Levels 2A Research Articles

Suspect screening strategy for pesticide application history based on characteristics of trace metabolites

Pesticides are widely used to protect crops but can also threaten public health as they can remain in the environment for a long time. Additionally, some transformation products (TPs) of unknown toxicity, stability, or bioaccumulation properties can further be formed from the hydrolysis, photolysis and biodegradation of pesticides. The identification and quantification of those TPs can be challenging for environmental regulation and risk assessment due to a limited understanding about them. In this study, a suspect screening strategy for pesticide application history was developed and then used to organic products (tea). Liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS) was used to screen and identify the TPs in crops and their toxicity was subsequently predicted with the open-source software (ECOSAR and admetSAR). Finally, the SIRIUS software was applied and 142 TPs from 20 pesticides were identified in tea plants based on the fragmentation-degradation relationship. Of these, standards (level 1) and 53 were considered as tentatively identified (levels 2a and 2b). Some TPs were also found to be present in tea plants and soil after 65 days, thus indicating higher persistency or stability than parent pesticides. While others from diafenthiuron and neonicotinoids had higher predicted toxicity of daphnid, and demonstrated positive for honeybee toxicity. Suspect screening is a powerful tool to screen pesticide TPs on the complex matrix of crops. Such screening can provide potential evidence of pesticide application, especially in cases of illegal practices in organic farming.

The role of calcium metabolism disorders in the formation of different density calculi with calcium oxalate nephrolithiasis

Objective To investigate the relationship between calcium metabolism disorders, stone formation inhibitor levels and stone density in primary and recurrent calcium-oxalate nephrolithiasis.Material and Methods Sixty nine patients with urolithiasis were examined, their average age was 41,4 ± 9,5 years. Two main groups were distinguished: Group 1 – primary calcium-oxalate nephrolithiasis (PN), Group 2 – recurrent calcium-oxalate nephrolithiasis (RN). Then each group was divided into two subgroups – A and B according to stone density: 500–1000 HU and from 1000–1500 HU, respectively. Stone density was determined by computed tomography (CT). PTH (parathormone), PTHrP (parathyroid hormone related protein), vitamin D, total blood calcium (Ca), ionized blood Ca, total blood protein, Ca and urine pH were also examined. After the examination, patients underwent surgical removal of the stones.Results It was found that 41.9% of group 1 and 46.9% of group 2 patients had grade I obesity. Average creatinine level in group 2 was 9.7% higher than in group 1 (p < 0.05). Urea level in both groups was not statistically significantly different. Glomerular filtration rate (GFR) was comparable. Groups 2A and 2B had higher PTHrP values (77.61 and 76.98 pg/mL, respectively) combined with relatively high PTH levels (2A – 4.4 pg/mL and 2B – 5.1 pg/mL), relatively low osteopontin concentration (2A – 0.044 pg/ mL, 2B – 1.106 pg/mL), compared to those in group 1 (p < 0.05). Pairwise unidirectional differences between groups 1A and 2A, 1B and 2B were found to correlate positively with density values: for osteopontin: r = 0.992 (p < 0.05); for vitamin D: r = 0.831 (p < 0.05); for blood Ca2+ ions: r = 0.836 (p < 0.05); for urine pH: r = 0.863 (p < 0.05). There was a negative correlation with the daily concentration of urinary calcium ions with the density of concrements: r = -0.663; p < 0.05. The concentration of osteopontin was significantly higher in Group 1B and 2B patients, and it was significantly lower in patients with stones of < 1000 HU density. Higher values of osteopontin concentration were noted in groups 1B and 2B in relation to groups 1A (p < 0.05) and 2A (p < 0.05). The increase of blood Ca2+ ions in patients in groups 1B and 2B in relation to groups 1A (p < 0.05) and 2A (p < 0.05) was also accompanied by higher values of vitamin D.Conclusion Patients with denser stones showed high values of osteopontin and PTHrP in serum and low values of urinary calcium ions, which may lead to the formation of concrements on the matrix with an organic base. Determination of calcium metabolism makes it possible to predict recurrence of KSD in primary calcium oxalate nephrolithiasis and assess the severity of mineral metabolism disorders in recurrent calcium oxalate nephrolithiasis.

Lateral Neck Dissection for Papillary Thyroid Cancer.

Introduction: Lateral neck metastases occur in ~15% of papillary thyroid cancer and in ~40% of medullary thyroid cancer. We present herein a systematic approach to a standard comprehensive lateral neck dissection, with attention to specific areas where thyroid cancer lymph node metastases may be missed during surgery.Materials and Methods: Video demonstration of a comprehensive levels 2a, 3, 4, and 5b lateral neck dissection for thyroid cancer.Results: A systematic step-wise approach to a standard comprehensive lateral neck dissection for thyroid cancer, inclusive of levels 2a, 3, 4, and 5b, is demonstrated. Areas where thyroid cancer lateral neck lymph nodes can be missed are noted, including low level 4 nodes and carotid-vertebral nodes, level 5B nodes, and subdigastric level 2 nodes medial to the carotid artery.Conclusion: A step-wise systematic approach to a comprehensive lateral neck dissection for thyroid cancer may lower the risk for missed thyroid cancer lateral neck lymph node metastases.No competing financial interests exist.Runtime of video: 8 mins 35 secs

Aesthetic outcome following prosthetic rehabilitation after ablative maxillary surgery. A Preliminary Study

Objective: Psychological impact of poor dento-facial aesthetics constitutes a major part of the low quality of life in maxillectomy patients. The purpose of this study was to present the aesthetic outcome following prosthetic rehabilitation after ablative maxillary surgery.Method: All consecutive patients that had surgery for tumours affecting the upper jaw and gave their consent were included in the study. Classification of maxillectomy was based on the Brown's classification. Facial attractiveness after final prosthetic rehabilitation was graded by two independent observers with a modified Liekert scale into four grades. For the purpose of comparison of facial attractiveness, the patients were divided into 2 groups: those below 2A and those above 2A.Result: Seventeen patients with tumours affecting the upper jaw were operated. Ten (58.8%) were females and 7 (41.2%) were males. The age range was 6-65 years, mean (SD), 37.6 (18.5) years. Two (11.8%) cases were children. There were 3 (17.6%) cases in the level 1, one case was 1A, two cases were 1B; 11 (64.7%) cases in level 2, 8 (47.1%) cases were 2A, 3 (17.6%) cases were 2B and 3 (17.6%) cases in level 3. Two (11.8%) patients, both in the level 2B had moderately attractive appearances and also, 2(11.8%) patients in the levels 2B and 3B respectively had least attractive appearances.Conclusion: Majority of our patients had resections at levels 2A and below and there was no obvious difference between the two groups, immediate prosthetic obturation may have minimized collapse of midface in those above 2A.

RELATIVE RADIOMETRIC NORMALIZATION USING SEVERAL AUTOMATICALLY CHOSEN REFERENCE IMAGES FOR MULTI-SENSOR, MULTI-TEMPORAL SERIES

Abstract. We propose a method for the relative radiometric normalization of long, multi-sensor image time series. This allows to increase the revisit time under comparable conditions. Although the relative radiometric normalization is a well-studied problem in the remote sensing community, the availability of an increasing number of images gives rise to new problems. For example, given long series spanning several years, finding features that are maintained through the whole period of time becomes arduous. Instead, we propose in this paper to use automatically detected reference images chosen by maximization of a quality metric. For each image, two affine correction models are robustly estimated using random sample consensus, using the two closest reference images; the final correction is obtained by linear interpolation. For each pair of source and reference images, pseudo-invariant features are obtained using a similarity measure invariant to radiometric changes. A final tone-mapping step outputs the images in the standard 8-bits range. This method is illustrated by the fusion of time series of Sentinel-2 at correction levels 1C, 2A, and Landsat-8 images. By using only the atmospherically corrected Sentinel-2 L2A images as anchors, the full output series inherits this atmospheric correction.

First Results of Phytoplankton Spatial Dynamics in Two NW-Mediterranean Bays from Chlorophyll-a Estimates Using Sentinel 2: Potential Implications for Aquaculture

Shellfish aquaculture has a major socioeconomic impact on coastal areas, thus it is necessary to develop support tools for its management. In this sense, phytoplankton monitoring is crucial, as it is the main source of food for shellfish farming. The aim of this study was to assess the applicability of Sentinel 2 multispectral imagery (MSI) to monitor the phytoplankton biomass at Ebro Delta bays and to assess its potential as a tool for shellfish management. In situ chlorophyll-a data from Ebro Delta bays (NE Spain) were coupled with several band combination and band ratio spectral indices derived from Sentinel 2A levels 1C and 2A for time-series mapping. The best results (AIC = 72.17, APD < 10%, and MAE < 0.7 mg/m3) were obtained with a simple blue-to-green ratio applied over Rayleigh corrected images. Sentinel 2–derived maps provided coverage of the farm sites at both bays allowing relating the spatiotemporal distribution of phytoplankton with the environmental forcing under different states of the bays. The applied methodology will be further improved but the results show the potential of using Sentinel 2 MSI imagery as a tool for assessing phytoplankton spatiotemporal dynamics and to encourage better future practices in the management of the aquaculture in Ebro Delta bays.

Abstract 17: Patterns of neck nodal metastases and recurrence in human papilloma virus-associated oropharyngeal squamous cell carcinoma after neck dissection

Abstract Background: The aim of this study is to address the paucity of data on the potentially unique patterns of neck nodal metastases in HPV-positive oropharyngeal squamous cell carcinoma (HPV+OPSCC). Methods: The neck dissection (ND) specimens of varying levels of HPV+OPSCC patients at University of California-San Francisco from 2010-2016 were reviewed for the numbers and frequencies of clinically evident and occult nodes by neck level, and for those with extra-capsular spread (ECS). Smoking history (>10 pack-years), T status, and local, regional and distal recurrences were also assessed for possible associations with nodal metastatic behavior. Results: Sixty HPV+OPSCC patients underwent primary site trans-oral robotic surgery and 65 NDs, of which 21 (32%) were elective. Forty-three (65%) NDs were in non-smokers. Overall, the mean number of positive nodes per ND was 2.5 (range 1-9). The frequencies of at least one pathologically positive node for neck levels 1b, 2, 2a, 2b, 3, 4, and 5 were 0% (0/41), 67.7% (44/65), 43% (23/53), 13% (7/53), 27.7% (18/65), 7% (4/54), and 8% (2/23), respectively. All positive level 5 positive nodes were clinically evident preoperatively. Five of 21 (24%) elective NDs had occult disease only in levels 2A, 2B, and 3, with a mean number of positive nodes of 1.8 (range 1-3). Three of 21 (14%) elective NDs had nodes with ECS. Six of 44 (13%) therapeutic NDs had occult nodes outside the known preoperative distribution in levels 2b, 3 and 4. There were no occult 2a nodes. Smoking history, primary site, and T status were not statistically significantly associated with a differing metastatic nodal behavior. Twenty-three of 60 and 18 of 60 patients underwent adjuvant radiation and adjuvant chemoradiation, respectively. Thirteen of the 19 patients who only underwent surgery had positive lymph nodes, of which five had N1 disease and four had N2b disease. All four of N2b disease patients refused adjuvant therapy and none have had a recurrence as of follow-up (mean 28 months, range 3-51). The overall mean follow-up was 29.1 months (range 2-76 months), with 72% of patients having at least 12 months. One of 65 (1.5%) NDs developed a neck recurrence in the skin overlying level 2 in a patient in the therapeutic ND cohort who had undergone chemoradiation for ECS. No undissected neck levels developed metastatic nodal disease. Two of 60 (3%) patients developed local recurrence. No patients developed distant metastases. One patient in the cohort died of an unrelated cause. There have been no cancer-related deaths. Conclusions: For HPV+OPSCC, therapeutic NDs should encompass any levels bearing suspicious nodes and levels 2a, 2b, 3, and 4, while elective NDs should be performed and encompass at least levels 2a, 2b, and 3. ECS may be present in occult nodes. For HPV+OPSCC, these selective ND plans, followed by the indicated adjuvant treatment, is associated with a low neck recurrence rate. Citation Format: Madeleine P. Strohl, Steven J. Wang, Patrick K. Ha, Jonathan R. George, Chase M. Heaton, Ivan H. El-Sayed, Jon Mallen St Clair, William R. Ryan. Patterns of neck nodal metastases and recurrence in human papilloma virus-associated oropharyngeal squamous cell carcinoma after neck dissection [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr 17.

Numerical study of selected military vehicle chassis subjected to blast loading in terms of tire strength improving

Abstract In the paper a chosen model of the light armoured vehicle was tested in terms of blast loading. More precisely, the blast propagation and interaction with the tire behaviour and suspension system elements of the light-armoured vehicle (LAV) was simulated. The chosen military vehicle meets the requirements of levels 2A and 2B of STANAG 4569 standard. Based on the obtained results, two modifications were proposed for the strength and resistance improvement of the wheel. The first consisted of inserting the rubber runflat ring inside the tire, whereas in the second the honeycomb-like composite wheel was implemented. Non-linear dynamic simulations were carried out using the explicit LS-Dyna code, with multi-material Arbitrary Lagrangian-Eulerian formulation for simulation the blast process.

Phase 1 Study of Bortezomib and Romidepsin in Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Indolent B-Cell Lymphoma, Peripheral T-Cell Lymphoma, or Cutaneous T-Cell Lymphoma: Updated Results

The combination of proteasome and histone deacetylase (HDAC) inhibitors has shown synergistic interactions in pre-clinical studies involving diverse hematologic malignancies. We have previously reported that the combination of the proteasome inhibitor bortezomib and the HDAC inhibitor romidepsin, administered at extremely low concentrations (eg, ~3-5 nM), results in a striking increase in apoptosis in primary chronic lymphocytic leukemia (CLL) cells, including cells obtained from patients with CLL refractory to standard treatments (Dai Y et al. Clin Cancer Res. 2008). Romidepsin is an approved agent for both cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma (PTCL). Based on these findings, a phase 1 trial was initiated, using a 3+3 design, with the primary objective of determining the maximum tolerated dose (MTD) for the combination of bortezomib and romidepsin in patients with relapsed or refractory CLL/small lymphocytic lymphoma (SLL), indolent B-cell lymphoma, PTCL, or CTCL.Eighteen patients (13 with CLL/SLL, 1 with CTCL, 2 with indolent B-cell lymphoma, and 2 with PTCL; 15 male, 3 female) were enrolled and treated. The median age was 56.5 years (range 31-76); ECOG performance scores ranged from 0 to 1; and the median number of prior therapies was 3 (range 1-6). Bortezomib was administered as an intravenous bolus followed by a 4-hour intravenous infusion of romidepsin on days 1, 8, and 15 of 4-week cycles. The dose levels were: dose level 1 = bortezomib 1.3 mg/m2, romidepsin 8 mg/m2 (n = 3); dose level 2A = bortezomib 1.3 mg/m2, romidepsin 10 mg/m2 (n = 9); and dose level 2B = bortezomib 1.6 mg/m2, romidepsin 8 mg/m2 (n = 6).Adverse events (AEs) and dose-limiting toxicities (DLTs) were determined using NCI-CTCAE version 4 and protocol guidelines. DLTs were determined in cycle 1 only. There was 1 DLT at dose level 2A (grade 3 fatigue), 2 DLTs at dose level 2B (grade 3 chills [associated with grade 2 cytokine release syndrome] and grade 3 vomiting), and no DLTs at dose level 1 (Table 1). Accrual to dose levels 2A and 2B took place using an alternating enrollment schema. Dose level 2A was identified as the MTD. Non-DLT grade 3 AEs for all treated patients possibly, probably, or definitely related to study treatment included anemia (6%), cytokine release syndrome (6%), fatigue (11%), leukopenia (6%), lymphopenia (6%), nausea (6%) neutropenia (11%), soft tissue infection (6%), vomiting (11%), and grade 4 neutropenia (17%). Common grade 2 AEs possibly, probably, or definitely related to study treatment included fatigue (44%), leukopenia (22%), nausea (44%), neutropenia (39%), and thrombocytopenia (39%).All 18 patients treated in this study were evaluable for response. One partial response has been observed to date in a patient with CLL who was ZAP70 positive and had received 4 lines of prior chemotherapy. After 4 cycles of romidepsin and bortezomib, this patient proceeded to a stem cell transplant from an unrelated donor and has remained in complete remission since 2012. Nine patients had a best response of stable disease (CLL/SLL = 6; CTCL = 1; indolent B-cell lymphoma = 2 [1 patient still on treatment]) and 8 had progressive disease. Correlative studies examining pre- and post-treatment expression of NF-кB, XIAP, Bcl-xL, and Bim were performed for 3 patients and yielded variable results. Although the small sample size did not permit correlations to be made between protein expression of these markers and treatment outcome, the ability to obtain these data supports the feasibility of the correlative methodology.The MTD was reached at dose level 2A (Table 1). The study is closed to accrual and one patient remains on treatment at dose level 2A. The safety profile is consistent with those reported for bortezomib and romidepsin, with reversible grade 2 to 4 AEs. The regimen appears to have modest activity in heavily pretreated patients with relapsed/refractory CLL/SLL, indolent B-cell lymphoma, or CTCL.Table 1Dose Level Enrollment and DLTsDose LevelBortezomib (mg/m2)Romidepsin (mg/m2)Patients treated/# DLTsDLT11.383/02A*1.3109/1Grade 3 fatigue2B**1.686/2Grade 3 chills (associated with cytokine release syndrome) Grade 3 vomiting*MTD**Exceeded MTD DisclosuresHolkova:Seattle Genetics, Inc.: Research Funding. Bose:Celgene: Membership on an entity’s Board of Directors or advisory committees. Roberts:Selexys: Research Funding.

Central Compartment Neck Dissection for Well-Differentiated Thyroid Cancer

Introduction: Central compartment neck dissection plays an important role in the appropriate treatment of metastatic papillary thyroid cancer at initial presentation and also in cases of recurrent disease. Surgeons caring for this group of patients should have familiarity and skill with this procedure. Case: A 31-year-old woman was found to have a 5-cm right thyroid lobe nodule with a fine-needle aspiration biopsy revealing papillary thyroid cancer. There was clinical evidence on ultrasound of central compartment lymphadenopathy and also right lateral neck lymphadenopathy, which was confirmed by fine-needle aspiration of a level 4 and level 6 lymph node to be metastatic papillary thyroid cancer. The patient underwent a total thyroidectomy and right central compartment neck dissection with excision of the prelaryngeal, pretracheal, and right paratracheal nodal regions. A right lateral neck dissection was also performed and included levels 2a, 2b, 3, 4, and 5. Conclusion: This video illustrates the technique of total thyroidectomy and right central compartment neck dissection with preservation of the right superior and inferior parathyroid glands and the right recurrent laryngeal nerve. There were no complications during the procedure. Postoperative fiberoptic laryngoscopy revealed bilateral true vocal fold mobility. At 3 months of follow-up, the patient was eucalcemic. Ralph P. Tufano, Consulting–Medtronic, Inc., Minneapolis, Minnesota. The authors report no other conflicts of interest. Running time of video: 10 mins, 53 secs

A Growing Lesion on the Cheek

Awoman in her 60swith a Fitzgerald skin type II presented to the clinic with a 4to 5-month history of a growing lesion on her right cheek. The physical examination demonstrated a 3.5-cm indurated, semifixed,multifocallyulceratingmass surroundedbyanerythematous rim overlying the zygomawith a subdermal and subcutaneous extension measuring 4.2 × 4.5 cm. It was nonpigmented except for a small patch along the inferior margin. The right facial and trigeminal nerve branches were intact. There was no lymphadenopathy. Twopunchbiopsy specimenswereobtained and later demonstrated amalignant neoplasm. The patient underwentwide local excision of the mass with a right parotidectomy and a right lymph node dissection of levels 2A, 2B, 3, and 4. Onhematoxylin-eosin staining (Figure, A andB), the lesion excised from the cheek was demonstrated to be invasive to a maximumdepth of 10mmwith perineural involvement and nests of infiltrating lymphocytes. The dermis was filled with atypical spindle cell proliferations organized in strands and cords splayed between collagen bundles and subcutaneous adipose. Immunohistochemical staining demonstrated a layer of normal overlyingmelanocytes positive forMart-1 (Figure, C). The underlying spindle cell proliferations staineddiffusely positive for S-100 (Figure, D), andCD10. The lymph nodes harvested from levels 2a, 2b, 3, and 4 were found to be benign. What is your diagnosis? A B

Abstract P4-16-11: Phase I trial of afatinib plus vinorelbine in Japanese patients with advanced solid tumors including breast cancer

Abstract Background: Afatinib, a potent irreversible ErbB Family Blocker, inhibits signaling from HER1, HER2 and HER4 dimers, and transphosphorylation of HER3. A Phase I trial was conducted to assess if afatinib 40 mg/day in combination with vinorelbine (VNR) 25 mg/m2 i.v. weekly could be safely administered to Japanese patients (pts). Patients and methods: The safety, tolerability and pharmacokinetics (PK) of daily oral afatinib plus weekly i.v. VNR in a 28-day cycle in Japanese pts was assessed using a 3+3 design. The primary endpoint was to determine the maximum tolerated dose (MTD), based on dose-limiting toxicities (DLTs) in Cycle 1 (see Table; dose Levels 1 and 2). When the MTD was exceeded, dose Levels 2a and 3 allowed modifications of VNR dosing as used in clinical practice. Eligible pts were ≥20 years old with histologically confirmed refractory advanced/metastatic solid tumours, and an ECOG performance status (PS) 0-1. Adverse events (AEs) were documented as per NCI CTCAE v3.0. Response was assessed using RECIST 1.1, and PK parameters for both drugs were analyzed by intra-individual comparison, based on frequent blood sampling. Results: Seventeen pts were recruited. Median age was 60 (range 40-68) years, all pts had received previous chemotherapy, and 7/9 pts with BC had received HER2-targeted therapy. No DLTs were observed at dose Level 1. When 3/5 pts developed DLTs in Cycle 1 at an afatinib dose of 40 mg in Level 2 (see Table), an intermediate cohort 2a was introduced at 20 mg/m2 VNR i.v. weekly. Tolerability at Level 2a was confirmed. With afatinib dose modification permitted, and VNR dose skipping allowed for ANC <1500/mm3, dose re-escalation to VNR 25mg/m2 i.v. weekly at Level 3 was performed to establish a recommended phase II dose. At Level 3, 7/24 planned doses of VNR were skipped due to Grade 2 and 3 neutropenia, not qualifying as DLTs. One DLT occurred in a pt with Grade 2 epigastralgia in Course 1, who required afatinib dose reduction. Overall, the most frequent drug-related AEs were leukopenia, neutropenia (100% each), diarrhea (94%), anemia (70%), stomatitis (64%) and rash (41%). Nine BC pts were treated in cohorts 2a and 3, and all experienced diarrhea, leukopenia and neutropenia. No PK drug-drug interactions between afatinib and VNR were observed. Safety and PK profiles did not appear to differ between Japanese pts and Caucasian pts in a previous Phase I study. Two pts with BC and prior trastuzumab treatment had partial responses. Tumor shrinkage was observed in four of six evaluable BC pts, but not in other tumor types. Conclusions: Afatinib 40 mg/day plus vinorelbine 25 mg/m2/week was tolerable and showed early signs of clinical activity in Japanese pts. AEs were as expected and were managed by dose modifications of both compounds. Final data will be presented at this congress. Dose LevelsAfatinibVinorelbineN treatedDLTs (n)120 mg/day25 mg/m2/week3None240 mg/day25 mg/m2/week5Grade 4 neutropenia for 7 days (1); Grade 3 febrile neutropenia (1); Grade 3 pharyngeal infection with Grade 4 lipase and amylase elevations (1)2a40 mg/day20 mg/m2/week3 (all BC)None340 mg/day25 mg/m2/week6 (all BC)Grade 2 epigastralgia (1) Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-16-11.

Late Pleistocene (MIS 3–4) climate inferred from micromammal communities and δ18O of rodents from Les Pradelles, France

The middle Paleolithic stratigraphic sequence of Les Pradelles (Charente, France) spans from the end of Marine Isotope Stage (MIS) 4 until the middle of MIS 3. Micromammal remains are present in all the stratigraphic levels, offering a rare opportunity to address the questions of both environmental and climatic fluctuations throughout this period. Climate modes were studied through the taphonomy, biodiversity and oxygen isotope compositions of phosphate (δ18Op) from 66 samples of rodent tooth enamel. The δ18Op values from the lower sedimentary levels provide summer mean air temperatures of 19±2°C (level 2/1) and of 16±2°C (levels 2A, 2B and 4A). Within the middle of sequence (level 4B), a paleobiodiversity change can be identified with an increase of Dicrostonyx torquatus, which is associated with the largest amplitude in δ18Op values and the highest maximal δ18Op values. At the top of the sequence (level 5-2), a biodiversity change is observed with the increase of Microtus arvalis, but without any change in δ18Op values. The association of cold rodent species with unexpected high and large amplitudes in the δ18Op values of their teeth, possibly indicative of aridity, suggests their deposition during a Heinrich event.

Phase I study of safety, pharmacokinetics, and efficacy of TSU-68 plus S-1 combination in patients with advanced hepatocellular carcinoma.

262 Background: Sorafenib is the standard chemotherapy for advanced hepatocellular carcinoma (HCC), but its efficacy is limited. TSU-68 is an oral anti-angiogenesis agent that blocks VEGFR-2 and PDGFR. TSU-68 and S-1 have shown favorable efficacy and safety profile for advanced HCC (Kanai et al. 2011; Furuse et al. 2010). This study investigated the safety, tolerability, pharmacokinetics (PK), and efficacy of the TSU-68 plus S-1 combination in patients (pts) with advanced HCC. We also determined the maximum tolerated dose of TSU-68 plus S-1 on the basis of the frequency of associated dose-limiting toxicity (DLT) in this population. Methods: Pts who had not received any prior systemic therapy received 400 mg/day TSU-68 orally and one of the following doses of S-1: 50 mg/m2 (level 0), 80 mg/m2 (level 1), or 100 mg/m2 (level 2). Treatment duration was 4 weeks followed by 2-week rest (A group) or 2 weeks followed by 1-week rest (B group). The starting treatment dose and duration level was 1B, followed by progression to levels 2A and 2B. Treatment safety and tolerability at each level were assessed by enrolling 6 pts according to CTCAE v3.0. Results: Eighteen pts (6 each at levels 1B, 2A, and 2B) were enrolled (age, 58-85 years; male/female, 15/3; HCV/HBV/nBnC, 12/3/4; Child-Pugh class A/B, 18/0). Two pts each at levels 1B (grade 3 gastrointestinal bleeding, grade 2 ascites) and 2A (grade 3 fatigue, grade 3 hand-foot skin reaction) showed DLTs, but no pts at level 2B showed DLTs. The common adverse events were hemoglobin decrease, hypoalbuminemia, and anorexia; these were mild in severity (grade 1-2). PK data from 12 pts at levels 1B and 2A indicated that the area under the curve (AUC) of TSU-68 and 5-FU was unlikely to be affected by TSU-68 plus S-1. Response rate, disease control rate, median time to progression, and median overall survival time were 27.8%, 61.1%, 160 days, and 391 days, respectively. Conclusions: Our findings revealed thatthe TSU-68 plus S-1 combination was well tolerated and had favorable efficacy in patients with advanced HCC, and we recommend treatment with 400 mg/day TSU-68 and 100 mg/m2 S-1 for 4 weeks followed by 2-week rest in these patients. Clinical trial information: Japic CTI-121970.

Phase I Study of Bortezomib and Romidepsin in Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Indolent B-Cell Lymphoma, or Peripheral T-Cell Lymphoma

Abstract 1794Preclinical studies have demonstrated synergistic interactions between proteasome and histone deacetylase (HDAC) inhibitors in diverse hematologic malignancies, including those of B-cell origin. We have previously shown that the combination of the proteasome inhibitor bortezomib and the HDAC inhibitor romidepsin, administered at extremely low concentrations (∼3–5 nM), results in a striking increase in apoptosis in primary CLL cells, including cells from patients with CLL refractory to standard treatments (Dai Y et al. Clin Cancer Res. 2008). These findings prompted initiation of a phase I trial, using a 3+3 design, with the primary objective of determining the maximum tolerated dose (MTD) for the combination of bortezomib and romidepsin in patients with relapsed or refractory chronic lymphocyte leukemia/small lymphocytic lymphoma (CLL/SLL), indolent B-cell lymphoma, or peripheral T-cell lymphoma (PTCL).To date, 11 patients have been enrolled and treated. All of the patients treated have been diagnosed with CLL/SLL (n=11). The male:female ratio was n = 10 (91%):1 (9%); the median age was 56 (range 46–66) years; ECOG performance scores ranged from 0 to 1; and the median number of prior therapies was 4 (range 2–6). The schedule of administration was intravenous bolus bortezomib followed by a 4-hour intravenous infusion of romidepsin on days 1, 8, and 15; on a 28-day cycle. Dose level 1 = bortezomib 1.3 mg/m2, romidepsin 8 mg/m2 (n=3); level 2A = bortezomib 1.3 mg/m2, romidepsin 10 mg/m2 (n=5); and level 2B = bortezomib 1.6 mg/m2, romidepsin 8 mg/m2(n=3). The study is currently enrolling to dose levels 2A and 2B.Adverse events were determined using CTCAE version 4. Dose limiting toxicities (DLTs) were determined per protocol and occur in cycle 1 only. Two DLTs have been observed: 1 at dose level 2A (grade 3 fatigue) and 1 at dose level 2B (grade 3 chills, associated with cytokine release syndrome). Both dose levels will be expanded to 6 DLT-evaluable patients. Non-DLT grade 3 or greater adverse events have included anemia (grade 3, 9%), fatigue (grade 3, 9%), leukopenia (grade 3, 9%), nausea (grade 3, 9%), neutropenia (grade 4, 18%), soft tissue infection (grade 3, 9%), and vomiting (grade 3, 9%). Serious adverse events that were deemed at least possibly related to treatment were grade 3 soft tissue infection with grade 4 neutropenia (1 patient); grade 2 fever/nausea/vomiting which precipitated hospitalization (1 patient); and grade 2 cytokine release syndrome with associated grade 3 shaking chills, and grade 2 nausea/vomiting/diarrhea/oral dysethesia/sweats/photophobia/macular rash (1 patient).All 11 patients treated were evaluable for response. One partial response has been observed to date; the patient (positive for ZAP70; 4 lines of prior chemotherapy) proceeded, after 4 cycles of romidepsin and bortezomib, to allogeneic stem cell transplant. Five patients had a best response of stable disease and 5 had progressive disease. Correlative studies examining pre- and post-treatment expression of NF-κB (nuclear RelA and p52 as a marker of p100 processing), the NF-κB-dependent proteins XIAP and Bcl-xL, and Bim are currently underway.Collectively, these findings indicate that the safety profile is consistent with those reported for bortezomib and romidepsin, with reversible grade 2 to 4 adverse events, in heavily pretreated patients with relapsed/refractory CLL/SLL. The MTD has not yet been reached. Pending identification of the MTD, phase II evaluation of this therapeutic strategy, if warranted, should determine its activity more definitively in this population. Disclosures:Shea:Millennium Pharmaceuticals: Research Funding.

Prospective gene signature study using microRNA to predict the tissue of origin (ToO) in pts with cancer of unknown primary site (CUP).

4151 Background: CUP patients present with metastatic disease without an identifiable primary. Accurate ToO assignment could help guide use of specific therapy, which may impact survival. MicroRNAs, 22-oligonucleotide RNA molecules involved in gene- expression regulation, are conserved through evolution and can exhibit high tissue specificity. We used a microRNA-based test to prospectively evaluate tumors from CUP pts. Methods: RNA was extracted from FFPE metastatic biopsies. The test measures expression of 48 microRNAs by qRT-PCR. The classifier combines predictions generated by 2 classifiers: a biologically motivated binary decision-tree and K- nearest-neighbors (KNN). Each classifier predicts one of 25 diagnoses. The test reports one predicted tissue origin when the 2 classifiers agree, or the 2 different tissue predictions when the 2 classifiers do not reach a consensus. Results: Tissue from 52 pts was evaluated. 6 failed due to inadequate RNA quality; 46 were processed successfully. Profile predictions were compared with clinical presentation (CP)—imaging, pathology (histology and IHC), and therapeutic response. A “level of agreement” tool was used to describe these results (Table). The microRNA test assigned a single putative primary in 14 (same results from 2 classifiers). In 32 pts, two ToO profiles were predicted, of which the one more concordant with the CP was accepted. Assay prediction was fully concordant with CP and pathology (level 1) in 39% of pts and clinically plausible (levels 2A and 2B) in an additional 43%. Additional samples data will be presented at the Meeting. Conclusions: This prospective study showed feasibility in retrieving microRNA and determining ToO from FFPE tissue of CUP pts and demonstrates concordance with the clinical presentation in 82% of cases. Level of agreement Criteria MicroRNA test results N=46 1 Molecular profile (MP) results concordant with latent primary OR histology and IHC 18 2A MP results with supportive IHC differential AND consistent CP 11 2B MP results with supportive IHC differential and unusual clinical presentation OR unhelpful IHC with consistent CP 9 3 Primary cancer differs from MP OR IHC and CP clearly discordant 8 Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Rosetta Genomics Rosetta Genomics Rosetta Genomics

Influence of study design on reported mortality and morbidity rates after abdominal aortic aneurysm repair.

The mortality and morbidity rates of elective abdominal aortic aneurysm (AAA) surgery, as reported over the past 12 years, were graded and analysed by levels of evidence. Articles on elective AAA surgery published between 1985 and 1996 were retrieved and classified into five levels of evidence. Level 1 contains prospective studies and is subdivided into population-based (level 1a) and hospital-based (level 1b) studies. Level 2 includes retrospective studies, subdivided into population-based studies (level 2a), hospital-based studies (level 2b) and hospital-based studies concerning a specified group of selected patients (level 2c). Operative mortality and systemic and local/vascular complication rates with 95 per cent confidence intervals were calculated for each level of evidence. Seventy-two articles describing a total of 37 654 patients could be included: two level 1a studies (692 patients), nine level 1b studies (1677 patients), 13 level 2a studies (21 409 patients), 32 level 2b studies (12019 patients) and 16 level 2c studies (1857 patients). The mean 30-day mortality rates of the two population-based levels were similar: 8.2 (95 per cent confidence interval 6.4-10.6) per cent for the prospective (la) and 7.4 (7.0-7.7) per cent for the retrospective (2a) series. These figures were significantly higher than the remarkably similar hospital-based mortality rates: 3.8 (3.0-4.8) per cent for the prospective (1b), 3.8 (3.5-4.2) per cent for the retrospective (2b) and 3.5 (2.8-4.4) per cent for selected patient group (2c) studies. The most frequent complication was of cardiac origin. In the population-based series the cardiac complication rates were 10.6 (8.5-13.2) and 11.1 (9.1-13.6) per cent for levels 1a and 2a respectively. This compared well with 12.0 (10.5-13.9) per cent for the prospective hospital-based series (level 1b). The cardiac complication rates in the retrospective hospital-based studies were significantly lower: 8.9 (8.4-9.5) and 6.1 (4.9-7.6) per cent for levels 2b and 2c respectively. There is a clear and consistent disagreement in reported mortality rates between hospital-based and population-based studies of elective surgery for AAA. Prospective studies give the best documentation of postoperative morbidity.