Predominant Tumor Research Articles

A Fibromyxoid Stromal Response is Associated with Muscle Invasion in Canine Urothelial Carcinoma

Canine urothelial carcinoma (UC) is the most common type of cancer of the lower urinary tract and tends to affect elderly neutered female dogs, with a high predisposition for Scottish terriers. Tumour stroma, inflammation and necrosis are poorly characterized in canine UC and their role as prognostic factors is unknown. The aims of this study were to (1) assess histologically 381 canine UCs, with emphasis on myxoid tumour stroma, inflammation and necrosis and (2) assess possible associations between these features and the available epidemiological data as well as bladder wall muscle invasion. In 103 of 381 (27%) cases, the stroma was mixed collagenous and myxoid (fibromyxoid), which was strongly associated with invasive growth of muscle (P<0.0001). Peritumoural and intratumoural inflammation was present in 308 of 345 (89%) and 287 of 381 (75%) cases, respectively, and was mostly mild and lymphoplasmacytic. One hundred and fifteen of the 381 (30%) cases showed a variable eosinophilic inflammation and 58 of 381 (15%) presented with formations of one or several lymphoid follicles. Twenty-four percent (91 of 381) of cases had tumour necrosis, which was typically mild. In 83 of 91 (91%) cases, the necrosis was comedo-like. Moderate to severe tumour necrosis was associated with the presence of moderate to predominant fibromyxoid tumour stroma (P<0.02). The results of this study indicate that fibromyxoid stroma is common in canine UC and is a strong indicator for invasive growth of muscle, which is consistent with a poor prognosis. Based on histomorphology, tumour necrosis in canine UC is best described as comedonecrosis.

Heterologous prime-boost vaccination protects against EBV antigen-expressing lymphomas.

The Epstein-Barr virus (EBV) is one of the predominant tumor viruses in humans, but so far no therapeutic or prophylactic vaccination against this transforming pathogen is available. We demonstrated that heterologous prime-boost vaccination with the nuclear antigen 1 of EBV (EBNA1), either targeted to the DEC205 receptor on DCs or expressed from a recombinant modified vaccinia virus Ankara (MVA) vector, improved priming of antigen-specific CD4+ T cell help. This help supported the expansion and maintenance of EBNA1-specific CD8+ T cells that are most efficiently primed by recombinant adenoviruses that encode EBNA1. These combined CD4+ and CD8+ T cell responses protected against EBNA1-expressing T and B cell lymphomas, including lymphoproliferations that emerged spontaneously after EBNA1 expression. In particular, the heterologous EBNA1-expressing adenovirus, boosted by EBNA1-encoding MVA vaccination, demonstrated protection as a prophylactic and therapeutic treatment for the respective lymphoma challenges. Our study shows that such heterologous prime-boost vaccinations against EBV-associated malignancies as well as symptomatic primary EBV infection should be further explored for clinical development.

A 10-Year Histopathologic Audit of Uterine Cervical Biopsies in Warri, Nigeria

The objective of the research was to determine the types, patterns of uterine cervical lesions and specific age distributions in which they occur.&#x0D; Methods. The data for this study were obtained from the records of patients seen in consultations in the Department of Histopathology, Central Hospital Warri during the 10-year period from 2007 to 2016. Relevant clinical information was extracted from the available histopathology records and permission for this study was conformed with the provision of the Declaration of Helsinki in 1995.&#x0D; Results. The study revealed that the peak age range for malignant neoplasm was between 40-49 years (27.52%) with the general age range between (20-80 years) mean age 52.39±13.69. Non-keratinizing squamous cell carcinoma constituted majority of squamous cell tumours (55.05%), while the keratinising variety was the second most common (26.61%) one. The study further revealed that ectocervical fibroepithelial polyps were more common than endocervical tumours especially in the reproductive years (30-50 years) with only one case of atrophic polyp recorded in a woman in the sixth decade. The study documented that 58 (22.48%) of the cervical biopsies were inflammatory with most cases occurring in the ectocervix (94.80%). Most cases of inflammation of the cervix (cervicitis) were disposed between 30 and 59 years with the peak age group occurring in the 4th age group (30-39 years).&#x0D; Conclusions. This audit of uterine cervical biopsies established that malignant tumours were the most common neoplasms. Squamous cell carcinomas accounted for most carcinomas. Similarly, leiomyoma was demonstrated as predominant stromal tumour.

The IL-1/IL-1 receptor axis and tumor cell released inflammasome adaptor ASC are key regulators of TSLP secretion by cancer associated fibroblasts in pancreatic cancer

BackgroundThe thymic stromal lymphopoietin (TSLP), a key cytokine for development of Th2 immunity, is produced by cancer associated fibroblasts (CAFs) in pancreatic cancer where predominant tumor infiltrating Th2 over Th1 cells correlates with reduced patients’ survival. Which cells and molecules are mostly relevant in driving TSLP secretion by CAFs in pancreatic cancer is not defined.MethodsWe performed in vitro, in vivo and ex-vivo analyses. For in vitro studies we used pancreatic cancer cell lines, primary CAFs cultures, and THP1 cells. TSLP secretion by CAFs was used as a read-out system to identify in vitro relevant tumor-derived inflammatory cytokines and molecules. For in vivo studies human pancreatic cancer cells and CAFs were orthotopically injected in immunodeficient mice. For ex-vivo studies immunohistochemistry was performed to detect ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain) expression in surgical samples. Bioinformatics was applied to interrogate published data sets.ResultsWe show in vitro that IL-1α and IL-1β released by pancreatic cancer cells and tumor cell-conditioned macrophages are crucial for TSLP secretion by CAFs. Treatment of immunodeficient mice orthotopically injected with human IL-1 positive pancreatic cancer cells plus CAFs using the IL-1R antagonist anakinra significantly reduced TSLP expression in the tumor. Importantly, we found that pancreatic cancer cells release alarmins, among which ASC, able to induce IL-1β secretion in macrophages. The relevance of ASC was confirmed ex-vivo by its expression in both tumor cells and tumor associated macrophages in pancreatic cancer surgical samples and survival data analyses showing statistically significant inverse correlation between ASC expression and survival in pancreatic cancer patients.ConclusionsOur findings indicate that tumor released IL-1α and IL-1β and ASC are key regulators of TSLP secretion by CAFs and their targeting should ultimately dampen Th2 inflammation and improve overall survival in pancreatic cancer.

Disorder in Pixel-Level Edge Directions on T1WI Is Associated with the Degree of Radiation Necrosis in Primary and Metastatic Brain Tumors: Preliminary Findings.

Co-occurrence of local anisotropic gradient orientations (COLLAGE) is a recently developed radiomic (computer extracted) feature that captures entropy (measures the degree of disorder) in pixel-level edge directions and was previously shown to distinguish predominant cerebral radiation necrosis from recurrent tumor on gadolinium-contrast T1WI. In this work, we sought to investigate whether COLLAGE measurements from posttreatment gadolinium-contrast T1WI could distinguish varying extents of cerebral radiation necrosis and recurrent tumor classes in a lesion across primary and metastatic brain tumors. On a total of 75 gadolinium-contrast T1WI studies obtained from patients with primary and metastatic brain tumors and nasopharyngeal carcinoma, the extent of cerebral radiation necrosis and recurrent tumor in every brain lesion was histopathologically defined by an expert neuropathologist as the following: 1) "pure" cerebral radiation necrosis; 2) "mixed" pathology with coexistence of cerebral radiation necrosis and recurrent tumors; 3) "predominant" (>80%) cerebral radiation necrosis; 4) predominant (>80%) recurrent tumor; and 5) pure tumor. COLLAGE features were extracted from the expert-annotated ROIs on MR imaging. Statistical comparisons of COLLAGE measurements using first-order statistics were performed across pure, mixed, and predominant pathologies of cerebral radiation necrosis and recurrent tumor using the Wilcoxon rank sum test. COLLAGE features exhibited decreased skewness for patients with pure (0.15 ± 0.12) and predominant cerebral radiation necrosis (0.25 ± 0.09) and were statistically significantly different (P < .05) from those in patients with predominant recurrent tumors, which had highly skewed (0.42 ± 0.21) COLLAGE values. COLLAGE values for the mixed pathology studies were found to lie between predominant cerebral radiation necrosis and recurrent tumor categories. With additional independent multisite validation, COLLAGE measurements might enable noninvasive characterization of the degree of recurrent tumor or cerebral radiation necrosis in gadolinium-contrast T1WI of posttreatment lesions.

Diagnostic Accuracy of Cytology Smear and Frozen Section in Glioma

Glioma is the commonest primary intracranial tumour and it has been the most predominant tumour in many studies. It accounts for 24.7% of all primary brain tumour and 74.6% of malignant brain tumour. Intraoperative diagnosis plays a crucial role in determining the patient management. Frozen section has been the established technique in providing rapid and accurate intraoperative diagnosis. However due to some disadvantages like ice crystal artefact, high expenditure and requirement of skilled technician, there is increase usage of cytology smear either replacing or supplementing frozen section technique. The aim of this review is to determine the diagnostic accuracy of cytology smear and frozen section in glioma and to see whether there is significant difference between those techniques. The overall diagnostic accuracy for frozen section in glioma ranging from 78.4% to 95% while for cytology smear, the diagnostic accuracy ranging from 50% to 100%. Based on certain literatures, no statistically difference was observed in diagnostic accuracy of cytology smear and frozen section. Thus, cytology smear provides an alternative method in establishing intraoperative diagnosis. Both cytology smear and frozen section are complimentary to each other. It is recommended to use both techniques to improve the diagnostic accuracy in addition with adequate knowledge, clinical history, neuroimaging and intraoperative findings.

Clinico-Pathologic Study of Salivary Gland Disorders at a Sub-Urban Nigerian Tertiary Hospital: A 5 Year Retrospective Review

Background: The spectrum of salivary gland lesions is wide and the relative incidence of neoplastic and non-neoplastic lesions is variable in different studies. Despite the relatively common nature of salivary gland disorders, there is dearth of literature on these lesions, especially in sub-Saharan Africa. We therefore embarked on this study to analyze the differential diagnosis of salivary gland lesions seen and managed at our institution. Methods: A retrospective review of salivary gland disorders that presented at our facility from January 2012 to December 2016 was done. Information on patients’ demographic details, type and location of salivary gland lesion, histologic diagnosis and treatment were retrieved and analyzed with SPSS version 20. Result: A total of 65 patients were treated for salivary gland lesions of various types during the study period. The age of the patients ranged from 3 months to 68 years [mean 33.8 ± 12.3]. Neoplastic lesions [n = 39, 60.0%] were the commonest followed by sialolithiasis [n = 14, 21.5%] while mucous retention/extravasation cysts accounted for 13.9% of the cases. Pleomorphic adenoma was the predominant tumor in this series [87.2%] and the commonest site was the parotid gland [58.8%]. On the contrary submandibular gland appeared to be the commonest site for sialolithiasis [57.1%]. The majority of mucous retention/extravasation cysts occurred in the sublingual gland [55.5%]. Conclusion: Neoplastic lesions remain the commonest salivary gland disorder and pleomorphic adenoma was the most prevalent. Sialolithiasis and mucous cysts are salivary gland lesions with equally wide disease spectrum.

A study of morphological prognostic factors in colorectal cancer and survival analysis.

Globally, colorectal cancer (CRC) is one of the leading causes of cancer death. Many Asian countries experience an increasing incidence of CRC due to changes in diet and lifestyle. Many pathological prognostic factors other than the tumor-node-metastasis (TNM) staging reflect the biological behavior of tumor tissue and influence the treatment and survival. The aim is to evaluate: (1) Various morphological prognostic factors of colorectal cancer, (2) the correlation of the prognostic factors with survival, and (3) the prognostic factors with independent prognostic significance. Descriptive study conducted in a tertiary care center in Kerala. Five hundred and eighty-seven resected specimens of CRC received from January 1, 2007 to October 31, 2012 were studied for various morphological prognostic factors. Overall survival and disease-free survival were obtained by Kaplan Meier survival analysis. Cox regression analysis was performed to identify the predictors of survival. CRC incidence was higher in the age group 40-60 years and males were dominant. Rectum was the common site with bleeding per rectum as a common symptom. Predominant tumors had ulcerative gross configuration, size ≤5 cm and were free of transverse, radial margin involvement. Majority of tumors were well-differentiated adenocarcinoma with invasion beyond muscularis propria, without vascular, perineural invasion, and lymph node involvement and were in Stage II. The overall and disease-free 3-year survival rates were 89.1% and 88%, respectively. Among the eight significant factors in univariate analysis, tumor histology, depth of invasion, and perineural invasion were found to have independent prognostic significance in multivariate analysis. In addition to the TNM staging, other morphological prognostic factors should be given importance, while considering the patients for adjuvant therapy to improve the survival rates in CRC.

The role of percutaneous transhepatic biliary biopsy in the diagnosis of patients with obstructive jaundice: an initial experience.

ObjectiveTo evaluate the accuracy of percutaneous transhepatic biliary biopsy (PTBB) in patients with suspected biliary obstruction.Materials and methods This was a retrospective analysis of 18 patients with obstructive jaundice who underwent PTBB. In each patient, three to ten fragments were collected from the lesion. The final diagnosis was confirmed in the pathology report. We also reviewed analyses of the results of laboratory tests performed before the procedure, as well as the Bismuth classification, clinical outcome, complications occurring during the procedure, access route, and materials used.ResultsTechnical success was achieved in 100% of the PTBB procedures. Among the 18 patients clinically diagnosed with bile duct stenosis, the pathological analysis confirmed that diagnosis in 17. In one case, the pathological findings were considered false-negative. The predominant tumor was cholangiocarcinoma (seen in 50% of the cases). Sixteen of the procedures (88.9%) were performed without complications. Transient hemobilia occurred in one case, and cholangitis occurred in another.ConclusionPTBB is a safe, viable, simple technique with a high rate of true-positive results for the definitive diagnosis of obstructive jaundice.

Heterogeneous distribution of Retinal Degeneration Protein 3 in normal human fetal tissues: Exploring the possible relevance to neuroblastoma genesis

Background: Our studies identified the loss of Retinal degeneration Protein 3 (RD3) in the predominant infant tumor, neuroblastoma, indicated its novel regulatory function in neuroblastoma pathogenesis and, showed its localization in tissues beyond retina. To explore the possible physiological role of RD3 in regulating the genesis of neuroblastoma, we examined its distribution in human fetal normal tissues. Methods: Constitutive mRNA levels (QPCR, RNAScope), protein expression (immunohistochemistry), and sub-cellular localization of RD3 were investigated in the array (20 sites) of human (n=5) fetal normal tissues. In silico RNA sequencing data from seven independent studies (total n = 407) of human fetal tissues (101 sites) was utilized to validate the differential expression of RD3 in developing tissues. Results: RNAscope and QPCR analysis indicated a steady state of RD3 transcription across the fetal tissues with measurable inter-tissue differences (For e.g. high in GI tissues vs low in adrenal gland). RNA-seq data on varying stages of development clearly indicated stage-dependent dynamic fluctuations in RD3 transcription as the development progress. Notably, RD3 transcription is stably expressed in choroid plexus and are relatively absent in spinal cord through the developmental stages. IHC analysis recognized the presence of RD3 protein in array of fetal normal tissues, the tissue- and cell-specific distinctions in protein expression, and the variances in sub-cellular localization with each tissue. Conclusion: For the first time, the results presented here revealed the tissue-specific transcription, expression and localization of RD3 in fetal tissues. Recognizing the heterogeneous expression of RD3 between and within the fetal tissues signify its possible function beyond photoreceptor cell survival and could shed light on its functional relevance in neuroblastoma genesis and/or evolution.

Cribriform pattern in lung invasive adenocarcinoma correlates with poor prognosis in a Chinese cohort

The 2011 International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society (IASLC/ATS/ERS) lung adenocarcinoma classification and the following 2015 WHO classification have both been validated for their predictive values of histologic subtypes for prognosis. We sought to investigate the clinicopathological and prognostic significance of the cribriform pattern in lung adenocarcinomas. Histologic subtypes were evaluated in 395 patients who underwent complete resection for invasive lung adenocarcinomas between 2011 and 2013. Cribriform pattern was correlated with clinicopathological factors as well as molecular and survival data. One hundred and thirty cases (33%) were present with cribriform pattern (5–100%; mean ± SD, 24% ± 22%). Thirty two (8%) of those were reclassified into cribriform predominant tumors. Presence of cribriform pattern (≥5%) was significantly associated with lymph/vascular invasion (P＜0.001), nodal positivity (P = 0.003), higher T stage(P = 0.005) and higher TNM stage (P = 0.001). Cribriform pattern (≥10%) was highly associated with worse disease-free survival (DFS) and overall survival (OS) (mean DFS: 42.6 months, P < 0.001; mean OS: 64.1 months, P = 0.012). The DFS or OS for cribriform predominant tumors was similar to that for solid or micropapillary tumors. In multivariate analysis, cribriform pattern (≥10%) or cribriform predominant subtype was an independent predictor for DFS. Cribriform pattern was a specific pattern compared to other acinar patterns, presenting with more aggressive behavior. Moreover, presence of cribriform pattern was a strong predictor for worse prognosis and should be considered a high grade pattern. Our study provides further evidence for cribriform pattern to be acknowledged as an independent subtype in the future classification.

Cardiac papillary fibroelastoma: Report of a surgical series

IntroductionPapillary fibroelastoma (PFE) is a rare primary benign tumor of cardiac origin that predominantly affects the cardiac valves. Although most patients are asymptomatic, serious complications may result given their propensity for embolization. Advances in imaging technology have enabled earlier detection and more accurate characterization of these tumors. We report a case series, describing clinical presentation, treatment and outcome. MethodsInstitutional records of a tertiary center between 1997 and 2015 were reviewed for all patients diagnosed with PFE treated surgically and confirmed histologically. Demographic and clinical characteristics, echocardiography findings and treatment modalities were analyzed and recurrence at follow-up was studied. ResultsA total of 26 patients (69% male), aged 54±18 years, had a PFE. Clinically, PFE presented with neurologic deficits in eight cases and was asymptomatic in 65.4%. The mitral valve surface was the predominant tumor location (53.8%), followed by the aortic valve (34.6%). Tumor size ranged between 3 mm and 22 mm, 26.9% had a pedicle and 42.4% were mobile. All patients were treated successfully by complete resection, isolated in 88.5% and with valve repair in three cases. No other cardiac procedure was performed concomitantly and there were no major postoperative complications. Median follow-up was 61±49 months and no tumor recurrence or embolic events were documented. ConclusionsFibroelastomas are generally small, single and detected by chance during routine imaging exams. Complete surgical resection of the tumor has an excellent prognosis and appears to be a good strategy.

On hepatocellular carcinoma in South America and early-age onset of the disease

Hepatocellular carcinoma (HCC) is one of the most predominant tumor types worldwide, being particularly prevalent in sub-Saharan Africa and East Asia. However, HCC is inexplicably underreported in South America, despite unsettling clinical epidemiological trends of the disease on this continent. Here, we review the current knowledge on HCC presentation in Peru. We emphasize the well-documented occurrence of an early-age nosological form of the disease in Andean descent populations. We further discuss the reasons for such HCC clinical presentation, as well as the implications for liver cancer screening, management, and prevention.

The efficacy of neutron radiation therapy in treating salivary gland malignancies

ObjectivesRadiation therapy is commonly used to treat head and neck malignancies. While there is abundant research regarding photon radiation therapy, literature on neutron radiotherapy (NRT) and oral complications is limited. This study aims to determine: (1) the 6-year and 10-year locoregional control and survival rates, (2) factors associated with locoregional control and survival and (3) the frequency of oral complications in patients undergoing NRT for salivary gland malignancies. Materials and methodsThis is a retrospective cohort study. The sample was composed of patients with salivary gland malignancies treated with NRT between 1997 and 2010. Data were extracted from patient charts, telephone surveys, and social security records. Multivariate competing risk and Cox regression models were used to assess predictors of locoregional control and survival. ResultsThe sample was composed of 545 subjects with a mean age of 54.2 years (±16). The predominant tumor and location were adenoid cystic carcinoma (47%) and the parotid (56%). Multivariate analysis indicated that positive surgical margins, biopsied/inoperable malignancies, neck involvement, and lymphovascular invasion were prognostic risk factors associated with decreased survival. The 6- and 10-year locoregional control rates were 84% and 79%. The 6- and 10-year survival rates were 72% and 62%. Osteoradionecrosis developed in 3.4% of subjects. ConclusionsThe 6- and 10-year locoregional control and survival rates compare favorably to rates reported for conventional photon radiation. Osteoradionecrosis rates were comparable to that of photon radiation treatment (2–7%). Given the potential benefits of NRT, healthcare professionals should be educated regarding its indications and oral complications.

Quantifying Upstage Rate as a Function of Delay from Diagnostic Imaging for Locally-Advanced Lung Cancer Patients

Diagnosis and characterization of non-small cell lung cancer is done with diagnostic F18-FDG PET imaging as it is superior in sensitivity and specificity compared to conventional helical CT scans. Due to the aggressive nature of NSCLC, upstaging of disease is a concern for patients scheduled to undergo radical radiotherapy. We have reviewed our institution’s experience with treatment planning PET-CT scans and quantified the upstage rates. As part of a REB-approved study, PET-CT images acquired for treatment planning purposes. They were compared with PET-CT scans used for initial staging by two independent assessors. Patients’ age at diagnosis, sex, tumor histology, stage & date at diagnostic PET-CT, stage & date at treatment PET-CT and survival/follow-up were collected prospectively. AJCC 7th edition TNM Staging System was applied. Reported stages were compared and differences were reconciled by a third independent party. Descriptive statistics were calculated and the estimates of the upstage rates were obtained using the Kaplan-Meier product-limit method. Between October 2009 and February 2012, 28 patients were accrued to the study. The mean age was 64 years (range: 41-81). Eight were female and 19 were male. The majority of patients had Stage IIIA disease (15), with others having Stage IIIB (11), Stage IIA (1) and Stage IIB (1) disease. Predominant tumor histology was adenocarcinoma (71%). Median time between diagnostic and planning PET-CT scans was 21 days (range: 2-73). Overall upstaging occurred in 25% of patients. The TNM upstage breakdown was as follows: T-stage 7%, N-stage 14% and M-stage 11%. The 3 patients were found to have metastatic disease were switched to treatment with palliative intent. New nodal stations were found in 32% of patients, thereby necessitating a change in the treatment volumes. With the Kaplan-Meier product limit method the rate of overall upstaging increased with delay between staging and treatment planning PET-CT scans: 13% at 20 days (95% CI: 4%-95%), 33% at 40 days (95% CI: 14%-86%), and 56% at 60 days (95% CI: 29%-71%). The use of a treatment planning PET-CT demonstrated upstaging which altered patients’ treatment plans. Lengthened interval period between diagnostic PET and planning PET scans showed an increase in upstaging. Our data is consistent with two published studies which showed similar upstaging rates.

Ivermectin inhibits the growth of glioma cells by inducing cell cycle arrest and apoptosis in vitro and in vivo.

Glioma, the most predominant primary malignant brain tumor, remains uncured due to the absence of effective treatments. Hence, it is imperative to develop successful therapeutic agents. This study aimed to explore the antitumor effects and mechanisms of ivermectin (IVM) in glioma cells in vitro and in vivo. The effects of IVM on cell viability, cell cycle arrest, apoptosis rate, and morphological characteristics were determined respectively by MTT assay/colony formation assay, flow cytometry, and transmission electron microscope. In addition, the expression levels of cycle-related and apoptosis-associated proteins were individually examined by Western blot analysis. Moreover, cell proliferation and apoptosis analyses were carried out by TUNEL, Ki-67, cleaved caspase-3, and cleaved caspase-9 immunostaining assay. Our results demonstrated that IVM has a potential dosage-dependent inhibition effect on the apoptosis rate of glioma cells. Meanwhile, the results also revealed that IVM induced apoptosis by increasing caspase-3 and caspase-9 activity, upregulating the expressions of p53 and Bax, downregulating Bcl-2, activating cleaved caspase-3 and cleaved caspase-9, and blocking cell cycle in G0/G1 phase by downregulating levels of CDK2, CDK4, CDK6, cyclin D1, and cyclin E. These findings suggest that IVM has an inhibition effect on the proliferation of glioma cells by triggering cell cycle arrest and inducing cell apoptosis in vitro and in vivo, and probably represents promising agent for treating glioma.

Abstract A20: Analysis of tumor infiltrating lymphocytes and expression of PD1 and PD-L1 in breast tumors prior to and after neoadjuvant chemotherapy

Abstract Introduction: The effect of chemotherapy on the presence of tumor-infiltrating lymphocytes (TILs) and expression of PD1 and PD-L1 is unclear. We sought to describe the differences in the percentage (%) of TILs, cytotoxic T lymphocytes (CTL), and expression of PD1/PD-L1 in tumors of patients (pts) with operable breast cancer (BC) treated with neoadjuvant chemotherapy (NAC) who were enrolled in a biomarker study at our institution (IRB protocol# 2010C0036). Methods: A multicolor immune-histochemical multiplex assay simultaneously detecting PD1, PD-L1, and CD8 expressing cells was performed on formalin-fixed, paraffin-embedded diagnostic pretreatment biopsy or resected tumor specimen following NAC in 18 of 26 pts participating in the study. A cut-off of ≥1% was considered positive for PD1 and PD-L1 expression. We evaluated stromal and intratumoral CTLs by estimating % of stroma and tumor that contained CD8+ cells. In addition, stromal TILs (sTILs) were identified on full-face hematoxylin and eosin stained sections and defined as the % of tumor stroma containing infiltrating lymphocytes. Pathologic complete or near-complete response (pCR) was analyzed based on residual cancer burden (RCB) score and defined as RCB class 0 or I. Analysis of all slides was performed by an expert breast pathologist. Since the number of pts was limited, we only provide descriptive statistics (mean, range). In addition, because most pts had only a biopsy or only residual tumor available for the analysis, we divided pts into 2 separate cohorts based on what tissue was available. Results: Of 18 pts, biopsy was analyzed in 7 (Bx cohort) and residual tumor was analyzed in 11 pts (RT cohort). The median age of study pts was 48 (range 32-70); 11 (61%), 6 (33%), and 1 (6%) of pts were Caucasian, African American, and Hispanic, respectively. Ten pts (5 in Bx and RT cohorts each) had triple-negative BC (TNBC), 4 had HER2+ BC (1 and 3 in Bx and RT cohorts, respectively), and 4 had hormone receptor-positive, HER2- BC (1 and 3 in Bx and RT cohorts, respectively). Eight pts (44%) had pCR. In the bx cohort, 85% of pts had pCR while 18% of pts in the RT cohort had minimal residual disease (RCB class I). In the Bx cohort, average % of sTILs was 30% (range 2-70%), including 1 pt (14%) with lymphocyte predominant tumor (≥50% of sTILs). The % of sTILs was similar in the 11 residual tumors (mean 22, range 2-60) with 2 pts having lymphocyte predominant tumors. Average % of CTLs was 19 (range 1-50) in the Bx cohort and 14 (range 1-50) in the RT cohort. An average % of intratumoral CTLs was 8 (range 1-30) and 7.5 (range 0-40) while the average % of stromal CTLs was 25 (range 1-60) and 19 (range 1-60) in the Bx and RT cohorts, respectively. Similar % and trends were seen in 10 TNBC pts. PD-L1 expression was seen in 86% and 36% of tumors in the Bx and RT cohorts, respectively, with majority of expression present in the stroma. All cases of intratumoral PD-L1 expression were also positive for stromal PD-L1 expression. This difference was also seen in the TNBC pts (80% vs. 40% of tumors were PD-L1+ in Bx and RT cohorts, respectively). An average PD-L1 intensity was approximately 3% in both cohorts (range 1-20%). Expression of PD1 was very low (1% intensity in 3 pts in Bx cohort and in 1 pt in RT cohort) and it was seen on CD8+ CTLs. Conclusion: Our study preliminarily shows that percent of sTILs and stromal and intratumoral CTLs does not differ between pretreatment biopsy and residual tumors following NAC. Lower proportion of residual tumors were PD-L1+ compared to pretreatment biopsy specimen. The study limitations include small number of subjects and lack of comparison in the same pts. Future studies are needed to confirm these findings. Citation Format: Robert Wesolowski, Zaibo Li, Christopher McQuinn, Maryam Lustberg, Bhuvaneswari Ramaswamy, Anne Noonan, Raquel Reinbolt, Sagar Sardesai, Jeffrey B. VanDeusen, Nicole Williams, William E. Carson, III. Analysis of tumor infiltrating lymphocytes and expression of PD1 and PD-L1 in breast tumors prior to and after neoadjuvant chemotherapy [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr A20.

Abstract SY08-02: Reshaping cancer care delivery through multi-disciplinary molecular tumor boards

Abstract Rapidly growing access to next-generation DNA sequencing technology has put the promise of precision oncology in reach, which is to individualize cancer care by matching molecular abnormalities found in a patient's tumor with specific treatments. As a result, clinicians strive to integrate molecular information into routine oncologic decision-making at accelerating pace. While some findings are associated with well-established treatment recommendations, such as KRAS mutations in colorectal cancer indicating lack of benefit of EGFR inhibitors, clinicians are frequently confronted with complex molecular findings that are difficult to interpret from a diagnostic and therapeutic perspective. In particular, tumors harboring multiple potentially targetable mutations or variants of unknown significance, pose challenges. Beyond this, perplexing complexities of cellular signaling networks dynamically responding to targeted therapies, intra-tumoral heterogeneity, as well as access to drugs as part of clinical trials or off-label use add to the difficulties in bringing precision oncology to patients. With the goal of assisting oncologists at the University of California San Francisco (UCSF) in addressing some of these challenges, we assembled the UCSF Molecular Tumor Board (MTB) in July of 2014. The Board constituents represent a wide spectrum of areas of expertise and include disease-area focused oncologists, pediatric oncologists, molecular pathologists, genetic counselors, pharmacists, clinical trialists, and molecular biologists. All patients undergoing molecular testing at UCSF are listed for possible MTB discussion by default unless the treating oncologist decides otherwise. The main source of molecular results is the UCSF500 test, a next-generation DNA sequencing targeted capture assay that is used to analyze paired tumor and normal DNA. On average, 22 cases are being discussed per month during initially weekly, now bi-weekly meetings. Approximately 20% of the cases are pediatric malignancies. As a result of differential utilization of the UCSF500 within the UCSF Comprehensive Cancer Center, CNS malignancies, colorectal, and neuroendocrine carcinomas as well as melanomas are the predominant tumor types discussed. In agreement with results published by other groups, pathogenic or likely pathogenic germline mutations are present in 15% of the cases, highlighting the importance of integration of genetic counselors in the process. Based on an in-depth analysis of 350 patients seen between April 2015 and November 2017, therapeutically actionable mutations were present in 67% of the cases. Molecularly targeted therapies were recommended in 73% of patients in this subset and recommendations to avoid particular therapies were made in 8%. In 21% of the cases with a recommendation for targeted therapies, clinical action was taken (e.g. drug prescription, clinical trial enrollment). In 62% of the cases with a recommendation, no action had been taken at time of data analysis, with the following reasons cited: patient performance status declined rapidly, patient continued standard therapy, patients declined MTB recommended therapy, or a plan is in place to take action in case of disease progression. Thus, only 16% of cases received treatment as recommended by the MTB. However, there was a trend that cases that were discussed at MTB had higher rates of clinical action taken compared to cases that were not discussed by the MTB. Overall, our experience with the UCSF Molecular Tumor Board is encouraging. Additional efforts need to be undertaken to further increase translation of molecular tumor board recommendations into clinical action. Citation Format: W. Michael Korn. Reshaping cancer care delivery through multi-disciplinary molecular tumor boards [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr SY08-02.

Abstract 3683: Reciprocal expressions of TFF-1 and TTF-1 in lung adenocarcinomas

Abstract The molecular targeted therapies against EGFR, ALK etc. have improved progression-free survival of patients with lung adenocarcinomas. However, targetable driver mutations have mainly been found in TTF-1-positive terminal respiratory unit (TRU)-type, but have yet been undiscovered in non-TRU type despite the advances in genomics technologies. In order to find the molecular candidate characterizing major subtype of non-TRU type adenocarcinomas, we compared TTF-1-positive/CDH1-positive adenocarcinoma cell lines (“TRU-type” cell lines) (n=11) and TTF-1-negative/CDH1-positive adenocarcinoma cell lines (“non-TRU-type” cell lines) (n=8), and found that TFF-1 (trefoil factor family-1), a gastric mucosal protective factor, was characteristically highly expressed in “non-TRU-type” cell lines. Immunohistochemical analysis of primary lung adenocarcinomas (n=70) revealed that TFF-1 expression was inversely correlated with TTF-1 expression (p=0.0116) and was very rare in primary lung adenocarcinoma cases (5.7%:4/70). So we focused on the non-TRU type adenocarcinomas on the basis of histologic pattern (acinar, solid or mucinous morphology predominant tumors without non-mucinous lepidic growth components) (n=43). Among them, TFF-1 was frequently expressed (62%:27/43), and significantly correlated with the expressions of MUC5AC, HNF4A and CK20 (p&amp;lt;0.0001, p=0.0001, and p=0.0007, respectively), and inversely correlated with TTF-1 expression (p=00039). Next generation sequencing analysis of the 43 cases revealed that KRAS gene mutations and Inactivating mutations and hypermethylation of the TTF-1 gene were frequent in TFF-1 positive cases. The analysis of publicly available data of 442 lung adenocarcinoma cases revealed that high expression of TFF-1 correlated with low expression of TTF-1 and worse prognosis. We confirmed that shRNA against TFF-1 inhibited the cell proliferation and the colony formation, and induced the apoptosis, in the TFF-1 positive “non-TRU-type” cell lines. These results indicate that TFF-1 is not only the marker but also can possibly be the molecular target of a subset of non-TRU-type lung adenocarcinomas. Citation Format: Daisuke Matsubara, Manabu Soda, Taichiro Yoshimoto, Yusuke Amano, Atsushi Kihara, Yuji Sakuma, Shunsuke Endo, Koichi Hagiwara, Masashi Fukayama, Hiroyuki Mano, Toshiro Niki. Reciprocal expressions of TFF-1 and TTF-1 in lung adenocarcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3683.

Surgical Strategy for and Anatomic Locations of Petroapex and Petroclival Meningiomas Based on Evaluation of the Feeding Artery

The anterior transpetrosal (ATP) approach is the most appropriate approach for petroclival meningiomas (PCMs), which are typically located from the dorsum sellae to the upper border of the internal auditory meatus (IAM). Although neurosurgeons can resect over this area if the tumor is detached from the dura, tumors within the indication area for PCMs are not appropriate for the ATP approach, because it can be difficult to evaluate whether the tumor is attached to or onlytouching the dura. In this study, we investigated the tumorextension area based on an evaluation of the feeding artery to achieve a more accurate assessment of the dural attachment area. Using various angiography techniques, we studied 51 feeding arteries from 24 patients who had undergone surgical treatment of primary petroapex meningiomas and PCMs via the ATP approach. We measured the lower and posterior extension distances, the extension rate of the cavernous sinus and Meckel's cave, and the midline extension rate of the tumors. The ascending pharyngeal artery (AphA) was the predominant feeding artery for tumors with lower extension. We determined that tumors extending over the lower border of IAM in cases in which the feeding artery was not the AphA can be resected using the ATP approach. This study shows an association between the predominant feeding artery and tumor extension area and demonstrates that an evaluation of the dural attachment area based on the feeding artery can aid selection of the appropriate surgical approach.