A1 Tumors Research Articles

NSCLC patients with a changing T grade after operation may represent a special subset of tumor staging.

There is consensus that postoperative adjuvant therapy is not recommended in patients with stage 1a non-small cell lung cancer (NSCLC). Meanwhile, it is still controversial whether postoperative adjuvant chemotherapy is recommended for NSCLC patients with T2aN0M0 (stage 1b). In some patients with stage 1b NSCLC without pleural invasion, tumor diameter was measured between 3 and 4cm by preoperative imaging and less than 3cm by postoperative pathology specimens. TNM staging in such patients is both radiologic stage 1b and pathologic stage 1a. Thoracic surgeons are often confused about whether such patients with NSCLC will require subsequent treatment and how the survival prognosis for this group of patients will be. All data of radiographic TNM stage 1b patients who underwent radical R0 resection at the department of thoracic surgery, the First Affiliated Hospital of Soochow University between January 2013 and July 2017 were retrieved, and 208 patients were finally included in the study. Clinical data, including imaging data, pathology data, were obtained by reviewing the patients' electronic medical records. Disease-free survival (DFS) and overall survival (OS) were obtained by telephone interview. Statistical analysis was performed using SPSS (SPSS 26.0 for windows, SPSS). A total of 208 patients were included in this study, 61 patients with T-stage migration (observation group) and 147 patients without T-stage migration (control group). There were significant statistical differences between the two groups in terms of preoperative FEV1/FVC and tumor diameter (specimens, CT and 3-dimensional measurements). Logistic regression results showed that lower FEV1/FVC and smaller CT measurements would make the patient's T stage more likely to migrate. Bland-Altman plots showed that tumor length measured by imaging was significantly higher than that measured by pathological specimens. Taking DFS as the outcome, the survival curve of the observation group was significantly better than that of the control group. Similarly, there was a significant difference in OS between the two groups. For NSCLC patients whose preoperative imaging evaluation was stage 1b (tumor diameter more than 3cm, no main bronchus, pleura, no atelectasis), the presence of lung tissue with smaller tumor diameter and/or higher air content may indicate that the postoperative pathological staging may be changed to stage 1a (tumor diameter less than 3cm). These patients had better survival prognosis than those who did not undergo TNM stage change and were diagnosed with stage 1b non-small cell lung cancer before and after surgery.

Evaluation of Survival Following Surgical Resection for Small Nonfunctional Pancreatic Neuroendocrine Tumors

The number of patients with small nonfunctional pancreatic neuroendocrine tumors (NF-PanNETs) is increasing. However, the role of surgery for small NF-PanNETs remains unclear. To evaluate the association between surgical resection for NF-PanNETs measuring 2 cm or smaller and survival. This cohort study used data from the National Cancer Database and included patients with NF-pancreatic neuroendocrine neoplasms who were diagnosed between January 1, 2004, and December 31, 2017. Patients with small NF-PanNETs were divided into 2 groups: group 1a (tumor size, ≤1 cm) and group 1b (tumor size, 1.1-2.0 cm). Patients without information on tumor size, overall survival, and surgical resection were excluded. Data analysis was performed in June 2022. Patients with vs without surgical resection. The primary outcome was overall survival of patients in group 1a or group 1b who underwent surgical resection compared with those who did not, which was evaluated using Kaplan-Meier estimates and multivariable Cox proportional hazards regression models. Interactions between preoperative factors and surgical resection were analyzed with a multivariable Cox proportional hazards regression model. Of the 10 504 patients with localized NF-PanNETs identified, 4641 were analyzed. These patients had a mean (SD) age of 60.5 (12.7) years and included 2338 males (50.4%). The median (IQR) follow-up time was 47.1 (28.2-71.6) months. In total, 1278 patients were in group 1a and 3363 patients were in group 1b. The surgical resection rates were 82.0% in group 1a and 87.0% in group 1b. After adjustment for preoperative factors, surgical resection was associated with longer survival for patients in group 1b (hazard ratio [HR], 0.58; 95% CI, 0.42-0.80; P < .001) but not for patients in group 1a (HR, 0.68; 95% CI, 0.41-1.11; P = .12). In group 1b, interaction analysis found that age of 64 years or younger, absence of comorbidities, treatment at academic institutions, and distal pancreatic tumors were factors associated with increased survival after surgical resection. Findings of this study support an association between surgical resection and increased survival in select patients with NF-PanNETs measuring 1.1 to 2.0 cm who were younger than 65 years, had no comorbidities, received treatment at academic institutions, and had tumors of the distal pancreas. Future investigations of surgical resection for small NF-PanNETs that include the Ki-67 index are warranted to validate these findings.

Validation of the Prognostic Usefulness of the Gene Expression Profiling Test in Patients with Uveal Melanoma

To validate the prognostic usefulness of gene expression profile (GEP) testing in patients with uveal melanoma. To determine whether combining tumor size with the GEP classification provides additional prognostic value. Retrospective analysis. Patients with a diagnosis of choroidal melanoma examined at Yale New Haven Hospital; University of California, San Diego; and Memorial Sloan Kettering Cancer Center. Patients' demographic and clinical data and tumor characteristics were collected. Univariate and multivariate Cox hazard regression analysis were used to assess the association between tumor characteristics and GEP classification with metastasis as an outcome. Metastasis-free survival (MFS). Of the 337 individuals included in the study, 87 demonstrated metastases. The mean follow-up time was 37.2 (standard deviation [SD], 40.2) months for patients with metastases and 55.0 (SD, 49.3) months for those without metastases. Tumors of larger thickness and GEP class 2 (vs. class 1) were associated significantly with increased risk of metastasis. Tumor thickness showed better prognostic usefulness than GEP classification (Wald statistic, 40.7 and 24.2, respectively). Class 2 tumors with a thickness of 7.0 mm or more were associated with increased risk of metastasis than tumors with a thickness of < 7.0 mm (hazard ratio [HR], 3.23; 95% confidence interval [CI], 1.61-6.51), whereas class 1 tumors with a thickness of 9.0 mm or more were associated with increased risk of metastasis than tumors with a thickness of < 9.0 mm (HR, 2.07; 95% CI, 0.86-4.99). No difference in MFS was found between patients with class 1A tumors compared with those with class 1B tumors (P= 0.8). Patients with class 2 tumors showed an observed 5-year MFS of 47.5% (95% CI, 36.0%-62.8%). Tumor size was the most significant predictor of metastasis and provided additional prognostic value independent of GEP classification. In addition, rates of metastasis for class 2 tumors were lower than estimates reported by Castle Bioscience, and no difference in rates of metastasis were found between class 1A and 1B tumors. This indicates that tumor size should be accounted for when relying on GEP for prognostication and that patients with GEP class 1A or 1B tumors may benefit from the same metastatic surveillance protocols. The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Evaluating surgical treatment options for small nonfunctional pancreatic neuroendocrine tumors in the NCDB.

645 Background: The role of surgery for small (≤2 cm), nonfunctional pancreatic neuroendocrine tumors (NF-PNETs) remains controversial due to the wide range of tumor aggressiveness. Consensus guidelines of the US, Europe, and Japan offer different recommendations for treatment of small NF-PNETs. The objective of this study is to evaluate the survival benefit of surgical resection for small NF-PNETs. Methods: Patients with NF-PNETs were identified in the National Cancer Database from 2004 to 2018. Small NF-PNETs were divided into two groups: group 1a (tumor ≤1 cm) and group 1b (tumor 1.1 – 2.0 cm). Cox regression models were used to compare the overall survival between resected and unresected small NF-PNETs patients. Interactions between preoperative factors and surgery were estimated using subgroup analyses. Results: We identified 1,278 patients in group 1a and 3,363 patients in group 1b. After adjusting for preoperative factors, surgery was associated with longer survival for patients in group 1b (HR, 0.58; 95% CI, 0.42–0.80; P &lt;0.001), but not for patients in group 1a (HR, 0.68; 95% CI, 0.41–1.11; P = 0.122). Interaction analysis found that age younger than 65 years, fewer comorbidities, treatment at academic institutions, distal pancreatic tumors, and clinical lymph node metastasis were factors associated with longer survival in group 1b by surgery. Conclusions: Findings from this large study support surgical resection for some patients with NF-PNETs (1.1 – 2.0 cm). This, of course, must be taken in context with the patient’s clinical situation. Based on data available for analysis in this study, resection for subcentimeter NF-PNETs does not appear to be of general benefit, but should also be investigated in the context of Ki-67 index.[Table: see text]

Lobar versus Sublobar Resection in the Elderly for Early Lung Cancer: A Meta-Analysis.

We performed a systematic review and meta-analysis of outcomes of lobectomy versus sublobar resection in elderly patients (≥65) with stage 1 nonsmall cell lung carcinoma (NSCLC). We searched for relevant articles using a set of inclusion and exclusion criteria. Meta-analytic techniques were applied. Twelve studies (n = 5834) were chosen. Our results indicate that in the elderly, lobectomy for stage 1 NSCLC confers a survival advantage over sublobar resection. Lobectomy patients had a lower risk of death within 5 years and lower odds of local cancer recurrence. Our results show that lobectomy had a better 5-year cancer-specific survival and 5-year disease-free survival that trended toward significance. The sublobar resection group showed better 30-day operative mortality that trended toward significance. Subgroup analysis of stage 1A cancer demonstrated no difference in 5-year overall survival rates. However, for stage 1B tumors 5-year overall survival favored lobectomy. Lobectomy for stage 1 NSCLC in elderly patients is superior to sublobar resection in terms of survival and cancer recurrence and should be afforded where possible. For stage 1A tumors, sublobar resection is noninferior and may be considered. Further randomized controlled trials in this topic is required.

GIPC2 is an endocrine-specific tumor suppressor gene for both sporadic and hereditary tumors of RET- and SDHB-, but not VHL-associated clusters of pheochromocytoma/paraganglioma

Pheochromocytoma/paraganglioma (PPGL) is an endocrine tumor of the chromaffin cells in the adrenal medulla or the paraganglia. Currently, about 70% of PPGLs can be explained by germline or somatic mutations in several broadly expressed susceptibility genes including RET, VHL, and SDHB, while for the remaining, mainly sporadic cases, the pathogenesis is still unclear. Even for known susceptible genes, how mutations in these mostly ubiquitous genes result in tissue-specific pathogenesis remains unanswered, and why RET-mutated tumors almost always occur in the adrenal while SDHB-mutated tumors mostly occur extra-adrenal remains a mystery. By analyzing 22 sporadic PPGLs using SNP 6.0 genotyping arrays combined with expression profiling of 4 normal and 4 tumor tissues, we identified GIPC2, a gene located at 1p31.1 with preferential expression in adrenal and inducible by adrenal glucocorticoid, as a novel putative tumor suppressor gene for PPGLs. Copy number deletion and GIPC2 promoter hypermethylation but not GIPC2 mutation, accompanied with reduced GIPC2 expression, were observed in 39 of 55 PPGLs in our cohort. Examination of a published expression database consisting of 188 PPGLs found little GIPC2 expression in Cluster 1A (SDHx-associated) and Cluster 2A (NF1/RET-associated) tumors, but less pronounced reduction of GIPC2 expression in Cluster 1B (VHL-associated) and Cluster 2B/2C tumors. GIPC2 induced p27, suppressed MAPK/ERK and HIF-1ɑ pathways as well as cancer cell proliferation. Overexpressing GIPC2 in PC12 cells inhibited tumor growth in nude mice. We found GIPC2 interacted with the nucleoprotein NONO and both proteins regulated p27 transcription through the same GGCC box on p27 promoter. Significantly, low expression of both GIPC2 and p27 was associated with shorter disease-free survival time of PPGLs patients in the TCGA database. We found that PPGL-causing mutations in RET and in SDHB could lead to primary rat adrenal chromaffin cell proliferation, ERK activation, and p27 downregulation, all requiring downregulating GIPC2. Notably, the RET-mutant effect required the presence of dexamethasone while the SDHB-mutant effect required its absence, providing a plausible explanation for the tumor location preference. In contrast, the PPGL-predisposing VHL mutations had no effect on proliferation and GIPC2 expression but caused p53 downregulation and reduced apoptosis in chromaffin cells compared with wild-type VHL. Thus, our study raises the importance of cortical hormone in PPGL development, and GIPC2 as a novel tumor suppressor provides a unified molecular mechanism for the tumorigenesis of both sporadic and hereditary tumors of Clusters 1A and 2A concerning SDHB and RET, but not tumors of Cluster 1B concerning VHL and other clusters.

Fisetin ameliorates atherosclerosis by regulating PCSK9 and LOX-1 in apoE-/- mice.

The purpose of the current study was to investigate the mechanism by which fisetin improves atherosclerosis (AS) by regulating lipid metabolism and senescence in apolipoprotein E-deficient (apoE-/-) mice. An AS model was established by feeding apoE-/- mice a high-fat diet. Mice were randomly divided into the model group (n=18), the fisetin group (n=18) and the atorvastatin group (n=18). The control group (n=18) was composed of wild-type C57BL/6 mice of the same age and genetic background. The fisetin and atorvastatin groups were respectively treated with aqueous solutions of fisetin (12.5 mg/kg) and atorvastatin (2 mg/kg) via oral gavage daily for 12 weeks. The pathological morphology, lipid accumulation, collagen deposition of the aortic sinus were observed, serum lipids, superoxide dismutase (SOD) and malondialdehyde (MDA) levels and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities were measured in the peripheral blood serum. Additionally, the expressions of proprotein convertase subtilisin/kexin type 9 (PCSK9), lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), tumor suppressor protein p53 (p53), cyclin-dependent kinase inhibitor 1A (p21) and multiple tumor suppressor-1 (p16) were analyzed in the aorta. The results of the current study indicated that compared with the control group, a large area of AS plaque in the aortic sinus that contained a large amount of red-stained lipids and decreased collagen fiber content were found in the model group, which exhibited higher total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein cholesterol (VLDL-C), oxidized low-density lipoprotein (ox-LDL) and MDA levels; higher ALT and AST activities, lower high-density lipoprotein cholesterol (HDL-C) and SOD levels and increased expression levels of PCSK9, LOX-1, p53, p21 and p16. Fisetin is a phytochemical and bioflavonoid that serves a potential role in chronic diseases including AS, obesity, diabetes and cancer due to its wide biological activities, such as regulating lipid metabolism and anti-aging, anti-oxidation and anti-inflammatory. Atorvastatin is recognized as a first-line treatment drug for AS; therefore it was used as a positive control in the current study. Following fisetin and atorvastatin treatment, both the AS plaque and the lipid accumulation in the aortic sinus were significantly reduced, and the expressions of PCSK9, LOX-1 and aging markers, including p53, p21 and p16 were downregulated.

AGA Clinical Practice Update on the Utility of Endoscopic Submucosal Dissection in T1b Esophageal Cancer: Expert Review

AGA Clinical Practice Update on the Utility of Endoscopic Submucosal Dissection in T1b Esophageal Cancer: Expert Review

RELATIONSHIP OF CLINICAL FEATURES AND BASELINE TUMOR SIZE WITH GENE EXPRESSION PROFILE STATUS IN UVEAL MELANOMA: A Multi-institutional Study.

To study the relationship between gene expression profile subclass and clinical features in a multicenter cohort of patients with uveal melanoma. A retrospective, multicenter study was undertaken with patients entered from nine major ocular oncology centers from across the United States. Eligible patients had uveal melanoma and underwent I-125 plaque brachytherapy with concurrent tumor biopsy with gene expression profile testing between January 1, 2010, and October 28, 2014. Data were collected regarding patient demographics, baseline tumor clinical features, and gene expression profile results. Statistical analyses were performed using the Fisher's exact test, Wilcoxon rank-sum test, Kruskal-Wallis test, and proportional-odds cumulative logit modeling. Inclusion criteria were met for 379 patients. Gene expression profile class divided the cohort into two main groups, Class 1 (n = 263) and Class 2 (n = 113). Class 1 tumors were further subdivided into Class 1a (n = 186) and Class 1b (n = 77). The differences between Class 1 and Class 2 tumors were similar to previous studies, except the finding of Class 2 tumors being more likely to have associated exudative retinal detachment (P < 0.001). There was no statistically significant difference between Class 1 and Class 2 tumors based on the presence of lipofuscin, drusen, or subretinal fluid. Class 1a tumor patients, compared with Class 1b, were significantly older (P = 0.034). Class 2 tumors, when compared with Class 1b, were associated with increasing patient age (P < 0.001), larger tumor height (P = 0.010), ciliary body involvement (P = 0.001), exudative retinal detachment (P = 0.024), and anterior tumor location (P < 0.001). When the tumors were grouped into Collaborative Ocular Melanoma Study size categories, increasing tumor size category was significantly associated with Class 2 status: 6% of small tumors, 32% of medium tumors, and 53% of large tumors were Class 2. In a multi-institutional setting, we found that the only significant difference in clinical features between Class 1a and Class 1b tumors was that patients with Class 1a tumors were older at the time of diagnosis. We also found that Class 1a and Class 1b have clinical features distinct from Class 2 tumors. The distribution of the gene expression profile subclasses among the size groups was similar to reported time-to-metastasis data among the same size groupings. Our clinical findings support the current molecular classification-based survival data previously reported in uveal melanoma.

Relationship between clinical features, GEP class, and PRAME expression in uveal melanoma.

Metastatic risk for uveal melanoma (UM) patients can be characterized by gene expression profiling (GEP) (Castle Biosciences, Friendswood, TX). Class 1A tumors carry low metastatic risk; class 1B tumors have intermediate risk; and class 2 tumors have high risk. Preferentially expressed antigen in melanoma (PRAME) is a tumor-associated antigen which is expressed in various neoplasms including UM. Recently, PRAME expression in uveal melanoma was first recognized to confer an additional metastatic risk beyond GEP status. This was a retrospective, consecutive, multicenter chart review study. All patients diagnosed with UM at two major ocular oncology centers from August 2016 to February 2018 who underwent both GEP and PRAME mRNA expression testing were included. Patient age at diagnosis, gender, and tumor variables such as thickness, largest basal diameter (LBD), tumor volume, TNM stage, and GEP class and PRAME status were extracted from the medical records. Statistical analysis was performed to analyze the association of PRAME +/- status with all clinical and molecular variables. One hundred forty-eight UM patients were identified. TNM was stage I in 51 (34.5%), stage IIA in 33 (22.3%), stage IIB in 34 (23%), stage IIIA in 20 (13.5%), and stage IIIB in 10 (6.8%) patients. Fifty-five patients (37%) were PRAME-positive, a significant fraction. There was no association between higher TNM stage and positive PRAME status (p = 0.129). PRAME expression was found to be independent of gender, patient age, and tumor thickness. PRAME expression was statistically associated with LBD and tumor volume. Higher GEP class was associated with higher TNM staging (p < 0.001). Worsening GEP class was associated with PRAME+ status with 28% of GEP class 1A tumors having PRAME+ status, 29% of GEP class 1B tumors having PRAME+ status, and 56% of GEP class 2 tumors having PRAME+ status. In this study cohort, PRAME+ status was significantly associated with LBD and tumor volume as well as worsening GEP class. Nearly a third of GEP class 1A tumors expressed PRAME. Given the recent published data on increased metastatic risk among patients with tumors expressing PRAME, this study suggests that a significant fraction of 1A patients may harbor an increased metastatic risk. Future large, multicenter studies with long-term follow-up will clarify this finding.

Comprehensive Surgical Staging in Stage 1 Clear Cell and Endometrioid Ovarian Carcinomas: Is it Necessary?

The objective of this article was to evaluate the presence of occult metastasis after comprehensive surgical staging of clear cell ovarian carcinoma (CCC) and endometrioid ovarian carcinoma (EMCA) that appeared to be confined to the ovary at time of surgery. Between 1998 to 2016, 85 patients with CCC and EMCA were identified who were comprehensively staged and felt to be stage 1 intraoperatively. Of the 85 patients who underwent surgical staging, 4 (4.7%) had omental and dense pelvic side-wall tumor adhesions. On final pathology, 67 (79%) patients were diagnosed as stage 1A of which 29 (43%) patients were upstaged to 1C1 due to intraoperative rupture. The remaining 18 (21%) patients were staged as 1C2/1C3. The 1- and 5-yr disease-free survival for pathology stage 1A tumors was 94% and 76%, respectively, and for 1C2/1C3 tumors was 100% and 75%, respectively. Among patients who received adjuvant chemotherapy, the 5-yr disease-free survival was near equal for pathology stage 1A and 1C2/1C3 groups (73% vs. 74%), with a lower 5-yr disease-free survival for CCC compared with EMCA (72% vs. 78%). There were 16 (19%) recurrences with 12 being pathology stage 1A. Of these 12 patients, 9 (75%) had CCC of which 2 received adjuvant chemotherapy. Even in the presence of dense adhesions (4.7%), the likelihood of extraovarian disease in CCC and EMCA confined to the ovary was very low. Accordingly, the findings in this study indicate that comprehensive surgical staging for what appears to be stage 1 CCC and EMCA may provide no benefit in detecting occult disease that would upstage the tumor.

Preoperative PD1 checkpoint blockade and receptor activator of NFkB ligand (RANKL) inhibition in non-small cell lung cancer (NSCLC) (POPCORN).

TPS129 Background: Preclinical studies indicate Receptor Activator of NF-κB Ligand (RANKL) blockade improves anti-tumor efficacy of immune checkpoint blockade (ICB). Clinical trials combining denosumab (anti-RANKL mAb) with ICB are underway in various cancers although the hypothesized mechanism of action of such combinations remains incomplete. RANKL and its receptor, RANK, are frequently expressed in NSCLC (tumor and immune cells). Denosumab demonstrated survival advantage over bisphosphonate in metastatic NSCLC (mNSCLC) to bone; a recent retrospective case series suggests a relationship between concurrent ICB and denosumab duration and survival in mNSCLC. Neoadjuvant nivolumab recently showed encouraging pathologic response rates in resectable NSCLC; neoadjuvant trials lend themselves to translational research. Methods: POPCORN is a multicenter phase 1b/2 study to determine the mechanism of action, activity and safety of neoadjuvant nivolumab plus denosumab versus nivolumab alone. 30 patients with resectable stage 1A (tumor &gt; 2cm) – 3A NSCLC will be randomized 1:1 to two arms (Table). Exclusion criteria include uncontrolled autoimmune disease, steroid contraindications, and unhealed dental disease. Tumor tissue at baseline, surgery and relapse, and peripheral blood at various timepoints (including on-therapy) will be collected. The primary endpoint is to define pharmacodynamic correlates of the two arms through investigations including T-cell receptor clonality, RNA/transcription profile changes (tumor and peripheral blood), and expression of tumor/immune markers of interest via multiplex immunohistochemistry, compared between groups. Secondary endpoints include pathologic response rates, toxicity, R0 resection, and PFS/OS (exploratory). Statistical analysis will be primarily descriptive on the intention-to-treat population. The trial is sponsored by Metro North Hospital and Health Service (Queensland, Australia) with funding from AMGEN, Inc. Clinical trial information: ACTRN12618001121257. [Table: see text]

Clinical and Pathologic Characteristics Predicted the Postoperative Recurrence and Progression of Pituitary Adenoma: A Retrospective Study with 10 Years Follow-Up

Tumor recurrence or residual regrowth are poor prognoses for pituitary adenoma (PA). However, there is no validated and well-accepted prognostic classification of PAs to predict the clinical outcome and guide clinical practice. We analyzed the relevant data of a large cohort of patients with PA and thereafter proposed a new clinicopathologic classification for prognostic prediction. Tumor recurrence or residual regrowth identified by magnetic resonance imaging scans and endocrine studies were analyzed along with associated clinical and pathological characteristics for patients who underwent surgery in 2008-2016 at West China Hospital. A new clinicopathologic classification was proposed and applied. After a median follow-up of 44.0 months, tumor recurrence and residual progression were identified in 48 (25.0%) and 29 (37.2%) patients, respectively. Proliferative potential (hazard ratio [HR], 2.188; P= 0.002), invasiveness (HR, 1.698; P= 0.029), larger tumor size (HR, 1.029; P= 0.004), high-risk PA subtype (HR, 2.151; P= 0.004), and postoperative residual (HR, 1.941; P= 0.007) were risk factors for recurrence/progression in the early stage after surgery. With respect to clinicopathologic classification, compared with grade 1a tumors, grade 1b, 2a, and 2b adenomas had poorer prognosis with an increased probability of tumor recurrence/progression of 5.133-fold, 4.467-fold, and 20.1-fold, respectively. The proposed clinicopathologic classification of PAs showed significant value in predicting prognosis and succeeded in identifying cases with more clinically aggressive lesions with recurrence or residual regrowth. This prognostic classification may be helpful when identifying aggressive PAs and deciding the appropriate therapeutic strategy for patients with PAs.

Uridine 5'diphospho-glucuronosyltransferase 1A expression as an independent prognosticator in urothelial carcinoma of the upper urinary tract.

To determine the expression status of uridine 5'diphospho-glucuronosyltransferase 1A, a major phase II drug metabolism enzyme, in upper urinary tract urothelial carcinoma, as well as to assess its prognostic significance. We immunohistochemically stained for uridine 5'diphospho-glucuronosyltransferase 1A in tissue microarray consisting of 99 upper urinary tract urothelial carcinoma samples and paired non-neoplastic urothelial tissues. We also assessed the effect of uridine 5'diphospho-glucuronosyltransferase 1A knockdown on urothelial cancer cell growth. Uridine 5'diphospho-glucuronosyltransferase 1A was positive in 92.9% (27.3% weak [1+], 37.4% moderate [2+], 28.3% strong [3+]) of tumors, which was significantly (P < 0.001) lower than in benign urothelial tissues (98.8%; 3.5% 1+, 18.8% 2+, 76.4% 3+). All 37 (100%) non-muscle-invasive versus 55 (88.7%) of 62 muscle-invasive tumors (P = 0.043) were immunoreactive for uridine 5'diphospho-glucuronosyltransferase 1A. The rates of moderate-to-strong uridine 5'diphospho-glucuronosyltransferase 1A expression and its positivity were also strongly associated with the absence of concomitant carcinoma in situ (P = 0.034) and lymphovascular invasion (P = 0.016), respectively. However, there were no statistically significant associations between uridine 5'diphospho-glucuronosyltransferase 1A expression and tumor grade or pN/M status. Uridine 5'diphospho-glucuronosyltransferase 1A loss in M0 tumors was strongly associated with lower progression-free survival (P < 0.001) and cancer-specific survival (P < 0.001) rates. Multivariate analysis further identified a strong correlation of uridine 5'diphospho-glucuronosyltransferase 1A positivity with reduced cancer-specific mortality (hazard ratio 0.28, P = 0.018). Meanwhile, uridine 5'diphospho-glucuronosyltransferase 1A knockdown in urothelial cancer cells resulted in significant increases in their viability and migration. These results suggest a preventive role of uridine 5'diphospho-glucuronosyltransferase 1A signals in the development and progression of upper urinary tract urothelial carcinoma. Loss of uridine 5'diphospho-glucuronosyltransferase 1A expression might serve as an independent predictor of poor prognosis in patients with upper urinary tract urothelial carcinoma.

Association between Tumor Regression Rate and Gene Expression Profile after Iodine 125 Plaque Radiotherapy for Uveal Melanoma

Gene expression profile (GEP) testing segregates uveal melanoma (UM) into 2 main prognostic classes. It is unknown if a greater tumor regression response after iodine 125 (I125) brachytherapy correlates with class 2 GEP status. The purpose of this study was to determine whether there is a significant relationship between the rate of UM height regression and GEP classification testing after I125 plaque brachytherapy. Multicenter, retrospective cohort study. Adult UM patients treated with I125 plaque brachytherapy who had concurrent tumor biopsy at the time of surgery with a GEP test result from January 1, 2010 through June 30,2014. Baseline clinical data and GEP class assignments were obtained. The ultrasonographic tumor height was recorded at baseline and at 3, 6, 9, and 12 months and at the most recent final follow-up visits. Subanalysis of paired cases based on pretreatment ultrasound height was performed. Statistical analysis was performed using Wilcoxon rank-sum tests, the Fisher exact test, and Kaplan-Meier analysis. Percentage change in tumor height from baseline. A total of 353 patients were included in the study. Median follow-up was 2.1 years (range, 0.5-5.3 years). Gene expression profile status was class 1 in 247 tumors (70%) and class 2 in 106 tumors (30%). Increased patient age, larger tumor dimensions, and greater tumor thickness were associated with class 2 GEP status (P= 0.006, P < 0.001, and P < 0.001, respectively). The percentage reduction in tumor height from baseline was significantly greater in class 1 than class 2 tumors at 3 months (17.5% vs. 11.8%; P= 0.007) and 6 months (26.8% vs. 17.1%; P= 0.007), respectively, but there was no significant difference in reduction between class 1 and 2 tumors at 9 months (P= 0.26) and 12 months (P= 0.57) after treatment. Class 1A and 1B tumors showed similar reduction compared with class 2 tumors (P < 0.05). Class 1 UM tumors tend to regress more rapidly than class 2 tumors in the first 6 months after plaque radiotherapy. Class 1A and 1B tumors regress at similar rates after plaque radiotherapy.

Totally laparoscopic total gastrectomy using the overlap method; early outcomes of 50 consecutive cases.

Construction of an esophagojejunostomy is still a challenging procedure in totally laparoscopic total gastrectomy (TLTG), and there is no standard anastomosing method. The aims of this study were to describe our TLTG with the overlap method using a linear stapler and report surgical outcomes. From January 2015 to April 2016, 50 patients underwent TLTG using the overlap method for gastric cancer. The procedures were performed by a single surgeon, and the patients' medical records were reviewed. Their clinicopathologic characteristics, operation time, date of flatus, hospital stay, morbidity, and mortality were analyzed. The median age and body mass index were 56years and 23.5, respectively. Stage 1A tumors were the most common. Mean operating time was 144.6min, and no cases required changing to open laparotomy during surgery. On average, flatus occurred 3.5days after surgery, and patients were discharged 6.8days after surgery. No patient experienced anastomosis leakage, stricture, duodenal stump leakage, luminal bleeding, pancreatic fistula, or wound problems. There were two cases of intra-abdominal bleeding that required additional surgery. Intra-abdominal fluid collection and mechanical ileus occurred in two patients, respectively, and were successfully managed with conservative treatment. We reported favorable surgical outcomes of TLTG using the overlap method. It is a feasible and safe option for treatment of gastric cancer.

Abstract 24: Intratumoral genomic heterogeneity of primary pulmonary adenocarcinoma in never smokers

Abstract Aim: Intratumoral genomic heterogeneity challenges personalized lung cancer care, especially where it relies upon small diagnostic samples. To explore genomic representation provided by tumor subsampling, we performed whole genome sequencing (WGS) of multiple regions of individual primary pulmonary adenocarcinomas (LUAC). Methods: An observational study was performed on three cases of never-smoking LUAC resected with curative intent. Post-diagnostic residual fresh tumor was procured with informed consent, along with constitutional samples from normal lung or blood. Selection criteria included: histologically confirmed LUAC; never-smoker [defined as fewer than 100 cigarettes consumed in a lifetime]; and no prior malignancy, cytotoxic therapy or thoracic radiotherapy. Tissue samples were procured by an anatomical pathologist and research scientist and snap frozen within 60 minutes of devascularization, then stored at -80 degrees celsius. Nine macrodissected subsamples met quality criteria of &amp;gt;40% tumor cellularity and &amp;lt;20% necrosis (Case 1, 4 regions; Case 2, 3 regions; Case 3, 2 regions) as assessed visually by 2 anatomical pathologists. High molecular weight DNA was extracted from tissue using Qiagen AllPrep DNA/RNA Mini Kit and from blood using Qiagen Blood Maxi Kit. WGS was performed on paired end libraries using Illumina's HiSeq 2000 platform to 80x (tumor), 40x (normal lung) and 30x (blood) coverage. Reads were aligned to GRCh37 with BWA-MEM. Duplicates were removed using Picard and local INDEL realignment and base quality recalibration were performed with GATK. Single nucleotide variants (SNVs) were called by MuTect, Varscan, Strelka and SomaticSniper. Variants were considered ‘high priority’ if predicted by SNPEff to have ‘moderate’ or ‘high’ functional significance. Structural variants were detected from WGS data using Breakdancer and Pindel. Sample genotyping was performed using Illumina's HumanOmni2.5-8 array and used to call copy number variations (CNVs) using the Genome Alteration Print tool. Results: All cases were Caucasian females. Case 1 consisted of a 37 year old with a well to moderately differentiated pathological stage IV (AJCC 7th Edition; T4 N1 M1a) tumor 75mm in maximal dimension for which DNA from 4 tumor regions and whole blood was available. Case 2 was an 80 year old with a 24mm, acinar predominant, moderately differentiated pathological stage 1A (T1b N0 M0) tumor for which DNA from 3 tumor regions and whole blood was available. Case 3 was an 82 year old with a 35mm, acinar predominant, pathological stage 1B (T2a N0 M0) tumor for which DNA from 2 tumor regions and non-tumor lung was available. Mean tumor cellularity (and mean sequencing coverage achieved) for regions 1, 2, 3 and 4 for case 1 were 50% (98x), 50% (100x), 73% (99x) and 58% (134x), respectively. Similarly, for regions 1, 2 and 3 of case 2, mean cellularity (and coverage) was 45% (93x), 45% (114x) and 40% (93x), respectively. Case 3 demonstrated 45% (107x) and 55% (97x) mean cellularity (and coverage) for regions 1 and 2, respectively. Less than 10% necrosis was observed in all tumor regions. Of 10275 SNVs detected in case 1, 3198 (3198/10275, 31%) were found in all 4 subsamples. 6911/15689 (44%) and 5595/9528 (59%) were shared among all subsamples in cases 2 and 3, respectively. The numbers of SNVs unique to each region relative to total SNVs observed for each region in case were: 869/5999 (14%), 1129/6437 (18%), 914/6969 (13%) and 517/5936 (9%). Similarly, the numbers of unique SNVs as a proportion of total SNVs for each region in case 2 were 1148/9835 (12%), 2556/11404 (22%) and 2632/10714 (25%); and for case 3 were 2293/7888 (29%) and 1640/7235 (23%). In case 1, 7 of 303 (2%) high priority variants were detected in all regions. Similarly, 44/303 (15%) and 29/302 (10%) high priority variants were detected in all tumor regions for case 2 and 3, respectively. Conclusion: Significant intratumoral heterogeneity was observed. These findings have significant implications not only for diagnostic testing of lung cancer but also for clinical trial design. Prospective clinical trials incorporating assessment of both geographic and temporal intratumoral heterogeneity will help explore the implications of this phenomenon on patient treatment. Acknowledgements: We acknowledge the patients, nurses, and staff of The Prince Charles Hospital for their contributions to this project. Funding: MD supported by Cancer Council Queensland and NHMRC PhD Scholarships. Supported by funding from NHMRC, Cancer Australia, TPCH Foundation, Queensland Health, Cancer Council Queensland. Citation Format: Marissa G. Daniels, Lutz Krause, Jonathan J. Ellis, Ian A. Yang, Rayleen V. Bowman, Vandana Relan, Kelly Chee, Felicia Goh, Brielle Parris, Leanne Morrison, Maria Martins, Linda Passmore, Elizabeth McCaul, Deborah Courtney, Edwina Duhig, Morgan Windsor, Rishendran Naidoo, Kwun M. Fong. Intratumoral genomic heterogeneity of primary pulmonary adenocarcinoma in never smokers. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Integrating Clinical Genomics and Cancer Therapy; Jun 13-16, 2015; Salt Lake City, UT. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(1_Suppl):Abstract nr 24.

Sublobar Resection for Clinical Stage IA Non–small-cell Lung Cancer in the United States

BackgroundThis study evaluated the use of lobectomy and sublobar resection for clinical stage IA non–small-cell lung cancer (NSCLC) in the National Cancer Data Base (NCDB). MethodsThe NCDB from 2003 to 2011 was analyzed to determine factors associated with the use of a sublobar resection versus a lobectomy for the treatment of clinical stage IA NSCLC. Overall survival was assessed using the Kaplan-Meier method and Cox proportional hazard modeling. ResultsAmong 39,403 patients included for analysis, 29,736 (75.5%) received a lobectomy and 9667 (24.5%) received a sublobar resection: 84.7% wedge resection (n = 8192) and 15.3% segmental resection (n = 1475). Lymph node evaluation was not performed in 2788 (28.8%) of sublobar resection patients, and 7298 (75.5%) of sublobar resections were for tumors ≤ 2 cm. After multivariable logistic regression, older age, higher Charlson-Deyo comorbidity scores, smaller tumor size, and treatment at lower-volume institutions were associated with sublobar resection (all P < .001). Overall, lobectomy was associated with significantly improved 5-year survival compared to sublobar resection (66.2% vs. 51.2%; P < .001, adjusted hazard ratio 0.66; P < .001). However among sublobar resection patients, nodal sampling was associated with significantly better 5-year survival (58.2% vs. 46.4%; P < .001). ConclusionDespite adjustment for patient and tumor related characteristics, a sublobar resection is associated with significantly reduced long-term survival compared to a formal surgical lobectomy among patients with NSCLC, even for stage 1A tumors. For patients who cannot tolerate lobectomy and who are treated with sublobar resection, lymph node evaluation is essential to help guide further treatment.

Clinical and pathologic features of young endometrial cancer patients with loss of mismatch repair expression

ObjectiveThis study examines premenopausal and early menopause patients in a unique population with endometrial cancer and loss of mismatch repair (MMR) gene expression. The purpose is to compare clinical and pathologic differences in patients with loss of expression (LOE) to those with normal expression (NE). MethodsEndometrial cancer patients under age 60 in-between 1998 and 2008 were identified from a single tumor registry. Clinical and pathologic data were abstracted from records. Staining for expression of MSH6, MSH2, MLH1, and PMS2 were performed on archived tissue blocks. Statistical analysis was performed. Results158 patients were analyzed; 58% Asian, 34% Pacific Islander, and 8% Caucasian. 31 demonstrated LOE of at least one MMR gene; 127 retained NE. 50% Caucasian, 21.9% Asian, and 12.5% Pacific Island populations had LOE of one or more MMR genes. LOE was found to have a higher incidence of Grade III (p=0.0013) and stage 3–4 tumors (p=0.0079), mean depth of myometrial invasion (p=0.0019), lymphovascular space invasion (p=0.0020), nodal metastases (p=0.0157), and a lower incidence of Grade I (p=0.0020) and stage 1A tumors (p=0.0085). LOE had a significantly lower mean BMI (p=0.0001). 35% of patients in the NE vs zero in the LOE group had a BMI greater than 40. ConclusionYounger patients with LOE endometrial cancer appear to represent a clinically significant subgroup of patients without features characteristically found in classic type 1 endometrial cancer generally demonstrating lower BMI and tumors associated with poor prognostic characteristics. It is unclear if the distinctive ethnicity found in Hawaii has a significant impact on outcome. Further investigation is necessary to identify appropriate treatment strategies.

The SARAH Domain of RASSF1A and Its Tumor Suppressor Function

The Ras association domain family 1A (RASSF1A) tumor suppressor encodes a Sav-RASSF-Hpo domain (SARAH), which is an interaction domain characterized by hWW45 (dSAV) and MST1/2 (dHpo). In our study, the interaction between RASSF1A and RASSF1C with MST1 and MST2 was demonstrated and it was shown that this interaction depends on the SARAH domain. SARAH domain-deleted RASSF1A had a similar growth-reducing effect as full-length RASSF1A and inhibited anchorage independent growth of the lung cancer cell lines A549 significantly. In cancer cells expressing the SARAH deleted form of RASSF1A, reduced mitotic rates (P = 0.001) with abnormal metaphases (P < 0.001) were observed and a significantly increased rate of apoptosis was found (P = 0.006) compared to full-length RASSF1A. Although the association with microtubules and their stabilization was unaffected, mitotic spindle formation was altered by deletion of the SARAH domain of RASSF1A. In summary, our results suggest that the SARAH domain plays an important role in regulating the function of RASSF1A.