bluuebunny/crossref_metadata_2025 huggingface dataset:
Delineating forest stands from grid data
Authors: Pukkala Timo
Published: March 2020

Background

Forest inventories are increasingly based on airborne laser scanning (ALS). In Finland, the results of these inventories are calculated for small grid cells, 16 m by 16 m in size. Use of grid data in forest planning results in the additional requirement of aggregating management prescriptions into large enough continuous treatment units. This can be done before the planning calculations, using various segmentation techniques, or during the planning calculations, using spatial optimization. Forestry practice usually prefers reasonably permanent segments created before planning. These segments are expected to be homogeneous in terms of site properties, growing stock characteristics and treatments. Recent research has developed methods for partitioning grids of ALS inventory results into segments that are homogeneous in terms of site and growing stock characteristics. The current study extended previous methods so that also the similarity of treatments was considered in the segmentation process. The study also proposed methods to deal with biases that are likely to appear in the results when grid data are aggregated into large segments.

Methods

The analyses were conducted for two datasets, one from southern and the other from northern Finland. Cellular automaton (CA) was used to aggregate the grid cells into segments using site characteristics with (1) growing stock attributes interpreted from ALS data, (2) predicted cutting prescriptions and (3) both stand attributes cutting prescriptions. The CA was optimized for each segmentation task. A method based on virtual stands was used to correct systematic errors in variable estimates calculated for segments.

Results

The segmentation was rather similar in all cases. The result is not surprising since treatment prescriptions depend on stand attributes. The use of virtual stands decreased biases in growth prediction and in the areas of different fertility classes.

Conclusions

Automated stand delineation was not sensitive to the type of variables that were used in the process. Virtual stands are an easy method to decrease systematic errors in calculations.
First sequence of influenza D virus identified in poultry farm bioaerosols in Sarawak, Malaysia
Authors: Bailey Emily S. , Fieldhouse Jane K. , Alarja Natalie A. , Chen David D. , Kovalik Maria E. , Zemke Juliana N. , Choi Jessica Y. , Borkenhagen Laura K. , Toh Teck-Hock , Lee Jeffrey Soon Yit , Chong Kuek-Sen , Gray Gregory C.
Published: March 2020

In 2018, our team collected aerosols samples from five poultry farms in Malaysia. Influenza D virus was detected in 14% of samples. One sample had an 86.3% identity score similar to NCBI accession number MH785020.1. This is the first molecular sequence of influenza D virus detected in Southeast Asia from a bioaerosol sample. Our findings indicate that further study of role of IDV in poultry is necessary.
Epilepsy surgery for refractory seizures: a systematic review and meta-analysis in different complications
Authors: Joudi Mashhad Maryam , Harati Hadi , Parooie Fateme , Salarzaei Morteza
Published: March 2020

Background

Nearly one-third of epilepsy patients are refractory/resistant to medical treatment. Developments made in surgical techniques have significantly increased the effectiveness and safety of these techniques, as such techniques have been demonstrated to improve seizure control/freedom outcomes.

Objectives

The aim of this systematic review and meta-analysis was to evaluate the complications of epilepsy surgery.

Patient and methods

The searches were conducted by three independent researchers to find the relevant studies published from January 1, 2009, until the end of January 6, 2019. For English published statistical studies, all studies conducted on epileptic patients who have undergone epilepsy surgery were included.

Statistical analysis

A meta-analysis was conducted in the STATA14 statistical software.

Results

A total of 6735 patients with epilepsy who had undergone the epilepsy surgery were studied. The overall prevalence of complications was 5%. The prevalence of major and minor complications was 5.4% and 3.2% respectively. The prevalence of complications related to the temporal epilepsy surgery and the extra-temporal epilepsy surgery based on 3 studies was 7.9% and 8.2 % respectively. The frequency of neurological and surgical complications after epilepsy surgery was 4.4% and 4.1% respectively.

Conclusion

The overall rate of complications caused by epilepsy surgery was reasonably low (5%), implying that epilepsy surgery especially temporal lobe resection can be safe preferably when performed by an experienced surgeon.
The effect of scale in quantifying fire impacts on species habitats
Authors: Wan Ho Yi , Cushman Samuel A. , Ganey Joseph L.
Published: March 2020

Background

Fire size and severity have increased in the western United States in recent decades, and are expected to continue to increase with warming climate. Habitats for many species are threatened by large and high-severity fires, but the effect of spatial scale on the relationship between fires and habitat modifications is poorly understood. We used the 2011 Wallow Fire—the largest wildfire in the state history of Arizona, USA—as a case study and assessed changes in predicted nesting habitat of the threatened Mexican spotted owl (Strix occidentalisXántus de Vésey) in the first three years following the fire. Our objective was to explore potential relationships between burn severity and changes in habitat suitability at different spatial scales. To accomplish this, we applied a multi-scale optimized habitat selection model to pre- and post-fire landscapes and compared the differences in predictions along a continuous scale gradient.

Results

Fire effects on habitat quality were spatially variable and the strength and direction of relationships were scale-dependent. Spatial patterns of burn-severity mosaic resembled the patterns of habitat suitability change. High burn severity reduced nesting habitat suitability and this relationship was strongest at broad scales. Pre-fire habitat suitability was positively related to burn severity, again at fairly broad scales, but the relationship was weak. Low-severity fires had little effect on habitat suitability.

Conclusions

Multi-scale analysis may influence the statistical measures of goodness of fit in assessing fire effects on species and their habitats. Future studies should explicitly address spatial scale when quantifying fire effects.
Fused behavior recognition model based on attention mechanism
Authors: Chen Lei , Liu Rui , Zhou Dongsheng , Yang Xin , Zhang Qiang
Published: March 2020

With the rapid development of deep learning technology, behavior recognition based on video streams has made great progress in recent years. However, there are also some problems that must be solved: (1) In order to improve behavior recognition performance, the models have tended to become deeper, wider, and more complex. However, some new problems have been introduced also, such as that their real-time performance decreases; (2) Some actions in existing datasets are so similar that they are difficult to distinguish. To solve these problems, the ResNet34-3DRes18 model, which is a lightweight and efficient two-dimensional (2D) and three-dimensional (3D) fused model, is constructed in this study. The model used 2D convolutional neural network (2DCNN) to obtain the feature maps of input images and 3D convolutional neural network (3DCNN) to process the temporal relationships between frames, which made the model not only make use of 3DCNN’s advantages on video temporal modeling but reduced model complexity. Compared with state-of-the-art models, this method has shown excellent performance at a faster speed. Furthermore, to distinguish between similar motions in the datasets, an attention gate mechanism is added, and a Res34-SE-IM-Net attention recognition model is constructed. The Res34-SE-IM-Net achieved 71.85%, 92.196%, and 36.5% top-1 accuracy (The predicting label obtained from model is the largest one in the output probability vector. If the label is the same as the target label of the motion, the classification is correct.) respectively on the test sets of the HMDB51, UCF101, and Something-Something v1 datasets.
Comparison of 1-year outcomes between MAKO versus NAVIO robot-assisted medial UKA: nonrandomized, prospective, comparative study
Authors: Leelasestaporn Chumroonkiet , Tarnpichprasert Tomorn , Arirachakaran Alisara , Kongtharvonskul Jatupon
Published: March 2020

Background

We have conducted a prospective cohort study with the aim of comparing operative time, intraoperative blood loss, and radiologic and clinical outcomes between imageless (NAVIO) and image-based (MAKO) robot-assisted unicompartmental knee arthroplasty (UKA) for medial compartment osteoarthritis (OA) of the knee.

Methods

A total of 33 patients with medial compartment OA of the knee were prospectively allocated on alternate operative days of their surgery to MAKO (16 patients) or NAVIO (17 patients) robot-assisted UKA. The primary outcome (Knee Society Score [KSS] and Knee Functional Score [KFS]) and the secondary outcomes (intraoperative time of seven steps [registration of hip and ankle, femur and tibia, ligament tension, implant planning, preparation femur, tibia and trial implant], component alignment [coronal and sagittal of femur, tibia implant], blood loss, complications, and revision at 1 year after surgery) were compared between two groups. Statistical significance was set atP< 0.05.

Results

Mean KSS measured at baseline and 1 year were, respectively, 70.3 (5.6) and 96.9 (5.7) in the NAVIO group and 72.3 (4.5) and 94.7 (10.01) in the MAKO group. Mean KFS measured at baseline and 1 year were, respectively, 95.5 (7.9) and 99.9 (0.25) in the NAVIO group and 67.3 (7.8) and 99.5 (1.2) in the MAKO group. There were no significant differences for KFS and KSS outcomes (P = 0.203 andP = 0.457, respectively) between the NAVIO and MAKO groups. Mean operative time and blood loss in the NAVIO versus MAKO robot-assisted UKA groups were 98 min versus 82.5 min and 136.3 ml versus 80 ml, respectively, and these differences were statistically significant. In the MAKO group, the intraoperative time was statistically significantly shorter in registration of hip and ankle center, femur and tibia, femur preparation, and trial implantation compared with the NAVIO group. There were no significant differences of component alignment and radiologic alignment at 1 year between the two groups. No perioperative or delayed complications (infection, periprosthetic fracture, thromboembolism, and compromised wound healing) and revisions were reported in either group.

Conclusions

This study demonstrated that two robotic systems showed no difference in clinical outcomes at 1 year and radiologic alignment of implants, whereas operative time and intraoperative blood loss were found to be less in MAKO robot-assisted UKA.

Trial registration

ClinicalTrials.gov,NCT03954912. Registered on 17 May 2019.

Level of evidence

II
Clinical or survival benefit to routine surveillance imaging for classical Hodgkin lymphoma patients in first complete remission.
Authors: Pingali Sai Ravi , Jewell Sarah , Havlat Luiza , Bast Martin , Thompson Jonathan , Eastwood Daniel , Bartlett Nancy , Armitage James O. , Wagner-Johnston Nina , Vose Julie , Fenske Timothy S.
Published: March 2020

8505

Background: Routine surveillance imaging (RSI) for patients in complete remission from classical Hodgkin lymphoma (cHL) is common practice. RSI offers the theoretical benefit of detecting asymptomatic relapse, which may allow for more successful second-line therapy. Despite this, evidence for a clinical benefit of RSI is lacking. We compared outcomes in cHL patients undergoing RSI versus clinical surveillance (CS) in which scans are only obtained to evaluate concerning signs or symptoms. Methods: Patients with cHL diagnosed at three tertiary care centers from 2001-2010, who achieved complete remission (CR) following frontline therapy, were analyzed retrospectively. Patients were stratified into two groups based on the surveillance strategy employed. Baseline patient characteristics, prognostic features, treatment records, and outcomes were collected. The primary objective was to compare overall survival for patients undergoing RSI versus CS. As a secondary objective we compared the success of second-line therapy for relapsed patients in each group. Results: 207 patients met eligibility criteria, with 131 RSI patients and 76 CS patients. Patient characteristics (age, gender, stage, sedimentation rate, Hasenclever index, bulky disease and B symptoms) were similar in each group. Chemotherapy consisted of ABVD in 79% and Stanford V in 15%. Patients in the RSI group more commonly received ABVD (91% vs. 57%) and less often radiation therapy (38% vs. 68%). Mean number of scans was 4.77 in RSI and 1.11 in CS groups, respectively. With a median follow up of 4 years, the overall survival was similar in both groups (p=0.74), with 5 (3.8%) deaths in the RSI group and 4 (5.3%) in the CS group. Six (4.6%) relapses occurred in the RSI group (4 of which were detected by RSI), and 5 (6.6%) in the CS group (p=0.64 for relapse at 5 years). All relapsed patients achieved second CR with second-line therapy. Conclusions: RSI did not yield a survival advantage in cHL patients who achieved CR after frontline therapy.Given the radiation exposure, cost, and risk for additional procedures associated with RSI, we conclude CS is the preferred strategy in cHL patients in first complete remission.
Randomized phase II study of mogamulizumab (KW-0761) plus VCAP-AMP-VECP (mLSG15) versus mLSG15 alone for newly diagnosed aggressive adult T-cell leukemia-lymphoma (ATL).
Authors: Jo Tatsuro , Ishida Takashi , Takemoto Shigeki , Suzushima Hitoshi , Uozumi KImiharu , Yamamoto Kazuhito , Uike Naokuni , Saburi Yoshio , Nosaka Kisato , Utsunomiya Atae , Tobinai Kensei , Fujiwara Hiroshi , Ishitsuka Kenji , Yoshida Shinichiro , Taira Naoya , Moriuchi Yukiyoshi , Imada Kazunori , Miyamoto Toshihiro , Tomonaga Masao , Ueda Ryuzo
Published: March 2020

8506

Background: Mogamulizumab (Moga), a defucosylated humanized anti-CCR4 antibody, was approved for the treatment of relapsed/refractory ATL in Japan in 2012. This multicenter, randomized, phase II trial was conducted to examine the efficacy of the combination of Moga with standard chemotherapy for untreated aggressive ATL. Methods: Previously untreated patients (pts) with CCR4-positive ATL were randomly assigned to receive mLSG15 plus Moga (arm A) or mLSG15 alone (arm B). The primary endpoint was CR rate (%CR), and secondary endpoints included ORR, PFS, OS and safety. Pts received 4 courses of mLSG15 regimen, with or without a total of 8 doses of Moga (1.0 mg/kg) once every 2 weeks. The planned sample size, 22 pts per arm, provided a probability of 80% that %CR in arm A would have larger %CR when true %CR for arm A is 15% better than that for arm B. Results: Of 54 pts randomized, 53 were treated (arm A: 29; arm B: 24). Male/female ratio was 53/47%, median age was 63 (37-81), and subtype was acute/lymphoma/unfavorable chronic, 70/25/6%. %CR and ORR in arms A and B was 52% (95%CI [CI]; 33, 71) vs. 33% (CI; 16, 55) and 86% (CI; 63, 96) vs. 75% (CI; 53, 90), respectively. The results in arm B were similar to the previously reported %CR of 40% and ORR of 72% with mLSG15 (Tsukasaki et al, JCO 2007). ORR according to the disease subtype, in arms A and B, was 55% vs. 29% for acute, 50% vs. 43% for lymphoma and 33% vs. 0% for unfavorable chronic. Median PFS was 259 days (CI; 197, -) for arm A and 192 days (CI; 147, -) for arm B. Median OS was not reached in both arms. The most common treatment-related AEs in each arm were neutropenia (100%, 96%), thrombocytopenia (100%, 96%), leukopenia (100%, 92%), lymphocytopenia (97%, 96%), anemia (97%, 92%) and febrile neutropenia (90%, 88%). In arm A, skin disorders were more frequent but manageable, and no serious skin disorder like Stevens-Johnson syndrome was observed. There was one treatment-related death, which was not related to Moga. Conclusions: The combination of Moga with mLSG15 was well tolerated and the study met its primary endpoint. These results suggest that Moga with mLSG15 is a rational treatment option for newly diagnosed aggressive ATL. Clinical trial information: NCT01173887.
Weekly MLN9708, an investigational oral proteasome inhibitor (PI), in relapsed/refractory multiple myeloma (MM): Results from a phase I study after full enrollment.
Authors: Kumar Shaji , Bensinger William , Zimmerman Todd M. , Reeder Craig B. , Berenson James R. , Berg Deborah , Hui Ai-Min , Gupta Neeraj , Di Bacco Alessandra , Yu Jiang , Shou Yaping , Niesvizky Ruben
Published: March 2020

8514

Background: MLN9708 is an investigational, orally bioavailable, potent, reversible, specific inhibitor of the 20S proteasome that has demonstrated antitumor activity in in vivo models of MM. We report safety, activity and pharmacokinetics (PK) of weekly oral MLN9708 in a phase 1 trial in patients (pts) with relapsed and/or refractory MM after full enrollment (NCT00963820). Methods: Pts received MLN9708 (days 1, 8, 15; 28-day cycles) at 0.24–3.95 mg/m2 (dose-escalation phase) and at the MTD, 2.97 mg/m2, in relapsed and refractory (RR), bortezomib (btz)-relapsed, PI-naïve, and prior carfilzomib (CZ) expansion cohorts. Adverse events (AEs) were graded by NCI-CTCAE v3.0. Response was assessed by IMWG uniform criteria. Results: 60 pts (33 male, median age 64 yrs [40–79]) were enrolled, 32 in the dose-escalation phase and 31 to the expansion cohorts (11 RR, 10 btz-relapsed, 6 PI-naïve, 4 CZ; 2 RR and 1 btz-relapsed pts included from MTD dose-escalation cohort). Median time from MM diagnosis was 4.9 yrs (1.5–18.8). Median number of prior regimens was 6 (2–18), including btz, lenalidomide, thalidomide, and CZ in 83%, 95%, 52%, and 13%, respectively; 76% were refractory to last therapy (17% btz-refractory). At data cut-off (Nov 29, 2012) pts had received a median of 2 cycles (1–11); 5 pts remained on treatment. All-grade/grade ≥3 drug-related AEs were seen in 83%/52% of pts; common drug-related grade ≥3 AEs were thrombocytopenia (33%), diarrhea, neutropenia (17%), decreased appetite, fatigue, and lymphopenia (8%). 6 pts (10%) had drug-related PN (no grade ≥3). 5 pts discontinued due to drug-related AEs; 1 pt died on study due to an unrelated AE. By investigator assessment in 41 evaluable pts, responses included1 VGPR, 5 PR, 1 MR, and 15 with SD. MLN9708 was rapidly absorbed, with a terminal half-life of 4–12 days (supporting weekly dosing) and a proportional increase in plasma AUC with dose (0.8–3.95 mg/m2). PK data were similar across expansion cohorts. Conclusions: Current data suggest weekly oral MLN9708 is generally well tolerated with infrequent PN, and shows activity in this heavily pretreated population with prior exposure to immunomodulatory drugs and btz. Clinical trial information: NCT00963820.
Preliminary safety and efficacy of IPI-145, a potent inhibitor of phosphoinositide-3-kinase-δ,γ, in patients with relapsed/refractory lymphoma.
Authors: Horwitz Steven M. , Flinn Ian , Patel Manish R. , Younes Anas , Foss Francine M. , Oki Yasuhiro , Sweeney Jennifer , Allen Kerstin , Dunbar Joi , Kelly Patrick Francis , Kahl Brad S.
Published: March 2020

8518

Background: Phosphoinositide-3-kinases (PI3Ks) are pivotal in cell signaling and regulate a variety of cellular functions relevant to oncogenesis. IPI-145, a potent oral inhibitor of the PI3KEδ and PI3K-γ isoforms, is in clinical development for patients (pts) with hematologic malignancies. Early results in pts with relapsed/refractory lymphoma from an ongoing Phase 1 study are reported here. Methods: This dose-escalation study evaluates the safety, maximum tolerated dose (MTD), clinical activity, and pharmacokinetics (PK) of IPI-145. Expansion cohorts (EC) < MTD are allowed. IPI-145 is given orally twice daily (BID) in 28-day cycles. Tumor response is based on standard disease-specific criteria. Results: 55 pts have been dosed with IPI-145. PK, available through 50 mg BID, are linear with complete inhibition of PI3K-δ at doses > 15 mg BID and increasing suppression of PI3K-γ with increasing dose. In the 36 pts with lymphoma who received 15 mg to 75 mg BID, the median [range] number of cycles was 2.4 [0.1–10] and 67% remain on study. Treatment-related adverse events (TRAEs) occurred in 50% of pts with lymphoma. Neutropenia and increased ALT were the most common ≥ Grade 3 TRAEs (4 pts each) and were not associated with increasing dose. > Grade 3 ALT elevations were more common in lymphoma pts (18%) compared to non-lymphoma pts (5%). Among evaluable pts with lymphoma (n=27), early clinical activity was observed in T-cell (n=6, 1 CR, 1 PR, 1 SD) and aggressive/indolent B-cell (n=21, 2 CR, 9 PR, 5 SD) lymphoma pts at ≤ 75 mg BID. 92% of responses were observed by 3 months. Conclusions: IPI-145 appeared well tolerated and has shown clinical activity in pts with relapsed/refractory advanced B- and T-cell lymphoma across the range of doses examined. The single agent MTD has not been determined and dose escalation continues. Updated safety and efficacy data from pts with lymphoma enrolled in dose escalation or ECs evaluating 25 mg BID and a higher dose (< MTD) of IPI-145 will be presented. Clinical trial information: NCT01476657.
A phase II trial of ifosfamide, methotrexate, etoposide, and prednisolone (IMEP) for previously untreated stage I, II extranodal natural killer/T-cell lymphoma, nasal type (NTCL): A multicenter study of the Korean Cancer Study Group.
Authors: Kim Tae Min , Kim Dong-Wan , Kang Yoon-Koo , Cho Goon Jae , Song Hong-Suk , Kim Hyo Jung , Kim Byung Soo , Lee Jong-Seok , Kim Hawk , Yang Sung Hyun , Yuh Young Jin , Bae Sung Hwa , Lee Kyung-Hee , Jeon Yoon-Kyung , Kim Chul Woo , Heo Dae Seog
Published: March 2020

8521

Background: Combination chemotherapy of IMEP was active as a first-line as well as a second-line treatment for NTCL in a retrospective analysis. Thus, we conducted a prospective, multicenter, phase II study of IMEP chemotherapy in previously, untreated stage I/II NTCL. Methods: Patients with chemo-naïve stage I/II NTCL were enrolled between December 2004 and February 2009 and they received 6 cycles of IMEP (ifosfamide 1.5 g/m2 on days 1 to 3; methotrextate 30mg/m2 on days 3 and 10; etoposide 100mg/m2 on days 1 to 3; and prednisolone 60mg/m2/day on days 1 to 5) followed by involved field radiotherapy (IFRT). Response was evaluated every 2 cycles of chemotherapy and 4 to 8 weeks after completion of IFRT using modified Response Evaluation Criteria in Solid Tumors. Results: Overall, 44 patients including 29 males were analyzed by the intent-to-treat principle. Overall response rates were 73% (complete remission [CR], 11 [27%] of 41 evaluable patients) after IMEP chemotherapy and 78% (CR, 18 [67%] of 27) after IMEP followed by IFRT. Grade 3 to 4 neutropenia and thrombocytopenia were documented in 33 (75%) and 7 (16%) patients, respectively. Only 8 (18%) patients experienced grade 3 febrile neutropenia. 2-year progression-free survival (PFS) and overall survival (OS) were 56% and 66%, respectively. High Ki-67 (≥ 70%) and Ann Arbor stage II independently reduced PFS (hazard ration [HR]=5.6, 95% confidence interval [CI] 1.8-17.6; P=.004) and OS (HR=4.8, 95% CI 1.9-12.2; P=.001), respectively. Conclusions: IMEP followed by IFRT is active and safe against patients with previously untreated stage I/II NTCL.
A pooled analysis of 1,546 patients with AIDS-related lymphoma (ARL): An assessment of prognostic factors by treatment era.
Authors: Barta Stefan K. , Samuel Michael , Xue Xiaonan , Lee Jeanette Y. , Mounier Nicolas , Kaplan Lawrence D. , Ribera Josep-Maria , Spina Michele , Tirelli Umberto , Weiss Rudolf , Galicier Lionel , Boue Francois , Wilson Wyndham Hopkins , Wyen Christoph , Dunleavy Kieron , Little Richard F. , Remick Scot C. , Goldfinger Mendel , Noy Ariela , Sparano Joseph A.
Published: March 2020

8524

Background: Management of ARL evolved in the last 2 decades. We previously reported prognostic factors in a pooled analysis of 1,546 patients with ARL, and here present analysis of these factors over time to determine if their prognostic significance has changed. Methods: Following a systematic review, we assembled individual patient data from 19 prospective phase 2/3 clinical trials (published 1993-2010) for ARL (n=1,546). Factors analyzed include age, sex, histology, CD4 count, prior history of (h/o) AIDS, & age-adjusted (aa) IPI. The endpoint was overall survival (OS) expressed as the hazard ratio (HR) for death. We used separate Cox proportional hazard models adjusted for the other covariates to determine the significance of each variable in the following time periods: pre-cART [combination antiretroviral therapy] (<1996; n=388), early cART (‘96-‘00; n=694), modern cART (‘01-‘04; n=282) & current era (‘05-‘10; n=182). We also combined all enrollments in one Cox model to test for difference in association with OS over enrollment periods. Results: Rituximab use was limited in the early cART (20%) compared with the modern cART (83%) and current (93%) eras. Histology & sex were not significantly associated with OS in any time period. Increasing age was associated with worse OS in the pre-cART (HR 1.02; p<0.01) and current (HR 1.05, p=0.04) eras. A prior h/o AIDS increased risk of death during early cART (HR 1.31, p=0.047) but was not significant after 2000. Meanwhile, baseline CD4 count <50 was a poor prognostic factor during early (HR 1.78, p<0.01) and modern cART (HR 2.76, p=0.001) eras, but not in the current era. The aaIPI predicted worse OS in each time period (pre-cART: HR 1.54, p<0.0001; early cART: HR 1.49, p<0.0001; modern cART: HR 1.52, p<0.01; current era: HR 2.34, p<0.0001). No significant interaction between each prognostic factor with enrollment was found. Conclusions: In this pooled analysis of 1,546 patients with ARL, aaIPI was the only consistently significant prognostic factor and its effect was magnified in the current era. HIV-related factors gained prognostic relevance in the early and modern cART era but may not be as relevant with current treatment strategies.
Phase II study of chidamide (CS055), a new subtype-selective oral histone deacetylase inhibitor, in patients with relapsed or refractory peripheral T-cell lymphoma.
Authors: Shi Yuan-Kai , Dong Mei , Hong Xiao-Nan , Zhang Wei-Jing , Feng Ji-Feng , Zhu Jun , Yu Li , Ke Xiao-Yan , Huang Hui-Qiang , Shen Zhi-Xiang , Fan Yun , Li Wei , Zhao Xie-Lan , Qiu Lu-Gui , Huang He
Published: March 2020

8525

Background: Chidamide (CS055) is a new benzamide type of histone deacetylase (HDAC) inhibitor with subtype selective activity against HDAC1, 2, 3 and 10. Chidamide has shown well-tolerated and favorable PK profiles in patients (pts) with advanced solid tumors and lymphomas. This phase II study was to evaluate the efficacy and safety of chidamide in relapsed or refractory peripheral T-cell lymphoma (PTCL). Methods: 102 PTCL pts were enrolled. In the exploratory trial, pts were randomized to receive chidamide 30mg or 50mg twice per week for 2 weeks, followed by 1 week of rest. In the pivotal trial, chidamide was administered 30mg twice per week w/o drug-free holiday. The primary endpoint was overall response rate (ORR). Responses were assessed using IWC criteria. Results: In the exploratory trial, 19 pts were enrolled with 9 and 10 to the 30mg and 50mg arms, respectively. ORR was 11.1% (1 CR) in the 30mg arm and 40.0% (1 CR, 1 CRu, 2 PR) in the 50mg arm. One pt in the 50mg arm experienced drug-related grade 4 thrombocytopenia. In the pivotal trial, 83 pts were enrolled. Most pts were stage III (35.2%) or IV (45.9%). 23 pts (29.1%) had confirmed responses out of 79 evaluable pts in the pivotal trial (8 CR, 3 CRu, and 12 PR). Responses of 19 pts (24.1%) maintained for ≥12 weeks. ORR with 27.8% was obtained by the Independent Review Committee. 68 pts (81.9%) experienced at least 1 AE in the pivotal trial, with 52.9% of AEs ≤ grade 2. The most common AEs were thrombocytopenia (50.6%), leucocytopenia (39.8%), neutropenia(21.7%), and fatigue (9.6%). 1 pt had a grade 3 QTc prolongation. 7 pts (8.4%) experienced at least one SAE, in which a grade 4 thrombocytopenia was considered to be drug-related. 2 pts with responses (CR) have received chidamide for > 43 months w/o evidence of cumulative toxicity. Conclusions: Chidamide as an oral single agent had significant and durable activity in pts with relapsed or refractory PTCL. Toxicities with the therapy were generally tolerable and manageable. The overall differences in pathological subtypes of pts enrolled and clinical profiles between chidamide and the two existing drugs, pralatrexate and romidepsin, will be discussed. Clinical trial information: ChiCTR-TNC-10000811.
Phase (Ph) I/II study of elotuzumab (Elo) plus lenalidomide/dexamethasone (Len/dex) in relapsed/refractory multiple myeloma (RR MM): Updated Ph II results and Ph I/II long-term safety.
Authors: Lonial Sagar , Jagannath Sundar , Moreau Philippe , Jakubowiak Andrzej J. , Raab Marc S. , Facon Thierry , Vij Ravi , Bleickardt Eric , Reece Donna Ellen , Benboubker Lotfi , Zonder Jeffrey A. , Deng Wei , Singhal Anil K. , Richardson Paul Gerard Guy ,   on behalf of the 1703 Study Investigators
Published: March 2020

8542

Background: Elotuzumab (Elo) is a humanized anti-CS1monoclonal antibody that enhances natural killer cell mediated antibody dependent cellular cytotoxicity of CS1 expressing myeloma cells. This study included a dose finding Ph I cohort (N=28) and a Ph II cohort (N=73). Here we update Ph II data and provide long term safety data from both cohorts. Methods: Patients (pts) treated with ≥1 (Ph I) or 1–3 (Ph II) prior therapies received Elo + Len/dex as described previously (Lonial JCO 2012; Richardson ASH 2012) until disease progression, unacceptable toxicity, or death. All pts received a premedication regimen including methylprednisolone, diphenhydramine or equivalent, ranitidine or equivalent, and acetaminophen to mitigate infusion reactions. Adverse events (AEs) in Ph I/II pts occurring ≤18 months (mo) (N=98) were compared to AEs with a >18 mo onset in a subgroup of pts treated >18 mo (n=49). This safety analysis excluded 3 Ph I pts treated with Elo 5 mg/kg. Results: In the Ph II cohort (median 63 yr), objective response rate (ORR) was 84%; 92% with 10 mg/kg (n=36) and 76% with 20 mg/kg (n=37). At a median follow-up of 20.8 mo, median progression free survival (PFS) was not reached (10 mg/kg) and 18.6 mo (20 mg/kg). Most common treatment emergent grade ≥3 AEs were lymphopenia (19%), neutropenia (18%), thrombocytopenia (16%) and anemia (14%). Most common grade 3/4 AEs emerging ≤18 vs >18 mo in Ph I/II cohorts are shown (Table). 15 pts discontinued due to AEs; none after 18 mo of treatment. There were 4 second primary malignancies; none were reported after 18 mo. Conclusions: Elo 10 mg/kg + Len/dex was generally well tolerated and resulted in a high ORR and encouraging PFS in pts with RR MM. AEs emergent after 18 mo of therapy were consistent with AEs during the initial 18 mo. Updated Ph II safety/efficacy data and long term safety data from Ph I/II cohorts will be presented.
Radiotherapy for nasal cavity and Waldeyer ring natural killer/T-cell lymphoma: Analysis in 131 patients.
Authors: Zhu Yuan , Liu Luying , Luo Jialing
Published: March 2020

8553

Background: Theaim of this study was to evaluate the efficacy and prognosis of chemotherapy and radiotherapy for patients with nasal cavity and Waldeyer ring natural killer/T cell lymphoma. Methods: Records of 131 patients who received chemotherapy or radiotherapy or chemoradiotherapy at Zhejiang Cancer Hospital between 2000 and 2010, were retrospectively reviewed. Ninety-eight patients received chemoradiotherapy. Thirty patients received radiotherapy, and three patients received chemotherapy. All patients had pathology and immunohistochemistry diagnosis. According to the Ann Arbor Staging System, majority of patients were staged as IE stage (116/131). 14 patients presented with IIE stage, and 1 IIIE stage. Thirty-four patients had B symptoms. Results: 109 patients were with nasal cavity NK/T cell lymphoma, and 22 patients with Waldeyer ring NK/T cell lymphoma. Complete response (CR) was achieved in 116 (89%) patients. The 5-year overall survival (OS) rate and disease-free survival (DFS) rate for all patients were 62.7% and 53.5%, respectively. 5-year OS in patients with RT dose ³a50Gy and < 50Gy were 64% and 45.4% respectively (p =0.024). No survival difference was observed between patients with nasal cavity and Waldeyer ring, treated with radiotherapy and chemoradiotherapy, with or without B symptoms, CD56(+) and CD56(-), and between stage IE and IIE patients. On multivariate analysis, the level of lactate dehydrogenase (LDH) before treatment and dose of RT were correlated with prognosis (p<0.05). Conclusions: Radiotherapy, as the primary therapy, can result in a favorable outcome in the treatment of nasal cavity and Waldeyer ring natural killer/T cell lymphoma. The patients with the lower level of LDH before treatment, RT dose ≥50Gy had better prognosis. Addition chemotherapy to radiotherapy didn’t improve the survival.
Limited utility of surveillance imaging for detection of relapse in non-Hodgkin lymphoma.
Authors: Truong Quoc Van , Shah Nilay , Knestrick Mark , Curley Brendan F. , Craig Michael , Hamadani Mehdi
Published: March 2020

8557

Background: Surveillance imaging with computerized tomography (CT) and positron emission tomography with CT (PET/CT) scans during follow-up after first-line therapies in patients with non-Hodgkin lymphoma (NHL) is commonly used in practice. However, most guidelines do not recommend surveillance imaging. We aimed to determine the value of routine imaging for the detection of first relapse in NHL patients in complete remission (CR) after first-line therapies. Methods: We retrospectively analyzed NHL patients referred to our center, who achieved CR after first-line therapies and subsequently relapsed. We evaluated whether the relapse was detected solely by routine CT or PET/CT or by patient-reported symptoms. Subgroup analysis was performed according to baseline histology (indolent vs. aggressive NHL). Data were also collected to determine the number of additional imaging, number of false positive scans, invasive procedures and iatrogenic complications, directly resulting from an abnormality detected on surveillance imaging. Results: Seventy-seven patients with first relapse of NHL between January 1, 2000 and December 31, 2010 were included. Majority of the relapses were detected by patient-reported symptoms as opposed to surveillance imaging (79.2% (n=61) vs. 20.8% (n=16); p<0.0001). There was no overall survival difference between the two groups (p=0.08). Patient-reported symptoms led to the detection of majority of relapses in aggressive (86.4% (n=45) vs. 13.6% (n=6); p<0.0001) and indolent NHL (69.7% (n=32) vs. 30.3% (n=10); p=0.037). There were greater number of scans done after a suspected relapse in the imaging versus symptoms group (1.94 versus 0.97; p=0.0004). Surveillance imaging led to 2 false positive scans/invasive procedures with one case of iatrogenic pneumothorax. Conclusions: Our limited retrospective analysis suggests that there is a limited role of surveillance imaging by CT or PET/CT for the detection of relapse in patients with NHL. There was no difference in survival outcome in our study between the two groups.
EBV-negative post-transplant lymphoproliferative disorder: Clinical characteristics, response to therapy, and survival.
Authors: Heil Daniel S. , Luskin Marlise Rachael , Stadtmauer Edward Allen , Schuster Stephen J. , Tsai Donald Edward , Reshef Ran
Published: March 2020

8578

Background: Post-transplant lymphoproliferative disorder (PTLD) is a potentially life-threatening complication of solid organ transplantation. PTLD is frequently linked with Epstein-Barr virus (EBV) and it was suggested that EBV negativity is associated with a poor prognosis and lack of response to reduction of immunosuppression (RI). We conducted a case-control study to identify the characteristics, outcome and response to therapy of EBVpos and EBVneg PTLD over a 20-year period. Methods: We reviewed data on patients diagnosed with PTLD at U. Penn. between 1982 and 2012. We determined EBV positivity on tumor samples according to WHO criteria. We compared clinical and pathologic characteristics, response to therapy, and survival of EBVpos and EBVneg patients. Results: Of 222 patients diagnosed with PTLD, we verified the EBV status of 169 patients, of whom 35% were EBVneg and 65% were EBVpos. Mean follow-up was 46.7 months. Median time from transplant to PTLD was 23.1 mo. in EBVpos vs. 59.3 mo. in EBVneg (p=0.003) with 42% of EBVpos patients being diagnosed within the first year after transplant vs. 15% in the EBVneg group (p<0.001). EBVneg PTLD was more likely to occur in non-thoracic vs. thoracic transplants (p=0.006). 28% of patients with EBVpos PTLD presented with disease originating from the graft vs. 14% in the EBVneg group (p=0.03). In terms of histology, 36% of EBVpos patients had polymorphic PTLD vs. 7% of EBVneg patients (p<0.001). Of patients who were treated with RI alone (40% of patients in both groups), the overall response rates were 50% and 48% in EBVpos and EBVneg patients respectively (p=NS). Response rates to rituximab were also similar. There was no difference in the mortality risk between groups (HR=1.04; p=0.84). The 5-year survival rates were 47% and 51% in EBVpos and EBVneg PTLD respectively (p=NS). Conclusions: In a large single-center series, EBVneg PTLD was associated with late occurrence after transplant, monomorphic histology and similar outcome in comparison with EBVpos PTLD. Importantly, the response of EBVneg PTLD to RI and rituximab was no different than EBVpos PTLD. These results have implications for the management of solid organ transplant recipients with PTLD.
Measures of immune recovery following autologous stem cell transplantation for multiple myeloma and outcome.
Authors: Hegerova Livia , Gertz Morie , Lacy Martha , Dispenzieri Angela , Buadi Francis , Hayman Suzanne R. , Dingli David , Porrata Luis F. , Kumar Shaji
Published: March 2020

8581

Background: Autologous stem cell transplant (ASCT) improves survival in patients with multiple myeloma (MM). Recent studies have elucidated the relationship in ASCT between absolute lymphocyte count (ALC) recovery and improved survival, highlighting the importance of immune recovery. We conducted a retrospective analysis of patients with multiple myeloma to observe the impact of different measures of immune recovery at day 100 post-ASCT on outcome. Methods: Retrospective analysis of data from the existing clinical databases identified 1184 patients with multiple myeloma that underwent ASCT at Mayo Clinic between 1987-2011. Markers of immune recovery analyzed on day 100 status-post ASCT included ALC, monocyte count, and immunoglobulin levels. Kaplan Meier analysis was performed to determine progression free survival (PFS) and overall survival (OS). Results: Among the 1184 patients, median age at diagnosis of multiple myeloma was 57 (range, 23-75 yr), and median age at time of transplantation was 59 (range, 24-75 yr); 59% were male. The median OS and PFS post-transplant were 80 months and 34 months respectively. 62% of patients were alive 5-years post-transplant. The median OS was not improved with normal vs. abnormal IgG levels at day 100 (p=.298). In contrast, monocyte recovery was a significant predictor of OS. Patients with normal monocyte counts of greater than 0.3 x 10⁹ cells/L at day 100 showed superior survival (65 vs. 37 months, p= .001). Similarly, patients with normal monocyte recovery at day 15 post-transplant showed a significant survival benefit (68 vs. 50 months, p=.007). Early ALC recovery, which has been shown to be a positive prognostic indicator at day 15 post-transplant, was not prognostic at day 100 (p= .960). Conclusions: The present study further elucidates prognostic indicators after ASCT for MM highlighting the importance of various markers of immune recovery. Immunoglobulin recovery was not associated with superior survival, while monocyte recovery at day 15 and day 100 post-transplant translated to an improved survival and requires further study. It may be hypothesized that early immune system reconstitution may have a positive effect against disease post-transplant.
Retrospective analysis of cardiovascular (CV) events following compassionate use of carfilzomib (CFZ) in patients (Pts) with relapsed and refractory multiple myeloma (RRMM).
Authors: Atrash Shebli , Tullos Amanda , Panozzo Susan , Waheed Sarah , Van Rhee Frits , Restrepo Alejandro , Muzaffar Jameel , Bakhous Aziz , Grazziutti Monica , Shahid Zainab , Apewokin Senu , Abdallah Al-Ola A. , Barlogie Bart , Usmani Saad Zafar
Published: March 2020

8595

Background: Herein, we report CV events observed in late-stage, heavily pretreated pts who received salvage CFZ under a compassionate use protocol. Methods: Pts received IV single-agent CFZ (20-45 mg/m2) over 2-30 min on days 1, 2, 8, 9, 15, and 16 of a 28-day cycle (C) or CFZ with weekly dexamethasone (4-40 mg) during C1, along with other agents (eg, lenalidomide, thalidomide, cyclophosphamide, doxorubicin, cisplatin, vorinostat) during C2 and beyond. CV events were grouped according to preferred terms. Serious CV events were defined as those that required hospitalization. B-type natriuretic peptide (BNP) values were measured at baseline; peak values were recorded during C1. Results: 143 pts (median age, 61 years old; 70% were male) received treatment. Prior to enrollment, pts received a median of 7 prior lines of therapy (range, 2-15), including doxorubicin (range, 0-360 mg/m2). Most pts (92%) had prior autologous stem cell transplants (ASCT), with 74% receiving ≥2 ASCT (range, 0-5). Pts received CFZ for a median of 2C (range, 1-36). Of pts with available BNP values at baseline and during C1 (n=69; 48.3%), the median peak BNP increase from baseline was 407 pg/ml (P<0.001). 27 pts (18.9%) experienced a serious CV event, 21 (77.7%) of which had preexisting CV risk factors. Of these 27 pts, 11 pts (7.7%) developed CHF or worsening of existing CHF (confirmed by echocardiogram [ECHO] ≤1 month from diagnosis), and 13 (9.1%) required hospitalization for hypotension (n=6), arrhythmia (n=2), hypertension (n=2), pulmonary edema (n=1), pulmonary embolism (n=1), or pulmonary hypertension (n=1). Additionally, 3 pts (2.1%) experienced cardiopulmonary arrest. Of the 11 CHF pts, 10 had a baseline ECHO (recorded ≤6 months before study); left ventricular ejection fraction decreased from a median of 55% (pretreatment) to 33% (posttreatment). Conclusions: Late-line, heavily pretreated pts with RRMM occasionally experienced CV events following administration of CFZ with or without other antimyeloma agents. Given the number of confounding factors and the uncontrolled nature of these data, causality for these CV events could not be definitively determined.
A comparison between next-generation sequencing and ASO-qPCR for minimal residual disease detection in multiple myeloma.
Authors: Takamatsu Hiroyuki , Murata Ryoichi , Zheng Jianbiao , Moorhead Martin , Terasaki Yasushi , Yoshida Takashi , Faham Malek , Nakao Shinji
Published: March 2020

8601

Background: Although molecular CR in multiple myeloma (MM) can be assessed by allele-specific oligonucleotide (ASO)-PCR, this technique requires preparation of clonotype-specific primers for each individual which is laborious and time-consuming. The usage of the LymphoSIGHT method, a next-generation sequencing (NGS)-based platform, may overcome these challenges and increase sensitivity and specificity. We compared the LymphoSIGHT approach with ASO-qPCR for minimal residual disease (MRD) detection in autografts in the autologous peripheral blood stem cell transplantation (ASCT) setting. Methods: Seventeen Japanese patients with newly diagnosed MM who received various induction regimens prior to ASCT were retrospectively analyzed. All patients had achieved a PR or CR after ASCT. Bone marrow (BM) slides from 13 MM patients and fresh BM cells from 4 MM patients at diagnosis as well as autografts were obtained for DNA extraction. Using universal primer sets, we amplified IGH variable (V), diversity (D), and joining (J) gene segments, IGH-DJ, and IGK from genomic DNA. Amplified products were subjected to deep sequencing using NGS. Reads were analyzed using standardized algorithms for clonotype determination. Myeloma-specific clonotypes were identified for each patient based on their high frequency in BM samples. The presence of the myeloma clonotype was then assessed in follow-up samples. Results: MRD in autografts was detected in 6 of 17 (35%) by ASO-qPCR and 13 of 17 (76%) by NGS. When MRD was assessed by NGS, 6 MRD (+) cases received post-ASCT therapy while 4 MRD (-) cases and 7 MRD (+) cases were followed without post-ASCT therapy. The MRD (-) cases tended to show a better PFS than the MRD (+) cases with post-ASCT therapy (P = 0.26) and those without post-ASCT therapy (P = 0.09) although overall survival rates were comparable among the three groups. There was no difference in PFS between MRD (-) and MRD (+) cases when MRD was assessed by ASO-qPCR (P = 0.6). These studies will be extended in 30 additional MM patients, and results will be presented. Conclusions: MRD-negativity in autografts revealed by NGS may be more closely associated with durable remission of MM than that revealed by ASO-qPCR.
Genetic variation in immunomodulatory genes as markers of melanoma recurrence-free and overall survival.
Authors: Rendleman Justin , Shang Shulian , Shields Jerry , Adaniel Christina , Fleming Nathaniel H. , Shapiro Richard , Berman Russell S. , Pavlick Anna C. , Shao Yongzhao , Osman Iman , Kirchhoff Tomas
Published: March 2020

9021

Background: Small reported studies have provided some evidence implicating immune related genes in melanoma susceptibility and prognosis; however candidate selection of these prior efforts has been limited. In this study, we performed an analysis of germline variants in immuno-modulatory genes for their association with melanoma survival in a well characterized cohort of prospectively accrued melanoma patients. Methods: Germline DNA isolated from blood samples of 817 melanoma patients was genotyped for 94 SNPs tagging 55 immuno-modulatory genes using Sequenom iPLEX. Cox models were used to test associations between each SNP and recurrence-free and overall survival (RFS and OS), with adjustments for age, gender, subtype, thickness, ulceration, and anatomic site. ROC curves were constructed from different SNP/clinical covariate combinations and the area under the curve (AUC) was used to assess their utility in the classification of 3-year recurrence. Results: The SNP rs2796817 in TGFB2 had strong associations with both RFS (HR=3.8, CI 95%: 1.3-11, p=0.02) and OS (HR=5.5, CI 95%: 1.6-19, p=0.029). Other interesting associations with OS came from IRF8 (rs4843861, HR=0.62, CI 95%: 0.39-0.99, p=0.017), CCL5 (rs4796120, HR=7.6, CI 95%: 2.3-25, p=0.035), and CD8A (rs3810831, HR=2.4, CI 95%: 0.91-6.2, p=0.048). A multivariate model including stage, subtype, and one of the SNPs (rs3810831 from CD8A), was shown to improve the AUC when compared to a model including only stage and subtype (0.77 vs. 0.79). Conclusions: We identified several immune-related loci associated with melanoma RFS and OS. The strongest association, rs2796817, maps in TGFB2, which among other functions suppresses IL-2 dependent T-cell growth. In addition to other associations found in the study these findings provide evidence for the involvement of immuno-modulatory genes in melanoma prognosis and suggest further investigations of immune related genes in disease progression. This is currently underway in the second stage validation analysis, which includes an expanded set of immune target genes as well as an additional independent cohort of melanoma patients.