Citations

Background: Thyroid lymphoma is a relatively rare disease often posing a diagnostic challenge. Reaching the final diagnosis can be delayed if insufficient biopsy material is obtained for immunohistochemistry analysis. The aim of this study was to evaluate the clinical, biochemical, and radiological features of thyroid lymphoma. Methods: A retrospective analysis was conducted of all Mayo Clinic patients evaluated between 2000 and 2014 who had a tissue biopsy positive for thyroid lymphoma. Results: Seventy-five subjects had biopsy-proven thyroid lymphoma, and 62.7% were primary thyroid lymphomas. The median age at diagnosis was 67 years (range 20–90 years). A total of 50.7% were male, and 54.7% had a history of Hashimoto's thyroiditis. Presenting symptoms included neck mass (88%), dysphagia (45.3%), and hoarseness (37.3%). The typical ultrasound appearance consisted of a solid, hypoechoic mass with increased vascularity and variable edge characteristics. Fine-needle aspiration (FNA) biopsies were abnormal in 70.7% of cases, and 42% indicated a specific lymphoma subtype. The diagnosis was confirmed in 53.3% by core biopsy, in 21.3% by thyroidectomy (partial or total), in 12% through incisional biopsy, and in 12% by lymph node biopsy. Core biopsy had a higher sensitivity compared with FNA (93% vs. 71%, p = 0.006). Conclusion: A rapidly enlarging neck mass in the setting of Hashimoto's thyroiditis should raise suspicion for thyroid lymphoma. Radiologically, this usually presents as a large, unilateral, thyroid-centered mass, hypoechoic by ultrasound, and expanding into adjacent soft tissues. Core-needle biopsy should be the first diagnostic test to expedite reaching the final diagnosis and decrease patient burden of additional tests and interventions.

AbstractIntroductionDespite advances in trauma care, hemorrhage continues to be the leading cause of preventable mortality in trauma. The evidence to support its use in non‐trauma patients is limited. We aim to report our experience with prehospital blood product transfusion. We hypothesize that it is safe, appropriately utilized, and that our protocol, which was designed for trauma patients, is adaptable to fit the needs of non‐trauma patients.MethodsPatients transfused with blood products, packed red blood cells (pRBCs) or plasma, in the prehospital environment between 2002 and 2014 were included. Trauma patients were compared to non‐trauma patients using descriptive statistics.ResultsA total of 857 patients (n = 549 trauma and n = 308 non‐trauma) were transfused with pRBCs (76 %, n = 654, mean 1.6 ± 1.1 units en route), plasma (53 %, n = 455, mean 1.7 ± 0.7 unit), or both (29 %, n = 252) during ground (12 %) or air (84 %) critical care transport. Mean age was 60.8 ± 21.6 years with 60.1 % (n = 515) males. Subsequently, in‐hospital blood transfusions were performed in 80 % of patients, operations in 44 %, and endoscopy in 31 %. Five percent (n = 41) of patients did not require any of these interventions. Thirty‐day mortality rate was 18 %, and one patient (<0.01 %) had a transfusion reaction. The majority of patients were non‐trauma (n = 549, 64 %). Of the non‐trauma patients, 219 (40 %) were surgical, 193 (35 %) gastrointestinal bleeds, and 137 (25 %) medical.ConclusionBoth non‐trauma and trauma patients require blood products for life threatening hemorrhage and the majority required further interventions. Further research on the benefits of transfusion among non‐trauma patients is warranted.

Abstract Background: Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy is standard of care for patients with newly diagnosed DLBCL. A majority of patients respond to R-CHOP, however ∼9% will have primary refractory disease and outcomes in these patients are extremely poor. While there is some knowledge of the pharmacogenomic (PGx) determinants of individual agents within R-CHOP, little is known about the PGx determinants of combination therapy. Our study aims to elucidate germline PGx determinants of drug bioavailability and undesirable side chain reactions in DLBCL patients treated with R-CHOP having potential to influence refractory disease. Methods: Newly diagnosed, DLBCL patients treated with R-CHOP between 2002 and 2012 with germline DNA and genotyping data were selected from the Molecular Epidemiology Resource within the Iowa/Mayo Lymphoma SPORE. Refractory disease was defined as either i) a best response of stable or progressive disease or ii) progressive disease by the end of the planned number of cycles of R-CHOP. PGx candidates within known pharmacokinetics and pharmacodynamics (PD) pathways for 11 genes (1,040 single nucleotide polymorphisms (SNPs)) were selected for study (CPT 2012;92(4):414-7). Odds ratios (ORs) and 95% confidence intervals (CI) were used to estimate the association of SNPs with refractory disease, controlling for age, gender, and age-adjusted International Prognostic Index. Results: The median age at diagnosis of 424 of DLBCL patients treated with R-CHOP was 62 years (range 18-92); 45.7% were female; and 58.4% had Ann Arbor Stage III-IV. By the end of initial therapy 40 patients had primary refractory disease. Of the 1,040 SNPs evaluated, 120 (12%) were significantly associated with refractory disease at the 5% significance threshold suggesting novel associations with drug metabolism. The top SNP from each PGx candidate gene are shown in Table, with ALDH5A1 and CYP2B6 showing the most significant associations. Conclusions: While needing replication, we identified associations within two PGx candidate genes that are potentially functionally related to cyclophosphamide PD: alleles within CYP2B6 may have relevance in R-CHOP outcomes due to potential competition with other drug metabolizing enzymes shared with prednisone and vincristine biotransformation in the liver, and alleles withinALDH5A1 may impact a deactivating side chain reaction in B lymphocytes. Table: R-CHOP PGx candidates with known side chain reactionsPGx candidaten SNPsTop SNPChrOR* (95% CI)P-valueMAFABCB1365rs3480093571.86 (1.14 – 3.04)1.32E-020.29ADH1A32rs122996841.66 (0.60 - 4.53)3.27E-010.038ALDH3A116rs2228100171.26 (0.71 - 2.22)4.28E-010.24ALDH5A1192rs946103466.30 (2.43 - 16.4)1.55E-040.030CBR110rs2835266212.10 (0.90 - 4.89)8.76E-020.052CBR356rs45527331212.12 (0.91 - 4.98)8.29E-020.050CYP2B6107rs1038376192.38 (1.44 - 3.94)7.74E-040.27CYP3A421rs2898858372.32 (0.80 - 6.78)1.23E-010.028CYP3A531rs778032871.69 (0.68 - 4.16)2.57E-010.054SLC22A16193rs11217403561.80 (1.06 - 3.03)2.78E-020.21SOD116rs1041740211.35 (0.83 - 2.19)2.26E-010.32Chr=chromosome, MAF=minor allele frequency, *Adjusted for age, sex, and age-adjusted International Prognostic Index Citation Format: Matthew K. Breitenstein, Susan L. Slager, Anne J. Novak, Matthew J. Maurer, Carrie A. Thompson, Umar Farooq, Brian K. Link, Thomas M. Habermann, Curtis L. Olswold, Andrew L. Feldman, Grzegorz S. Nowakowski, Stephen M. Ansell, Thomas E. Witzig, Richard M. Weinshilboum, Liewei Wang, James R. Cerhan. Pharmacogenomic of refractory response to R-CHOP therapy in diffuse large B-cell lymphoma (DLBCL) patients. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B143.

Abstract Background: OPB-111077 is a new chemical entity with anticancer activity in vitro and in human tumor xenograft models. The compound modulates STAT3 phosphorylation but has no marked effect on activity of any of 69 tested human tyrosine or serine/threonine kinases. This P1 study evaluated safety, pharmacokinetics, and antitumor activity of OPB-111077 in subjects with advanced cancers. Methods: Primary objectives determined safety, tolerability, and maximum tolerated dose (MTD) of OPB-111077 given orally once daily to subjects with advanced cancer. Secondary objectives included pharmacokinetics (PK) and antitumor activity. In the first 2 cycles of dose escalation, Day 1 dose was followed by 2 days off study therapy for PK. The starting dose was 100 mg once daily. Single subject cohorts with dose level doublings were studied until the first ≥ Grade 2 AE that was possibly drug-related. Then a 3+3 design was used. After MTD determination, expansion cohorts were opened for subjects with malignancies possibly susceptible to inhibition by OPB-111077, including breast, cervical, colorectal, gastric, kidney, myeloma, non-small cell lung, non-Hodgkin's lymphoma, ovarian, and prostate cancers, as well as “rare tumors” for which STAT3 inhibition might generate clinical activity. Results: Overall 145 subjects received OPB-111077. Mean age was 61 years (range 21-88), and 51% of subjects were female. Dose escalation occurred in 18 subjects. Four DLTs were observed: 2 at 400 mg QD (G3 nausea/vomiting), and 2 at 300 mg QD (G3 vertigo and G3 nausea/vomiting). The MTD was 250 mg QD. All subjects recovered from DLTs after drug discontinuation. Adverse events (AEs) that may be attributable to OPB-111077 include nausea (71%), vomiting (46%), fatigue (44%), dizziness/vertigo (26%), and hypothyroidism (19%). Most AEs were CTCAE Grades 1 or 2 and manageable with supportive treatment. OPB-111077 exposures increase dose proportionally and linearly with increasing single and multiple doses up to 250 mg. Median time to peak plasma concentration (tmax) is about 4 hours. Mean maximum plasma concentration (Cmax) is 16 μmol/L and mean trough concentration is 6 μmol/L after multiple doses of 250 mg QD. Terminal half-life is about 23 hours and steady state was reached by about 1 week. The major metabolites in plasma are pharmacologically inactive and unlikely to contribute to efficacy. Administration with a high fat meal did not significantly alter OPB-111077 bioavailability. Expansion cohorts enrolled 127 subjects, including NSCLC (13), breast (13), ovarian (11), kidney (11), colorectal (10), prostate (8), lymphoma (8), gastric (7), cervical (3) cancers, and myeloma (1). Rare tumors with STAT rationale included sarcomas (13), neuroendocrine tumors (7), squamous cell carcinomas (5), other carcinomas (12), and other malignant tumors (5). One RECIST Partial Response occurred in a subject with Diffuse Large B Cell Lymphoma. In addition, 7 subjects with had stable disease for at least 8 treatment cycles, including gastric (2), cholangiocarcinoma, kidney, prostate, K-Ras mutant colon cancer, and esthesioneuroblastoma. Conclusions: OPB-111077 can be given safely and achieves clinically active drug levels in humans. Single agent clinical activity was observed. Translational work is ongoing to determine factors driving clinical activity Citation Format: Gregory Cote, Kyriakos Papadopoulos, Amita Patnaik, Drew Rascoe, Lon Smith, Andrea Bullock, Keith Flaherty, Geoffrey Shapiro, Jordan Berlin, Manish Monga, Thomas Habermann, Thomas Witzig, Chester Lin, Lin-Feng Tsai, Agnes Elekes, Naoto Ohi, Kunihiko Tatsumi, Anthony Tolcher. A phase 1, open-label multiple dose escalation trial to determine safety and tolerability of once daily OPB-111077 in subjects with advanced cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B118.

BACKGROUNDPrior studies have shown that a higher hospital volume or physician caseload is associated with better outcomes for complex and uncommon surgical procedures. Similar studies in the medical management of rare diseases such as hematologic cancers are limited. This retrospective, observational study using the US National Cancer Data Base determined the extent to which the number of new non‐Hodgkin lymphoma (NHL) patients treated annually at a treatment facility affected overall survival (OS).METHODSThere were 278,985 patients treated at 1151 facilities from 1998 to 2006. Treatment facilities were classified by quartiles based on the average number of new NHL patients seen annually: quartile 1 (Q1), 2 to 13 patients; quartile 2 (Q2), 14 to 20 patients; quartile 3 (Q3), 21 to 32 patients; and quartile 4 (Q4), 33 or more patients. The outcome of interest was OS according to facility volume.RESULTSThe unadjusted median OS was 61.8 months for Q1, 65.9 months for Q2, 71.4 months for Q3, and 83.6 months for Q4. A multivariate analysis that was adjusted for demographic (sex, age, race, and ethnicity), socioeconomic (income and insurance type), geographic (area of residence), disease‐specific (NHL subtype and stage), and facility‐specific factors (type and location) showed that the facility volume was associated with OS. Compared with patients at Q4 facilities, patients at lower quartile facilities had higher mortality (hazard ratio for Q3, 1.05 [95% confidence interval, 1.04‐1.06]; hazard ratio for Q2, 1.08 [95% confidence interval, 1.07‐1.10]; hazard ratio for Q1, 1.14 [95% confidence interval, 1.11‐1.17]).CONCLUSIONSNHL patients treated at higher volume facilities may survive longer than those treated at lower volume facilities. Further work is needed to understand the mechanisms of these differences and whether volume should be considered in the determination of referrals for NHL patients. Cancer 2016;122:2552–9. © 2016 American Cancer Society.

BackgroundSynchronous colon cancers, defined as two or more primary colon cancer detected simultaneously at the time of initial diagnosis, account for up to 5% of all colon cancer diagnoses. Management principles and outcomes remain largely undefined.MethodsA retrospective institutional review of patients undergoing curative intent resection for colon adenocarcinoma (Stages I–III) from 1995 to 2007 was performed. Hereditary causes or inflammatory bowel disease were excluded. Matching was performed and Kaplan–Meier analysis was used to compare overall survival.ResultsOf 2,387 patients, 100 (4.2%) had synchronous cancers. Patients with synchronous lesions tended to be older (median 77 vs. 72 years, P < 0.001) with more advanced tumors (41.0% vs. 31.4% Stage III, P = 0.04). After matching, there were no differences in demographics or tumor factors (all P > 0.05). Compared to solitary, synchronous cancers demonstrated an inferior 10‐year overall survival (53.9% vs. 36.5%, P = 0.009). Subset analysis of patients with synchronous cancers showed no difference in overall survival between those with extended versus segmental resections at 120‐months (P = 0.07).ConclusionSynchronous colon cancer is associated with decreased overall survival compared to patients with solitary tumors. Extended resection does not confer a survival benefit in these patients. Further research is needed to determine how to mitigate the poor outcomes. J. Surg. Oncol. 2016;114:80–85. © 2016 Wiley Periodicals, Inc.

Purpose: In the current health care environment, cost effectiveness is critically important in policy setting and care of patients. This study performed a health economic analysis to assess the implications to providers and payers of expanding the use of frozen section margin analysis to minimize reoperations for patients undergoing breast cancer lumpectomy. Methods: A health care economic impact model was built to assess annual costs associated with breast lumpectomy procedures with and without frozen section margin analysis to avoid reoperation. Results: If frozen section margin analysis is used in 20% of breast lumpectomies and under a baseline assumption that 35% of initial lumpectomies without frozen section analysis result in reoperations, the potential annual cost savings are $18.2 million to payers and $0.4 million to providers. Under the same baseline assumption, if 100% of all health care facilities adopted the use of frozen section margin analysis for breast lumpectomy procedures, the potential annual cost savings are $90.9 million to payers and $1.8 million to providers. On the basis of 10,000 simulations, use of intraoperative frozen section margin analysis yields cost saving for payers and is cost neutral to slightly cost saving for providers. Conclusion: This economic analysis indicates that widespread use of frozen section margin evaluation intraoperatively to guide surgical resection in breast lumpectomy cases and minimize reoperations would be beneficial to cost savings not only for the patient but also for payers and, in most cases, for providers.