bluuebunny/crossref_metadata_2025 huggingface dataset:
An analysis of a moderate earthquake, eastern flank of the Red Sea, Saudi Arabia
Authors: Abdelfattah Ali K. , Al-amri Abdullah , Sami Soliman M. , Zaidi Faisal K. , Qaysi Saleh , Fnais Mohamed , Almadani Sattam , Al-Arifi Nassir
Published: March 2020

The present study presents the analysis of a moderate earthquake (Mw 4.0) and its largest aftershocks located along the Red Sea coast, southwestern Saudi Arabia, with the aim to understand the enigma of peculiar seismicity in the Arabian Shield. We analyzed a high-quality waveform dataset collected from ten well-recorded earthquakes of moment magnitude ranging from 2.0 to 4.0 in order to determine the hypocenter locations and focal mechanisms. The focal mechanisms were retrieved from the regional moment-tensor inversion for the mainshock and using the P-wave polarities for the corresponding aftershocks of Mw ≥ 2.0, respectively. The focal mechanism solutions were inverted to retrieve the seismogenic stress using the stress tensor inversion. The combination of the nearby fault trends and the obtained results from hypocentral relocations, focal mechanism solutions, and stress tensor inversion emphasizes that the NE fault trend is likely to be the causative fault resulting in the 2017 Namas earthquake sequence, implying that the local tectonic setting is incompatible with the large-scale regional tectonics of the Red Sea opening. On the contrary, estimates of low-stress drops exhibit typical values compatible with those reported for the shallow plate-boundary earthquakes that occurred in the Red Sea, suggesting that the existing weak zones in the southernmost part of the Arabian Shield may be attributed to the large-scale regional tectonics of the Red Sea opening.
Bisphenol A enhances adipogenic signaling pathways in human mesenchymal stem cells
Authors: Salehpour Amin , Shidfar Farzad , Hedayati Mehdi , Neshatbini Tehrani Asal , Farshad Ali Asghar , Mohammadi Saeed
Published: March 2020

Background

The endocrine disruptor Bisphenol-A (BPA), has been involved in dysregulating adipose tissue development and increasing the risk of obesity. The objective of this experiment was to investigate whether treatment of human mesenchymal stem cells with BPA could modulate adipogenesis and adipocyte differentiation.

Methods

In this experimental study, the human adipose-derived mesenchymal stem cells (hASCs) were cultured for 2 weeks with continuous exposure to 10− 10 M or 10− 8 M concentrations of BPA. The extent of triglyceride accumulation was visualized by Oil Red O staining. To evaluate BPA effect on the expression levels of key adipogenic trascripotion factors and proteins, we used Quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) and ELISA.

Results

The results presented a dose-dependent triglyceride accumulation in treated cells with BPA. Additionally, we observed that BPA induced transcription of the Peroxisome proliferator-activated receptor-gamma (PPARγ), CCAAT-enhancer-binding protein-alpha (C/EBPα), CCAAT-enhancer-binding protein-beta (C/EBPβ), sterol regulatory element-binding protein-1c (SREBP1c), Fatty acid synthase (FASN), and lipoprotein lipase (LPL); BPA suppressed the expression of Fatty acid binding protein-4 (FABP4) and Estrogen receptor-beta (ERβ).

Conclusions

Our findings supported the hypothesis that BPA enhances adipogenic differentiation thereby may play a role in development of obesity and dysregulation of metabolic homoeostasis.
Evaluation of heritability of β-eudesmol/hinesol content ratio in Atractylodes lancea De Candolle
Authors: Tsusaka Takahiro , Makino Bunsho , Ohsawa Ryo , Ezura Hiroshi
Published: March 2020

Background

Atractylodes lancea De Candolle is a medicinal plant distributed in East Asia. Its rhizome has been used as an important crude drug in traditional Chinese and Japanese medicines for the treatment of numerous diseases and disorders. In recent years, the demand for mass production of the crude drug with a stable quality has increased. Its major active compounds are sesquiterpenoids, such as β-eudesmol and hinesol that have closely related chemical structures with each other. As the criteria for evaluating the quality of A. lancea, the β-eudesmol/hinesol content ratio is considered important. In A. lancea, the ratio could be considered to be influenced by genetic factors, geographical environment factors and these interactions. Few studies of a detail genetic analyses for β-eudesmol/hinesol content ratio have been reported. Therefore, we evaluated the heritability and genotype–environment interaction on the β-eudesmol/hinesol content ratio in A. lancea using clonal lines propagated with division of rhizome.

Results

The heritability of the β-eudesmol/hinesol content ratio in A. lancea was evaluated through the cultivation of clonal lines of A. lancea in both different years (2016, 2017) and locations (Hokkaido, Ibaraki). Correlations between β-eudesmol and hinesol contents were identified in all clonal lines, with high correlation coefficients (r = 0.73–0.99). The broad-sense heritability of the β-eudesmol/hinesol content ratio was revealed to be high at 0.92. The effects of cultivation year were smaller than that of genotype, and few genotype–environment interactions were observed. In addition, the influence of cultivation location was also smaller than that of genotype, and the correlation between the two cultivation locations on the β-eudesmol/hinesol content ratio was high. The results suggested that the β-eudesmol/hinesol content ratio in A. lancea is highly dependent on genetic factors.

Conclusion

We demonstrate that the heritability of β-eudesmol/hinesol content ratio is high and that the effects of genetic factors were stronger than that of environmental factors such as cultivation location and year. Our findings suggested that selective breeding and clonal propagation are effective strategies for the production of A. lancea with stable qualities for use in the production of crude drugs.
Thyroid cancer and post thyroidectomy tracheomalacia: algorithm for decoding a diagnostic dilemma!
Authors: Shah Shagun B. , Kulkarni A.
Published: March 2020

Adult tracheomalacia can be caused by long standing goitre or malignant infiltration and has a high morbidity. We anticipated possibility of postoperative tracheomalacia (based on preoperative dynamic cervical sonography and radiographic evidence), in both the cases presented here. A high index of suspicion helped in timely detection of this complication. An algorithm to decode tracheomalacia is constructed here. Elective endotracheal tube (ETT) retention postoperatively, followed by a planned, trial tracheal extubation with gradual ETT withdrawal under bronchoscopic guidance in the OT, several days post-surgery was employed. ETT re-insertion followed by an elective tracheostomy was performed on bronchoscopic confirmation of tracheomalacia.
Randomized phase III study of adjuvant chemotherapy for high-risk, node-negative breast cancer (BC) comparing FAC with FAC followed by weekly paclitaxel: First efficacy analysis of the GEICAM/2003-02 trial.
Authors: Martin Miguel , Lluch Ana , Ruiz Amparo , Ruiz Borrego Manuel , Barnadas Agust , Gonzalez Sonia , Calvo Lourdes , Margeli Vila Mireia , Anton Antonio , Rodriguez-Lescure Alvaro , Seguí-Palmer Miguel Angel , Munoz-Mateu Montserrat , Dorca Ribugent Joan , Lopez-Vega Jose Manuel , Mendiola Fernandez Cesar , Andres Raquel , Plazaola Arrate , Rodriguez Cesar , Casas Maria Isabel , Carrasco Eva Maria ,   Spanish Breast Cancer Research Group GEICAM
Published: March 2020

1001

Background: Adjuvant weekly paclitaxel (wP) sequential to anthracyclines improves the outcome of operable node-positive BC patients (pts) [Sparano NEJM 2008, Martin BCRT 2009]; however, most BC pts are currently node-negative at diagnosis. The role of wP in these pts is not well established yet. Methods: Pts aged 18-70, with T1-T3/N0 operable BC and at least one high-risk St Gallen 1998 criteria (size >2 cm, hormone-receptor [HR] negative, grade 2/3, age <35 years,) were eligible. HER2+ pts were allowed, after 792 entered the trial, the study was amended to exclude them. Pts were stratified by site, menopausal status, nodal status diagnostic method (sentinel-node biopsy versus lymphadenectomy) and HR status and randomized to receive FAC x6 (500/50/500 mg/m2 every 3w) or FAC x4→wP x8 (paclitaxel 100 mg/m2 weekly). The primary endpoint was DFS. The trial was designed to detect an absolute 5-y DFS increase of 5% (80% FAC, 85% FAC→wP); a sample size of 1812 evaluable patients (906 per arm) was required to detect this difference (α=0.05, β= 80%). Assuming a drop-out rate of 6%, 1929 pts were required. The first analysis of DFS was planned when a median follow-up of 5 years was reached. Results: Between September 2003 and October 2008, 1925 pts (FAC 974, FAC→wP 951) were randomized. Patient characteristics were well balanced between arms, median age was 50, 73% of pts were HR positive and 9% HER2 positive. 97% of pts with FAC and 85% of pts with FAC→wP completed all treatment as planned. The median dose intensity was 98% with FACx6, 99% with FACx4 and 98% with wP. The most frequent grade 3-4 toxicities (>3% in either arm) with FAC vs FAC→wP were neutropenia (25% vs 22%) with 4% vs 3% of febrile neutropenia, fatigue (3% vs 8%), sensory neuropathy (0 vs 5%), and vomiting (4% in each arm). After a median follow-up of 5.3 years, the proportion of patients disease free is 93% and 90% with FAC→wP and FAC (HR for relapse 0.732, 95% CI: 0.542 to 0.990; log-rank p-value=0.0423). Conclusions: For pts with high-risk node-negative BC, adjuvant FAC→wP was associated with a small but significant improvement in DFS compared with FAC, with manageable toxicity.
A prognostic nomogram for prediction of recurrence following surgical resection of desmoid tumors.
Authors: Crago Aimee Marie , Denton Brian , Mezhir James J. , Hameed Meera , Gonen Mithat , Singer Samuel , Brennan Murray F.
Published: March 2020

10015

Background: Desmoid tumors can respond to novel chemotherapeutics (e.g., sorafenib). We sought to construct a postoperative nomogram identifying desmoid patients who are at high-risk for local recurrence and potential candidates for systemic therapy. Methods: Desmoid patients undergoing resection from 1982-2011 were identified from a single-institution prospective database. Cox regression analysis was used to create a desmoid-specific recurrence nomogram integrating clinical risk factors. Results: Desmoids were treated surgically in 495 patients (median follow-up 60 months). Of 439 patients undergoing complete gross resection, 100 recurred (92 within 5 years of operation). Five-year recurrence-free survival (RFS) was 71%. Only 8 patients died of disease, all after R2 resection (6 with intraabdominal desmoids). Radiation was associated with worse RFS (p<0.001). Multivariate analysis suggested associations between recurrence and extremity location, young age, and large tumors, but not margin (Table). Abdominal wall tumors had the best outcome (5-year RFS 92% vs. 34% in patients <25y.o. with large, extremity tumors). Age, site and size were used to construct an internally-validated nomogram (concordance index 0.703). Integration of margin, gender, depth, and presentation status (primary vs. recurrent disease) did not improve concordance significantly (0.707). Conclusions: A postoperative nomogram including only size, site and age predicts local recurrence and aids in counseling patients. Systemic therapies may be tested in young patients with large, extremity desmoids, but surgery alone is curative for most abdominal wall lesions. [Table: see text]
Activity of sorafenib in radiation-associated breast angiosarcomas harboring MYC and FLT4 amplifications.
Authors: D'Angelo Sandra P. , Antonescu Cristina R. , Keohan Mary Louise , Carvajal Richard D. , Dickson Mark Andrew , Gounder Mrinal M. , Moraco Nicole H. , Singer Samuel , Schwartz Gary K. , Tap William D.
Published: March 2020

10019

Background: Angiosarcomas (ASs) are rare, aggressive vascular malignancies of endothelial cell differentiation which arise de novo or secondary to radiation therapy (RAS.) A subset of patients(pts) with AS harbor mutations in KDR (VEGFR-2) or overexpression of MYC and/or FLT4(VEGFR-3). MYC & FLT4 gene amplifications occur almost exclusively in RAS. These alterations provide a rationale for investigating agents that target angiogenesis in RAS. In a phase II trial of sorafenib, AS pts had a partial response (PR) of 14%; targeting the appropriate pt population may be essential. We hypothesize that co-amplification of MYC & FLT4 may be predictive of response to sorafenib. Methods: Using our institutional sarcoma database & data query system, we identified AS patients treated with sorafenib at Memorial Sloan-Kettering Cancer Center between 1992-2011. Molecular analysis performed on available tissue. With IRB approval, clinical information was collected. Results: We identified 10 women with RAS that received sorafenib. Average age 68 (range 51-84.) 7 pts had distant metastatic disease. Median lines of systemic therapy prior to sorafenib: 2 (range 1-4.) Sorafenib was first line in 60% of pts, administered at 400mg daily and adjusted for toxicity. Best responses included: complete response (CR) 2/9(22%), PR 1/9(11%), stable disease (SD) 5/9(56%) range 5-23m, progressive disease 1/9(11%) for a clinical benefit rate of (CR+PR+SD) 89%. Responses were seen in patients with lung metastases (n=2) and locally advanced disease (n=1) and were durable for 17, 42 and 26 months. Median duration on therapy was 15 months (range 0-42 months.) 7 pts underwent molecular analysis: co-amplification of MYC & FLT4 3 pts (30%); MYC amplification 4 pts (40%); KDR mutation 0 patients. Of the 3 responders, MYC & FLT4 co-amplification were observed in 2 patients and not evaluated in one. Conclusions: Sorafenib is active against RAS of the breast. In this small series, complete and partial responses were seen in patients with co-amplification of MYC & FLT4. This observation requires further study. Performing molecular studies on all AS pts will help define the pathophysiology of this deadly disease to guide rationale clinical trials.
Phase II study of sorafenib mesylate (So) in patients (pts) with evolutive and advanced epithelioid hemangioendothelioma (EHE) or hemangiopericytoma/solitary fibrous tumor (SFT).
Authors: Chevreau Christine , Le Cesne Axel , Ray-Coquard Isabelle , Bui Nguyen Binh , Bompas Emmanuelle , Isambert Nicolas , Chaigneau Loic , Bay Jacques-Olivier , Collard Olivier , Cottura Ewa , Domont Julien , Blay Jean-Yves , Fournier Charles , Clisant Stephanie , Gauthier Eric , Penel Nicolas ,   French Sarcoma Group (GSF/GETO)
Published: March 2020

10020

Background: There is no standard of care for both rare sarcomas. Regarding, the important vascularization of EHE and SFT, we explored the activity/toxicity of So in pts with these sarcomas. Methods: We conducted a multicenter one-step phase II trial of So (800 mg/d). The primary endpoint was the 9-months progression-free rate (9-PFR). According to EORTC criteria, So is considered as promising drug if 6-PFR≥14%. All pts have had documented progressive disease at entry. Results: 20 pts (15 EHE & 5 SFT) were enrolled from June 2009 to February 2011 in the 8 participating institutions. 12 men and 8 women. Median age was 57. The most common primaries were superficial trunk (8 cases) and liver (4 cases). PS were 0 in 10 cases, 1 in 7 cases and 2 in 3 cases. 16 pts had metastasic disease , especially in lung (15), liver (6) and bone (4). Eight pts received prior chemotherapy (Doxorubicin : n= 8 cases and taxane : n =3). The median So treatment duration was 124 days. 9 pts experienced grade-3 toxicities; the most frequent grade-3 toxic events were hand foot syndrome (5 pts), myalgia (1), stomatitis (1), anorexia (1), diarrhea (1) and arterial hypertension (1).Because of this toxicity, treatment discontinuation was necessary in 6 cases and dose reduction was necessary in 5 pts. The 9-PFR was 6/18 (33.3% [11.5-55.1]). The 2, 4 and 6 PFR were 15/18 (83.3%), 8/18 (44.4%) and 7/18 (38.8) respectively We observed 2 partial responses lasting 2 and 9 months in 2 pts with EHE. Analysis of the predictive value of circulating pre-angiogenetic biomarkers is ongoing. Conclusions: According to the STBSG-EORTC criteria (3-PFR≥40% & 6-PFR≥14%), So is a promising drug for EHE and SFT pts. Further trials is needed, especially a discontinuation randomized trial.
Advanced chondrosarcomas: Role of chemotherapy and survival.
Authors: Bui Nguyen Binh , Cioffi Angela , Piperno-Neumann Sophie , Chaigneau Loic , Bertucci François , Penel Nicolas , Duffaud Florence , Le Cesne Axel , Italiano Antoine
Published: March 2020

10023

Background: There are no data about the role of chemotherapy in patients with advanced chondrosarcomas. Methods: From 2000 to 2011, 98 patients with a confirmed diagnosis of advanced chondrosarcomas were referred to one of the 8 participating institutions, and their medical records reviewed. Results: Median age was 46 years (range 16-82). The most frequent histological subtype was conventional chondrosarcoma (n=60, 61%). 83 patients (85%) had metastatic disease ( lung n=71, bone n=23, liver n=6) and 15 patients (15%) had locoregional unresectable disease. 30 patients (31%) had ≥ 2 metastatic sites. 63 patients (64%) received 1st-line combination agent chemotherapy. 70 patients (71%) received a 1st-line anthracycline-containing regimen (doxorubicin + cisplatin +/- ifosfamide: n=30, doxorubicin or pegylated liposomal doxorubicin: n=18, doxorubicin + ifosfamide +/- dacarbazine: n=16, others= 6). RECIST objective response was observed in 14 patients (14%), all but two treated with anthracyclines. 30 patients (31%) had stable disease > 6 months. Median progression-free survival (PFS) and overall survival (OS) were 5.3 months (95% CI: 2.8-7.7) and 19 months (95% CI: 14-24) respectively. Performance status (PS) ≥ 2 was the sole factor significantly associated with OS. Conclusions: Chemotherapy is associated with a 6-month non-progression rate of about 45% in patients with advanced chondrosarcoma. Best supportive care should be considered in patients with poor PS. These data should be used as a reference for response and outcome in the assessment of investigational drugs in advanced chondrosarcoma.
Phase I study of doxorubicin (D) plus anti-insulin-like growth factor 1 receptor (IGF-1R) antibody cixutumumab (IMC-A12) in advanced soft tissue sarcoma (STS).
Authors: Chugh Rashmi , Griffith Kent A. , Brockstein Bruce , Undevia Samir D. , Stadler Walter Michael , Schuetze Scott ,   University of Chicago Phase II Consortium
Published: March 2020

10028

Background: IGF1R is overexpressed in many STS, but its exact role in the biology of the disease is unclear. Anti-IGF1R antibody cixutumumab (C) has shown acceptable toxicity in a single-agent phase 2 study of STS. Here we performed a dose escalation study of C with D in STS. Methods: Eligible pts had advanced STS, ECOG ≤2, age>16, ≤1 prior chemotherapy, fasting glucose<120 mg/dL and acceptable organ function. C was administered IV over 60 min on D1,8,15 at one of three dose levels and D as a 48 hr infusion on D1 of a 21-day cycle. After 6 cycles of combination rx, pts with SD or better continued on single agent C. The Time-to-Event Continual Reassessment Method (TITE-CRM) was used to estimate the probability of DLT at each dose level and to assign patients to the dose with the estimated probability of DLT closest to but not exceeding 30%. Results: 30 pts with STS were enrolled between 9/08-1/12. Median age was 64 (range 29-80); 17M/13 F, 7 pts received prior chemo. One pt withdrew prior to rx; 5 pts are on active rx. Reasons for discontinuation were: progression (18), toxicity (3), death (1), pt decision (2). DLTs observed were hyperglycemia and mucositis. Grade 3 decrease in cardiac left ventricular ejection fraction was observed in 2 pts at dose level 2 after 4 or more cycles. Common G1/2 nonhematologic AEs: nausea (73%), fatigue (68%), pain (59%), diarrhea (41%), constipation (36%), hyperglycemia (32%), mucositis (32%), nail changes (27%), weight loss (27%). Gr3/4 toxicities in >10%: hyperglycemia (18%), lymphopenia (18%), anemia (14%), neutropenia (14%), thrombocytopenia (14%). Median PFS was 5.3 months, 95% CI 2.7 -7.9 months. Four of 22 pts (18%) evaluable for response achieved a PR. Conclusions: C and D is tolerable and the recommended phase II dosing is dose level 3. The potential of cardiotoxicity should be monitored and assessed further in ongoing studies of this regimen. [Table: see text]
Neoadjuvant treatment of locally advanced GIST: Results of APOLLON, a prospective, open label phase II study in KIT- or PDGFRA-positive tumors.
Authors: Hohenberger Peter , Langer Claus , Wendtner Clemens Martin , Hohenberger Werner , Pustowka Annette , Wardelmann Eva , Andre Elisabeth , Licht Thomas
Published: March 2020

10031

Background: Imatinib may significantly downstage the metastatic GIST. This prospective, phase II, open-label trial of neoadjuvant imatinib evaluated the overall tumor response and progression rate of disease in locally advanced, non-metastic patients. Methods: Inclusion criteria were: KIT (n=39) or PDFRA (n=6) positive GIST, proven by biopsy and IHC. Tumors had to be locally advanced, potentially resectable, M0. Patients received 400 mg of imatinib daily (KIT exon 9 mutations: twice daily) for 6 months, in the absence of disease progression or unacceptable toxicity. At two months 18F-FDG-PET examination was performed to assess response in paralle to CT imaging. Adjuvant treatment postoperatively was not part of the study protocol (CST1571-BDE43, NCT00112632). Median follow-up is 36 months in 39 patients. Results: From 7/2005 to 10/ 2009, 41 patients (16f, 25 m, mean age 54 yrs) were recruited to the trial with an average tumor size of 10.8 cm. One patient died from myocardial infarction 3 weeks after start of treatment, all other patients completed the protocol. In two patients dose reduction/interruption due to toxicity was required. 34/41 patients underwent resection of the tumor after a median of 200 d (range 57-394), while two patients had to be operated early due to disease progression. R0 resections were performed in 30/34 patients, two patients showed M1 disease at resection. Five patients showed developed progression postop., resulting in a PFS rate at 3 years of 85.2%. No patient has died so far from the disease. Conclusions: Neoadjuvant treatment with imatinib for six months is a safe treatment in patients with locally advanced disease. The extent of the operation can be significantly downsized after pretreatment. Despite the fact that no adjuvant treatment was foreseen, the progression-free rate at 3 years postoperatively is promising.
Phase I trial of panobinostat (P) and imatinib (IM) in patients with treatment-refractory gastrointestinal stromal tumors (GIST).
Authors: Bauer Sebastian , Hilger Ralf A. , Grabellus Florian , Nagarajah James , Hoiczyk Mathias , Reichardt Annette , Ahrens Marit , Pink Daniel , Mühlenberg Thomas , Scheulen Max E. , Schuler Martin H. , Reichardt Peter
Published: March 2020

10032^

Background: Panobinostat (LBH589; P) is a pan-deacetylase-inhibitor that has preclinical activity in combination with IM in GIST models in vitro and in vivo. Aim of this study was to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of escalating doses of P in combination with IM in patients with GIST who have failed IM and sunitinib treatment. Methods: This was a two-center phase I study using a 3+3 design with a prespecified expansion of the MTD cohort. IM was administered at a dose of 400mg qd. Following a 7 day run-in phase, escalating doses of P were added. The starting dose for P was 20 mg given as a three-times-per-week (MWF schedule) oral dose for 3 out of 4 weeks. Doses were increased by 10 mg if no dose limiting toxicities emerged. Blood samples were drawn for PK and biomarker assessments of IM, its main metabolite N-desmethyl-IM, and P using a validated RP-HPLC method. Acetylation of histone A3 was evaluated in peripheral blood mononuclear cells (PBMNC) as pharmacodynamic marker for P activity. Metabolic response using PET (EORTC-PET study criteria) was assessed on day 7 of IM run-in and after 3 weeks of combined treatment with IM and P. Results: In total 12 extensively pretreated (median 5 pretreatments) pts (4 f, 8 m; median age 56 y, 34-75 y) received study treatment at 2 dose levels (DL). 2 dose-limiting toxicities (grade 4 thrombocytopenia) occurred at DL 2 (30 mg). Most common AEs were thrombocytopenia, anemia, fatigue, nausea, emesis, diarrhea, creatinine elevation, abdominal cramping, and weight loss. DL 1 (20mg) was declared MTD, and 5 additional pts were enrolled at DL1. Analysis of P and IM PK revealed mean peak concentration of 14.8 +/- 9.5 ng/ml for P (20 mg). IM plasma concentrations with 400 mg once-daily administration were 2.8 ± 1.1 μg/mL at peak and 1.2 ± 0.4 μg/mL at trough. Histone A3 acetylation was demonstrated in PBMNC from pts treated at DL 1. 11 pts were evaluable for PET response: 1 had mPR, 7 had mSD and 3 had mPD. Longest treatment duration was 17 weeks (median: 6wks). Conclusions: P in combination with IM is moderately tolerated. Evidence of target inhibition at the MTD was associated with limited clinical activity in heavily pretreated pts with GIST.
Analysis of a neoadjuvant regimen with a fixed dose of doxorubicin followed by a 10-day course of 27 Gy radiation in the treatment of soft tissue sarcoma (STS) of the extremity/trunk.
Authors: Mathews John , Maale Gerhard , Schwarz Donald E. , Strauss James Fredric , Feldman Mark , Posada Juan G. , Bhat Ashwini
Published: March 2020

10037

Background: Local tumor control and preservation of limb function are major goals of treatment of STS. With current standard of combining limb-sparing surgery and 5-6 weeks of neoadjuvant or adjuvant 50-65 Gy radiation, reducing local recurrence has been a challenge with rates of 15-30%. Eilber et al. (Cancer Treatment Symposia 1985; 3:49-57) used a fixed daily dose of doxorubicin for three days with radiation of 35Gy. This yielded a 5% local recurrence, while wound complication rate was 35 %. We reduced the radiation dose to lower the wound complications rate. We report a cohort of patients treated in this manner at our institution. Methods: After a baseline echocardiogram, patients received a radiosensitizing dose of intravenous doxorubicin (30mg/day) for 3 consecutive days, then radiation with 2.7 Gy in 10 fractions, followed by limb sparing surgery. After IRB approval, we retrospectively analyzed records of 191 patients during the treatment period from 1991 to 2010. Data extracted included local tumor recurrences and wound complications defined as non-healed wound at 1 month, number of limb salvage surgeries and involvement of surgical margins. Results: Of the 191 patients, median age was 53 (range, 13-89). Stages at presentation included I, II, III and IV, with 2%, 33%, 61%, 4% respectively. The median follow up was 5 years. Of the 24 types of sarcomas treated, pleomorphic sarcoma was the most common at 21%. The local recurrence rate was 5% (95% CI, 2.7-8.6%) and local wound complications were 21% (95% CI, 15-28%). Most (172 or 90%) of patients were able to undergo limb salvage surgery while 19 (10%) required amputation. Of the 172 patients that had limb salvage, 97% (95% CI, 93-98%) had wide surgical margins, three had < 2 cm margins and two had involved margins. Conclusions: To our knowledge, this is the largest study showing that this short two week course of chemoradiation is effective in achieving high rate of local control, acceptable wound complication rate, wide surgical margins and limb salvage in the treatment of STS. Randomized trials are warranted to confirm results.
Early response to neoadjuvant chemotherapy (NAC) in combination with regional hyperthermia (RHT) to predict long-term survival for adult-type high-risk soft tissue sarcoma (HR-STS): Results of the EORTC-ESHO intergroup phase III study.
Authors: Issels Rolf D. , Kampmann Eric , Lindner Lars , Dieterle Nelli , Mansmann Ulrich Robert , Verweij Jaap , Kirchner Thomas , Wendtner Clemens Martin , Wessalowski Ruediger
Published: March 2020

10054

Background: A randomized phase III completed trial showed that RHT added to NAC was beneficial in terms of local progression-free (LPFS), and disease-free (DFS) survival. Overall survival (OS) was improved in patients (pts) who completed the preoperative induction therapy with RHT (Lancet Oncol 2010). Here we analyzed both the radiographic (RR) and histopathologic (HR) response as early predictors for survival. Methods: 341 pts were randomized to receive 4 cycles of NAC + RHT (169 pts) or NAC alone (172 pts) as induction therapy. RR (CR/PR vs NC/PD) and HR (>75% vs <75% necrosis) were used to define responder vs non-responder. Predictive impact of response on LPFS, DFS, DDFS (distant disease-free survival) and OS was evaluated by intention-to-treat using Kaplan-Meier estimates and the log-rank test. Stratified (surgery before study entry yes/no; extremity vs non-extremity tumors) multivariate analyses were carried out by Cox regression. Results: Early response in pts with measurable disease was performed in 238 pts (103 pts not evaluable because of surgery before study entry). In the NAC+RHT group (114 pts) response rate was 49.1% (56 responders: RR: 18; HR: 22; RR + HR: 16) and substantially higher (p<0.001) compared to the NAC alone group (124 pts) which was 26,6% (33 responders: RR: 7; HR: 17; RR + HR: 9). In the NAC + RHT group, tumor response was associated with improved DFS (HR 0.58 CI 0.36-0.95; p=0.031) and OS (HR 0.50 CI 0.27-0.90; p=0.020) but not LPFS (HR 0.91 CI 0.49-1.71; p=0.78). For responders, OS median time was > 120 months vs 33 months for non-responders. For the entire NAC + RHT group (169 pts, including pts with surgery before study entry) response remained predictive for better OS (HR 0.54 CI 0.32-0.94; p=0.028) and was also associated with better DDFS (HR 0.47 CI 0.27-0.83; p=0.009). Conclusions: Adding RHT to NAC as induction therapy compared to NAC alone leads to significantly higher early response in almost half of the pts classified as responders which translates in better OS and prevention of distant metastases.
Targeting the androgen receptor (AR) in women with AR+ ER-/PR- metastatic breast cancer (MBC).
Authors: Gucalp Ayca , Tolaney Sara M. , Isakoff Steven J. , Ingle James N. , Liu Minetta C. , Carey Lisa A. , Blackwell Kimberly L. , Rugo Hope S. , Nabell Lisle , Forero-Torres Andres , Stearns Vered , Momen Lamia , Gonzalez Joseph , Giri Dilip D. , Patil Sujata , Feigin Kimberly , Hudis Clifford , Traina Tiffany A. ,   Translational Breast Cancer Research Consortium (TBCRC)
Published: March 2020

1006

Background: Patients (pts) with ER-/PR- MBC do not benefit from endocrine treatment (tx). Doane et al (Oncogene 2006;25:3994) described a subset of ER-/PR- BC with a gene expression profile similar to ER+ BC but characterized by AR expression and AR-dependent growth in vitro. Hence, we conducted a multicenter phase II trial (NCT00468715) of the AR antagonist, bicalutamide (B) for pts with AR+ ER-/PR- MBC. Methods: Pts with ER-/PR- (IHC <10%) MBC were consented to AR testing, confirmed centrally at MSKCC. If AR+ (DAKO IHC ≥10%), pts were eligible for tx if ECOG performance status (PS) <2 and normal organ function. No limit on prior tx except prior trastuzumab required if HER2+. Eligible AR+ pts who consented to tx received B 150mg orally daily in 28-day cycles (C). Toxicity assessed q4wks, response q12wks. Primary endpoint = clinical benefit rate (CBR): CR + PR + stable disease (ds) >6mo (SD). B would be considered worthy of further study if ≥4/28 pts have clinical benefit. Results: As of 12/21/11,436 pts consented for AR testing. 24 were ineligible, 12 await testing. 47/400 tested were AR+ (12%). 26 received tx with B (6 ineligible for tx, 15 are eligible for tx with B at progression (POD) if clinically appropriate and study slots remains). Two AR+ pts treated with B were ER+ and removed from study. Three have received tx <12wks. Treated pt characteristics (n=24): median(med)age 64 (41-83), PS 0 (0-1), HER2+ 1, visceral metastases 17. Prior chemotherapy: neo/adjuvant 16; med # regimens for MBC 1 (0-8). Med C# 3 (2-49+). Best response: (21 evaluable pts): CBR 19% (95% CI 5-42%), SD>6mo 4, CR/PR 0, SD<6mo 3, POD 14. Conclusions: ~12% of ER-/PR- MBC pts are AR+. For these pts, AR-inhibition with B is feasible, well tolerated, and has activity based on pre-specified criteria. This study has closed to accrual for AR testing as of 1/2012. These results of the primary endpoint are not expected to change by accrual of the 2 remaining pts. Supported by TBCRC/Breast Cancer Alliance/AstraZeneca. [Table: see text]
Global differences in chemotherapeutic regimens of soft tissue sarcoma (STS): Results of PALETTE, an EORTC 62072/GSK VEG110727 global network phase III trial of pazopanib versus placebo.
Authors: Marreaud Sandrine , Graaf Winette T.A. Van der , Blay Jean-Yves , Chawla Sant P. , Lee Jeeyun , Bui Nguyen Binh , Casali Paolo Giovanni , Aglietta Massimo , Staddon Arthur P. , Beppu Yasuo , Le Cesne Axel , Gelderblom Hans , Judson Ian Robert , Araki Nobuhito , Ouali Monia , Dewji Mohamedraza , Powell Alex , Demetri George D. , Hohenberger Peter
Published: March 2020

10067

Background: The global PALETTE EORTC/GSK network study on advanced STS patients (pts) randomized 223 European (EU), 43 American (US), 81 Asian, and 22 Australasian (AUS) pts between pazopanib and placebo. Prior to study entry pts should have received at least one anthracycline containing regimen, and preferably, if pts’condition allowed, all available standard chemotherapy treatments for STS in their countries. We investigated the differences in chemotherapy pts received prior- and post-protocol at a global level. Methods: Pts were grouped by continent. Pre- and post-protocol chemotherapeutic treatments (txs) were analyzed. The number of prior lines of systemic tx for advanced STS was divided between 0-1 vs 2 or more. Chemotherapy was studied in detail between Asian and other countries. Fisher’s exact test was used for statistical analysis. Results: Data from all 369 pts were analyzed. (Neo-) adjuvant systemic tx was given in 21% of EU, 23% of US, 36 % of Asian and 41% of AUS pts. In advanced STS: 2 or more lines of prior systemic txs were administered in 60% of EU, 84% of US, 42% of Asian, 22% of AUS pts before study entry. Prior to study entry 68% of EU, 65% of US, 84% of Asian and 68% of AUS pts received ifosfamide(or analogs); after protocol 21 % of EU, 14% of US, 13% of Asian and 5% of AU pts. There were significant differences in chemotherapy between Asian (n=81) and other (n=288) pts: prior to protocol trabectedin was administered in 1 vs 21%; gemcitabine 19 vs 39 %; cisplatin: 36 vs 5%; etoposide 32 vs 4% (all p<0.001), and docetaxel: 17 vs 31 % (p=0.004) of pts. Post-protocol trabectedin was given to 4 vs 34% (p<0.001), gemcitabine both in 19%; cisplatin 10 vs 4% (p=0.01); etoposide 12 vs 6%, and docetaxel 20 vs 12 % (both, p=0.02) of pts. Conclusions: The PALETTE study showed considerable intercontinental differences in chemotherapeutic txs for advanced STS pre- and post study drug. These differences might be due to availability and reimbursement of drugs, clinical studies and the practice patterns of sarcoma specialists world-wide. This is of particular interest for the design of future randomised global clinical trials in advanced STS.
Multimodality therapy for pulmonary metastasis in sarcoma patients: Results of a single institution.
Authors: Vohra Nasreen A. , Tejiram Shawn , Chai Christy Yoon-Hee , Conley Anthony Paul , Reed Damon R. , Toloza Eric M. , Fontaine Jacques , Bui Marilyn M , Cheong David , Letson Douglas D , Kim Jongphil , Gonzalez Ricardo Jorge
Published: March 2020

10070

Background: Pulmonary metastasectomy (PM) for sarcoma can result in significant long term survival in carefully selected patients (pts). We report our experience with pulmonary metastasectomy. Methods: After IRB approval, 120 pts who underwent PM for sarcoma at Moffitt Cancer Center from 1999 to 2011 were reviewed. Survival was calculated according to the Kaplan-Meier method with Cox proportional hazard univariate (UV) and multivariate (MV) models used to analyze relationships between clinicopathologic variables and overall survival (OS). P-value < 0.05 was considered significant. Results: Median age was 51 yrs, 95(79%) pts had soft tissue sarcomas with pleomorphic being most common. Of the 25(21%) osseous sarcomas, osteosarcoma was most common. 20(15%) had synchronous metastasis (mets); of the pts with local disease only, median time to recurrence from primary resection was 13 months (mo). OS from initial resection was 55 mo for pts with local disease only vs. 27 mo for pts with synchronous mets. On UV analysis, use of radiation, number of index lesions, presence of synchronous mets and time to recurrence achieved significance. On MV analysis, only shorter time to recurrence (p=.03) and presence of synchronous mets (p=.04) were independent predictors of poor survival. 63(52%) pts [26(22%) neoadjuvant, 19(16%) adjuvant, 18(15%) both] received chemotherapy for the primary tumor, while 57(48%) did not. There was a trend towards poor survival in pts receiving chemotherapy compared to pts receiving no chemotherapy (p=0.06, HR 1.59). In addition 40(34%) pts received chemotherapy prior to PM with no difference in OS compared to pts who did not get chemotherapy (p=0.1, HR 1.55). 71(59%) had 1 PM, 32(27%) had 2 and 17(14%) had 3 or more PM with OS being 17 mo, 37 mo and 34 mo in each group, respectively. A higher number of PM was associated with improved survival (p=.01). Conclusions: Pts with a shorter disease free interval have a decreased OS as do pts with synchronous mets. Pts undergoing multiple PM have a survival benefit likely resulting from favorable disease biology. Failure of chemotherapy to show a survival benefit may be a result of selection bias for patients with aggressive disease being treated with chemotherapy.
Study of the expression of integrin pathway's proteins as predictive markers of response to neoadjuvant chemotherapy in pretreatment biopsies of patients with high-grade osteosarcoma.
Authors: Cohen-Jonathan Moyal Elizabeth Laurence , Le Guellec Sophie , Filleron Thomas , Delisle Marie-Bernadette , Chevreau Christine , Rubie Herve , Castex Marie Pierre , Roche Henri Hubert , Sales De Gauzy Jerome , Bonneviale Paul , Brouchet Anne
Published: March 2020

10076

Background: Up to now, chemosensitivity to neoadjuvant chemotherapy performed for patients with osteosarcoma is evaluated on the surgical resection by the evaluation of the percentage of necrotic cells. No predictive profile of chemotherapy has been described yet. Because we have previously shown that integrin pathway controls genotoxic-induced cell death and hypoxia via ILK, FAK and RhoB, we hypothesized that the expression of the proteins involved in this pathway in pre-treatment biopsies could be associated with sensitivity to chemotherapy in osteosarcoma. Methods: We studied by immunohistochemistry β1, β3, β5, integrins, ILK, FAK, GSK-3β, RhoB and Ang-2 expression in 36 osteosarcomas biopsies of patients obtained before treatment. All the patients were treated by the SFOP OS94 chemotherapy protocol and underwent wide conservative surgery. Response to preoperative chemotherapy was assessed on the surgical resection by the Rosen’s protocol. An immunoreactive score (IRS) was assessed, combining the percentage of positive tumour cells and staining intensity. We evaluated the correlation of the selected markers expression with response to preoperative chemotherapy and clinical outcome. Results: FAK expression was statistically linked with ILK expression (rho=0.43; p=0.020), β1integrin expression with FAK expression (rho=0.51); p=0.003), RhoB with ILK expression (rho=0.55; p=0.002), and β1 with β3integrin expression (rho=0.70; p<.001), suggesting that a regulation of the integrin pathway that we studied might exist in high grade osteosarcoma. Moreover, the combination of β5 integrin, FAK and GSK-3β discriminated good and poor responder to chemotherapy (89.9%; 95% CI= [77.4;1.00], yielding a sensitivity of 94.1%, a specificity of 85.7% and a diagnostic accuracy of 90.3%. Conclusions: We report for the first time a protein expression profile on pre-treatment biopsies associating β5 integrin FAK and GSK-3β related with a poor response to neoadjuvant chemotherapy. This profile could help to select patients for clinical trials using inhibitors of this pathway in association with chemotherapy.
Primary localized gastrointestinal stromal tumors (GIST) of the duodenum: Final results of a French Sarcoma Group (FSG) retrospective review of 110 patients (pts).
Authors: Huynh Thanh Khoa , Cassier Philippe A , Bachet Jean Baptiste , Boucher Eveline , Bouche Olivier , Le Cesne Axel , Landi Bruno , Mancini Julien , Marchal Frederic , Bay Jacques-Olivier , Bertucci François , Spano Jean-Philippe , Italiano Antoine , Collard Olivier , Chaigneau Loic , Isambert Nicolas , Lebrun-Ly Valerie , Blay Jean-Yves , Duffaud Florence ,   French Sarcoma Group
Published: March 2020

10078

Background: Duodenal GISTs represent 3-5% of all GISTs with limited understanding of patient outcomes from small series. We conducted a retrospective analysis of primary localized duodenal GISTs over the past 18 years. Methods: Pts were identified in two ways: a group of 101 pts reported via survey from 20 FSG centers, and a group of 9 pts enrolled in the BFR14 trial. Results: Pts were:55 females, 55 males, with a median age of 57 years (30-84), and median ECOG 0 (0-3). Abdominal pain, anemia, and GI bleeding were the most common symptoms. Tumors (T) originated mainly in D2 (41%), or D3 (27%), with a median size of 5 cm (1.5-30). All pts except four had resection of the primary T. Surgical procedures were: local resection (LR) [segmental duodenectomy (n=31), wedge local resection (n=31), local excision (n=6)], and duodenopancreatectomy (DP, n=20). Resections were R0 in 84 pts (79%), R1 in 6 pts (6%). T characteristics included: KIT+ (n=100), CD34 + (n= 54), mitoses/50 HPF ≤ 5 (n= 70), or > 5 (n=24), Miettinen low-risk (n=37), and high-risk (n=19), necrosis (n=29), spindle cell (n=84). Genotype was evaluated in 36 cases: KIT exon 11 mutant (n=30), no mutation (n=4), and KIT exon 9 mutant (n=2). 12 pts received neoadjuvant imatinib (IM) therapy resulting in 6 PR, 3 SD, 1 PD. 17 pts received adjuvant IM therapy. With a median FU of 32 months (1-250), 95 pts (86%) are alive. Twenty-eight (26%) pts relapsed: 6 LR, and 26 metastases. The 4-year OS and EFS rates were 89.5% and 68.2 %. The 6-year OS and EFS rates were 89.5% and 36.5%. Univariate analysis showed that: age and ECOG PS have an impact on OS (p= 0.008, p <0.001), necrosis, spindle-cell type, T size, mitoses/50 HPF, and Miettinen risk were predictive of relapse (p< 0.001). In multivariate analysis tumor size and mitoses/ 50 HPF only were predictive of relapse (p< 0.001). Conclusions: Pts with resected duodenal GIST have a reasonably favourable prognosis. LR rather than DP should be pursued if possible to preserve optimal pancreas function. Neoadjuvant IM may potentially allow a proportion of patients requiring DP to undergo LR. Adjuvant IM should be systematically discussed with a patient based on the individual-risk of recurrence.
Activity of MK1775, a selective Wee1 inhibitor, alone or in combination with gemcitabine, in sarcomas.
Authors: Kreahling Jenny , Reed Damon R. , Foroutan Parastou , Martinez Gary , Gillies Robert , Altiok Soner
Published: March 2020

10084

Background: Sarcomas consist of more than 50 subtypes of mesenchymal tumors. Doxorubicin alone or in combination has been the primary therapy for treatment of sarcomas; however, the response rates are suboptimal in many of the more common adult subtypes of soft tissue sarcoma. Accordingly, new agents are needed for the treatment of this heterogeneous group of diseases. Wee1 is a critical component of the G2/M cell cycle checkpoint control and mediates cell cycle arrest by regulating the phosphorylation of CDC2. Methods: MK1775 treatment of multiple sarcoma preclinical models at clinically relevant concentrations leads to unscheduled entry into mitosis and initiation of apoptotic cell death. In our current study we have investigated the therapeutic efficacy of MK1775 in sarcoma cell lines, patient-derived tumor explants ex vivo and in vivo in a xenograft model of osteosarcoma both alone and in combination with gemcitabine. Results: In patient-derived bone and soft tissue sarcoma samples ex vivo treatments show MK1775 in combination with gemcitabine causes significant apoptotic cell death suggesting that this treatment may represent a novel approach in the treatment of sarcomas. The cytotoxic effect of Wee1 inhibition on sarcoma cells appears to be independent of p53 mutational status. Furthermore, in a patient-derived osteosarcoma xenograft mouse model we show the therapeutic efficacy of MK1775 in vivo by utilizing magnetic resonance imaging (MRI) and diffusion MRI methods. Our data shows MK1775 in combination with gemcitabine dramatically slows tumor growth, increases apoptotic cell death and increases CDC2 activity. Cell viability, a clinically established prognostic indicator of survival, was lowest with the combination and very low in animals treated with MK1775 alone. This was mainly due to increased mineralization of the tumors. Caspase-3 was increased in MK1775 treated animals by immunohistochemistry as well. Conclusions: These results together with the promising safety profile of MK1775 strongly suggest that this drug can be used as a potential therapeutic agent alone or in combination with gemcitabine in the treatment of both adult as well as pediatric sarcoma patients.
SDHA and SDHB mutations in KIT/PDGFRA WT gastrointestinal stromal tumors.
Authors: Nannini Margherita , Pantaleo Maria A. , Astolfi Annalisa , Urbini Milena , Formica Serena , Indio Valentina , Gnocchi Chiara , Saponara Maristella , Lolli Cristian , Pallotti Maria Caterina , Mandrioli Anna , Gatto Lidia , Maleddu Alessandra , Casadio Rita , Biasco Guido
Published: March 2020

10087

Background: KIT/PDGFRA wild-type (WT) GISTs harbour mutations on SDHB and SDHC and, more recently, we described mutations on SDHA using massively parallel sequencing approach. We sequenced SDHA and SDHB genes in a larger series in order to validate the data. Methods: SDHA gene (1-15 exons) and SDHB gene (1-8 exons) (even not all exons in all samples) were sequenced on tumor (T) and/or peripheral blood (PB) of WT GIST patients by Sanger Sequencing method. DNA was extracted from tumor specimens by the QIAmp DNA Mini kit (Qiagen, Milan, Italy) and amplified with specific primer pairs designed to amplify exons but not SDHA pseudo-genes located on chromosomes 3 and 5. Then, PCR products were purified with the Qiaquick PCR purification kit (Qiagen, Milan, Italy) and sequenced on both strands using the Big Dye Terminator v1.1 Cycle Sequencing kit (Applied Biosystems). Sanger sequencing was performed on ABI 3730 Genetic Analyzer (Applied Biosystems). Results: SDHA gene exons were sequenced on a total of 27 WT GIST patients, in particular on T, PB and both from 12, 6 and 9 patients respectively. SDHB gene exons were sequenced on a total of 18 out of 27 patients, in particular on T, PB and both from 7, 8 and 3 patients respectively. 8 SDHA mutations were found in 5 samples (18.5%). Besides those previously identified, 5 new SDHA mutations were found in other 3 samples: one sample harboured R171C and R589Q heterozygous missense mutation in exons 5 and 13 respectively. The other one harboured G419R and E564K heterozygous missense mutations in exons 9 and 13 respectively. The third sample harboured a delCAG immediately upstream of exon 5, in heterozygosis on PB and in homozygosis on T. A SDHB heterozygous mutation (301delT) in exon 4 was found on 1 PB sample. Conclusions: the presence of SDHA mutations has been confirmed in a subgroup of WT GIST patients. All subunits of SDH complex should be sequenced on WT GIST patients in order to explore the frequency and any linkage between each other and the pathogenetic and clinical significance.