bluuebunny/crossref_metadata_2025_split huggingface dataset:
Metastases outside the abdomen (MOA) are associated with initial high tumor burden (TB) in gastrointestinal stromal tumors (GIST)
Authors: Aliberti S. , Grignani G. , Allione P. , Rota-Scalabrini D. , Carnevale-Schianca F. , Bucci A. , Caravelli D. , Galla A. , Ferraris R. , Aglietta M. 
Published: March 2020

9546 Background: In GIST MOA are rare events (8–10%) with a prognostic and predictive impact (JCO 2005;23:5795). To stage GIST, NCCN recommends either CT or abdominal MRI + chest imaging, suggesting PET scan only if early response assessment is needed. Therefore, MOA may be missed by standard work up. We evaluated if TB (largest tumor diameter > 12 centimetres) at diagnosis was associated to a higher incidence of MOA. Methods: From 01/02 to 12/05, 66 pts affected by GIST were either treated or followed-up at our hospital. Routine initial work up consisted in: chest CT + CT or MRI abdominal scan. Pet scan was performed if: uncertainties after standard imaging, to monitor “neoadjuvant” therapy or within clinical trials. Identified MOA if unique, would be considered for fine needle biopsy whilst multiple MOA would be monitored by most appropriate imaging technique. Results: Twenty-three pts (34%) had TB between 13 and 31 centimetres. At diagnosis 10 pts (15%) had MOA located in: lung (7 pts), bone (2 pts) subcutaneous tissue (1 pts). In this unfavourable group 9 pts (14%) were affected by tumors larger than 12 cm. Pts without MOA were 56 (85%) of whom 14 (21%) had TB. The association between initial TB and MOA was statistically significant (p<0.001). Conclusions: In this small series, high tumor burden is positively correlated to MOA. If these data should be confirmed, initial diagnostic work up could usefully include both chest CT and PET scan in abdominal mass beyond 12 centimetres wide. A precocious recognition of MOA would allow to better control therapeutic response and to better identify high-risk patients. No significant financial relationships to disclose.
Surgical interventions for focal progression of gastrointestinal stromal tumors under imatinib therapy
Authors: Nishida T. , Hasegawa J. , Nishitani A. , Takahashi T. , Kanda T. , Hatakeyama K. 
Published: March 2020

9548 Background: Although Imatinib has shown high activity oin advanced gastrointestinal stromal tumors (GIST), secondary resistance appears as focal or systemic progressions during chronic therapy. At present, there are limited therapeutic options for Imatinib-resistant GIST. This retrospective study examines the safety and short-term outcomes of surgical interventions for focal progressions under Imatinib. Patients and Methods: Between Jan. 2002 and May 2005, 16 patients (pts) with focal progressions of secondarily-resistant GIST (Male:Female, 12:4; median age, 61 years) underwent surgical interventions including resection (N=13), radiofrequency ablation (RFA) (n=2), and their combination (n=1). Doses of Imatinib were 400 (n=10) or 600 (n=6) mg/day. Results: Postoperative complications including liver abscess (n=1), minor bile leak (n=1), wound infection (n=1) and transient ileus (n=1) were occurred to 4 patients, who recovered from them within a few weeks. There was no in-hospital deaths. Median time to progression (TTP) was 5.5 months. Only one patient died of the of disease, 16 months after the resection, and the remaining 15 pts are alive, with a median follow-up of 13 months. Pts with total eradication of resistant lesions (n=7) had longer TTP than those with incomplete (n=9) (p<0.05). Total eradication could be performed in patients with a smaller number (P=0.014) and size (P=0.018) of resistant lesions. Overall survival after Imatinib therapy was 100% at 1 year and 93% at 3 years, with a median follow-up of 39 months. Conclusions: These data suggest that surgical interventions for focal progressions of secondarily-resistant GIST under Imatinib may be safe and that total eradication of resistant lesions may result in a survival benefits under conditions of limited treatment modality. No significant financial relationships to disclose.
Terminal phase in patients (pts) with advanced sarcomas: A perspective study for a better assistance
Authors: Comandone A. , Oliva C. , Boglione A. , Garetto F. , Bergnolo P. , Dal Canton O. , Chiado Cutin S. , Pochettino P. , Gino G. , Brach Del Prever E. 
Published: March 2020

9551 Background: Sarcoma are rare tumors, with an incidence <1% of all neoplasms. Very few data are available on the clinical and psychological needs of the pts in terminal phase of these diseases. In terminal phase the goal is no more cure or prolongation of life, but the control of symptoms related to the disease progression. Methods: As a specialized interdisciplinary group we have started to treat the pts afflicted from soft tissue and bone sarcomas since 1994. We have recorded in a perspective study the problems of the terminal pts from 1998 until 2005. We have followed 178 pts with sarcomas in terminal phase for at least 3 months: 95 males and 83 females, median age 57 years, median PS 50 Karnofsky. Histologically 143 had soft tissue sarcomas, 28 osteosarcomas, 7 Ewing sarcomas. Extremities were the origin of the disease in 33.7% of the cases, abdomen in 29.2%, trunk in 21.9% and other sites in 15.2%. Site of recorded metastases: lung 48.3%, liver 18.5%, bone 15.7%, brain 7.9%, nodes 4.5%. Inoperable primary tumors or local relapse 30.9%. Results: During the last part (1 months) of their lives the pts complained with: pain 78.7%, dyspnoea 48.9%, anxiety 16.9%, gastrointestinal obstruction 24.7%, anorexia 51.1%, bleeding 7.9%. 57.3% of these pts died at home, 42.7% at the hospital. To control pain, dyspnoea and the other symptoms radiotherapy (43%), supportive care (100%) and palliative chemotherapy (36%) were used. Psycological support was offered to the majority of pts (63.5%) as well as physical rehabilitation (56.8%). Conclusions: Supportive care of pts with advanced sarcomas is an underestimated aspect in clinical oncology. We have demonstrated that these pts have specific needs, on some aspects, different from those of the pts afflicted from the most common cancers. A complex, multidisciplinary approach is necessary in order to improve the assistance and quality of life of these pts. No significant financial relationships to disclose.
Assessment of trabectedin (T) induced liver toxicity with correlation to liver morphology in a phase I study of T + pegylated liposomal doxorubicin (PLD)
Authors: Yver A. , Cohen R. , Williams D. , Von Mehren M. 
Published: March 2020

9568 Background: T (ET-743) is a first-in-class compound that binds the minor groove of DNA. T has activity in soft tissue sarcoma and ovarian cancers with predictable, transient, non-cumulative and reversible hepatic toxicity, compatible with long term treatment. The combination of T and doxorubicin had preclinical synergistic activity. This study tested T + PLD in advanced malignancies. Methods: Eligibility included normal cardiac and liver functions, prior doxorubicin exposure <250 mg/m2. PLD 30 mg/m2 was administered iv 1-hour followed by 1 of 6 T doses (0.4 -1.3 mg/m2) iv 3 hours q 21 days. In select subjects (4 at pre/post cycle 1, 4 under long term treatment -cycle 14, 20, 30 and 30), liver biopsies were done with expert independent review. Results: Six dose levels of T were evaluated in 30 subjects. The DLTs were 1 grade 3 AST and 2 grade 4 ALT elevations seen at T 1.3 mg/m2. Grade 3–4 toxicities were: ALT elevation (4%), neutropenia (3%), hand-foot syndrome (2%), AST elevation (1%) and nausea/vomiting (1%). Liver biopsies were obtained from 8 subjects (1 in 0.6, 7 in 1.1 mg/m2 T dose cohorts), age 45–78 years, with sarcoma (4), and ovarian (2), uterine (1), and head and neck (1) cancers. T and PLD mean drug exposure for these subjects was 15 (2–36) and 12 (2–24) cycles, respectively. Mean total doses for T and PLD were 23.2 (3.4–39) and 597 (94–1296) mg, respectively. Findings included NASH (nonalcoholic steatohepatitis), severity ranging from minimal steatosis to moderate steatosis with fibrosis. Pre/post treatment biopsies showed no change in NASH pre/post in 3 cases, one subject had minimal post-treatment steatosis. No mitochondrial abnormalities or stellate cell activation were observed. Review concluded no evidence of persistent liver pathological abnormalities attributable to T. Conclusions: The MTD of T is 1.1 mg/m2 with 30 mg/m2 PLD q 21 days, and is well tolerated when both drugs are administered at near full therapeutic doses for prolonged periods. Liver biopsies did not demonstrate clinically relevant hepatic tissue toxicity. As reported previously, this is an active regimen which is being further evaluated in an ongoing Phase III study in relapsed ovarian cancer. [Table: see text]
The role of adjuvant radiotherapy after marginal excision for local control of extremity and truncal soft tissue sarcoma
Authors: Kim Y. B. , Shin K. H. , Kim G. E. , Han S. B. , Roh J. K. , Suh C. O. 
Published: March 2020

9573 Background: Adjuvant radiotherapy (RT) has been shown to improve local control (LC) in patients with extremity and truncal soft tissue sarcoma (STS). The purpose of this study was to analyze how much RT promoted LC in patients with marginally excised STS compared with patients with widely excised STS. Methods: Two hundred and thirty-two patients with STS (173 extremity cases and 59 trunk cases) who had received conserving surgery were divided into 3 groups according to marginal status and the addition of RT; (1) wide excision alone (n = 56, Group A), (2) wide excision plus RT (n = 64, Group B) and (3) marginal excision plus RT (n = 112, Group C). LC, overall survival, and morbidity rates were retrospectively compared among 3 groups. Results: There were no differences in age, gender, pathologic type, and tumor site among three groups, but Group A had the higher incidence of small-sized tumor and low grade tumor than other groups. Thirty-eight patients experienced local failures (LF) after completion of treatment. Group C had similar incidence of LF compared with Group B (Group A; 4%, Group B; 21%, and Group C; 19%). Overall 5-year and 10-year LC rates were 80% and 70%, and there were no significant differences between Group B and Group C in 10-year LC rate (Group A; 84%, Group B; 65%, and Group C; 68%). Tumor grade and tumor site were found to be significant predictors of LF. Group C had lower 10-year overall actuarial survival rate compared with Group B (Group A; 85%, Group B; 78%, and Group C; 69%). This was associated with significantly different incidence of distant failure (Group A; 11%, Group B; 16%, and Group C; 29%, p=0.008). Seven patients suffered from wound dehiscence, and 1 patient from bone necrosis. The incidence of Grade 3–4 late complication was higher in Group B than Group A and Group C (Group A; 0%, Group B; 9.3%, and Group C; 1.7%, p=0.03). Conclusions: Our data indicate that RT seems to promote LC in patients with positive or close margin up to that of patients with wide margin in extremity and truncal STS. We suggest that conserving surgery and RT for patients with marginal STS should be the alternative choice rather than aggressive surgery for better LC without deteriorating limb-function or causing serious complication. No significant financial relationships to disclose.
Multimodality treatment in retroperitoneal sarcoma
Authors: Minea L. N. , Anghel R. , Stanculeanu D. , Georgescu T. , Bacinschi X. , Tarlea A. , Oprea L. , Negrei C. , Barna M. , Gheta C. 
Published: March 2020

9579 Background: Soft tissue sarcomas account for less than 1% of all malignancies; 10% of them arise in the retroperitoneal tissues. Surgical resection is considered as the most important treatment but it is often difficult to perform because of late presentation, anatomical conditions and invasion of adjacent structures. Adjuvant treatments have limited efficacy. Methods: We evaluate two year survival rate and safety profile of multimodal treatment in retroperitoneal sarcomas. Between Jan 1999 - Dec 2003, 37 patients with retroperitoneal sarcomas were treated in our institution. Median age 48.2 years (range 20 - 70), sex ratio M:F - 15:22, PS ECOG 0:1:2 - 25:8:4, tumor grading G1:G2:G3 - 8:14:15. Surgery was performed in 34 cases (29 complete resection, 5 partial resection) and 3 patients were only biopsied. All the patients received adjuvant radiochemotherapy and 4 more chemotherapy cycles thereafter. The chemotherapy regimen consisted of Ifosfamide 1,500 mg/sqm/day day 1–5 with mesna uroprotection and Epirubicin 50 mg/sqm day 1, repeated on days 29–33 during RT. They received external beam RT up to 45 - 50 Gy, conventional fractionation. The Ifosfamide and Epirubicin doses were increased at 1,800 mg/sqm and 75 mg/sqm respectively after chemoradiotherapy if no grade 3–4 toxicities occurred. Results: The overall 2 year survival rate was 70.27%. The 2 year survival rate was 100% - 71.43% - and 53.33% for G1, G2 and G3 tumors respectively; the figures are 82.75% - 40% and 0% for complete resection, partial resection and diagnostic biopsy respectively. All patients received the intended treatment. There were only 8 cycle delays for grade 3 toxicities. 6 patients had grade 3–4 hematological toxicities and 4 patients had grade 3–4 digestive toxicities. Retroperitoneal fibrosis occurred in 3 cases. Conclusions: This combined modality treatment can be successfully delivered. We have no major toxicities. We obtained similar results as cited in the literature. Better results could be obtained with newer radiation techniques (conformal RT or IMRT). No significant financial relationships to disclose.
BCIRG 007: Randomized phase III trial of trastuzumab plus docetaxel with or without carboplatin first line in HER2 positive metastatic breast cancer (MBC)
Authors: Forbes J. F. , Pienkowski T. , Valero V. , Eiermann W. , Von Minckwitz G. , Martin M. , Smylie M. , Crown J. M. , Noel N. , Pegram M. 
Published: March 2020

LBA516 Background: Based on preclinical synergism between docetaxel (T), carboplatin (C) and trastuzumab (H), BCIRG conducted a phase III trial for women with HER2+ MBC to evaluate efficacy and safety of H in combination with T or TC. Methods: 263 patients (pts) with HER2 FISH+ MBC were randomized to TH, (H with T 100 mg/m2) or TCH, (H with T 75 mg/m2 and C AUC=6). Chemo was given q3 wks for 8 cycles with wkly H at 2 mg/kg (loading dose of 4 mg/kg), followed by H q3 wks at 6 mg/kg until progression. Pts were stratified by centre and prior (neo) adjuvant taxane chemotherapy. Primary endpoint was TTP with 80% power (0.05 significance) to detect a 50% improvement in median TTP between the 2 arms. Secondary endpoints include overall survival, response rate, duration of response (DR), clinical benefit (CB) and safety. Results: 131 pts were treated in each arm. Pt characteristics were well balanced in both groups. Importantly, only 52% of pts received C at the protocol specified dose (RDI > 0.9). Efficacy analysis was conducted at 204 events. There was no significant difference between TH and TCH in median TTP (11.1 vs 10.4 mos, p = 0.57), ORR (73% in both arms), DR (10.7 vs 9.4 mos) and CB (67% in both arms). The most common gr 3/4 toxicities were: infection (44% vs 30%), neutropenic infection (22% vs 12%), thrombocytopenia (2% vs 15%), febrile neutropenia (12% vs 13%) asthenia (5% vs 12%), anemia (5% vs 11%), and diarrhea (2% vs 9%). Two pts died (1.5%) due to sepsis in TCH. Absolute LVEF decline > 15% were seen in 5.5% vs 6.7% of pts. One pt (0.8%) had a symptomatic CHF in TH arm Conclusions: The already effective TH regimen does not benefit from the addition of C, when the T dose in TH is 100 mg/m2 and 75 mg/m2 in TCH, in women with HER2+ MBC. No significant financial relationships to disclose.
Docetaxel (T) given concurrently with or sequentially to anthracycline-based (A) adjuvant therapy (adjRx) for patients (pts) with node-positive (N+) breast cancer (BrCa), in comparison with non-T adjRx: First results of the BIG 2–98 Trial at 5 years median follow-up (MFU)
Authors: Crown J. P. , Francis P. , Di Leo A. , Buyse M. , Balil A. , Anderson M. , Nordenskjöld B. , Jakesz R. , Gutierrez J. , Piccart M. 
Published: March 2020

LBA519 Background: The activity of T in metastatic BrCa mandated evaluation as adjRx. We compared the efficacy of T with, or after A, both followed by CMF (cyclophosphamide/ methotrexate/ 5-fluorouracil), versus non-T adjRx. Methods: Random assignment trial in resected N+ pts, 18–70 yrs, stratified by: center, 1–3 vs >3 nodes and age <50 vs ≥50. The treatment arms were (mg/m2, intravenously unless otherwise stated): Ia: A 75 q 3 weeks × 4 ⋄ CMF ×3 (oral C 100 day 1–14, F 600 + M 40 d 1+8; q 28 days). Arm Ib; AC 60/600 × 4⋄CMF × 3. Arm II: A75 × 3 ⋄T100 ×3 ⋄CMF ×3. Arm III: AT 50/75 ×4 ⋄ CMF × 3. Pts subsequently received hormono-(receptor+), and radiotherapy per local guidelines. Randomization was in the ratio (1:1:2:2). The trial was designed to have 80% power to detect a 78% hazard ratio (HR) for relapse in II+III v I, with final analysis at 1215, and interim at 405 and 810 events. The primary comparison between the II+III and I would be done at a one-tailed significance level of 0.025. Secondary comparisons of II vs Ia and III vs Ib would be done using a closed testing procedure at a one-tailed significance level of 0.025. The 95% confidence limits of the HR of III v II would be calculated. Due to a low relapse rate, the plan was amended with main analysis after 810 events or 5 years MFU. Results: 2887 pts were enrolled (6/1998–6/2001). Characteristics were well-balanced, 46% had >3N+. Grade 3/4 toxicity occurred in 22.9, 24.7, 35.3 and 28.6 % of pts in Ia, Ib, II and III respectively. At 62.2 months MFU (3/2006), 732 pts (25%) had events. Planned event-free survival (EFS) comparisons were: Conclusion: In this study, the HR for T v non-T adjRx was of borderline significance. There were possibly important differences related to schedule, sequential but not concurrent appearing superior to non-T adjRx. Overall survival analysis will require longer follow-up. Translational studies are underway. [Table: see text] [Table: see text]
Volatile Anesthetic Sevoflurane Attenuates Toll-Like Receptor 1/2 Activation
Authors: Mitsui Yusuke , Hou Lifei , Huang Xiayi , Odegard Kirsten C. , Pereira Luis M. , Yuki Koichi 
Published: March 2020

BACKGROUND:
Although immunomodulatory effects of anesthetics have been increasingly recognized, their underlying molecular mechanisms are not completely understood. Toll-like receptors (TLRs) are one of the major receptors to recognize invading pathogens and danger signals from damaged host tissues to initiate immune responses. Among the TLR family, TLR2 and TLR4 recognize a wide range of ligands and are considered to be important players in perioperative pathophysiology. Based on our recent finding that volatile anesthetics modulate TLR4 function, we tested our hypothesis that they would also modulate TLR2 function.

METHODS:
The effect of anesthetics isoflurane, sevoflurane, propofol, and dexmedetomidine on TLR2 activation was examined by reporter assays. An anesthetic that affected the activation was subjected to in silico rigid docking simulation on TLR2. To test our prediction that sevoflurane and a TLR1/TLR2 ligand Pam3CSK4 would compete for the same pocket of TLR2, we performed Pam3CSK4 competitive binding assay to TLR2 using HEK cells stably transfected with TLR2 (HEK-TLR2) with or without sevoflurane. We examined the effect of different anesthetics on the functions of human neutrophils stimulated with TLR2 ligands. Kruskal–Wallis test and Mann–Whitney U test were used for statistical analysis.

RESULTS:
We observed that the attenuation of TLR1/TLR2 activation was seen on sevoflurane exposure but not on isoflurane, propofol, or dexmedetomidine exposure. The attenuation of TLR2/TLR6 activation was not seen in any of the anesthetics tested. The rigid docking simulation predicted that sevoflurane and Pam3CSK4 bound to the same pocket of TLR1/TLR2 complex. The binding of Pam3CSK4 to HEK-TLR2 cells was impaired in the presence of sevoflurane, indicating that sevoflurane and Pam3CSK4 competed for the pocket, as predicted in silico. The stimulation of neutrophils with Pam3CSK4 induced L-selection shedding but did not affect phagocytosis and reactive oxygen species production. L-selectin shedding from neutrophils was attenuated only by sevoflurane, consistent with the result of our reporter assays.

CONCLUSIONS:
We found that TLR1/TLR2 activation was attenuated by sevoflurane, but we found no evidence for attenuation by isoflurane, propofol, or dexmedetomidine at clinically relevant concentrations. Our structural analysis and competition assay supported that sevoflurane directly bound to TLR2 at the interphase of the TLR1/TLR2 complex. Sevoflurane attenuated neutrophil L-selectin shedding, an important step for neutrophil migration.
Using machine learning techniques to develop risk prediction models to predict graft failure following kidney transplantation: protocol for a retrospective cohort study
Authors: Senanayake Sameera , Barnett Adrian , Graves Nicholas , Healy Helen , Baboolal Keshwar , Kularatna Sanjeewa 
Published: March 2020

Background:A mechanism to predict graft failure before the actual kidney transplantation occurs is crucial to clinical management of chronic kidney disease patients. Several kidney graft outcome prediction models, developed using machine learning methods, are available in the literature. However, most of those models used small datasets and none of the machine learning-based prediction models available in the medical literature modelled time-to-event (survival) information, but instead used the binary outcome of failure or not. The objective of this study is to develop two separate machine learning-based predictive models to predict graft failure following live and deceased donor kidney transplant, using time-to-event data in a large national dataset from Australia. Methods:The dataset provided by the Australia and New Zealand Dialysis and Transplant Registry will be used for the analysis. This retrospective dataset contains the cohort of patients who underwent a kidney transplant in Australia from January 1st, 2007, to December 31st, 2017. This included 3,758 live donor transplants and 7,365 deceased donor transplants. Three machine learning methods (survival tree, random survival forest and survival support vector machine) and one traditional regression method, Cox proportional regression, will be used to develop the two predictive models (for live donor and deceased donor transplants). The best predictive model will be selected based on the model’s performance.Discussion:This protocol describes the development of two separate machine learning-based predictive models to predict graft failure following live and deceased donor kidney transplant, using a large national dataset from Australia. Furthermore, these two models will be the most comprehensive kidney graft failure predictive models that have used survival data to model using machine learning techniques. Thus, these models are expected to provide valuable insight into the complex interactions between graft failure and donor and recipient characteristics.