bluuebunny/crossref_metadata_2025 huggingface dataset:
PET/CT in restaging, prognosis, and recurrence in patients with malignant melanoma
Authors: El-Shourbagy Kholoud H. , Mashaly Emad M. , Khodair Sameh A. , Houseni Mohamed M. , Abou Khadrah Rania S.
Published: August 2020

Background

Cutaneous malignant melanoma (CMM) is a highly aggressive tumor with high tendency of return despite complete surgical removal. It has a high risk of dissemination to regional lymph nodes and visceral organs. The prognosis is highly dependent on lymph node involvement and distant metastases. Positron Emission Tomography with Computed Tomography (PET/CT) is a valuable non-invasive tool for the diagnosis and staging of patients with MM. The purpose of the present study was to evaluate the role of integrated (PET/CT) in staging, restaging, prognosis, and prediction of recurrence in patients with malignant melanoma.

Results

Fifty malignant melanoma patients with age ranged from 28 to74 years (mean age 55.94 + 13.40 years) were 28 males (mean age 56.71 + 12.82) and 22 females (mean age 54.95 + 14.34). All our patients were histopathologically proven to have malignant melanoma. Twenty-one patients came for initial staging by 18F-FDG PET/CT. Their findings were compared with the reference standards and showed the sensitivity of 93.33%, specificity of 60%, and accuracy of 85.71% for primary staging. 18F-FDG PET/CT scan in 11 clinical suspicion patients of relapse after treatment showed the sensitivity of 100%, specificity of 66.66%, positive predictive value of 88.88%; negative predictive value of 100%; and accuracy of 90.90%. FDG-PET/CT of whole body scan in 18 cases of stage IV melanoma showed sensitivity of 100%, specificity of 66.66%, and overall accuracy of 94.44% for detection of distant metastases. SUVmean and SUVmax in all studied groups were significantly higher in true positive more than true negative or false-positive patients diagnosed by PET/CT with high sensitivity (82.88–100%).

Conclusion

PET/CT imaging enhanced diagnostic performance in detection of the primary malignancy, in follow-up of high-risk patients and patients with suspected or known local or distant recurrence, and in restaging of patients with known distant metastatic disease to assess tumor response.
Upper GI series in infants and children with vomiting: insights into ACR appropriateness criteria
Authors: Mohammad Shaimaa AbdelSattar , Hamed Eman Ahmed , Shalaby Mennatallah Hatem , Eldieb Leila M. Rawash
Published: August 2020

Background

Although upper gastrointestinal series (UGI) series are frequently requested in pediatric radiology department, there are few articles investigating its value in children with vomiting. The purpose of this study was to review imaging findings perceived during UGI series in infants and children presented with vomiting in correlation to their symptoms based on the ACR appropriateness criteria. This was to identify clinical scenarios with higher diagnostic yield.

Results

A cross-sectional study including UGI series of 76 patients presented with vomiting (1 month–17 years) was performed. Patients were grouped according to their age into 5 groups and stratified according to the type of vomiting into 3 groups (bilious vomiting, new-onset nonbilious vomiting, intermittent nonbilious vomiting since birth). Associated symptoms were described with calculation of a novel clinical score. Radiological abnormalities in different age groups were described in relation to the type of vomiting. All patients with bilious vomiting or nonbilious vomiting associated with melena or dysphagia had abnormal findings. Gastroesophageal reflux was detected in 25% of cases. Patients with normal and abnormal study were compared according to their clinical score. The clinical score was significantly higher in the group of patients with abnormal findings (p < .001). Patients with recurrent chest symptoms and loss of weight had significantly higher rate of abnormal findings.

Conclusion

UGI series had a higher diagnostic yield in patients with bilious vomiting, children with nonbilious vomiting with higher clinical scores when associated with recurrent chest symptoms, loss of weight, dysphagia, or GIT bleeding especially melena.
Religion and psychiatry: research, prayer and clinical practice
Authors: Cook Christopher C. H.
Published: August 2020

Religious concerns, manifested in thought and behaviour, have a complex, bidirectional and sometimes conceptually overlapping relationship with mental health and mental disorder. Psychiatry, concerning itself with what is measurable in research, and with the relief of distress in clinical practice, has a different perspective on these complex interrelationships than does theology or religion. That which is transcendent, and therefore not measurable, is often important to patients, and sometimes distress may (theologically) be a sign of human well-being. The giving of careful attention to transcendence and distress may variously be conceived of as prayer, religious coping or clinical care. Applications of research to clinical practice, addressing as they do a sensitive and controversial boundary between psychiatry and religion, must therefore be patient centred and culturally sensitive.
Access to specialist community alcohol treatment in England, and the relationship with alcohol-related hospital admissions: qualitative study of service users, service providers and service commissioners
Authors: Roberts Emmert , Hillyard Miriam , Hotopf Matthew , Parkin Stephen , Drummond Colin
Published: August 2020

Background

Since 2012 England has seen year-on-year reductions in people accessing specialist community alcohol treatment, and year-on-year increases in alcohol-related hospital admissions.

Aims

We examined perceived barriers to accessing specialist treatment, and perceived reasons behind hospital admission increases.

Method

We conducted focus groups (n = 4) with service users and semi-structured interviews (n = 16) with service providers and service commissioners at four specialist community alcohol services in England, which experience either high or low rates of alcohol dependence prevalence and treatment access. Themes and subthemes were generated deductively drawing upon Rhodes’ risk environment thesis. Data were organised using the framework approach.

Results

Data reveal a treatment sector profoundly affected at all levels by changes implemented in the Health and Social Care Act (HSCA) 2012. Substantial barriers to access exist, even in services with high access rates. Concerns regarding funding cuts and recommissioning processes are at the forefront of providers’ and commissioners’ minds. The lack of cohesion between community and hospital alcohol services, where hospital services exist, has potentially created an environment enabling the reduced numbers of people accessing specialist treatment.

Conclusions

Our study reveals a treatment sector struggling with a multitude of problems; these pervade despite enaction of the HSCA, and are present at the national, service provider and individual service level. Although we acknowledge the problems are varied and multifaceted, their existence is echoed by the united voices of service users, service providers and service commissioners.
Randomized Comparison of Pazopanib and Doxorubicin as First-Line Treatment in Patients With Metastatic Soft Tissue Sarcoma Age 60 Years or Older: Results of a German Intergroup Study
Authors: Grünwald Viktor , Karch Annika , Schuler Markus , Schöffski Patrick , Kopp Hans-Georg , Bauer Sebastian , Kasper Bernd , Lindner Lars H. , Chemnitz Jens-Marcus , Crysandt Martina , Stein Alexander , Steffen Björn , Richter Stephan , Egerer Gerlinde , Ivanyi Philipp , Zimmermann Silke , Liu Xiaofei , Kunitz Annegret
Published: August 2020

PURPOSE

Doxorubicin is a standard of care in patients with advanced, inoperable soft tissue sarcoma (STS). We tested whether pazopanib has efficacy comparable to that of doxorubicin in elderly patients with STS and offers superior tolerability for hematologic toxicity.

PATIENTS AND METHODS

Patients age 60 years or older without previous systemic treatment for progressive advanced or metastatic STS who had Eastern Cooperative Oncology Group performance status of 0 to 2 and adequate organ function were included. Treatment consisted of pazopanib 800 mg once per day or doxorubicin 75 mg/m2 once every 3 weeks (≤ 6 cycles) after being randomly assigned in a 2:1 ratio. Noninferiority was assumed for progression-free survival (PFS), if the upper limit of the 95% CI for the hazard ratio (HR) was less than 1.8. Neutropenia and febrile neutropenia were key secondary end points. The European Organisation for Research and Treatment of Cancer (30-item) Quality of Life Questionnaire and geriatric assessment were used to measure patient-reported outcomes. Cox regression analysis and Kaplan-Meier curves were used for analysis.

RESULTS

Pazopanib and doxorubicin were given to 81 and 39 patients, respectively. The median age was 71 years (range, 60-88 years). PFS was noninferior (HR, 1.00; 95% CI, 0.65 to 1.53) and the incidence of grade 4 neutropenia and febrile neutropenia favored pazopanib. Objective response rates for pazopanib and doxorubicin were 12.3% and 15.4%, respectively. Overall survival did not differ significantly between arms (HR, 1.08; 95% CI, 0.68 to 1.72; P = .735). Geriatric assessment revealed 2 or more comorbidities in 15.8% of the patients and impairment of activities of daily living in 28.3% of patients.

CONCLUSION

Pazopanib was noninferior to doxorubicin, rendering pazopanib a putative therapeutic option in the first-line treatment of STS in patients age 60 years or older. The distinct adverse event profile may be used to counsel patients and tailor therapy to individual needs.
Phase III trial of gemcitabine plus docetaxel (GD) compared to capecitabine plus docetaxel (CD) with planned crossover to the alternate single agent in metastatic breast cancer (MBC)
Authors: Seidman A. D. , Brufsky A. , Ansari R. H. , Rubinsak J. R. , Stein R. S. , Schwartzberg L. S. , Stewart J. F. , Zhao L. , Gill J. , Tai D.
Published: August 2020

1000

Background: GD and CD are efficacious in patients (pts) with MBC. This study compared safety and efficacy of GD and CD induction regimens, where the alternate, single-agent, crossover therapy (GD to C or CD to G) was predetermined. Primary endpoint was time to progressive disease (TTP). Secondary endpoints included toxicities, overall response (ORR), and overall survival (OS). Methods: This multicenter, open-label, phase III study enrolled MBC pts with possible prior anthracycline therapy, adjuvant or neoadjuvant taxane therapy, but no taxane therapy for MBC ≤6 months prior to entry. Enrollment of 442 pts (221 per arm) was planned with 385 progressions required to achieve 80% power for a 2-month observed difference in median TTP between arms. Pts were randomized to: GD: G 1,000mg/m2 Days 1, 8 plus D 75 mg/m2 Day 1, q21 days; or CD: C 1,000 mg/m2 BID, Days 1–14 plus D 75 mg/m2 Day 1, q 21 days. Upon disease progression, pts were given crossover C or G at doses and schedules identical to induction. ORR was assessed by RECIST. Results: Demographics of 472 enrolled pts were balanced between arms; 57% had prior anthracycline. GD caused greater myelosuppression than CD, but without greater febrile neutropenia. Gastrointestinal toxicities, mucositis, and hand-foot syndrome were greater with CD. More pts in the CD arm (n=61, 26.2%) versus the GD arm (n=41, 17.2%) discontinued due to toxicity (p=0.023). ORR, TTP, and OS were not significantly different comparing GD and CD. However, ORR and TTP were significantly greater for the GD to C crossover monotherapy compared to CD to G. Post-hoc analysis of crossover pts showed that the TTP sum from induction through crossover was 6.1 months greater for GD to C. Conclusions: GD and CD had similar efficacy with toxicity profiles consistent with prior clinical experience. Results suggest that the GD to C crossover sequence may provide a clinical benefit over CD to G.

[Table: see text]

[Table: see text]
Association of primary mediastinal B-cell lymphoma (PMBL) in children (C) and adolescents (A) with a significantly inferior prognosis: Final results of the FAB/LMB 96 trial
Authors: Gerrard M. , Waxman I. , Sposto R. , Auperin A. , Harrison L. , Pinkerton R. , Perkins S. L. , McCarthy K. , Raphael M. , Patte C. , Cairo M. S.
Published: August 2020

10001

Background: Single pediatric cooperative group studies have demonstrated an EFS ranging from 65 - 75% in C & A with large cell lymphomas arising in the mediastinum (Lones/Cairo et al, J Clin Oncol, 2000; Burkhardt/Reiter et al, Br J Haematol, 2005; Seidman/Reiter et al, J Clin Oncol, 2003). Recently, Staudt and Shipp have independently demonstrated that following gene expression profiling by oligonucleotide microarray that PMBL resembles more like classical Hodgkin lymphoma than diffuse large B-cell lymphoma with enhanced NF-κB pathway gene expression (Rosenwald et al, J Exp Med, 2003; Abramson et al, Blood, 2005). It remains to be determined what the optimal therapy for C & A with PMBL is and if poor outcome subgroups can be identified. Methods: We analyzed the results of C & A with PMBL treated with group B therapy on FAB/LMB 96 (Patte/Cairo et al, Blood, 2007). Results: There were 528 patients with stage III/IV disease treated on group B therapy on FAB/LMB 96 resulting in a 2 yr EFS of 84% (CI95: 82–86%). Forty-two of these patients had PMBL; M/F: 26/16; 10 - 14 vs 15 -19 yrs: 28/14; and LDH < 2 vs ≥ 2 upper normal: 20/22. Response to COP reduction: 1 CR (100%), 33 IR (20–99%) and 7 NR (< 20%). There was no significant difference in EFS with respect to age, gender, COP response and initial LDH. 5 yr EFS and OS were 54% (CI95: 38–68%) and 73% (CI95: 56–84%), respectively. 5 yr EFS was significantly inferior compared to the remainder of the other patients with stage III disease treated on group B therapy (54%: CI95 38–68% vs 85%: CI95 81–88%) (p < 0.001). Conclusions: PMBL in C & A is associated with a significantly inferior EFS compared to other histological forms of stage III/IV mature B-NHL. Alternate treatment strategies including consideration of underlying biological differences need to be developed to improve EFS in C & A with this poor-risk sub-group of mature B-NHL.

No significant financial relationships to disclose.
Identification of SGK1 as a novel predictive marker for treatment response in medulloblastoma
Authors: Sturm D. , Remke M. , Pleier S. , Witt H. , Reifenberger G. , Felsberg J. , Kulozik A. , Korshunov A. , Lichter P. , Pfister S.
Published: August 2020

10006

Background: We have recently demonstrated that both gains (5-year OS 16%) and losses (5-year OS 100%) of chromosome 6q define distinct clinical and biological subgroups of medulloblastoma. However, the underlying molecular mechanisms accounting for the prognostic impact of these aberrations so far remained unclear. Methods: To identify potential candidate genes on chromosome 6q targeted by these genomic aberrations, a genome wide mRNA expression profiling study was performed for 47 well-characterized medulloblastoma samples and correlated to chromosome 6q DNA copy-number status. Results were validated by real-time quantitative PCR (RTQ-PCR). SGK1 protein expression was examined by immunohistochemistry on a tissue-microarray which represents a large independent cohort of uniformly treated medulloblastoma patients (n = 260). Results of both studies were correlated with survival data available for all investigated samples. Results: Expression profiling revealed the AKT homologue SGK1 as an interesting candidate gene on chromosome 6q showing very close correlation to 6q copy-number status. Direct correlation could be confirmed by RTQ-PCR showing that SGK1 mRNA levels were significantly upregulated in tumors with gain of chromosome 6q (median log2-ratio when normalized against normal cerebellum = 3.88) and, in contrast, downregulated in cases carrying deletions of this region (median log2-ratio = -1.97). On protein level, we found high SGK1 protein levels to be highly associated with poor overall survival as assessed by immunohistochemistry (Kaplan-Meier method; p < 0.00001). Conclusions: We identified SGK1 as an interesting novel candidate gene on chromosome 6q contributing to the striking differences in overall survival of cases with chromosome 6q gain or loss, who are known to have a very poor or especially good prognosis, respectively. The fact that SGK1 encodes for a serum- and glucocorticoid inducible kinase which is both structurally and functionally homologous to the antiapoptotic kinase AKT further underlines the potential role of this gene. Based on the reported results, we propose SGK1 protein expression as a novel prognostic marker in medulloblastoma.

No significant financial relationships to disclose.
Phase I study of fenretinide (4-HPR) oral powder in patients with recurrent or resistant neuroblastoma: New Approaches to Neuroblastoma Therapy (NANT) Consortium trial
Authors: Marachelian A. , Kang M. H. , Hwang K. , Villablanca J. G. , Groshen S. , Matthay K. K. , Maris J. , DeSantes K. B. , Reynolds C. P. , Maurer B. J.
Published: August 2020

10009

Background: Fenretinide (4-HPR), a cytotoxic retinoid, achieved limited and variable plasma levels when tested in a corn oil-based capsule. 4HPR/Lym-X-Sorb (LXS) oral powder is a new formulation intended to increase bioavailability, especially in children. Methods: This trial sought to define the toxicities, dose limiting toxicities (DLTs), maximum tolerated dose (MTD), and pharmacokinetics of 4-HPR/LXS oral powder when given mixed in Slim-Fast nutritional shakes, twice a day for 7 days, every 21 days. Eligible patients had high-risk neuroblastoma with recurrent/progressive disease, or disease refractory or persistent after frontline therapy. Dose escalation was in 30% increments using the traditional 3 + 3 design. Plasma levels were measured by HPLC. Results: Thirty-two patients accrued to 8 Dose Levels (DL) (352 –2210 mg/m2/day); 30 patients were evaluable. No MTD was identified. There was a DLT elevation of alkaline phosphatase on DL1. No other DLT's were observed. Other toxicities included dry skin, elevated triglycerides, reversible nyctalopia, and transient transaminase elevation. Course 1 day 7 peak 4HPR plasma levels (Dose (mg/m2/day) - mean, (range)) were: 352 –6 μM (3.8–9.6); 458–11.5 μM (9.7–14.9); 595–17.6 μM (6–24.3); 774–15 μM (9.1–25.3); 1006–6.7 μM (5.2–9.2); 1308–13.9 μM (2.9–23.8); 1700–19.7 μM (17.3–24.3); and 2210–10.8 μM (4–16.5). Course 2 day 7 peak plasma levels trended higher than course 1 at DL5–8. Three patients with isolated bone marrow disease and one with MIBG avid bone lesions, had complete responses (DL4, DL4, DL7, DL8) receiving 10, 17, 18 and 10 courses of therapy, respectively. Six patients had stable disease for 4–27 courses (median 5.5) (DL3, DL4, DL4, DL5, DL6, DL8). Twenty patients had progressive disease. Central review of responses is pending. Conclusions: 4-HPR/LXS oral powder was well tolerated, obtained 2 - 5 fold higher 4HPR plasma levels than fenretinide capsules on the same dose and schedule (P < 0.01), and showed anti-tumor activity (complete responses in 4/15 patients at DL4–8). Based on pharmacokinetic data, a recommended Phase II dose and schedule is 1700 mg/m2/day × 7days every 3 weeks.

No significant financial relationships to disclose.
Significance of tumor biology compared to metastatic pattern (INSS 4 versus 4s) and age for prognosis of neuroblastoma less than 18 months of age
Authors: Taggart D. R. , London W. B. , Schmidt M. L. , Zhang Y. , Dubois S. G. , Monclair T. , Pearson A. D. , Cohn S. L. , Matthay K. K.
Published: August 2020

10010

Background: Neuroblastoma is a heterogeneous disease with variability in outcome among different risk groups. Historically, INSS stage 4s neuroblastoma (age less than 12 months, stage 1 or 2 primary tumor with metastases limited to liver, skin and bone marrow) has a more favorable outcome than infant stage 4 disease. The aim was to determine if metastatic pattern (4 vs 4s) predicted favorable prognosis in infants < 12 months or in toddlers aged 12–18 months when stratifying by biology. Methods: Outcome was analyzed by log rank tests and Cox models for 656 infants with stage 4s neuroblastoma and 1,019 stage 4 patients < 18 months of age in the International Neuroblastoma Risk Group database (n=8,800). Prognostic factors (tumor ploidy, histology, grade, MKI, LDH, MYCN, 11q, 1p, primary site) were tested for association with age/stage subgroups (Fisher's exact test) and in Cox models. Results: MYCNamplification, 1p aberration, diploidy, and high MKI and LDH were more frequent in infant stage 4 than infant 4s tumors. The incidence of unfavorable biology was higher in toddlers aged 12–18 months, but did not differ with stage 4 vs. 4s pattern. EFS was significantly better for infants <12 months with stage 4s than stage 4 (p=0.0004). EFS was similar for toddlers 12–18 months for stage 4 vs. 4s pattern (p=0.3893). Within the 717 patients with 4s pattern of metastases, age 12–18 months had worse EFS than <12 months (p<0.0001). After adjustment for age in 6 separate models, MYCN, 11q, 1p, MKI, and LDH were statistically significant prognostic factors. Although treatment regimens differed, EFS was similar for <12 months vs. 12–18 months for MYCN not amplified patients in both 4S pattern (p=0.8469) and stage 4 (p=0.3783). Conclusions: For patients with MYCN not amplified tumors, outcome for patients 12–18 months is similar to those <12 months regardless of the pattern of metastases. Tumor biology is more critical than metastatic pattern for prognosis of patients aged 12–18 months with stage 4 neuroblastoma. [Table: see text]

No significant financial relationships to disclose.
A phase I trial and pharmacokinetic study of IMC-A12 in pediatric patients with relapsed/refractory solid tumors: A Children's Oncology Group Phase I Consortium study
Authors: Malempati S. , Weigel B. , Ingle A. M. , Ahern C. H. , Carroll J. M. , Roberts C. T. , Fox F. E. , Voss S. , Adamson P. C. , Blaney S. M.
Published: August 2020

10013

Background: IMC-A12, a fully human IgG1 monoclonal antibody to the Insulin-Like Growth Factor-I Receptor (IGF-IR), is active preclinically in a variety of pediatric solid tumors. We performed a phase I trial to determine the toxicities, maximum tolerated dose (MTD), pharmacokinetics (PK), and pharmacodynamics (PD) of IMC-A12 in children with refractory solid tumors. Methods: IMC-A12 was administered as a weekly 1 hr IV infusion, without interruption. Two dose levels, 6 and 9 mg/kg, were evaluated using a standard 3+3 cohort design. After defining initial safety, patients (pts) with refractory Ewing sarcoma (ES) were treated in an expanded cohort at each dose level. Results: 24 eligible patients (11 male), median 15.3 yrs (range, 7.0 to 21.5), were enrolled. Among the 12 pts enrolled on the dose-escalation component, DLT (grade 4 thrombocytopenia) occurred in 1/6 pts at 6 mg/kg. No DLTs occurred in 6 pts at 9 mg/kg or in the ES cohort. 1/10 evaluable pts with ES at the 6 mg/kg dose had a partial response; no CRs were observed. Grade 2 or higher non-DLTs possibly attributable to IMC-A12 observed in the first course include anemia (n=4), leukopenia (n=1), lymphopenia (n=2), neutropenia (n=2), opportunistic infection (n=1), ↑liver transaminases (n=2), and hyperglycemia (n=1). No ≥ grade 3 hyperglycemia occurred. Mean (± SD) trough IMC-A12 concentrations were 59.8 ± 31.1 and 117 ± 70.8 μg/ml at the 6 and 9 mg/kg dose levels, respectively. A majority of pts at both dose levels exhibited > 50% reduction in PBMC IGF-IR protein levels. Conclusions: In order to exceed target trough concentrations associated with optimal anti-tumor activity in pre-clinical models, 9 mg/kg IV weekly is the recommended Phase II IMC-A12 dose in children. A phase II protocol for children with refractory solid tumors will be performed.

[Table: see text]
Frontline treatment of localized osteosarcoma without methotrexate: Results of the St. Jude Children's Research Hospital OS99 trial
Authors: Daw N. C. , Neel M. D. , Rao B. N. , Billups C. A. , Wu J. , Jenkins J. J. , Villarroel M. , Luchtman-Jones L. , Quintana J. , Santana V. M.
Published: August 2020

10036

Background: Standard treatment of osteosarcoma includes cisplatin and high-dose methotrexate (HD-MTX), but both agents are associated with significant toxicity and MTX administration requires complex pharmacokinetic monitoring. In our previous OS91 trial, the combination of carboplatin and ifosfamide with doxorubicin and HD-MTX yielded outcomes comparable to those of cisplatin-based regimens with less long-term toxicity in localized osteosarcoma. Methods: Between 1999 and 2006, we conducted a multi-institutional trial (OS99) to evaluate the activity of carboplatin, ifosfamide, and doxorubicin without HD-MTX in newly-diagnosed patients with localized osteosarcoma. Treatment comprised 12 cycles of chemotherapy given every 3 weeks: 3 consecutive cycles of carboplatin (dose targeted to AUC 8 mg/ml×min on day 1) and ifosfamide (2.65 g/m2 daily for 3 days) and one cycle of doxorubicin (25 mg/m2 daily for 3 days) followed by definitive surgery (week 12) and 2 additional cycles of carboplatin/ifosfamide and 3 cycles each of ifosfamide/doxorubicin and carboplatin/doxorubicin for a total of 35 weeks. The log rank test was used to compare survival and event-free survival (EFS) distributions. Results: A total of 72 eligible patients were enrolled. The median age was 13.4 years and 41 (57%) were male. The most common tumor site was the femur (n = 46; 64%). The median follow-up for survivors was 4.4 years. Forty of the 66 (60.6%) evaluable patients had good histologic response (tumor necrosis > 90%) to preoperative chemotherapy. There was no difference in EFS or survival distributions between OS99 and OS91. Four-year estimates of EFS were 68.1 ± 6.7% for OS99 compared to 70.2 ± 6.6% for OS91 (p = 0.89). The 4-year OS was 82.4% ± 5.7% for OS99 compared to 74.5% ± 6.3 for OS91 (p = 0.25). Conclusions: OS99 produced outcomes similar to cisplatin or HD-MTX containing regimens and offers an alternative treatment regimen especially for patients with renal compromise and institutions where pharmacokinetic monitoring of MTX is not available.

No significant financial relationships to disclose.
Fifteen years experience of the Brazilian Osteosarcoma Treatment Group (BOTG)
Authors: Petrilli A. S. , de Camargo B. , Odone Filho V. , Lustosa D. , Borsato M. L. , Calheiros L. M. , Brunetto A. L. , Barreto J. H. , Ferraro A. A.
Published: August 2020

10039

Background: This is a 15-year analysis of disease characteristics and treatment outcome from three consecutive studies of BOTG. Results from protocols III and IV were previously published (J Clin Oncol. 24:1161–8, 2006). Methods: 604 histologically confirmed high-grade osteosarcoma patients were enrolled into these multicentric studies (with 4, 5, and 20 institutions in studies III, IV, and 2000, respectively). Results: Of the 604 patients, 578 were evaluable with osteosarcoma of extremities, mean age at enrollment of 14, mean time to diagnosis of 4.4 months, advanced disease (tumors diameter > 12cm) in 45% and metastatic disease in 30% of the patients. Statistically significant prognostic factors were: tumor size, histological response (Huvos grade), presence of metastasis at diagnosis and type of surgery. Time to diagnosis was not predictable of survival. Advanced disease was associated to presence of metastasis and to a poorer histological response. During the first 5 years, 53% of the patients had conservative surgery with 19.6% of local recurrence and these numbers were 65.5% and 14% in the next 5 years and 62.3% and 11% during the last 5 years. The overall survival (OS) at 5 years was 44%, 45% and 46% respectively. In the whole cohort of patients, overall survival (OS) was 45.7% at 5 years and 43% at 10 years and event free survival (EFS) was 43% and 34%. For non-metastatic patients, OS was 56.5% and 54% and EFS was 53% and 44%, respectively. Conclusions: Over these 15 years, we were able to increase limb salvage procedures with a significant drop in local recurrence, reaching survival rates similar to some international studies. This cumulative experience enabled the expansion of the collaborative group, the identification of prognostic factors, dissemination of knowledge, and the development of the current protocol for osteosarcoma treatment, which is a multicentric, randomized study with good quality data collection over 26 sites in Latin America.

No significant financial relationships to disclose.
Neratinib in combination with trastuzumab for the treatment of advanced breast cancer: A phase I/II study
Authors: Swaby R. , Blackwell K. , Jiang Z. , Sun Y. , Dieras V. , Zaman K. , Zacharchuk C. , Powell C. , Abbas R. , Thakuria M.
Published: August 2020

1004

Background: Neratinib (HKI-272) is an orally administered irreversible pan-ErbB receptor tyrosine kinase inhibitor. In an ongoing phase II study, the preliminary objective response rate was 26% in patients with ErbB2+ advanced breast cancer with prior trastuzumab therapy. This study assessed the safety and preliminary efficacy of the combination of neratinib plus trastuzumab. Methods: Patients with advanced ErbB2+ breast cancer that progressed following trastuzumab therapy were enrolled. The primary endpoint was 16-week progression free survival rate (PFS). In part 1 (dose escalation), patients received neratinib 160 mg or 240 mg daily plus trastuzumab 4 mg/kg IV loading dose then 2 mg/kg weekly. In part 2, patients received weekly trastuzumab with neratinib 240 mg daily. Timed blood samples were collected for PK analyses. PK analysis is ongoing. Results: 45 patients (part 1 n = 8; part 2 n = 37) were enrolled (mean age 52 yr); 9 are active. In part 1, cohorts 1 and 2 were fully enrolled with 4 patients each. No dose limiting toxicities were observed. Most common AEs, any grade, were diarrhea (91%), nausea (51%), anorexia (40%), vomiting (38%), and asthenia (27%). Grade 3/4 AEs were diarrhea (13%), nausea (4%), vomiting (4%). Two patients receiving neratinib 240 mg reported AEs leading to withdrawal. No AEs of congestive heart failure and no significant drops of left ventricular ejection fraction were reported. Among 33 patients evaluable for efficacy, objective response rate was 27% (95% CI, 13% - 46%); 16-week PFS rate (for part 2) 47% (95% CI, 29% - 63%); median PFS was 19 weeks (95% CI 15 - 32 weeks). Conclusions: Neratinib plus trastuzumab was well tolerated with no significant or unexpected toxicities, and demonstrated clinical activity.

[Table: see text]
Successful treatment with minimal chemotherapy followed by low-dose involved field radiotherapy in children with Hodgkin's disease: A 20-year experience in a single institution in Greece
Authors: Pourtsidis A. G. , Doganis D. , Baka M. , Bouhoutsou D. , Varvoutsi M. , Servitzoglou M. , Kosmidis S. , Synodinou M. , Strantzia C. , Kosmidis H.
Published: August 2020

10052

Background: The vast majority of children with Hodgkin's disease (HD) nowadays have an excellent chance of definite cure. The high curative rates as well as the prevention of late effects have to be among aims when managing children with HD. The purpose of our retrospective study was to report the outcome and prognostic factors of patients (pts) less than 15 years of age with HD treated with chemotherapy (CT) followed by low dose radiation from 1987 to 2006. Methods: We studied 58 children analyzing the following data: age, sex, stage, histology, therapy correlating these with the outcome of pts. Among 35 boys and 23 girls, age at diagnosis 4.5 - 15 years (median 12), all aged 7 years or less were boys (8/58). Nodurar sclerosis was the predominant histology subtype (69%) and 45% had advanced disease (stages III or IV). According the study period pts with early stage received 4 cycles of ABVD or VBVP and those with advanced stage disease alternating 3 cycles of MOPP/ABVD or 2 of MOPP/ABVP for stage III and alternating 3 cycles of MOPP/ABVD or 2 OPPA plus 4 COPP for stage IV. All pts had a good response (more than a 70% reduction) after initial CT and received 20 Gy of RT to initially involved fields. Results: Complete remission (CR) was achieved in all patients. Chemo- and radio-therapy were well tolerated. Fifty-three pts (DFS: 91.4%) live in their first complete remission. In 5 pts (8.6 %) relapse occurred, 20 -65 months from dx (median 25 mo). All received salvage treatment in combination with high dose CT and autologous stem-cell transplantation (SCT). Of the 5 relapsed all live 21 - 207 months (median 75 mo) from the dx of relapse and 41 - 232 mo (median 99) from the dx of disease. Second (thyroid cancer) plus third malignancy in one (osteosarcoma) was detected in 3 pts and all are alive. Finally for our group the overall survival is 100% and all children are alive 25 - 264 mo from dx (median 145 mo) and the event free survival is 86.2% (50/58). No factors related to the outcome were detected. Conclusions: In conclusion combined-modality therapy remains the standard of care for children with HD. However, there may be a significant number who can be cured with chemotherapy alone. At this moment the main question is: who can be cured without RT?

No significant financial relationships to disclose.
Treatment of relapsed/refractory pediatric sarcomas with gemcitabine and docetaxel
Authors: Cruz O. , Mora J. , Parareda A. , de Torres C.
Published: August 2020

10059

Background: Cure rates for children andadolescent's cancer have improved steadily for most tumor types. However, recurrent disease or progressive-refractory sarcomas remain incurable and most of these patients die within 1 to 2 years after diagnosis. In this report we describe experience with gemcitabine-docetaxel (G+D) in pediatric patients with relapsed or refractory sarcomas. Methods: Ten relapsed/refractory pediatric sarcoma patients including 6 Ewing sarcoma, 2 synovial sarcoma, 1 osteosarcoma, and 1 undifferentiated sarcoma were treated in an outpatient setting with gemcitabine 1000 mg/m2 over 90 minutes on day 1 and 8, and docetaxel 100 mg/m2 ver 3 to 4 hours on day 8 of a 21-day cycle, as an investigational rescue therapy. Results: A median of 7 cycles were given per patient (range, 4 to 10), and a total of 70 cycles were administered. To date, 2 patients continue on treatment. All symptomatic patients responded clinically to this regimen. No grade 3–4 toxicities were encountered. Five patients (50%) had a CR/functional CR, 4 patients (40%) had a PR/SD, and 2 patients (20%) had PD, which provides an overall response rate (CR+PR/SD) of 90%. Prolonged disease stabilization was achieved even for multiple relapsed patients with the G + D regimen, median duration of responses 11 months. Five out of the 10 patients (50%) are alive, median follow-up 48 months from diagnosis. Conclusions: The G + D regimen seems to be active against advanced pediatric sarcomas. It does not exacerbate pre-existing toxicities and allows good quality of life. Evaluation in a large, formal phase II trial for ES patients is ongoing.

No significant financial relationships to disclose.
Progression-free survival (PFS) of patients with HER2-negative, estrogen-receptor (ER)-low metastatic breast cancer (MBC) with the addition of lapatinib to letrozole: Biomarker results of EGF30008
Authors: Finn R. S. , Press M. , Dering J. , Florance A. , Platek G. , Arbushites M. , Koehler M. , Johnston S.
Published: August 2020

1018

Background: Lapatinib (Lap), an oral, dual inhibitor of EGFR/HER-2, is approved with capecitabine for treatment of HER-2+ MBC for recurrence after taxane, anthracycline, and trastuzumab-based therapy. Letrozole (Let) has activity in hormone-receptor positive (HR+) BC. It has been hypothesized that peptide growth factor signaling and hormone signaling pathways interact and dual targeting of these pathways results in therapeutic synergy. We report a blinded analysis of HER-2, ER, and progesterone receptor (PR) expression for patients (pts) with HR+ MBC at first diagnosis or post-adjuvant relapse and response to Lap + Let versus Let. Methods: 1286 pts were randomized 1:1 to 2.5 mg Let daily plus either 1500 mg Lap daily or placebo. The primary endpoint was PFS in HR+, HER-2+ MBC pts; secondary endpoints included PFS in the intent-to-treat population. Blinded, centralized commerical laboratory analysis of archived tumor tissue for HER-2 (IHC and/or FISH) and academic laboratory semi-quantitative analysis of ER/PR (IHC, H-score) was performed and correlated with clinical outcome. Results: In 219/1286 (17%) HER-2+ (FISH+ or IHC3+) pts, a significant improvement in median PFS was observed for Lap + Let versus Let (8.2 v 3.0 mos, HR = 0.71, 95% CI 0.53, 0.96, p = 0.019). No significant difference in median PFS was seen in 952 (74%) HER-2-negative pts (13.4 v 13.7 mos, HR = 0.90, 95% CI 0.77, 1.05, p = 0.188). 821/952 (86%) HER-2-negative pts had tissue available for quantitative ER and PR analysis. Analysis of ER and PR by quartile identified a subgroup of HER-2-negative pts that benefitted from adding Lap to Let. Pts with the lowest quartile of ER expression (H-score <160, n = 207) had a significant improvement in median PFS (13.6 mos v 6.6 mos, HR = 0.65, 95% CI 0.47, 0.9, p < 0.005). Pts with higher levels of ER did not significantly benefit from adding Lap to Let. Analysis of PR expression did not identfiy a subgroup that benefited from Lap. Conclusions: Pts with HER-2-negative, ER+ MBC and low ER expression may benefit from the addition of lap to let. Additional analyses of EGFR, other biomarkers, and prior hormone therapy will be presented.

[Table: see text]
N0337: Phase II study of capecitabine in combination with vinorelbine and trastuzumab for the first or second treatment of HER2+ metastatic breast cancer
Authors: Tan W. , Allred J. , Salim M. , Flynn P. , Kugler J. W. , Stella P. J. , Wiesenfeld M. , Bernath A. M. , Fitch T. R. , Perez E. A.
Published: August 2020

1020

Background: Trastuzumab-containing regimes have dramatically improved outcome of patients with HER2+ breast cancer. Efforts to improve efficacy and tolerability of combination regimens with this monoclonal antibody are important for patient care. Thus, we conducted a multi-institutional phase II study of a triplet combination in patients eligible to receive either first- or second-line treatment for HER2+ metastatic breast cancer (MBC). Methods: A phase II study designed to test that the true confirmed response rate (CRR) was at most 45% versus a true CRR of at least 65% was done (March 2005-June 2008). This design required that at least 25/45 confirmed responses in evaluable patients for the treatment to be considered promising. Patients received capecitabine 825 mg/m2 po (days 1–14), vinorelbine intravenously (IV) 25 mg/m2 days 1 and 8 every 3 weeks and trastuzumab IV 8mg/kg day 1, week 1, and then 6 mg/kg q 3 weeks. Tissue and blood have been collected for future studies on biomarkers. Results: 47 women were accrued, one patient cancelled participation prior to receiving any study drug, and another had a major protocol violation. 45 patients were evaluable and 30 (67%) achieved a confirmed response, (26 patients, 58% had a confirmed partial response and 4 patients, 9% had a confrimed complete response). Median progression free survival was 11.3 months (95% CI 8.4–23.2 months), median overall survival was 27.2 months (95% CI: 26.6-NA months), and among the 30 responders, the median duration of response time was 15.5 months (95% 7.7–26.1 months). The most common grade 3 events include neutropenia 61%, fatigue 13%, skin reaction-hand-foot 11%, and leukopenia 11%. Alopecia was not noted with this regimen. Conclusions: This triplet combination is effective, safe, and is promising in patients with HER2+ MBC. A phase III study should be conducted to compare the best doublet with this triplet combination whether this would lead to better clinical outcomes.

[Table: see text]
Bevacizumab and oral chemotherapy for patients with lymphangitic breast cancer: A phase II randomized study of bevacizumab with sequential versus concurrent oral vinorelbine plus capecitabine
Authors: Locatelli M. A. , Curigliano G. , Fumagalli L. , Ghisini R. , Mancuso P. , Bertolini F. , Viale G. , Lunghi L. , Goldhirsch A.
Published: August 2020

1031

Background: Antiangiogenic agents are most likely to be effective in patients (pts) with an extensive cutaneous neo-angiogenic trait of disease. There is a compelling need to monitor the biological activity of such agents and identify markers of efficacy. Methods: We evaluated the activity and biological effects of bevacizumab (B) (15 mg/kg, iv q 3 weeks) in a phase II randomized trial in pts with locally advanced breast cancer (BC) with lymphangitic spread to the chest wall. Primary aim was to assess activity and toxicity of B administered alone followed by sequential oral vinorelbine (V) plus capecitabine (C) (arm A) or with concurrent V plus C (arm B). Secondary aim was to evaluate predictive role of circulating progenitor cells (CECs) and progenitor endothelial cells (CEPs) as surrogate markers of antiangiogenic activity. We collected blood samples of all pts at baseline, at day 12, 42, and at progression. Results: Planned accrual was of 43 pts of whom 23 were enrolled (9 pts in arm A; 14 pts in arm B). Median age was 51 years (range 35–68). Most of the pts had a “triple negative” phenotype [19/23 (82%)]. 10/23 pts (43%) received ≥ 2 previous lines of chemotherapy. 19 pts (82 %) are evaluable for response and all 23 pts are evaluable for toxicity. We observed 5 PR (45%) and 6 SD (55%) in arm B. In arm A, while on B alone, 6 (75%) of the pts had PD and 2 (25%) had a short term SD. Adding VC to B 2 PR (25%), 3 SD (37.5%), and 3 PD (37.5%) were observed. Toxicity profile was typical for use of B (hypertension). The absolute mean number of CECs was 158/ml (range 45–461) (n = 23) at baseline, 116/ml at +12 (range 47–275), and 194/ml at +42 (range 36–891). Mean absolute value of CEPs was 270 (range 28–1060) at baseline, 245/ml at D+12 (range 14–981), and 143/ml (range 5–610) at D+42. The fraction of apoptotic/necrotic CECs was 54±19% at baseline, 64±21 at+12, and 52±18 at+42. Conclusions: Preliminary data showed that B alone is not an effective treatment in pts with lymphangitic spread of BC to the chest wall. Additional data on CECs and CEPs are needed to clarify their potential usefulness as a surrogate markers of antiangiogenic activity of B-based regimen.

No significant financial relationships to disclose.
Gene expression differences between disseminated tumor cells and tumor cells from overt bone metastases in patients with metastatic breast cancer
Authors: Broom R. J. , Amir E. , Cawthorn T. , Freedman O. , Gianfelice D. , Barth D. , Galica J. , Wang D. , Done S. J. , Clemons M.
Published: August 2020

1040

Background: Despite extensive work evaluating molecular differences between primary tumors, circulating tumor cells, disseminated tumor cells (DTCs) and established metastases, it is not apparent which genetic alterations are required to form viable, independent bone metastases (BM). A major limitation in exploring the genetic differences between DTCs and established BM is the paucity of fresh BM tissue available. Methods: Ten breast cancer patients with BM underwent a CT-guided BM biopsy and a bone marrow aspiration (for DTCs). Tumor cells were enriched by immunomagnetic separation and RNA was extracted from each sample. Gene expression profiling was conducted using Illumina Human Ref-8 bead arrays. Microarray data was analyzed using BeadStudio software to identify differentially expressed genes. Ingenuity Pathway Analysis software was used to identify genes integral to specific pathways involved in tumor dissemination. Results: The yield of analyzable malignant cells from BM and bone marrow aspirates was 60% and 80%, respectively. A signature of 133 genes was identified that was differentially expressed between the two sample types. Paired analysis of samples from the same patients identified a subset of 161 genes, of which 52 overlapped with the initial unmatched signature. Several genes relevant to breast cancer metastasis to bone (i.e., osteopontin, CTGF, parathyroid hormone receptor, EGFR) were significantly over-expressed in the BM compared to the DTCs. Conclusions: Results suggest that there are specific subsets of genes, which are required for DTCs in the bone marrow to form overt BM. A number of genes identified are already known to participate in osteolytic BM formation. This signature may allow identification of patients at increased risk for developing BM.

No significant financial relationships to disclose.
Effect of adjuvant chemotherapy on survival in FNCLCC grade 3 soft tissue sarcomas: A multivariate analysis of the French Sarcoma Group database
Authors: Italiano A. , Delva F. , Brouste V. , Terrier P. , Trassard M. , Michels J. , Collin F. , Coindre J. , Blay J. , Bui B.
Published: August 2020

10504

Background: The SMAC meta-analysis failed to demonstrate that adjuvant chemotherapy (AC) significantly improves overall survival (OS) in adult patients with localised resectable soft-tissue sarcoma (STS). We report here the analysis of the impact of AC in the population of STS patients included in the prospective database of the French Sarcoma Group. Methods: Between 1980 and 1999, 2,029 pts with STS were admitted to one of the 20 tertiary cancer centers of the GSF for the management of a first tumoral event and were included prospectively in a comprehensive database. 152 pts were excluded from the study because of metastatic disease at diagnosis. All the cases were reviewed by the pathology subcommittee of the GSF. Tumor grade was assessed according to the FNCLCC system based on tumor differentiation, mitotic count, and necrosis. Results: 283 pts (14.5%) had grade 1, 736 (39.5%) grade 2 and 858 (46%) grade 3 tumors. 1,102 pts (59%) had extremity tumors. The commonest pathological subtypes were MFH 22.5%, liposarcoma 18%, leiomyosarcoma 13%, and synovial sarcoma 10%. 1,122 pts (60%) received adjuvant radiotherapy. AC was delivered in 16 grade 1 pts (6%), 167 grade 2 pts (23%) and 323 grade 3 pts (38%). The majority of patients who received AC had tumors with a deep topography (91%) and/or > 5 cm (75%) and/or located in the limbs (61%). The median follow-up was 9 years. The 5 year-OS was 90% for grade 1 pts, 63% for grade 2 pts and 46% for grade 3 pts. On multivariate analysis ( table 1 ), AC was strongly associated with improved metastasis-free survival (MFS) (5 year MFS: 53% vs 47%, HR 0.7 [0.5–0.9], p=0.003) and overall survival (OS) (5 year OS: 56% vs 44%, HR 0.7 [0.5–0.8], p=0.004) in grade 3 pts. This association was not observed in grade 2 pts (5 year MFS: 73% vs 72%, HR 0.9 [0.6–1.4], p=0.9; 5 year OS: 73% vs 65%, HR 0.7 [0.5–1.1]). Conclusions: This large cohort-based analysis with long-term follow-up indicates that FNCLCC grade 3 pts are likely to benefit from AC. [Table: see text]

[Table: see text]