Search

Supplemental Table Legends

Purpose: The median survival following surgical resection of pancreatic ductal adenocarcinoma (PDAC) is currently Experimental Design: We sequenced the exomes of eight PDACs from patients who survived ≥10 years. On the basis of the results of the exomic analysis, targeted sequencing of selected genes was performed in a series of 27 additional PDACs from VLTSs.Results: KRAS mutations were identified in 33 of 35 cancers (94%) from VLTSs and represented the most prevalent alteration in our cohort. TP53, SMAD4, and CDKN2A mutations occurred in 69%, 26%, and 17%, respectively. Mutations in RNF43, which have been previously associated with intraductal papillary mucinous neoplasms, were identified in four of the 35 cancers (11%). Taken together, our data show no difference in somatic mutations in carcinomas from VLTSs compared with available data from PDACs unselected for survival. Comparison of clinicopathologic features between VLTSs and a matching control group demonstrated that younger age, earlier stage, well/moderate grade of differentiation, and negative resection margins were associated with VLTS. However, more advanced stage, poor grade, or nodal disease did not preclude long-term survival.Conclusions: Our results suggest that in most patients, somatic mutations in commonly mutated genes are unlikely to be the primary determinant of very long-term survival following surgical resection of PDAC. Clin Cancer Res; 21(8); 1944–50. ©2015 AACR.

Supplementary Table 3. Somatic mutations in targeted sequencing from Validation Set

Supplementary Table 2. Somatic mutations identified in exome sequencing of VLTSs

Supplementary table 1. Findings of multivariable linear regressions analyzing genetic associations between candidate gene SNPs and lipid profiles in exemestane-treated participants complementary to statistically significant findings in letrozole-treated participants. Supplementary table 2. Findings of multivariable linear regressions analyzing genetic associations between candidate gene SNPs and lipid profiles in only Caucasian women taking both letrozole and exemestane complementary to statistically significant findings in letrozole-treated participants. *new significant finding (in letrozole only), and corresponding data for exemestane (additive rs1062033 and dominant rs1062033 models were not included due to number of homozygotes

Supplementary Table 1. Summary of exome sequencing data for VLTSs

Supplementary Methods. This document provides detailed methods for library preparation, sequencing, and SafeSeq.

Supplementary Figure 1a. Manhattan plots demonstrating associations between variants in the CYP19A1 gene and absolute changes HDL-C using dominant (A) and additive (B) in letrozole treated participants taking lipid lowering medication.

Purpose: Aromatase inhibitors can exert unfavorable effects on lipid profiles; however, previous studies have reported inconsistent results. We describe the association of single-nucleotide polymorphisms (SNP) in candidate genes with lipid profiles in women treated with adjuvant aromatase inhibitors.Experimental Design: We conducted a prospective observational study to test the associations between SNPs in candidate genes in estrogen signaling and aromatase inhibitor metabolism pathways with fasting lipid profiles during the first 3 months of aromatase inhibitor therapy in postmenopausal women with early breast cancer randomized to adjuvant letrozole or exemestane. We performed genetic association analysis and multivariable linear regressions using dominant, recessive, and additive models.Results: A total of 303 women had complete genetic and lipid data and were evaluable for analysis. In letrozole-treated patients, SNPs in CYP19A1, including rs4646, rs10046, rs700518, rs749292, rs2289106, rs3759811, and rs4775936 were significantly associated with decreases in triglycerides by 20.2 mg/dL and 39.3 mg/dL (P < 0.00053), respectively, and with variable changes in high-density lipoprotein (HDL-C) from decreases by 4.2 mg/dL to increases by 9.8 mg/dL (P < 0.00053).Conclusions: Variants in CYP19A1 are associated with decreases in triglycerides and variable changes in HDL-C in postmenopausal women on adjuvant aromatase inhibitors. Future studies are needed to validate these findings, and to identify breast cancer survivors who are at higher risk for cardiovascular disease with aromatase inhibitor therapy. Clin Cancer Res; 22(6); 1395–402. ©2015 AACR.

Supplementary Table 1 from RNAi-Mediated Silencing of Nuclear Factor Erythroid-2–Related Factor 2 Gene Expression in Non–Small Cell Lung Cancer Inhibits Tumor Growth and Increases Efficacy of Chemotherapy

Supplementary Figure 1 from Estimating CDKN2A Carrier Probability and Personalizing Cancer Risk Assessments in Hereditary Melanoma Using MelaPRO

Supplementary Table 1 from Estimating CDKN2A Carrier Probability and Personalizing Cancer Risk Assessments in Hereditary Melanoma Using MelaPRO

PRO-cision medicine refers to personalizing care using patient-reported outcomes (PROs). We developed and feasibility-tested a PRO-cision Medicine remote PRO monitoring intervention designed to identify symptoms and reduce the frequency of routine in-person visits.We conducted focus groups and one-on-one interviews with metastatic breast (n = 15) and prostate (n = 15) cancer patients and clinicians (n = 10) to elicit their perspectives on a PRO-cision Medicine intervention's design, value, and concerns. We then feasibility-tested the intervention in 24 patients with metastatic breast cancer over 6-months. We obtained feedback via end-of-study surveys (patients) and interviews (clinicians).Focus group and interview participants reported that remote PRO symptom reporting could alert clinicians to issues and avoid unneeded/unwanted visits. However, some patients did not perceive avoiding visits as beneficial. Clinicians were concerned about workflow. In the feasibility-test, 24/236 screened patients (10%) enrolled. Many patients were already being seen less frequently than monthly (n = 97) or clinicians did not feel comfortable seeing them less frequently than monthly (n = 31). Over the 6-month study, there were 75 total alerts from 392 PRO symptom assessments (average 0.19 alert/assessment). Patients had an average of 4 in-person visits (vs. expected 6.5 without the intervention). Patients (n = 19/24) reported high support on the end-of-study survey, with more than 80% agreeing with positive statements about the intervention. Clinician end-of-study interviews (n = 11/14) suggested that PRO symptom monitoring be added to clinic visits, rather than replacing them, and noted the increasing role of telemedicine.Future research should explore combining remote PRO symptom monitoring with telemedicine and in-person visits.

The Long-Term Oxygen Treatment Trial demonstrated that long-term supplemental oxygen did not reduce time to hospital admission or death for patients who have stable chronic obstructive pulmonary disease and resting and/or exercise-induced moderate oxyhemoglobin desaturation, nor did it provide benefit for any other outcome measured in the trial. Nine months after initiation of patient screening, after randomization of 34 patients to treatment, a trial design amendment broadened the eligible population, expanded the primary outcome, and reduced the goal sample size. Within a few years, the protocol underwent minor modifications, and a second trial design amendment lowered the required sample size because of lower than expected treatment group crossover rates. After 5.5 years of recruitment, the trial met its amended sample size goal, and 1 year later, it achieved its follow-up goal. The process of publishing the trial results brought renewed scrutiny of the study design and the amendments. This article expands on the previously published design and methods information, provides the rationale for the amendments, and gives insight into the investigators' decisions about trial conduct. The story of the Long-Term Oxygen Treatment Trial may assist investigators in future trials, especially those that seek to assess the efficacy and safety of long-term oxygen therapy. Clinical trial registered with clinicaltrials.gov (NCT00692198).

The criteria for resection of solitary pancreatic side-branch intraductal papillary mucinous neoplasm (IPMN) have been well described by the Sendai consensus statement. However, the management of multiple pancreatic cystic lesions is less certain, with no clear guidelines in the literature to date. The purpose of this study was to evaluate the histopathologic findings in pancreatic IPMNs in patients with multiple (≥ 4) pancreatic cysts.The CT scans of all patients with a pathologically proven IPMN at our institution were reviewed, and a total of 52 patients with four or more pancreatic cysts were found. Each case was reviewed for the number of cysts and the presence of signs of invasive malignancy including a coexistent solid pancreatic mass, pancreatic ductal dilatation, and mural nodularity.A total of 52 patients (19 men, 33 women; mean age, 71.8 years) were found to have multifocal IPMNs, defined as four or more cysts, on CT. Of these 52 patients, nine also had evidence of a solid pancreatic mass on CT. Retrospective review of the pathologic results for the remaining 43 patients (17 men, 26 women; mean age, 71.76 years) showed 18 cases of an IPMN with either high-grade dysplasia or a coexistent invasive carcinoma. Most important, 37% (7/19 patients) had no CT findings of an invasive malignancy according to the Sendai criteria (i.e., cysts ≥ 3 cm in the axial plane, main pancreatic ductal dilatation ≥ 6 mm, or mural nodularity within a cyst) but were found to have an IPMN with either high-grade dysplasia or invasive carcinoma. When the pancreas contained 10 or more cysts, high-grade dysplasia or invasive carcinoma tended to be more likely than low- or intermediate-grade dysplasia (odds ratio, 3.83; 95% CI, 0.87-16.8; p = 0.075).The presence of multiple pancreatic cysts should be looked on with suspicion, particularly when there are a large number of cysts, even when none of the cysts individually meet the imaging criteria for resection according to the Sendai consensus recommendations. At the very least, these patients need to be followed very closely.

The purpose of this study was to evaluate 18F-FDG PET/CT scanning as an early predictor of response to immune checkpoint inhibitors (ICIs) in patients with advanced melanoma. Methods: Twenty patients with advanced melanoma receiving ICI prospectively underwent 18F-FDG PET/CT at 3 scan intervals: before treatment initiation (SCAN-1), at days 21–28 (SCAN-2), and at 4 mo (SCAN-3). This study was approved by the institutional review board, and informed consent was received from all patients who were enrolled between April 2012 and December 2013. Tumor response at each posttreatment time point was assessed according to RECIST 1.1, immune-related response criteria, PERCIST (PERCIST 1.0), and European Organization for Research and Treatment of Cancer (EORTC) criteria. Performance characteristics of each metric to predict best overall response (BOR) at ≥ 4 mo were assessed. Results: Twenty evaluable patients were treated with ipilimumab (n = 16), BMS-936559 (n = 3), or nivolumab (n = 1). BOR at ≥ 4 mo included complete response (n = 2), partial response (n = 2), stable disease (n = 1), and progressive disease (n = 15). Response evaluations at SCAN-2 using RECIST 1.1, immune-related response criteria, PERCIST, and EORTC criteria demonstrated accuracies of 75%, 70%, 70%, and 65%, respectively, to predict BOR at ≥ 4 mo. Interestingly, the optimal PERCIST and EORTC threshold values at SCAN-2 to predict BOR were >15.5% and >14.7%, respectively. By combining anatomic and functional imaging data collected at SCAN-2, we developed criteria to predict eventual response to ICI with 100% sensitivity, 93% specificity, and 95% accuracy. Conclusion: Combining functional and anatomic imaging parameters from 18F-FDG PET/CT scans performed early in ICI appears predictive for eventual response in patients with advanced melanoma. These findings require validation in larger cohorts.

We previously demonstrated the ability to detect metastatic prostate cancer using N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-4-(18)F-fluorobenzyl-L-cysteine ((18)F-DCFBC), a low-molecular-weight radiotracer that targets the prostate-specific membrane antigen (PSMA). PSMA has been shown to be associated with higher Gleason grade and more aggressive disease. An imaging biomarker able to detect clinically significant high-grade primary prostate cancer reliably would address an unmet clinical need by allowing for risk-adapted patient management.We enrolled 13 patients with primary prostate cancer who were imaged with (18)F-DCFBC PET before scheduled prostatectomy, with 12 of these patients also undergoing pelvic prostate MR imaging. Prostate (18)F-DCFBC PET was correlated with MR imaging and histologic and immunohistochemical analysis on a prostate-segment (12 regions) and dominant-lesion basis. There were no incidental extraprostatic findings on PET suggestive of metastatic disease.MR imaging was more sensitive than (18)F-DCFBC PET for detection of primary prostate cancer on a per-segment (sensitivities of up to 0.17 and 0.39 for PET and MR imaging, respectively) and per-dominant-lesion analysis (sensitivities of 0.46 and 0.92 for PET and MR imaging, respectively). However, (18)F-DCFBC PET was more specific than MR imaging by per-segment analysis (specificities of 0.96 and 0.89 for PET and MR imaging for corresponding sensitivity, respectively) and specific for detection of high-grade lesions (Gleason 8 and 9) greater than 1.0 mL in size (4/4 of these patients positive by PET). (18)F-DCFBC uptake in tumors was positively correlated with Gleason score (ρ = 0.64; PSMA expression, ρ = 0.47; and prostate-specific antigen, ρ = 0.52). There was significantly lower (18)F-DCFBC uptake in benign prostatic hypertrophy than primary tumors (median maximum standardized uptake value, 2.2 vs. 3.5; P = 0.004).Although the sensitivity of (18)F-DCFBC for primary prostate cancer was less than MR imaging, (18)F-DCFBC PET was able to detect the more clinically significant high-grade and larger-volume tumors (Gleason score 8 and 9) with higher specificity than MR imaging. In particular, there was relatively low (18)F-DCFBC PET uptake in benign prostatic hypertrophy lesions, compared with cancer in the prostate, which may allow for more specific detection of primary prostate cancer by (18)F-DCFBC PET. This study demonstrates the utility of PSMA-based PET, which may be used in conjunction with MR imaging to identify clinically significant prostate cancer.

Solid-pseudopapillary neoplasms (SPNs) are rare pancreatic tumors, which occur most frequently in young women and are associated with an excellent prognosis. Computed tomography (CT) is used most commonly to identify these lesions, but there are few studies evaluating the role of endoscopic ultrasound (EUS) and fine needle aspiration (EUS-FNA) in the assessment of SPN. The aim of the study was to determine the incremental diagnostic yield of EUS-FNA compared with CT or EUS in the evaluation of patients with SPN. A retrospective chart review of consecutive patients diagnosed with SPN who underwent CT, EUS, and EUS-FNA at five centers from three countries from 1998 to 2013. Patient demographics, imaging, endoscopic studies, cytopathology, and histology were reviewed. Thirty-four patients were identified with SPN. There were 31 (91.2 %) females, with a mean age at diagnosis of 37 years (range 16-81). The most common presenting symptom was abdominal pain which was present in 59 %. SPNs were incidentally detected in 14 (41.2 %) of the patients. The median tumor size was 4.2 cm (range 1.9–9.4). No patient had evidence of local or distant metastases. The most common appearance on EUS was of a mixed solid-cystic lesion (67.6 %). The diagnostic yield of CT and EUS alone was 23.5 and 41.2 %, respectively. CT and EUS combined had a diagnostic yield of 52.9 %. The addition of EUS-FNA significantly increased the diagnostic yield to 82.4 % compared with either CT or CT and EUS (p