liposarcoma With Tumor Behavior and Patient Outcome

Dedifferentiated liposarcoma (DDLS), as a most common intermediate- to high-grade lipomatous neoplasm, has metastatic potential and much poorer prognosis than atypical lipomatous neoplasm/well-differentiated liposarcoma (ALN/WDLS). Although tumor location and grade of DDLS have been shown to have prognostic significance, knowledge of genetic alterations for prognosis of DDLS remains limited. Genetic abnormalities underlying the pathogenesis and behavior of DDLS are not well understood. The aim of this study is to evaluate the correlation of specific CNAs with DDLS behavior and patient outcome to identify prognostic markers for risk stratification of liposarcoma patients. FFPE tumor tissues from 47 DDLS with clinical and pathological information were obtained for DNA extraction and cytogenomic microarray analysis (CMA) using a cancer-specific genomic microarray designed by Cancer Genome Consortium (CGC). The results show that copy number alterations including chromosomal gains, amplifications, and losses were very common in DDLS. Amplification of genes (defined as 5 or more copies) within the 12q13-15 region were most common as previously described. CNAs in 12 regions of interest were compared with DDLS FNCLCC grade and clinical disease status. Unlike the findings in previous studies by FISH, Q-PCR, and MLPA in DDLS, our study using CMA showed that higher levels of amplification of MDM2 correlate with an increased risk of adverse event including local recurrence, metastasis, and/or death related to disease in our cohort of DDLS patients. In addition, higher levels of MDM2 amplification were also significantly more likely to be found in retroperitoneal tumors compared to all other sites. Similar to findings in previous studies, we also found that high amplification levels of CDK4 correlated with increased risk of any adverse event related to disease and decreased disease specific survival. Correlations of other copy number alterations with DDLS tumor behavior and prognosis will also be reported and discussed.