bluuebunny/crossref_metadata_2025 huggingface dataset:
Micronutrient status of Palestinian school children following salt and flour fortification: a cross-sectional study
Authors: Massad Salwa , Gebre-Medhin Mehari , Dary Omar , Abdalla Marwah , Holleran Steve , Karmally Wahida , Bordelois Paula , Khammash Umaiyeh , Deckelbaum Richard J.
Published: August 2020

Background

In 1996 and in 2006, Palestine initiated salt iodization and multiple micronutrient fortification of wheat flour, respectively as a strategy to prevent deficiencies of these nutrients. In 2009, we assessed the impact of these interventions on the health and nutritional status of schoolchildren residing in the West Bank.

Methods

We surveyed a sample of 22 schools run by the UN Relief and Works Agency for Palestine Refugees in the Near East (UNRWA) and the Palestinian Government. We randomly selected students from the first (mean age 6.7 years [SD 0.5]), sixth (11.8 years [0.6]), and ninth grades (14.8 years [0.6]). Data were obtained from 1484 (99%) of 1500 students planned for enrollment.

Results

Our results suggest that iodine intake appears adequate and there was essentially no iodine deficiency. As to the status of other micronutrients, the main nutritional micronutrient risks for schoolchildren in the West Bank continue to be low serum levels of iron, zinc, and vitamin B-12; folate levels were seemingly high. The overall prevalence of anemia was 9.6%, but there were pockets of anemia in certain districts. Almost 42% of the anemia in our sample was explained by iron deficiency. There were significant differences in iron deficiency between girls and boys, 29.5% vs. 15.7%, respectively (p = 0.0001). There were no cases of lead toxicity in the studied sample.

Conclusions

Wheat flour and salt fortification has had a major influence on improving the micronutrient status of Palestinian children, for some but not all micronutrients. The recommended key blood and biochemical parameters to be incorporated in the surveillance system are iron, zinc, and vitamin B12.
UMBRELLA protocol: systematic reviews of multivariable biomarker prognostic models developed to predict clinical outcomes in patients with heart failure
Authors: Vazquez-Montes Maria D. L. A. , Debray Thomas P. A. , Taylor Kathryn S. , Speich Benjamin , Jones Nicholas , Collins Gary S. , Hobbs F. D. R. Richard , Magriplis Emmanuella , Maruri-Aguilar Hugo , Moons Karel G. M. , Parissis John , Perera Rafael , Roberts Nia , Taylor Clare J. , Kadoglou Nikolaos P. E. , Trivella Marialena ,   on behalf of the proBHF group
Published: August 2020

Background

Heart failure (HF) is a chronic and common condition with a rising prevalence, especially in the elderly. Morbidity and mortality rates in people with HF are similar to those with common forms of cancer. Clinical guidelines highlight the need for more detailed prognostic information to optimise treatment and care planning for people with HF. Besides proven prognostic biomarkers and numerous newly developed prognostic models for HF clinical outcomes, no risk stratification models have been adequately established. Through a number of linked systematic reviews, we aim to assess the quality of the existing models with biomarkers in HF and summarise the evidence they present.

Methods

We will search MEDLINE, EMBASE, Web of Science Core Collection, and the prognostic studies database maintained by the Cochrane Prognosis Methods Group combining sensitive published search filters, with no language restriction, from 1990 onwards. Independent pairs of reviewers will screen and extract data. Eligible studies will be those developing, validating, or updating any prognostic model with biomarkers for clinical outcomes in adults with any type of HF. Data will be extracted using a piloted form that combines published good practice guidelines for critical appraisal, data extraction, and risk of bias assessment of prediction modelling studies. Missing information on predictive performance measures will be sought by contacting authors or estimated from available information when possible. If sufficient high quality and homogeneous data are available, we will meta-analyse the predictive performance of identified models. Sources of between-study heterogeneity will be explored through meta-regression using pre-defined study-level covariates. Results will be reported narratively if study quality is deemed to be low or if the between-study heterogeneity is high. Sensitivity analyses for risk of bias impact will be performed.

Discussion

This project aims to appraise and summarise the methodological conduct and predictive performance of existing clinically homogeneous HF prognostic models in separate systematic reviews.

Registration: PROSPERO registration number CRD42019086990
Preliminary clinical assessment of dynamic carbon-11 methionine positron-emission tomography/computed tomography for the diagnosis of the pathologies in patients with musculoskeletal lesions: a prospective study
Authors: Shinya Takayoshi , Otomi Yoichi , Nishisho Toshihiko , Beuthien-Baumann Bettina , Kubo Michiko , Otsuka Hideki , Bando Yoshimi , Yanagawa Hiroaki , Sairyo Koichi , Harada Masafumi
Published: August 2020

Background

This study prospectively assessed the diagnostic capacity of dynamic carbon-11 methionine (C-11 MET) positron-emission tomography (PET)/computed tomography for the diagnosis of pathologies in patients with primary unknown musculoskeletal lesions (MSLs). In total, 13 patients with MSLs underwent dynamic scans (5–10 [phase 1], 10–15 [phase 2], 15–20 [phase 3], 20–25 [phase 4], 25–30 [phase 5], and 30–35 [phase 6] min post-injection of C-11 MET). We statistically compared the maximum standardised uptake values (SUVmax) and corresponding retention index for dynamic scans (RI-SUV) for five benign MSLs (BMSLs), five primary malignant musculoskeletal tumours (PMMSTs), four metastatic musculoskeletal tumours (MMSTs), and three malignant lymphoma (ML) cases and explored their diagnostic capacities using receiver operating characteristic (ROC) curve analyses.

Results

SUVmax gradually decreased or remained similar with minimal fluctuations in all BMSL cases and four of five PMMST cases. In contrast, SUVmax increased over time in one case of PMMST and in all cases of MMST and ML. Significant differences were observed in SUVmax for all time phases and RI-SUV between BMSLs and MMSLs, in SUVmax for all time phases between PMMSTs and BMSLs, in SUVmax for all time phases and RI-SUV between non-PMMST-malignant tumours and BMSL, and in RI-SUV between non-PMMST-malignant tumours and PMMST. In ROC analyses, the areas under the curve yielded the highest values at 1.00 for differentiating most intergroup comparisons.

Conclusions

Dynamic C-11 MET PET scans have the potential to be good predictors of discriminating MSLs in patients with primary unknown MSLs in clinical practice.
Childbearing and mortality among women with personality disorders: nationwide registered-based cohort study
Authors: Kouppis Efthymios , Björkenstam Charlotte , Gerdin Bengt , Ekselius Lisa , Björkenstam Emma
Published: August 2020

Background

People with a personality disorder have a higher mortality and reduced life expectancy than the general population. Childbearing is thought to have a protective effect on morbidity and mortality. Yet, there are no studies on whether childbearing is related to a lower mortality among women with personality disorder.

Aims

This study examined associations between childbearing and mortality among women with personality disorder. Our hypothesis was that parity would be associated with lower mortality.

Method

This register-based cohort study included 27 412 women treated for personality disorder in in-patient or specialised out-patient care between 1990 and 2015. We used nationwide population-based registers to obtain information on sociodemographics, child delivery, healthcare use and mortality. Mortality risk estimates were calculated as hazard ratios (HRs) with 95% CIs using Cox regression. Adjustments were made for year of birth, educational level, age at diagnosis, comorbidity and severity of personality disorder.

Results

Nulliparous women had a nearly twofold increased mortality risk (adjusted HR = 1.78, 95% CI 1.50–2.12) compared with parous women and over twofold mortality risk (adjusted HR = 2.29, 95% CI 1.72–3.04) compared with those giving birth after their first personality disorder diagnosis. Those giving birth before their first personality disorder diagnosis had a 1.5-fold higher risk of mortality than those giving birth after their first personality disorder diagnosis (adjusted HR = 1.48, 95% CI 1.06–2.07). There was a threefold risk of suicide in nulliparous women compared with those giving birth after their first personality disorder diagnosis (adjusted HR = 2.90, 95% CI 1.97–4.26).

Conclusions

Childbearing history should be an integral part of the clinical evaluation of women with personality disorder.
Patient-Centered Outcomes in ARIEL3, a Phase III, Randomized, Placebo-Controlled Trial of Rucaparib Maintenance Treatment in Patients With Recurrent Ovarian Carcinoma
Authors: Oza Amit M. , Lorusso Domenica , Aghajanian Carol , Oaknin Ana , Dean Andrew , Colombo Nicoletta , Weberpals Johanne I. , Clamp Andrew R. , Scambia Giovanni , Leary Alexandra , Holloway Robert W. , Gancedo Margarita Amenedo , Fong Peter C. , Goh Jeffrey C. , O’Malley David M. , Armstrong Deborah K. , Banerjee Susana , García-Donas Jesus , Swisher Elizabeth M. , Cella David , Meunier Juliette , Goble Sandra , Cameron Terri , Maloney Lara , Mörk Ann-Christin , Bedel Josh , Ledermann Jonathan A. , Coleman Robert L.
Published: August 2020

PURPOSE

To investigate quality-adjusted progression-free survival (QA-PFS) and quality-adjusted time without symptoms or toxicity (Q-TWiST) in a post hoc exploratory analysis of the phase III ARIEL3 study of rucaparib maintenance treatment versus placebo.

PATIENTS AND METHODS

Patients with platinum-sensitive, recurrent ovarian carcinoma were randomly assigned to rucaparib (600 mg twice per day) or placebo. QA-PFS was calculated as progression-free survival function × the 3-level version of the EQ-5D questionnaire (EQ-5D-3L) index score function. Q-TWiST analyses were performed defining TOX as the mean duration in which a patient experienced grade ≥ 3 treatment-emergent adverse events (TEAEs) or the mean duration in which a patient experienced grade ≥ 2 TEAEs of nausea, vomiting, fatigue, and asthenia. Q-TWiST was calculated as μTOX × TOX + TWiST, with μTOX calculated using EQ-5D-3L data.

RESULTS

The visit cutoff was Apr 15, 2017. Mean QA-PFS was significantly longer with rucaparib versus placebo in the intent-to-treat (ITT) population (375 randomly assigned to rucaparib v 189 randomly assigned to placebo; difference, 6.28 months [95% CI, 4.85 to 7.47 months]); BRCA-mutant cohort (130 rucaparib v 66 placebo; 9.37 months [95% CI, 6.65 to 11.85 months]); homologous recombination deficient (HRD) cohort (236 rucaparib v 118 placebo; 7.93 months [95% CI, 5.93 to 9.53 months]); and BRCA wild-type/loss of heterozygosity (LOH) low patient subgroup (107 rucaparib v 54 placebo; 2.71 months [95% CI, 0.31 to 4.44 months]). With TOX defined using grade ≥ 3 TEAEs, the difference in mean Q-TWiST (rucaparib v placebo) was 6.88 months (95% CI, 5.71 to 8.23 months), 9.73 months (95% CI, 7.10 to 11.94 months), 8.11 months (95% CI, 6.36 to 9.49 months), and 3.35 months (95% CI, 1.66 to 5.40 months) in the ITT population, BRCA-mutant cohort, HRD cohort, and BRCA wild-type/LOH low patient subgroup, respectively. Q-TWiST with TOX defined using select grade ≥ 2 TEAEs also consistently favored rucaparib.

CONCLUSION

The significant differences in QA-PFS and Q-TWiST confirm the benefit of rucaparib versus placebo in all predefined cohorts.
A phase I study of zoledronic acid (ZA) and low-dose cyclophosphamide (CTX) in children with recurrent/refractory neuroblastoma (NB): A New Approaches to Neuroblastoma Therapy (NANT) study
Authors: Russell H. , DeClerck Y. , Ara T. , Groshen S. , Villablanca J. G. , Marachelian A. , Park J. , Katzenstein H. , Matthay K. , Blaney S.
Published: August 2020

10022

Background: ZA, a bisphosphonate, delays progression of bone metastases in adult malignancies. Bone metastases occur in 60% of children with advanced NB. A xenograft mouse model demonstrated ZA with low dose chemotherapy delayed progression of NB bone lesions prompting a phase I trial of ZA. Methods: Three dose levels of intravenous ZA (2, 3, or 4 mg/m2) administered every 28 days were evaluated with continuous daily oral CTX (25 mg/m2/day) in patients with recurrent/refractory NB and bone metastases. The primary objective was to determine a recommended dose of ZA for future trials. PKs with the first dose of ZA and serial serum IL-6 levels (stimulator of osteoclast activity) were evaluated. Results: 21 patients (14 male), median age 7.9 years (0.8–26.6 years), were enrolled at ZA dose levels 2 mg/m2 (n=4), 3 mg/m2 (n=3), and 4 mg/m2 (n=13). Seventy-five cycles were administered with median of 1 cycle per patient (range 1–18). Two DLT (Gr 3 hypophosphatemia) occurred at 4 mg/m2 ZA. Other Gr 3 or 4 toxicities included hypocalcemia (n = 2), elevated transaminases (n = 2), neutropenia (n = 2), anemia (n = 1), lymphopenia (n = 1), and hypokalemia (n = 1). A fracture related to osteosclerosis occurred after 18 cycles. There were no renal or dental complications. There was 1 complete response, 9 stable disease median 4.5 cycles (range 3–18), and 10 progressions (central review pending). At 4 mg/m2, mean serum IL-6 levels decreased from 3.9 pg/mL (95% CI: 2.8–5.2 pg/mL) (n = 11) to 2.9 pg/mL (95% CI: 1.8–4.4 pg/mL) after cycle 1 (n = 8). ZA PK were similar to adults. Conclusions: ZA with low dose CTX is well tolerated with evidence of clinical benefit in children with recurrent/refractory NB. The recommended ZA dose for future study is 4 mg/m2 every 28 days.

No significant financial relationships to disclose.
Adolescent psychopathology and adult health behaviors in long-term survivors of childhood cancer: Findings from the Childhood Cancer Survivors Study
Authors: Krull K. R. , Huang S. , Hudson M. M. , Gurney J. G. , Srivastava D. K. , Klosky J. , Ness K. K. , Leisenring W. , Termuhlen A. , Robison L. L.
Published: August 2020

10027

Background: Psychological problems have been identified as important risk factors for poor health behavior in a variety of noncancer populations. We report the association between adolescent psychopathology and future health behaviors in adult survivors of childhood cancer. Methods: Study participants included 1,656 survivors of childhood cancer (50.8% female); 12 - 17 years old and ≥ 5 years post diagnosis at baseline assessment and 18 - 27 years of age at study follow-up. Parents provided medication information and ratings of psychopathology for adolescents at baseline, including symptoms of depression/anxiety, social withdrawal, inattention, and oppositional and antisocial behavior. Survivor self-report of health behavior was collected 6 - 10 years post baseline. Odds ratios (OR) were calculated comparing those with psychopathology to those without on outcomes of obesity, physical activity, smoking, and sunscreen use. Estimates were adjusted for cancer diagnosis, cancer therapy, sex, age, and history of special education. Results: Adult obesity was associated with adolescent social withdrawal (OR 1.5, 95% CI 1.1–2.1) and adolescent use of stimulant medications (OR 1.9, 95% CI 1.1–3.2). Physical inactivity among adults was also associated with adolescent social withdrawal (OR 1.7, 95% CI 1.1–2.5) and to antidepressant use during adolescence (OR 3.2, 95% CI 1.2–8.2). These impacts on obesity and inactivity were above and beyond the risk associated with high body mass index at baseline. Stimulant medication use was associated with decreased likelihood of poor sunscreen use as an adult (OR 0.4, 95% CI 0.2–0.8). Adult smoking was associated with adolescent antisocial behavior (OR 2.6, 95% CI 1.6–4.2). Conclusions: These results suggest that psychological problems in adolescence predict future health behavior in adult survivors of childhood cancer. Furthermore, psychopharmacologic therapy for such problems may increase risk for certain conditions, and decrease risk for others. Increased psychological screening and medication monitoring is warranted to reduce overall risk of poor outcomes.

No significant financial relationships to disclose.
Quantitative assessment of HER2 status and correlation with efficacy for patients (pts) with metastatic breast cancer (MBC) in a phase II study of trastuzumab-DM1 (T-DM1)
Authors: Krop I. E. , Burris H. A. , Rugo H. , O'Shaughnessy J. , Vogel C. L. , Amler L. , Strauss A. , Wong E. K. , Klencke B. , Pippen J.
Published: August 2020

1003

Background: The antibody-drug conjugate T-DM1 combines the biological activity of trastuzumab with targeted delivery of an anti-microtubule agent (DM1) to HER-2-expressing cancer cells. This analysis examines correlation of response to T-DM1 with HER-2 status, as assessed by fluorescent in situ hybridization (FISH), immunohistochemistry (IHC), mRNA quantitative real-time polymerase chain reaction (qRT-PCR), and enzyme-linked immunosorbent assay (ELISA) (HER-2 extracellular domain [ECD]), for pts enrolled in TDM4258g, a phase II study of T-DM1 in pts with MBC. Methods: TDM4258g is an open-label, single-arm study of T-DM1 administered at 3.6 mg/kg IV q3w. Pts had progressed on HER-2-directed therapy and received chemotherapy in the metastatic setting and were HER-2 + based on local testing. Archival tissue (paraffin block or >7 unstained tumor slides) was collected for retrospective central laboratory testing. HER-2 DNA amplification was determined by FISH, and protein levels by IHC. qRT-PCR for HER-2 was performed on extracted RNA; baseline HER-2 ECD ELISA was performed on pt sera. HER-2 data for each pt were compared with pt's best response. Results: As of August 29, 2008, 112 pts had enrolled; 107 were efficacy-evaluable pts with median 4.4 mos follow-up. There were 42/107 (39.3%) partial responses (PR) (investigator assessment). Of 86 pts centrally tested, 64 (74.4%) were confirmed HER-2+ (FISH+ and/or IHC 3+), with 32/64 (50%) PR. Of 76 pts tested by both FISH and IHC, 15/76 (19.7%) were confirmed HER-2- (FISH- and IHC 2+/1/0), with 2/15 (13.3%) PR. In HER-2+ pts, response rates did not correlate with high versus low FISH+ counts, nor with HER-2 ECD levels. Among 39 HER-2+ (FISH+ and/or IHC3+) efficacy-evaluable pts with qRT-PCR data, there were 13/19 (68.4%) PR for pts with qRT-PCR above median levels, and 7/20 (35.0%) PR for pts with qRT-PCR below median. Conclusions: HER-2+ pts (by central retesting) had better responses to T-DM1 than HER-2- pts, although a small number of PR were observed in HER-2- pts. Assessment of HER-2 expression by qRT-PCR may identify pts more likely to respond to T-DM1 therapy. Updated data, including additional diagnostic markers, will be presented at the meeting.

[Table: see text]
Outpatient administration of high-dose methotrexate for osteosarcoma treatment in Brazil
Authors: Macedo C. R. , Cappellano A. M. , Noguchi D. T. , Martinho A. P. , Dias C. G. , Dias C. G. , Malheiros R. C. , Dutra A. H. , Grings M. , Pires A. L. , Petrilli A. S.
Published: August 2020

10038

Background: We describe the experience with outpatient administration of high dose methotrexate (HDMTX) and leucovorin rescue for osteosarcoma treatment at Instituto de Oncologia Pediátrica. Methods: HDMTX (12g/m2) is administered as part of the Brazilian Osteosarcoma Treatment Group Protocol in an ambulatory basis. Daily MTX serum levels and fluid controls follows until the serum level is <0,2 μ/L. Families were oriented to measure urinary pH and volume, PO intake and to adjust leucovorin dose as needed. To achieve treatment adherence, a family education program was developed. Concomitantly to HD chemotherapy, low dose oral cyclophosphamide and MTX (metronomic treatment) were provided to metastatic (M) patients. This is a retrospective analysis of the HDMTX courses administered between 2006 and 2008. Results: Out of 341 HDMTX infusions, administered to 42 patients, 42.5% had abnormal serum levels at hour 24, 8.8% at hour 48 and 33.2% at hour 72. After required interventions, 2.9% (n = 8) had serum levels >0.2 μ/L at hour 72 leading to delayed excretion. Of these, 7 had also creatinine elevation and main adverse events were mucositis, reversible transaminasis elevation and one sepsis. In the overall analysis, other toxicities included mucositis grade II (20%), nefrotoxicity (5.6%) and neutropenia grades III and IV (25.4%). Serious adverse events of seizure, allergic reaction, and Steven Johnson's Syndrome lead to suspension of future HDMTX administration in 4 patients (01 metastatic). The main differences found between M and non-M patients were 16.8% versus 8.7% of leucopenia grade IV and 12.1% versus 6.6% of anemia grades III and IV. Conclusions: Similar to other authors’ experience, outpatient administration of HDMTX lead to elevated serum levels in 42.5% of the infusions, demonstrating the importance of a well trained staff and early introduction of supportive therapies to avoid associated toxicities. To a developing country, this approach helps lowering treatment costs and infection risks and increases patient adherence to treatment, with acceptable toxicities, even with the introduction of metronomic treatment.

No significant financial relationships to disclose.
Dasatinib plus capecitabine (Cap) for progressive advanced breast cancer (ABC): Phase I study CA180004
Authors: Somlo G. , Atzori F. , Strauss L. , Rybicki A. , Wu X. , Gradishar W. , Specht J.
Published: August 2020

1012

Background: SRC family kinases (SFK) mediate numerous signal-transduction pathways relevant to breast cancer as well as osteoclast function. Dasatinib, a potent oral inhibitor of SFK and other kinases has preclinical activity in breast models and in vitro synergy with Cap in some breast cancer cell lines (KPL-4 and HCC-70). A phase I trial of dasatinib plus Cap was conducted to define dose-limiting toxicities (DLT), maximum tolerated (MTD), and recommended phase II (RP2D) doses. Methods: Sequential cohorts of pts with ABC were treated with Cap twice daily (BID) on days 1–14 and dasatinib daily in 21-day cycles using dose levels (DL) for Cap (mg/m2) and dasatinib (mg): DL1: Cap 825 + dasatinib 50 BID; DL2: Cap 825 + dasatinib 70 BID; DL3: Cap 1000 + dasatinib 70 BID; DL3a: Cap 1000 + dasatinib 100 once daily (QD). All pts had ECOG performance status 0–1, had prior anthracycline and/or taxane, and received ≤2 regimens in advanced setting. MTD was based on DLT in first cycle and RP2D also based on tolerability of additional cycles. Results: 31 pts with ABC, median age 53 years (range 36–78) were treated. Number of pts treated/evaluable for DLT/reported DLT (event) were DL1: 7/6/1 (headache, grade 3); DL2: 9/7/0; DL3: 6/6/1 (diarrhea, grade 3), and DL3a: 9/9/1 (pneumonia, grade 3). Most frequent AEs related to either drug and occurring at any time on study (n pts) were nausea (12), vomiting (7), diarrhea (6), abdominal pain (2), fatigue (8), headache (7), musculoskeletal pain (1), and pleural effusion (4); hand-foot syndrome (5) was as expected for Cap alone. 11 patients experienced a Grade 3–4 non-hematologic AE at some point during the study. Laboratory abnormalities were uncommon. To date, 20 pts have continued treatment for ≥6 weeks and 9 pts for ≥12 weeks. Number of pts who (at any time) reduced dasatinib/reduced Cap/discontinued for toxicity were DL1: 2/2/1; DL2 2/2/3; DL3: 2/1/2; DL3a: 0/1/1. Updated safety and efficacy data will be presented. Conclusions: Dasatinib + Cap was tolerated without unexpected combined-treatment toxicity; few pts required dose reduction in later cycles. The recommended phase II dose, Cap 1000 plus dasatinib 100 QD, is well tolerated and will be studied for efficacy in an expanded patient cohort.

[Table: see text]
Randomized phase II trial of gefitinib plus anastrozole or fulvestrant in postmenopausal, metastatic breast cancer
Authors: Carlson R. W. , O'Neill A. , Vidaurre T. , Gomez H. L. , Badve S. , Sledge G.
Published: August 2020

1013

Background: Preclinical data documents interactions between the signal transduction pathways for ER and for EGFR, and these interactions may relate to endocrine resistance in ER+ breast cancer. Limited clinical data is available. Methods: This multi-institutional, single-stage, non-comparative, randomized phase II study tested the EGFR tyrosine kinase inhibitor gefitinib 250 mg daily PO plus endocrine therapy with either anastrozole 1 mg/day PO (AG Arm) versus fulvestrant 250 mg IM every 4-weeks (FG Arm). Eligible pts were postmenopausal women with ER+ and/or PgR+ measurable metastatic breast cancer with no prior endocrine therapy for metastatic disease, no prior adjuvant AI or fulvestrant, no more than two chemotherapy regimens for metastatic disease, ECOG status 0–2, no CNS metastasis, and adequate bone marrow, liver, and renal function. Primary endpoint was RECIST determined clinical benefit (CR+PR+SD for ≥6 mos) and secondary endpoints were toxicity and interaction of biomarkers with clinical benefit. Results: 148 pts were registered, and 142 pts are eligible and analyzable, 73 to AG and 69 to FG. Treatment groups were balanced for race, age, ECOG status, and sites of disease. Median follow-up is 35 mos. Median N of 4-week cycles of treatment is 6 (range 1–42) in both groups. Treatment was terminated for disease progression in 74% v 75%, toxicity 7% v 10%, death 1% v 3%, withdrawal 8% v 1%, and other 3% v 7% in the AG v FG arms, respectively. Clinical benefit rate (95% CI) is 42% (30%-53%) v 38% (28%-52%) for AG v FG, respectively. Response rates are CR 3% v 4%, PR 21% v 17%, SD for ≥6 mos 18% v 17% for AG v FG. Median PFS is 5.7 mos v 5.2 mos and median OS is 30.2 mos v 23.8 mos for AG v FG, respectively. Overall worst toxicity grade experienced for AG is G1 and 2 = 62%; G3 = 28%; G4 = 4%, G5 = 3%; for FG was G1 and 2 = 58%; G3 = 27%; G4 = 7%; G5 = 4%. G3 + G4 + G5 toxicities occurring in ≥5% of either treatment are diarrhea (5% v 13%), SGOT elevation (7% v 8%), and infection without neutropenia (1% v 6%) for AG v FG. Conclusions: Both anastrozle and fulvestrant are active endocrine agents in combination with gefitinib and both are generally well tolerated. Anastrozole plus gefitinib appears to be the better combination to take forward for phase III comparisons.

[Table: see text]
Relationship between survival and estrogen receptor (ER) status in pts with metastatic breast cancer (MBC) treated with capecitabine (C) and docetaxel (D): An exploratory data analysis
Authors: Gluck S. , Russell C. , O'Shaughnessy J. , Yuan G. , Odom D. , Sherrill B. , Blum J.
Published: August 2020

1024

Background: Previous studies in pts with MBC have shown that women with ER+ tumors have a longer survival time compared to women with ER- tumors. An exploratory analysis was conducted to describe the relationship between survival and ER status among MBC pts treated with combination therapy consisting of C+D. Methods: This analysis used data from an open-label, randomized phase III trial of C+D vs D alone in pts with advanced and/or MBC. Survival analysis was used to investigate the effect of baseline ER status of the primary and metastatic tumors on overall survival (OS). ER status was defined as positive if positive for any tumor, negative if at least 1 negative test, otherwise unknown. Results: Among 506 intent-to-treat pts (randomized, received ≥1 dose), ER status was identified in 356. C+D: 90 ER+, 88 ER-; D alone: 95 ER+, 83 ER-. The unadjusted log-rank test showed a significant difference in OS between the C+D and D groups for ER+ but not ER- pts. In the ER+ group, median OS was longer in C+D vs D pts (538.5 vs 379.0 d) (hazard ratio [HR] 0.65; P=0.007). OS was significantly longer in ER+ vs ER- pts in the C+D group (538.5 vs 329.0 d) (HR 0.68; P=0.019) but not in the D group (379.0 vs 301.0 d) (HR 0.90; P=0.514). OS by time from diagnosis to recurrence and baseline tumor size showed no significant differences between ER+ and ER- pts. Conclusions: This exploratory analysis suggested a significant difference in OS between the C + D and D groups in ER+ (HR 0.65) but not ER- (HR 0.90) pts. Also, within the C+D group, the median OS was significantly longer in ER+ than ER- pts (HR 0.68).

[Table: see text]

[Table: see text]
A specific nomogram to predict subsequent brain metastasis in metastatic triple-negative breast cancer patients
Authors: Pusztai L. , Rouzier R. , Pusztai L. , Ibrahim N.
Published: August 2020

1028

Background: The development of brain metastases is usually a fatal event in the history of breast cancer patients with metastatic disease other than brain (MDOB). We previously developed a global nomogram that includes immune-histochemical phenotype to predict the occurrence of brain metastasis (BM). We hypothesized that a nomogram specific to triple negative tumor (TN) could improve prediction BM occurrence in patients with MDOB, thus allowing allocation of preventive treatment more efficiently. Methods: Patients with metastatic BC presenting between 2000 and February 2007 treated at M. D. Anderson Cancer Center were included in this retrospective analysis. We tested 17 variables and developed a multivariate model to predict occurrence of subsequent BM in TN tumors and created a nomogram that could be used for individual prediction. The model was cross-validated by bootstrapping and compared to the global nomogram. Results: Among 2,136 patients with metastatic breast cancer including 641 patients with TN tumors, 362 developed BM during follow-up: young age, histological characteristics, short delay between initial diagnosis and MDOB, number of metastatic sites and initial number of metastatic nodes were significantly and independently associated with subsequent BM. The nomogram to predict BM developed on the TN population provided a better discrimination (area under the ROC curve [AUC] = 0.62) than the global nomogram (AUC = 0.58) for the TN tumors. Prediction with the specific nomogram and the global nomogram were highly correlated (correlation factor = 0.67, p < 0.0001). However, when a threshold at 15% was used, we observed 27% of discordant cases and the sensitivity of the specific nomogram was better. Conclusions: We developed a specific tool to predict subsequent BM in patients with metastatic TN breast cancer. This nomogram outperformed a global nomogram.

No significant financial relationships to disclose.
Hepatobiliary abnormalities in patients with metastatic cancer treated with lapatinib
Authors: Moy B. , Rappold E. , Williams L. , Kelly T. , Nicolodi L. , Maltzman J. D. , Goss P. E.
Published: August 2020

1043

Background: Lapatinib (LAP), a dual tyrosine kinase inhibitor (TKI), is effective in the treatment of HER-2-positive metastatic breast cancer. Liver toxicity has been reported as a side effect of several TKIs. We analyzed the liver safety of LAP using available data from 16 metastatic cancer trials. Methods: LAP (as monotherapy or in combination) was administered to 2,968 patients (pts) in metastatic cancer trials. Liver function tests were prospectively evaluated. We defined liver toxicity events as either NCI CTCAE grade (Gr) 3 or 4 alanine and aspartate aminotransaminases (ALT/AST) or meeting Hy's Law criteria (liver injury with jaundice). Results: Overall Gr 3 and 4 ALT/AST events were seen in 45/2,968 (1.5%) and 2/2,968 (0.07%) pts, respectively. Of LAP monotherapy pts, Gr 3 and 4 ALT/AST was seen in 13/1,470 (0.9%) and 1/1,470 (0.07%), respectively. Of LAP + monoclonal antibody (mAb) pts (trastuzumab or bevacizumab), Gr 3 and 4 ALT/AST was seen in 2/199 (1.0%) and 1/199 (0.5%), respectively. Ten of 645 pts (1.6%) treated with LAP + chemotherapy (capecitabine or paclitaxel) had Gr 3 ALT/AST. Twenty of 654 pts (3%) treated with LAP + letrozole had Gr 3 ALT/AST. Among 2,968 pts, Hy's law toxicity occurred in 8 (0.3%) pts: 2/1,470 (0.14%) pts treated with LAP alone, 1/199 (0.5%) pts treated with LAP + mAb, 4/645 (0.6%) pts treated with LAP + chemotherapy, and 1/654 (0.2%) pts treated with LAP + letrozole. Alternative causes of liver toxicity such as metastatic liver disease, infectious hepatitis, and heart failure will be reported at the meeting. Conclusions: Review of data from 16 clinical trials in metastatic cancer revealed low levels of liver toxicity for LAP. Oncologists should be vigilant for this rare side effect of LAP. A proposed monitoring algorithm of symptom assessment and frequency of hepatobiliary laboratory monitoring will be shown.

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Tolerability and efficacy of 500 mg fulvestrant in postmenopausal women with estrogen receptor (ER)+ advanced breast cancer
Authors: Come S. E. , Parker L. M. , Wulf G. , Kuter I. , Ryan P. D. , Tkaczuk K. , Borges V. , Kasper H. , Gelman R. , Winer E. P.
Published: August 2020

1050

Background: At the approved dosage (AD) of 250 mg q 28d, fulvestrant has no dose-limiting toxicity and may not optimally inhibit/downregulate levels of ER. We evaluated the tolerability, efficacy, and pharmacokinetics of fulvestrant given at twice the AD. Methods: 35 postmenopausal patients with ER+ evaluable metastatic breast cancer who had not received endocrine therapy for advanced disease and were at least 12 months from the completion of any adjuvant endocrine therapy were enrolled in a single stage, phase II study. The median age was 64. 15 patients had received prior adjuvant endocrine treatment. 14 had visceral metastases. Treatment consisted of fulvestrant 500 mg (2 x 5 mL injections) on days 1, 15, 29, and q 28d thereafter. Toxicity and response were assessed q 28d by history, exam, and laboratory testing, and q 3 months by imaging. The primary endpoint was clinical benefit rate (CBR) defined as complete responses (CR) plus partial responses (PR) plus stable disease (SD) for > 6 months. This trial was powered to detect a 20% improvement in the 57% CBR reported for AD fulvestrant in the first-line metastatic setting (J Clin Oncol. 2004;22:1605–613). Results: Median time on study is 13 months (mo). 17 patients remain on treatment (8+ to 54+ mo). There has been no grade (gr) 3 or 4 treatment-related toxicity. Transient injection site discomfort or pruritis occurred in 13 patients (11 gr 1, 2 gr 2). A CBR of 86% was observed (95% CI 70%- 95%). The median time to progression is 22 mo. In the subset of 24 patients fulfilling RECIST criteria, 1 CR and 6 PR, and 15 SD were observed (overall response rate 29%, CBR 92%). Conclusions: Doubling the AD of fulvestrant does not increase toxicity. Monthly bilateral 5 mL injections are well tolerated. Importantly, the CBR is improved at this dose and schedule compared to the AD.

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Frequency of β-catenin heterozygous mutations in extra-abdominal fibromatosis as a surrogate marker for disease management
Authors: Dômont J. , Salas S. , Lacroix L. , Brouste V. , Dufresne A. , Terrier P. , Blay J. , Le Cesne A. , Coindre J. , Benard J. , Bonvalot S.
Published: August 2020

10501

Background: Fibromatosis, a rare soft-tissue and locally invasive neoplasm, consist of distinct clinical entities including sporadic extra-abdominal fibromatosis (EAF). The potential morbidity of loco-regional treatments combined with the high local recurrence rate have led investigators to assess the possibility to design a “wait and see” policy in a subset of patients (pts). Up to date, molecular biomarkers of local recurrence of EAF remain unknown. As dysregulation of β-catenin (βC) expression hallmarks fibromatosis, herein we searched for βC mutations in a large retrospective European multi-centric tumors series to relate with clinicopathologic parameters. Methods: From 1987 to 2007, 155 pts with fibromatosis from all sites were gathered by the Conticanet Network were analysed. Direct sequencing of exon 3 βC gene was performed for 155 frozen tissues. All mutated cases were confirmed by an independent analysis. From this cohort, 101 pts with EAF surgically treated with curative intent and follow-up allowed us to relate βC mutational status to disease outcome. Results: Mutations of βC were detected in 84% of all cases. Among 101 pts with EAF surgically treated, similar mutations types and rates (87%) were observed, namely T41A (39.5%), S45P (9%), S45F (36.5%) and deletion (2%). There were 36 men and 65 women. Majority of pts were treated for primary EAF (57%). Most of surgical margin were RO (38%) or R1 (34%). Few pts were treated after surgery with radiation therapy (18%) and medical treatment (8%). With a median follow-up of 62 months, 51 pts (51%) relapsed. Neither clinicopathologic parameters were found to be significantly associated with βC mutational status. The five-year recurrence free-survival was significantly worse in βC mutated tumors regardless of a specific genotype, than in wild-type tumors (49 versus 93%, respectively, p=0.02). No significant difference was observed in considering either T41A, or S45F or S45P mutants, even if 45Fmutation appears to show a weak trend of significance for a dismal outcome. Conclusions: A high frequency (87%) of βC mutation hallmarks EAF from a large multicentric retrospective study. Moreover, wild type βC appears as a good prognosis marker that can be useful for therapeutic management of the EAF.

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Consolidation with high-dose chemotherapy for responding patients to standard chemotherapy in advanced, metastatic soft tissue sarcoma (STS): A randomized trial from FNCLCC-French Sarcoma Group
Authors: Binh N. N. , Chevreau C. , Penel N. , Bay J. , Coindre J. , Mathoulin-Pelissier S. , Ray-Coquard I. , Italiano A. , Genève J. , Blay J.
Published: August 2020

10505

Background: Whether high dose (HD) chemotherapy improves disease-free (DFS) or overall (OS) survival has been suggested in phase II trial, but never explored in a randomized setting. This randomized, open, phase III study was designed to assess whether or not an HD chemotherapy with peripheral blood stem cells (PBSC) would improve OS in patients with advanced or metastatic STS responding to MAID chemotherapy. Methods: Pts aged 18 to 65 and with advanced STS were enrolled. After 4 courses of MAID, patients in PR or CR, or in whom complete surgical removal of all lesions was performed, were proposed for randomisation between 2 more cycles of MAID (control arm) vs 1 MAID followed by an intensification with MICE, ie: mesna (3.6g/m2, d1–5), ifosfamide (4g/m2, d1–4), carboplatin (UCA5, d2–4) and etoposide (300mg/m2, d1–4), followed by PBSC (HD arm). The primary endpoint was OS and the study was designed to detect by logrank test a 25% difference between the arms. Results: From 03/00 to 06/08, 266 patients were included and 87 were randomised (15 centres); low accrual and new treatment concepts lead to an IDMC in 11/08 who analysed 45 treated in the control arm (41 with full treatment) and 40 in the HD arm [only 21 received MICE, because consent withdrawal (6), insufficient PBSC harvest (5), tumor reprogression (4)]. Baseline characteristics (pts and tumors) were similar between treatment arms. With a 39 months follow-up, 25 pts were alive in the control arm, and 19 in the HD arm. The 3 years OS was 45.5% for control arm versus 35.8 for HD arm (HR = 1.12; 95% CI 0.58, 2.14; p = 0.72 Intention to treat analysis); PFS was 29.9% and 12.1 respectively (HR = 1.48; 95% CI 0.87, 2.53; p = 0.14). Higher rate of grade 3 - 4 hematologic (87% vs 46%), and digestive toxicity (33% vs 0%) were observed in the HD arm. Two treatment-related deaths occurred, both in the HD arm. Conclusions: In this study, HD chemotherapy for STS patients didn't improve OS and DFS. Consolidations with new concepts have to be explored.

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Updated outcome with long-term follow-up of imatinib for the treatment of progressive or recurrent aggressive fibromatosis (desmoid tumor): A FNCLCC/ French Sarcoma Group phase II trial
Authors: Dufresne A. , Penel N. , Salas S. , Le Cesne A. , Perol D. , Bui B. , Brain E. , Ray-Coquard I. , Jimenez M. , Blay J.
Published: August 2020

10518

Background: We present updated results from a previously reported phase II trial assessing clinical efficacy of imatinib in progressive or recurrent aggressive fibromatosis (Fayette et al. ASCO 2007) Methods: Patients with aggressive fibromatosis not amenable to radiotherapy or non-mutilating surgery were eligible and received imatinib 400mg daily (increased to 800mg daily in case of progression) up to 1 year then stopped. The primary end point was non-progressive disease rate at 3 months. Independent radiological committee reviewed responses. The number of patients was calculated according to a optimal 2-stages design. Results: Forty patients were included between September 2004 and October 2005 in 15 centers. The median follow up is 33 months [95% CI: 32–35]. Toxicity of imatinib is similar to that previously reported. At 3 months, the nonprogression rate was 91% [95% CI: 77–96] with 1 (2%) complete and 3 (8%) partial confirmed responses observed. The non progression rates at 6, 9, and 12 months were 80%, 69% and 66% respectively. The median time to progression was 9.5 months. The 2-year progression-free survival (PFS) was 55%. No plateau was observed. The 2-year-overall survival was 95%. Two patients with mesenteric aggressive fibromatosis died from progressive disease. In multivariate analysis including clinical factors, only previous radiotherapy was associated with reduced progression free survival. None of the biological factors tested using IHC on TMA (PDGFR α, PDGFR β, β catenin, c-kit, E cadherine, MCSFR, cycline D1 and Erk) were found correlated to response, progression free or overall survival. Conclusions: With a 2.8 years median follow up, this is the largest study which confirms the high efficacy of imatinib (400 mg daily) in patients presenting with aggressive fibromatosis failing local treatment and with documented evidence of progressive disease before imatinib treatment.

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Association of Notch signaling pathway expression in liposarcomas with outcome, and targeting with gamma-secretase inhibitors
Authors: Meng R. D. , Qin L. , Shelton C. C. , Li Y. , Maki R. G. , Brill E. R. , Singer S. , Schwartz G. K.
Published: August 2020

10526

Background: The Notch pathway directs normal fat cell development, but its aberrant activation may promote the development of sarcomas. The expression of the Notch pathway in liposarcoma (LPS), however, is unknown. We examined Notch signaling components in LPS's and suppressed Notch activation with drug targeting in LPS cell lines. Methods: RNA was isolated from 18 normal fat and 140 LPS tissue samples from five LPS subtypes: well-differentiated (33%), de-differentiated DD (25%), myxoid (12%), round cell (6%), and pleomorphic (13%), and were hybridized to Affymetrix U133A arrays. Microarray data were normalized with the RMA method. Correlation analysis identified genes expressed between sample classes, using Empirical Bayes t-test, and genes associated with survival, using Cox regression. The Notch pathway in two LPS lines, DDLS and LS141, was suppressed with a novel gamma-secretase inhibitor (GSI) or with siRNA to Notch receptors. Viability was assessed by colony formation, apoptosis by DAPI staining, and Notch expression by immunoblotting. Results: Expression of Notch-3 and its targets, Hes-1, Hey-1, and survivin, was increased in LPS subtypes, compared to fat tissue (p<0.001). Inhibition of Notch signaling with GSI's or siRNA to Notch-1 suppressed the viability of both DD LPS lines (p<0.05), inducing a G1/S arrest followed by apoptosis. Transfection of siRNA to each Notch receptor, especially Notch-3, also suppressed the viability of DD LPS's (p<0.05). Expression of Notch-3 (p=0.027, HR=2.64), Notch-4 (p=0.026, HR=2.70), the ligand JAG-2 (p=0.049, HR=2.32), and Hey-1 (p=0.001, HR=4.25) was associated with reduced distant recurrence free survival in patients with DD LPS's. Expression of the negative Notch regulator Fbxw7 was associated with improved overall survival in patients with LPS (p=0.008, HR=-1.42). Conclusions: Elements of the Notch pathway (receptors, ligands, targets, and modifiers) are overexpressed in LPS's compared to normal fat tissue and associate with outcome. Suppression of Notch signaling decreased DD LPS cell line viability and induced apoptosis. Notch inhibition may represent a new therapeutic strategy for patients with LPS's and deserves further validation in a clinical trial.

No significant financial relationships to disclose.
Molecular epidemiology of GISTs: Incidence of PDGFRA and KIT exon 9 mutations in the large French population-based study molecGIST
Authors: Emile François J. , Brahimi S. , Coindre J. , Monges G. , Scoazec J. Y. , Blay J. , Bouché O. , Aegerter P.
Published: August 2020

10535

Background: KIT exon 11, KIT exon 9, and PDGFRA exon 18 mutations are present in 67%, 10% and 5% of gastrointestinal stromal tumors (GIST). However most of these data are based on analyses of patients with overtly metastatic tumors. The MolecGIST study was design to evaluated prospectively the histological, molecular and clinical characteristics of all GISTs diagnosed at all stages. Methods: All patients leaving in France, whose diagnosis of GIST was achieved between June 1, 2006 and May 31, 2008 were includable in the study. MolecGIST was approved by French ethical comities. Samples were collected in 11 reference centers for histology review, immunohistochemistry and detection of mutations within exon 9, 11, 13, and 17 of KIT and 12, 14, and 18 of PDGFRA. Results: In December 2008, 738 patients were referred to MolecGIST, corresponding to 5.95/million/year incidence of GIST en France (62 millions inhabitants). The median age at diagnosis 63.1 years (range [15–96]), and female/male ratio 0.98. GIST originated in the stomach in 56.3% and small bowel in 29.3% of the cases. Tumors were KIT+ in 90,4% of cases. CD34 was expressed by more than 20% of tumor cells in 83.8% of gastric GIST and 39.7% of small bowel GIST respectively (P<0.0001). The risk of metastatic relapse was moderate or high in 62.7% of the patients, according to Fletcher classification, while only in 44% according to Miettinen's. Mutation analyses were achieved in 438 cases (to be updated), and mutations of either KIT or PDGFRA were detected in 66.2% and 12.6% of the patients, and absent in 21.2%. The most frequent mutations were KIT exon 11 (59.1%), PDGFRA exon 18 (9.8%) and KIT exon 9 (4.3%). The incidence of PDGFRA exon 18 and KIT exon 9 were significantly different than the published data (P=0.0008 and P<0.0001 respectively). Among GIST of the small bowel, the mutations were KIT exon 11 (69.1%) and KIT exon 9 (13.1%). Conclusions: The PDGFRAexon18/KITexon9 mutation ratio is 4.5 times higher in our population based study than in patients included in phase III trials. The incidence of GIST with PDGFRA mutations and intestinal GIST exon KIT exon 11 mutations is underestimated in published series as compared to ours, probably because of the better prognosis.

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