bluuebunny/crossref_metadata_2025 huggingface dataset:
Field-testing of a rapid survey method to assess the prevalence and causes of hearing loss in Gao’an, Jiangxi province, China
Authors: Bright Tess , Shan Xin , Xu Jinling , Liang Jianguo , Xiao Baixiang , Ensink Robbert , Mactaggart Islay , Polack Sarah , Yip Jennifer L. Y.
Published: March 2020

Background

The Rapid Assessment of Hearing Loss (RAHL) survey protocol aims to measure the prevalence and causes of hearing loss in a low cost and rapid manner, to inform planning of ear and hearing services. This paper reports on the first field-test of the RAHL in Gao’an County, Jiangxi Province, China. This study aimed to 1) To report on the feasibility of RAHL; 2) report on the estimated prevalence and causes of hearing loss in Gao’an.

Methods

A cross-sectional population-based survey was conducted in September–October 2018. Forty-seven clusters in Gao’an County were selected using probability-proportionate-to-size sampling. Within clusters, compact segment sampling was conducted to select 30 people aged 50+. A questionnaire was completed covering sociodemographics, hearing health, and risk factors. Automated pure-tone audiometry was completed for all participants, using smartphone-based audiometry (hearTest), at 0.5, 1, 2, 4 kHz (kHz). All participants had their ears examined by an Ear Nose and Throat (ENT) doctor, using otoscopy, and probable causes of hearing loss assigned. Prevalence estimates were age and sex standardised to the Jiangxi population. Feasibility of a cluster size of 30 was examined by assessing the response rate, and the proportion of clusters completed in 1 day.

Results

1344 of 1421 eligible participants completed the survey (94.6%). 100% of clusters were completed in 1 day. The survey was completed in 4.5 weeks. The prevalence of moderate or greater hearing loss (pure-tone average of 0.5, 1, 2, 4 kHz of > = 41dBHL in the better ear) was 16.3% (95% CI = 14.3, 18.5) and for any level of hearing loss (pure-tone average of > = 26dBHL in the better ear) the prevalence was 53.2% (95% CI = 49.2, 57.1). The majority of hearing loss was due to acquired sensorineural causes (91.7% left; 92.1% right). Overall 54.0% of the population aged 50+ (108,000 people) are in need of diagnostic audiology services, 3.4% were in need of wax removal (7000 people), and 4.8% were in need of surgical services (9500 people). Hearing aid coverage was 0.4%.

Conclusion

The RAHL survey protocol is feasible, demonstrated through the number of people examined per day, and the high response rate. The survey was completed in a much shorter period than previous all-age surveys in China. Some remaining challenges included assignment of causes of probable sensorineural loss. The data obtained from this survey can be used to scale-up hearing services in Gao’an.
Assessment of wheat’s water footprint and virtual water trade: a case study for Turkey
Authors: Muratoglu Abdullah
Published: March 2020

Background

Many countries are experiencing significant water scarcity and related problems due to limited availability, uneven distribution of water resources and high demand. Therefore, increasing water use efficiency and better management of existing resources have become substantially important. The agricultural sector is responsible for around 80% of global freshwater withdrawal. Wheat is one of the most important crops having large volumes of virtual water (VW) which is defined as the hidden water embedded in the products.

Methods

Water footprint (WF) is an indicator showing the total volume of freshwater consumption of a product or process. Blue water concept is defined as the amount of exploited surface and groundwater resources. Green water represents the total volume of rainwater allocated by the product. WF methodology brings a new approach to inter-regional water use and management by quantifying the amount of direct and indirect water use and tracing the hidden links between production, consumption and trade. The main objective of this study is to analyze Turkey’s national blue and green WF of wheat production, consumption and virtual water trade between 2008 and 2019. Detailed province-based quantification of wheat’s water exploitation is provided using spatial interpolation method.

Results

Total consumptive WF of wheat production and consumption of Turkey is calculated as 39.3 and 48.1 Gm3/year, respectively. The average blue and green VW contents of wheat production through Turkey are assessed to be 1161 and 748 m3/ton, respectively. The water footprint parameters of each province are calculated and discussed using climatic and agricultural data. VW transfer of Turkey’s international wheat trade is also analyzed. Total national water saving is calculated as 7.8 Gm3/year which is mostly imported from Russia. Global VW deficit due to international wheat trade is calculated to be 1.76 Gm3/year.

Conclusion

Despite its high contribution to global wheat production, increasing population and strong wheat-based diet, quantitative, comparative and up-to-date analyses of the blue and green WF and the VW transfer of wheat production in Turkey are not available. This study contributes to the national and international water management and planning studies to increase the water allocation efficiency of agricultural products.
Diamine oxidase-modified screen-printed electrode for the redox-mediated determination of histamine
Authors: Torre Ricarda , Costa-Rama Estefanía , Nouws Henri P. A. , Delerue-Matos Cristina
Published: March 2020

Histamine is an important biogenic amine because of its role in immune responses and the regulation of physiological functions. It is also used as a food freshness indicator, so its maximum concentration in fish is legally regulated. Although several robust and sensitive methods for histamine detection are already available, it continues to be a challenge to develop simple and portable devices that allow rapid histamine screening at any point of the fish production chain. Thus, in this work, a simple, miniaturized and low-cost sensor for histamine analysis was developed. The construction of the sensor only takes 30 min and consists of the immobilization of the enzyme diamine oxidase on the surface of a screen-printed carbon electrode by cross-linking. The quantification of histamine was achieved by chronoamperometry (+ 0.2V, 120 s) using hexacyanoferrate (III) as a redox mediator. This selective sensor provided a low limit of detection (0.97 mg L−1) and accurate and precise results and was successfully applied to the analysis of spiked tuna and mackerel extracts, obtaining recovery values of 99–100%. Moreover, the sensor shows good stability, maintaining 87.7% of its initial signal after 35 days.
Mutations of KIT tyrosine kinase (TK) gene predict relapse in adult patients (pts) with core binding factor acute myeloid leukemia (CBF AML): A Cancer and Leukemia Group B (CALGB) study
Authors: Paschka P. , Marcucci G. , Ruppert A. S. , Mrózek K. , Chen H. , Kittles R. A. , Vukosavljevic T. , Perrotti D. , Larson R. A. , Bloomfield C. D.
Published: March 2020

2

Background: Multi-course high-dose cytarabine (HDAC) has largely improved the outcome of CBF AML pts with t(8;21)(q22;q22) and inv(16)(p13q22). Yet, ∼50% of pts relapse within 5 years (yrs), indicating the need for markers identifying high-risk pts who require more aggressive and/or novel therapies. KIT mutations (mKIT) of exons 17 (mKIT17) and 8 (mKIT8) are good candidates to be such markers. Previous studies showed that mKIT17 impacted adversely on outcome of t(8;21), but not inv(16), pts. Methods: Sixty-one pts with inv(16) and 49 with t(8;21), assigned to HDAC consolidation on CALGB protocols,were analyzed at diagnosis for mKIT17 and mKIT8 by denaturing high-performance liquid chromatography and direct sequencing. The median follow-up was 5.3 yrs. Results: Among pts with inv(16), 10 had mKIT17 (3 with concurrent mKIT8) and 8 sole mKIT8; among pts with t(8;21), 9 had mKIT17 (2 with mKIT8) and 2 sole mKIT8. In each cytogenetic group, complete remission rates were similar for pts with wild-type KIT (wtKIT) and those with mKIT or mKIT17. In both groups, cumulative incidence of relapse (CIR) was higher for pts with any mKIT [inv(16), P=.050, 5-yr CIR 56% vs 29%; t(8;21), P=.017, 5-yr CIR 70% vs 36%], and also for the subsets of pts with mKIT17 [inv(16), P=.002, 5-yr CIR 80% vs 29%; t(8;21), P=.014, 5-yr CIR 75% vs 36%] compared to wtKIT. Neither mKIT nor mKIT17 significantly affected overall survival (OS). In multivariable analyses (see table ), mKIT [in t(8;21)] and mKIT17 [in inv(16) and t(8;21)] independently predicted worse CIR; worse OS correlated significantly with mKIT only in inv(16) pts. Conclusions: We show for the first time that mKIT17 confer significantly higher relapse rates in inv(16) pts and confirm their adverse impact on t(8;21) pts. Thus, this subset of pts may benefit from more aggressive treatment and/or, since mKIT17 lead to constitutive KIT activation, from therapy that includes TK inhibitors, such as imatinib or PKC412.

[Table: see text]

No significant financial relationships to disclose.
Prognostic factors for patients with Ewing sarcoma (EWS) at first recurrence
Authors: Leavey P. , Mascarenhas L. , Marina N. , Chen Z. , Krailo M. , Miser J. , Bernstein M. , Granowetter L. , Grier H.
Published: March 2020

10011

Background: The prognosis for patients with recurrent Ewing sarcoma (EWS) is very poor with 5-year survival of 13%. Since 30–40% of patients with newly diagnosed, non-metastatic EWS develop recurrence, the Children's Oncology Group (COG) sought to evaluate prognostic factors for these patients. Data was derived from the phase III, multi-institutional study INT 0091. Methods: Between 1988 and 1994, five hundred and seventy-eight eligible patients with previously untreated EWS or PNET of bone were enrolled on INT 0091. Patients who experienced recurrence or disease progression as their first analytic event were considered. Survival was calculated from date of disease progression to death or last patient contact. Comparisons of the risk for death across groups were accomplished using the log-rank test. Survivor functions were estimated by the method of Kaplan and Meier. Results: Two hundred and sixty-two patients experienced disease progression or recurrence. The median time to first recurrence was 1.3 years (range 0–7.4 years) for all patients, 1.4 years (range 0 to 7.4 years) for patients with initially localized disease and 1 year (range 0 to 6 years) for patients with initially metastatic disease. Time to first recurrence from date of initial diagnosis was a predictor of post-recurrence survival (p<0.0001). Twenty-one percent of patients whose disease recurred or progressed experienced first recurrence 2 or more years from initial diagnosis and had an estimated 5 year post-recurrence survival of 30%. This compares with 7% for those whose first recurrence or progression was earlier. No statistical difference was detected when patients whose disease recurred < 12 months were compared with those whose recurrence was 12–24 months from initial diagnosis. Significant risk factors for death after recurrence included metastatic disease at initial diagnosis, elevated LDH at initial diagnosis and female gender. In patients non-metastatic at initial diagnosis pelvic primary site was also a risk factor for death after recurrence. Conclusions: Patients with longer time to first recurrence represent the subset of patients most likely to survive following recurrence. All patients with recurrent Ewing sarcoma would benefit from collaborative trials to investigate new therapeutic options.

No significant financial relationships to disclose.
Risks of recurrence and survival after relapse in patients with Ewing tumor
Authors: Jürgens H. , Ranft A. , Dirksen U. , Vieth V. , Paulussen M. , Franzius C. , Bölling T. , Craft A.
Published: March 2020

10012

Background: Ewing tumor treatment has resulted in long term survival rates of approx. 70% in localized, and 30% in metastatic disease. Survival following relapse has remained poor with survival rates well below 30%. Methods: All histological proven Ewing tumor patients from three consecutive GPOH trials since 1981 (CESS81 & CESS86 & EICESS92; N=1,549) were included to conduct a meta-analyses of time to and type of recurrence. The follow up has been recently updated in 2006 resulting in a maximum observation period of 25 years. The cumulative incidences of the types of first relapse excluding progress under therapy were computed with competing risk analysis. Multivariate stepwise regression analyses according to the Cox proportional hazard model researched the influences of time to and type of relapse on survival after relapse. Results: More than 70% of first recurrences occurred within 2 years, and 85% within 3 years from initial diagnosis. Most common relapses were systemic with a 3-year cumulative incidence of approx. 0.10 each for lung metastases, bone metastases and multisystem metastases including other sites, followed by local and combined relapses both with a 3-year cumulative incidence of approx. 0.05. Multivariate analyses identified both early (<2 years after diagnosis) and combined relapses as most unfavorable prognostic factors for survival after relapse, with hazard ratios >2.5 (p<.001). Comparing relapse types, patients with local relapses, and pulmonary metastases only, had a better prognosis. Conclusions: The risk of relapse is markedly reduced 2–3 years after diagnosis. The treatment strategies should take the time at risk for relapse into consideration. New strategies for treatment of relapses are needed in particular for the most unfavorable bone, multisystem and combined relapses. Supported by Deutsche Krebshilfe Grants DKH M43/92/Jü2, DKH 70–2551 Jü3, and EU BIOMED Grants BMH1-CT92–1341 and BMH4–983956

No significant financial relationships to disclose.
Continuous daily dosing (CDD) of sunitinib malate (SU) compares favorably with intermittent dosing in pts with advanced GIST
Authors: George S. , Blay J. Y. , Casali P. G. , Le Cesne A. , Morgan J. A. , Pokela J. , Quigley M. T. , Tassell V. , Baum C. M. , Demetri G. D.
Published: March 2020

10015

Background: SU, an oral multitargeted tyrosine kinase inhibitor of KIT, PDGFRs, VEGFRs, RET and FLT3, is approved multinationally for the treatment of imatinib (IM)-resistant or -intolerant GIST. SU 50 mg/d on a 4/2 schedule (6-wk cycles: 4 wks on treatment, 2 wks off) has demonstrated efficacy and acceptable tolerability in pts with advanced IM-resistant GIST. The current study assesses the efficacy and safety of CDD of SU in this pt population. Methods: In this multicenter phase (ph) II trial, pts with IM-resistant/intolerant GIST were randomized to receive morning or evening dosing of SU 37.5 mg daily. The primary endpoint was clinical benefit rate (CBR; percentage of pts with confirmed CR, PR or SD for =24 wks per RECIST). Investigator-assessed efficacy and safety data compiled in this ph II study and an earlier ph III study were compared informally, and the PK of SU and its metabolite were also analyzed. Results: Of 61 pts randomized, 60 received treatment with SU (30 pts/arm; ITT population). At a median duration on study of 30 wks (range: 4–52+), 33 pts remain on study and 27 have discontinued. The SU dose was reduced to 25 mg/d in 9 pts due to AEs. The most common non-hematologic AEs of any cause (primarily grade [gr] 1/2) were diarrhea (40%), asthenia (38%) and fatigue (35%). Gr 3 AEs were asthenia (13%), fatigue (7%) and diarrhea (7%); gr 4 abdominal pain was reported in 3% pts. Hematologic toxicities included gr 3 anemia (10%), neutropenia (17%, all non-febrile) and thrombocytopenia (7%) and gr 4 anemia (3%). Toxicities were similar in the morning and evening dosing groups. Preliminary PK data indicated no unexpected accumulation with CDD. To date, median PFS is 27 wks (CI: 24–41) and overall CBR is 24%, including 11% pts with PRs, which compares favorably with results obtained with the approved regimen of SU 50 mg/d on the 4/2 schedule (N=207; PR: 7%; CBR: 25%; PFS 28 wks [CI: 14–34]; phase III study). Conclusions: SU is well tolerated and clinically active when given as 37.5 mg CDD in pts with IM- resistant/-intolerant GIST. The AE profile for SU CDD appears similar to that of the 4/2 schedule. Morning and evening dosing seem to have similar tolerability. SU CDD appears to be a safe and effective alternative dosing strategy for pts with IM-resistant/intolerant GIST.

No significant financial relationships to disclose.
Utility of PET scan in predicting chemotherapeutic response in soft tissue sarcoma patients
Authors: Mintzer D. M. , King J. J. , Alavi A. , Staddon A. P. , Lackman R. D. , Hartner L. , Fox E. J. , Ogilvie C. M.
Published: March 2020

10021

Background: The response to chemotherapy in soft tissue sarcomas (STS) is often used to guide the further management of these neoplasms. The goal of this study was to determine if an overall metabolic response assessed by PET scan can be used to predict survival. Methods: Records of 12 STS patients (10m, 2f) who underwent pre- and post-chemotherapy PET scans were retrospectively renewed. PET scans were evaluated by a senior nuclear medicine physician and the response was compared to patient survival. Disease progression on PET was defined as a SUV increase in any lesion, appearance of new lesions, or presence of extended areas of disease activity during chemotherapy. A stable response was defined as a decrease in SUV <40% of the initial value of over half the lesions. A partial response was defined as a =40% decrease in SUV compared to the initial value in over half of the lesions. Patient survival was measured from the date of the post-treatment PET to the date of death or last follow-up. Results: Of the 12 patients, 6 had disease progression (all with metastases before treatment), 1 had stable disease with metastasis before treatment, and 5 had partial(4) or complete(1) responses of which 2 had metastases on presentation. The 6 patients who had progressive disease during treatment had a mean survival of 4 months (range 1.5–10.9 months, 0 alive at last follow-up). The patient with stable disease died at 13 months post-treatment. The 5 patients with partial to complete responses had a mean survival of 19 months (range 1.9–37.4, 3 alive). Patients with a partial or complete response had a longer mean survival than did patients with progression during chemotherapy, although this was not significant (p=0.49, Wilcoxon). When considering only patients with metastatic disease, the 3 patients without progression during chemotherapy had a longer mean survival (20 months, range 13–24, 1 alive) than the 6 patients with progression during chemotherapy, although this was not significant (p=0.17, Wilcoxon). Conclusions: A trend of decreased survival was seen in patients who had disease progression seen on PET during chemotherapy. Further studies with larger numbers of subjects need to be conducted to evaluate the correlation between the metabolic response to chemotherapy seen on PET to patient outcome in STS.

[Table: see text]
Imatinib mesylate as a preoperative therapy in dermatofibrosarcoma: Results of a multicentric phase II study on 25 patients
Authors: Misset J. , Kerob D. , Porcher R. , Verola O. , Dalle S. , Maubec E. , Madelaine-Chambrin I. , Calvo F. , Mathieu-Boue A. , Pedeutour F. , Lebbe C.
Published: March 2020

10032

The treatment of dermatofibrosarcoma protuberans (DFSP) relies on a wide local excision with frequent need of reconstructive surgery. A (17,22)translocation with Co1A1-PDGF fusion is present in > 90 % of the cases. Some patient's observations and a report on 9 patients suggest that Imatinib mesylate (IM), targeting PDGFRβ, has a clinical interest in DFSP. The primary aim of this phase II multicentric study was to define the percentage of clinical responders (RECIST) to a preoperative 2 months 600mg IM daily before wide local excision. The secondary goals were to determine tolerance, imaging (ultrasound and MRI), pathological responses and to analyse PDGFRβ phosphorylation status and tumour cell apoptosis in sequential tissues specimen. A flexible design with interim analysis after recruitment of 6 patients was used. 18 to 28 patients had to be enrolled to detect a 30% clinical response rate (relative decrease of tumor of at least 30%) with power 80%, using a one-sided test against 5%, at the 2.5% one-sided level. The interim analysis yielded a clinical response in 3 of 6 patients without severe adverse event. An independent committee advised to continue the trial to obtain a total number of at least 24 patients, in order to reduce the confidence interval of response rate. Twenty-five adults suffering from primary or recurrent DFSP have been included from July 2004 to May 2006, 13F and 12 M, median age 42.4 years [range 23.0–72.5]. Tumour characteristics were as follows: primary (n=20), recurrence (n=5) involving trunk(n=14), head or neck (n=3), limbs (n=6), other n=2; median size was 4.5cm [range 2.4–16]. Translocation t(17;22) was detected in 12 of 12 informative tumours following caryotype or FISH analysis. A clinical response was achieved in 9 (36%) patients(95%CI 18.9–57.5). The median relative decrease of tumor was of 20.0% [range -12.5;100]. Apart from expected grade 1 or 2 side effects, we observed 1 grade 3 neutropenia, 1 grade 3 maculopapular rash and 1 grade 4 transient transaminitis. Imatinib has been recently approved for the treatment of unresectable or metastatic dermatofibrosarcoma. Our results should prompt us to analyse the clinical benefit of a longer duration neoadjuvant treatment for patients with DFSPin order to reduce surgical margins

[Table: see text]
Incidence of gastrointestinal stromal tumors (GISTs) in France: Results of the PROGIST survey conducted among pathologists
Authors: Monges G. , Coindre J. , Scoazec J. , Bouvier A. , Blay J. , Loria-Kanza Y. , Mathieu-Boue A. , Bisot-Locard S.
Published: March 2020

10047

Background: GISTs are the most common mesenchymal tumors of the gastrointestinal tract but data on the annual incidence of this tumor is scarce due to previous lack of well-defined pathologic criteria. The aim of this study was to investigate the incidence of GISTs in France and describe the distribution according to age, sex, circumstances of discovery, localization and risk categories. Methods: This prospective epidemiologic study was performed among pathologists who were asked to declare all the cases of GIST over a one year period. All pathology centers (330 centers) in France were proposed to participate and asked to report exhaustively the cases diagnosed from 1 December 2004 to 30 November 2005. Results: 591 cases of GISTs were reported, 535 new cases and 56 cases of relapse. However, some large centers were not able to participate. So, the annual estimated incidence was 12 cases/million inhabitants in France. The main characteristics of the new cases of GIST were as follows: mean age 65 (± 13.2) (range: 16–93) years, 48.6% men and 51.4% women, circumstances of discovery: fortuitous 163 (30.5%), symptomatic 249 (46.5%), unknown 123 (23%). The primary tumor locations were: stomach 341 (63.7 %), small intestine 115 (21.5%), mesentery 35 (6.5%), colon/rectum 17 (3.2%), esophagus 4 (0.7%), unknown 23 (4.3%). 95.3% of GISTs were cKIT (CD117) + and 3.7 % were cKIT -. According to the Fletcher consensus criteria, based on tumor size and mitotic rate, among the 490 localized GISTs 14.7% were considered to be at very low prognostic risk, 25.5% at low-risk, 23.1 % at intermediate risk and 23.1 % at high-risk. For 13.6 % data were missing. Conclusions: This study is providing for the first time an estimation of the annual incidence of GISTs and a description of the characteristics of these tumors in France based on pathology registration. The true incidence may be slightly higher as some large centers were not able to reported their cases. These results are comparable to what has been reported in recent studies in other European countries.

No significant financial relationships to disclose.
A population based study of the incidence, clinical course and prognostification of GIST in Scotland in the pre-imatinib era (1995–1999)
Authors: Graham J. S. , Dunbar G. , Walsh S. , Dick C. , White J. D.
Published: March 2020

10050

Background: GIST's are rare tumours characterised by C-KIT and or CD34 positivity. Population based studies have been performed in countries including Iceland, Spain, Sweden and Holland but this is the first in the United Kingdom. Methods: Pathology records from the entire country were screened for actual or potential GIST cases and the tissues stained with CD117 for C-KIT to confirm a genuine diagnosis of GIST. The primary endpoint was to calculate the incidence of GIST in Scotland from 1995–1999. Secondary endpoints included information re stage, site, survival, sex, age and geographical distribution, and to validate the NIH (National Institute for Health) prognostic index currently used. To date 132 patients have been confirmed with GIST who were previously diagnosed as having either GIST or another similar malignancy. We await final information from 1 region. Results: Primary Endpoint. The incidence of GIST in Scotland from 1995–1999 was 5.2/million/year. Secondary endpoints. Median age at time of diagnosis was 69 with a similar male to female ratio. Original tumour site was 55.8% gastric, 38 % small bowel, 2.3 % colorectal; other sites were < 1 % each. 50.4% were originally diagnosed as GIST's. Other diagnosis included leiomyoma (21.7%) and leiomyosarcoma (14%). All others were <5% each. According to the prognostic index 10.9% were very low risk, 26.4% low risk, 23.3% intermediate, 30.2% high risk Conclusions: Although C- KIT staining was not standard practice during the study period a high percentage of patients were correctly diagnosed originally. Despite a study designed to maximise case ascertainment we report an incidence of GIST in Scotland lower than that of other studies (11 to 14.5 million/ year). This discrepancy may be due to differing study designs and/or failures in the original pathology coding; fundamental in our methodology. Ongoing work to assess the importance of original tumour site, size, prognostic index, etc is underway and this data will be available prior to the 2007 Annual Meeting.

No significant financial relationships to disclose.
Tyrosine kinases as possible therapeutic targets in pulmonary artery intimal sarcoma
Authors: Dewaele B. , Floris G. , Sciot R. , Prenen H. , Wozniak A. , Guillou L. , Coindre J. , Fletcher C. , Schöffski P. , Debiec-Rychter M.
Published: March 2020

10055

Background: Pulmonary artery intimal sarcomas (PAIS) are very rare, highly malignant and clinically aggressive tumors, with yet elusive underlying pathogenic mechanisms and histogenesis. Our aim was to gain molecular insight in the oncogenic events leading to PAIS development, and to investigate the possibility of a pharmacological approach for the treatment of PAIS, specifically targeting the receptor tyrosine kinases (RTK) activated in these tumors. Methods: Fourteen cases of advanced high grade poorly differentiated PAIS were analyzed by immunohistochemistry and selectively by a variety of cytogenetic/molecular techniques, e.g. karyotyping, FISH, mRNA in situ hybridization, array-CGH, tyrosine kinases RT-PCR assay and Western blotting analysis. The study was supplemented by sequencing of PDGFRA, PDGFRB, KIT, VEGFR-1, VEGFR-2 and EGFR genes. Ex vivo functional assays were applied to test the sensitivity of PAIS primary tumor cells to different, clinically approved RTK inhibitors. Results: We demonstrate that (1) PAIS do not have mutations within the kinase domains of PDGFRs, KIT, VEGFRs or EGFR, (2) all cases show a similar cytogenetic molecular profile, characterized by amplification of PDGFRA/KIT/VEGFR2 and MDM2/CDK4 genes, while EGFR, PDGFRB and VEGFR1 are frequently polysomic but rarely highly amplified, (3) high level of expression of PDGFRA, VEGFR1/VEGFR2 and EGFR is uniformly present in the tested tumors, (4) PAIS demonstrate activation (phosphorylation) of PDGFRA and downstream PI3K-AKT and MAP-Kinase signaling pathways, (4) in ex vivo assays, a potent effect of BMS354825 on proliferation and survival of primary cells of PAIS is proven. Conclusions: PDGFRA is amplified and activated in PAIS, thus constituting one of many possible targets for the therapy. Tested inhibitors showed differential efficacy for inhibition of PAIS cells by ex vivo assays.

No significant financial relationships to disclose.
Phase I/II study of docetaxel (D), gemcitabine (G), and bevacizumab (B) in patients (pts) with advanced or recurrent soft tissue sarcoma (STS)
Authors: Verschraegen C. F. , Fekrazad H. M. , Rabinowitz I. , Quinn R. , Snyder D. , Judson P. , Purdy M. , Lee F. C.
Published: March 2020

10056

Background: The combination of G and D has shown efficacy against refractory STS (Hensley, JCO 2002). STS have a high content of VEGF, which is associated with poor prognosis. This phase I/II study assesses the safety, tolerability, efficacy, and pharmacodynamics (PD) of B in combination with G+D, given on a two-weekly schedule to minimize adverse events (AEs). We are reporting the phase I results. Methods: Untreated pts with advanced or recurrent STS and ECOG PS =2 were eligible. Some pts were treated in a neoadjuvant setting, when surgically appropriate. Planned doses were G 1,000, 1,250, and 1,500 mg/m2, D 50 mg/m2, and B 5 mg/kg iv, every 2 wks. G doses were escalated in serial pt cohorts to determine the maximum tolerated dose (MTD) of G with fixed doses of D and B. MTD was assessed on the first 2 cycles (1 cycle = 2 wks). Treatment was continued until progression or unacceptable toxicity. For neoadjuvant therapy, B was given only for 4 cycles, followed by 4 cycles without B in anticipation of surgery and pts came off study at that point. PD and antitumor efficacy were also assessed. Results: Nine pts have been treated on the phase I escalation arm, including 3 in the neoadjuvant setting. There were no dose limiting toxicities. After 4 cycles with G at 1,500 mg/m2, there was 1 asymptomatic grade 4 bowel perforation at the site of the tumor in a pt with initially inoperable leiomyosarcoma (LMS). After emergency surgery, the pt is free of disease. Observed grade 1 and 2 AEs include alopecia, diarrhea, fatigue (5 each), rigors (4), nausea, dyspnea, headaches (3 each), chest pain, epistaxis, stomatitis, anemia (2 each), rash, hypertension, neuropathy, leukopenia (1 each). There were 1 CR (angiosarcoma), 2 PR, (myxoid sarcoma, undifferentiated sarcoma), 4 NC (2 LMS, liposarcoma, PNST), and 2 PD (myxoid sarcoma, PNST). Necrosis was observed, including in NC disease. Three pts are free of disease after surgery. Conclusions: The combination of G, D, and B given every 2 weeks is safe and has demonstrated some activity in pts with advanced or recurrent STS. The phase II arm is ongoing at G 1,500 mg/m2 with 4 pts already enrolled. Mature data including PD will be reported at the meeting.

No significant financial relationships to disclose.
Impact of the smallest surgical margin on local recurrence in soft tissue sarcoma treated with surgery with or without radiotherapy: First ten year results of a prospective treatment protocol at Helsinki University Central Hospital
Authors: Tarkkanen M. , Sampo M. , Huuhtanen R. , Tukiainen E. , Bohling T. , Blomqvist C.
Published: March 2020

10064

Background: A single-institution experience using a prospective treatment protocol for soft tissue sarcoma (STS) of the extremity and trunk wall was reviewed. Special interest of smallest surgical margin on local control was taken. Methods: Between 1987 and 1997 361 patients with STS were treated by the STS Group at Helsinki University Central Hospital. Patients with borderline malignancies or metastatic disease were excluded leaving 270 patients to the present study. All patients included underwent surgery. Postoperative radiotherapy was administered if the smallest surgical margin was less than 2.5 cm when there was no natural barrier, irrespective of tumor grade. Results: With a median follow-up of 6.6 years, the 5-year local control for the whole study population was 76 %. On multivariate analysis, the smallest surgical margin in centimeters, adequacy of treatment according to protocol and postirradiation sarcoma were prognostic for local control. A margin of at least 2,5 cm yielded recurrence-free rate of 89 % at five years. Conclusions: Our findings show that size, depth and grade of the tumor, and patient`s age at diagnosis do not have independent prognostic effect on local control, nor has recurrent disease at referral. Instead, surgical margin in centimeters and adequacy of treatment according to protocol had independent prognostic value for local control. This is encouraging since these factors can be affected by aggressive local treatment. Soft tissue sarcomas should be referred to a specialized multimodality treatment group before biopsy or any surgery. A surgical margin of 2–3 cm yield a reasonable local control in STS even without radiotherapy.

No significant financial relationships to disclose.
High-dose Ifosfamide (HDIFX) as a 14-day continuous infusion (ci) in advanced adult soft tissue sarcoma (STS): A single- institution retrospective case series analysis
Authors: Coco P. , Fumagalli E. , Bertulli R. , Dileo P. , Grosso F. , Stacchiotti S. , Piovesan C. , Sanfilippo R. , Accolla M. , Casali P. G.
Published: March 2020

10067

Background: High-dose IFX (≥12 g/sqm) is active even in STS patients pretreated with standard-dose IFX, though with substantial toxicity. Prolonged continuous infusion, through a portable pump, may be an alternative way of administration. A Phase II study thereof is ongoing in Italy, but some pts have been treated off the study, either prior to its start or for practical reasons. Such consecutive pts seen at a single institution have been retrospectively reviewed. Methods: Between July 2001 and September 2006, 45 adult patients (M:F = 25:20; mean age 47 yrs; PS 0–1) with progressing advanced/metastatic STS, all previously treated with anthracyclines and standard-dose IFX, were given ciHDIFX, at the dose of 14 g/sqm as a 14-day continuous infusion every 4 weeks, using two portable infusional devices, with equidose Mesna, lasting 7 days each. Diagnosis was leyomiosarcoma in 12 patients, synovial sarcoma in 9, liposarcoma in 5, and other histological types in 19. Disease was advanced inoperable in 6 pts, and metastatic in 39. The total number of cycles was 176 (median number per pt: 4). Results: A PR was seen in 5 pts (synovial sarcoma, 2; leyomiosarcoma, 1, liposarcoma, 1; chondrosarcoma, 1), and SD in 22 (>6 mos in 12), for a clinical benefit rate = 37%. PFS at 6 months was 35%. Median PFS was 11 mos in pts with PR and 6 in those with SD. Median PFS was 8 months in 9 patients undergoing complete tumor resection. Most common side effects were nausea (G1–2 in 14 pts) and asthenia (G1–2 in 15 pts). G2 anemia was seen in 8 pts, G2 neutropenia in 6. One pt with a single kidney had a reversible G2 hypercreatininemia. No grade 3–4 toxicity were recorded. Conclusions: In this series, ciHDIFX was associated with a PR and 6-mos PFS rate in the range of active second-line agents in advanced STS. This regimen was exceedingly well tolerated.

No significant financial relationships to disclose.
Secondary sarcomas after radiation in patients with breast cancer
Authors: Mery C. M. , George S. , Raut C. P.
Published: March 2020

10072

Background: Studies have shown that radiation (RT) predisposes patients with breast cancer (BCa) to develop a secondary sarcoma (SS). Few have analyzed recent incidence trends or have been powered to assess specific histologies. The goal of this study was to quantify the risk of developing different types of SS after RT in BCa and assess time trends using the Surveillance, Epidemiology, and End Results (SEER) database. Methods: Females with microscopically-confirmed non-metastatic BCa reported to SEER between 1973 and 2003 were included. Development of SS was analyzed with Kaplan-Meier curves and proportional hazard models, and reported as hazard ratios (HR) with 95% confidence intervals. Descriptive variables were analyzed with chi square. Results: The cohort of 482,469 BCa patients (age 60.1±13.4yrs) was divided in 2 groups: RT (37%) and no RT, based on treatment. RT patients were younger (p<0.0001) and had more partial mastectomies (p<0.0001). RT usage increased with time (from 23% in 1973–1977 to 48% in 2001–2003, p<0.0001). 874 patients developed SS 12–343 months after BCa diagnosis. RT patients had a higher incidence of all SS (30 vs 21 cases/100,000 person-years, HR: 1.57 [1.4–1.8]), angiosarcomas (HR: 7.8 [4.9–12.2]) and malignant fibrous histiocytomas (MFH) (HR: 2.5 [1.6–3.9]). Risk was increased in sites close to the RT field (chest and ipsilateral arm) (HR: 4.17 [3.2–5.5]) but not in others (HR: 1.07 [0.91–1.3]). Risk increased with age and time period at BCa diagnosis (p<0.0001). RT remained a significant predictor of SS development after adjustment for these variables (HR: 1.5 [1.3–1.7]). The hazard of developing SS after RT increased over the first several years after diagnosis of BCa, peaked at 10–14 years, and then decreased again, reaching the non-RT hazard at ∼22 years. 5-yr survival after SS diagnosis was 38%. Conclusions: Administration of RT for BCa increases the risk for development of SS, in particular angiosarcomas and MFH in sites associated with the RT field. Risk of SS has increased with time, independently of RT usage. Patients receiving RT for BCa should be followed closely for more than 20 years.

No significant financial relationships to disclose.
Synovial sarcoma of the extremities and trunk: A long lasting disease
Authors: Merimsky O. , Soyfer V. , Goffman A. , Issakov J. , Bickels J. , Dadia S. , Kollender Y. , Meller I.
Published: March 2020

10073

Background: Synovial sarcoma (SS) of an extremity or trunk is a relatively rare type of soft tissue sarcoma. SS most commonly affects adolescents and young adults. SS usually originates at an extremity, carries a t(X;18)(p11;q11) translocation, and approached by limb sparing surgery, radiation therapy, and chemotherapy. Methods: A retrospective analysis of clinical and histopathological data of 73 patients with proven SS, treated at the National Unit of Orthopedic Oncology, from January 1991 through December 2004 was performed. Results: At a median follow-up time of 6 years, a local-recurrence was observed in 17.8% of the patients, while systemic recurrence in 35.6% (local-only in 6.8 %, systemic-only in 24.6 %, and combined in 11%). Accumulation of events of local and systemic recurrence following a limb sparing approach, did not reach a plateau even after 192 months from diagnosis. The 10-year local recurrence free survival (LRFS), the 10-year systemic recurrence-free survival (SRFS), and the 10-year overall survival (OS) were 78%, 68%, and 61%, respectively. The median SRFS time was 180 months, while the median LRFS and OS have not been reached yet. LRFS was significantly better for ILP treated patients; SRFS was influenced by a shorter delay in diagnosis. Conclusions: The practical aspects of our observations are the need for long-term follow-up for diagnosis of recurrence, the fact that not all local or distant recurrences are necessarily associated with shortening of overall survival, and the important role of induction ILP with TNF in cases of extremity SS.

No significant financial relationships to disclose.
Localized myxoid/round cell liposarcoma in adult patients. IL6 protein expression analysis
Authors: Gomez-Roca C. A. , Ruiz-Soto R. , Castaing M. , Marty V. , Bonvalot S. , Terrier P. , Le Pechoux C. , Domont J. , Cioffi A. , Le Cesne A.
Published: March 2020

10075

Background: Myxoid/round cell liposarcoma (MLPS) is an uncommon soft tissue sarcoma with a relatively favorable prognosis and is considered a low grade malignancy. Methods: Retrospective analysis of 123 localized MLPS adult patients (pts) treated at our institution from 1987 to 2005 was performed. Paraffin embedded tissue was analyzed for IL6, IL6 receptor, NFkB and bcl-2 protein expression (positive (+) or negative) by tissue microarray immunostaining. Results: The median age of the 77 males and 46 females was 42 years (yr) (range 15–70). Lower extremity (LE) was the site more affected (77 pts). Median tumor size was 11 cm (range 2.5–40 cm), 87 were deep tumors and 63 were grade 1 tumors. Preoperative biopsy was carried on 38 pts. All but 2 pts underwent surgery (R0 24%, R1/R2 76%); 44 pts had a second surgery. Chemotherapy (CT) and radiation therapy were given to 30% and 52% of pts respectively. Complete remission was achieved in 98% of pts. After a median follow up of 6 yr (range 0.1–19 yr) 53 pts relapsed (43%); 37 locally, 11 distant and 5 both. Metastases occurred in 26 pts, 17 solitary and 9 multiple. The 5-yr, 10-yr and 15-yr DFS were 56%, 48% and 44% respectively. Median time to first relapse was 6.5 yr (range 0.1–16 yr). The 5-yr, 10-yr and 15-yr OS are 90%, 79% and 64% respectively. Tumor site, pre-surgical biopsy, R0 surgery and second surgery correlates with a better DFS in the multivariate analysis. So far 19 tumors have been studied for, NFkB (+) 57%, IL6 (+) 47% and Bcl2 (+) 30%, positivity. All tumors (+) for IL6 were also (+) for IL6 receptor. None of the proteins correlated to DFS and/or OS. Conclusions: Pts with localized resected MLPS require a prolonged follow-up since relapses occur after 10 yrs. PFS and OS correlate with an optimal loco-regional treatment. Half of MLPS expressed IL6, probably involving an autocrine phenomenon; whether this cytokine is involved in tumor aggressiveness, remains to be established.

No significant financial relationships to disclose.
Survival results with AP23573, a novel mTOR inhibitor, in patients (pts) with advanced soft tissue or bone sarcomas: Update of phase II trial
Authors: Chawla S. P. , Tolcher A. W. , Staddon A. P. , Schuetze S. , D'Amato G. Z. , Blay J. Y. , Loewy J. , Kan R. , Demetri G. D.
Published: March 2020

10076

Background: AP23573 is an mTOR inhibitor that has demonstrated single-agent activity in a broad range of sarcoma tumor types in phase I phase II trials. Overall survival (OS) was monitored to characterize OS in the treated population and in the subset of patients who achieved a clinical benefit response (CBR). Methods: Pts with advanced sarcomas, with no restrictions on prior therapies, were enrolled into 4 cohorts based on histologic subtype, in a phase 2, Simon's 2-stage trial. AP23573 (12.5 mg, i.v.) was administered daily × 5 every 2 wks. Efficacy was assessed using RECIST, with CBR defined as a complete or partial response or stable disease for at least 16 wks duration. OS was defined as the time from the first dose of AP23573 to the date of death from any cause. Kaplan-Meier estimates of the survival times of the population were calculated with OS time censored at the last date the pt was known to be alive when the confirmation of death is absent or unknown. Patients are continuing to be followed for OS in this ongoing trial. Results: 212 pts (105 M/107 F; median age, 50.6 yrs ([17–79 yrs]) were treated. Most pts (79%) had received =2 prior treatments, and over 90% of pts had disease progression at time of enrollment. The overall CBR rate was 29%, including 5 PRs (4 bone sarcoma, 1 MFH). The median OS was 40.1 wks for the entire study population. In the subset of patients achieving CBRs the median time to OS was 67.6 wks, suggesting that achievement of CBR, which is a measure of tumor control, correlates with extending OS. Conclusions: AP23573 exhibits single-agent activity in pts with advanced sarcomas as demonstrated by the CBR rate as a primary efficacy endpoint. The results of the OS analysis suggest that achieving a CBR in this pt population can result in prolonged survival. The consistency of this finding should be further examined with other pt factors that are also hypothesized to correlate for survival in this pt population.

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Serum proteomic prediction of progression-free survival in HER2-negative metastatic breast cancer patients receiving docetaxel as first-line treatment
Authors: Goncalves A. , Deblock M. , Esterni B. , Toiron Y. , Tarpin C. , Charaffe-Jauffret E. , Chabannon C. , Extra J. M. , Viens P. , Borg J. P.
Published: March 2020

1010

Background: Docetaxel has become a standard in management of metastatic breast cancer (MBC) patients (pts). However, there is no validated clinical or biological marker allowing to predict which pts are most likely to benefit from it. We evaluated the ability of Surface enhanced laser desorption/ionization-time of flight mass spectrometry (SELDI-TOF MS) to identify serum proteins that could predict for docetaxel activity. Methods: We prospectively collected pretreatment serum of 81 HER2- MBC pts receiving docetaxel as first-line treatment. Serum samples were denatured, and then incubated in triplicates with three different ProteinChip arrays (Ciphergen): H50, IMAC30-Cu and CM10. Arrays were analysed using a PBSIIc ProteinChip reader (Ciphergen). Results: Pt characteristics were the following: median age, 53 ys (34 -71); Hormonal Receptivity (HR) (yes/no/na, %) 76/15/9; Disease-free interval (DFI) (≤24 months/>24 months, %) 42/58; visceral disease (yes/no, %) 35/65; metastatic sites (<3/≥3,%) 85/15; Median follow-up, 19.8 months (95%CI, 16.1–21.9); Median Progression-free survival (PFS), 12.9 months (95%CI, 8.8–18). Overall, 521 protein peaks were resolved. Univariate Cox proportional hazards regression identified 20 proteins significantly associated to PFS (P < 0.01). A stepwise procedure using the Akaike information criterion was applied to build a Cox model with 7 protein peaks allowing to calculate a risk index for each pt. Using the risk index median value as cut-off, high-risk and low-risk populations with dramatic differences in PFS were identified (2-year PFS of 0% and 54.6%, p = 1.45 10–8). Validation methods included leave-one-out cross validation and iterative resampling. In a multivariate Cox regression including conventional prognostic factors (HR, DFI, visceral metastasis) and serum protein risk index, the latter retained the strongest independent prognostic significance for PFS. Identification of proteins with differential expression according to clinical outcome is ongoing. Conclusions: Serum proteomic profiling may help select MBC Pts who will benefit from treatment with docetaxel. Validation on an independent dataset is planned.

No significant financial relationships to disclose.
Central nervous system (CNS) metastases (mets) in HER2+ metastatic breast cancer (MBC) patients (pts): Patterns of relapse and impact on survival
Authors: Verma S. , Azzi J. S. , Vandermeer L. A. , Spaans J. N.
Published: March 2020

1017

Background: Several studies have documented an increase in the incidence of CNS mets in HER2+ MBC pts (Bendell, 2003; Heinrich, 2003). Of interest is whether there are any specific patterns of CNS metastasis and if they have an impact on survival. Methods: This retrospective study included 100 HER2+ MBC pts who received trastuzumab with or without chemotherapy for their disease between Jan 1/00 and Jan 1/05. Pts were selected for the presence (n=50) or absence (n=50) of CNS mets. Demographics, location of mets and timeline-related variables (survival) were compared. Results: In 50 MBC pts with CNS mets, the most common site was the cerebellum (82%); and symptoms were related to increased intracranial pressure, primarily as a result of disease-related cerebral edema (73%). Compared to 50 pts without CNS mets, there was no statistically significant difference in overall survival from the time of initial diagnosis of breast cancer. Of interest, pts with CNS mets lived longer (61.3 months) than pts without CNS mets (47.1 months). However, survival after disease progression or recurrence significantly favoured patients with CNS mets (36.8 months v. 22.0 months respectively; p=0.02). Causes of death in both cohorts were also examined. Conclusions: In our observation, CNS mets did not have an adverse effect on overall survival. In fact, pts who developed CNS mets lived longer than those pts without CNS mets. This may in part be due to more aggressive management of CNS mets, or lack of extracranial progression.

No significant financial relationships to disclose.