bluuebunny/crossref_metadata_2025 huggingface dataset:
Weekly vinblastine in chemotherapy-naive children with unresectable or progressive low grade glioma: A Canadian cooperative study.
Authors: Bouffet Eric , Scheinemann Katrin , Zelcer Shayna M. , Hukin Juliette , Wilson Beverley , Jabado Nada , Carret Anne Sophie , Lafay Cousin Lucie , Larouche Valerie , Hawkins Cynthia , Pond Gregory Russell , Poskitt Ken , Bartels Ute Katharina , Tabori Uri
Published: March 2020

10029

Background: Vinblastine has shown promising activity in a phase II study in children with recurrent/refractory LGG. The aim of this study was to assess the activity of vinblastine in chemotherapy naïve children. Methods: Patients < 18 years old with unresectable or progressive LGG were eligible if they had not received any previous treatment with chemotherapy or radiation. Vinblastine was administered weekly at a dose of 6 mg/m2over a period of 70 weeks. Patients who showed progression on 2 consecutive imaging studies or evidence of clinical progression were removed from treatment. Results: 54 patients (23 female) were enrolled between 2007 and 2010. Median age at inclusion was 7 years, 13 patients were < 3 years. 32 had chiasmatic/hypothalamic tumours, 6 had evidence of dissemination. 13 had neurofibromatosis type 1. Histology was pilocytic astrocytoma (25), pilomyxoid astrocytoma (4), low grade astrocytoma variant (8); 17 patients had no histological diagnosis. Treatment was well tolerated; however, only 14 patients received full dose for the duration of the study. Most common toxicity was haematological: 40 patients who experienced grade 3+ neutropenia. There were only 6 episodes of febrile neutropenia, 3 RBC transfusions and no toxic death. Best response to chemotherapy was assessed centrally by an independent radiologist: 1 CR, 10 PR, 3 MR, 28 SD, 12 PD, for a response rate of 24.5%. With a median follow-up of 2 years (9-48 months), progression-free survival at 2 years was 72.1% (95%CI: 58.1-82.2). One patient died of progression. Conclusions: Weekly vinblastine is well tolerated in paediatric LGG patients. Although the response rate appears inferior to other common LGG regimens, progression free survival at 2 years favourably compares to most currently used regimens. Supported by a grant from the Ontario Institute Cancer Research. Clinical trial information: 1000011227.
A phase II trial of radiation and cetuximab followed by irinotecan/cetuximab for children with newly diagnosed diffuse pontine tumors and high-grade astrocytomas.
Authors: Macy Margaret , Kieran Mark W. , Chi Susan N. , Cohen Kenneth J. , MacDonald Tobey , Smith Amy A. , Etzl Michael Matthew , Narendran Aru , Gore Lia , DiRenzo Jennifer , Trippett Tanya M. , Foreman Nicholas K. , Dunkel Ira J.
Published: March 2020

10030

Background: Diffuse intrinsic pontine gliomas (DIPG) and high-grade astrocytomas (HGA) have dismal prognoses. We previously demonstrated in a phase 1 study that cetuximab and irinotecan was a safe and tolerable regimen. Consequently, we initiated this 2-strata phase 2 trial to investigate the safety and efficacy of weekly cetuximab given with involved field external beam radiation therapy followed by 10 cycles of cetuximab and irinotecan for DIPG and HGA as determined by the 1-year progression-free survival. Methods: Eligible patients aged 3-21 years with newly diagnosed HGA or DIPG were enrolled to parallel strata. All patients received radiation therapy (5940 cGy) with concurrent cetuximab at 250mg/m2 IV weekly for 6 weeks. Following radiation, patients received cetuximab (250mg/m2 IV) weekly and irinotecan (16mg/m2/day IV) daily x 5 for two weeks every 21 days for 30 weeks. Tumor, serum, and CSF samples were collected for correlative studies. Sera collected at the onset of rash were analyzed for inflammatory and immune-related cytokines. Results: Forty-eight patients (27 DIPG, 21 HGA) were enrolled and 45 were treated (median age 8 years; range: 3–19). Toxicities were manageable; the most common adverse events were fatigue, gastrointestinal complaints, neutropenia, rash, headache, electrolyte abnormalities, elevated ALT/AST, and fever. Grade 3-4 events in ≥10% of patients were hypokalemia and lymphopenia. 4 patients experienced cetuximab-related hypersensitivity reactions (2 grade 3 reactions). The median PFS was 9.5 months (95% CI: 7.0-12.2) for HGA and 7.8 months (7.0-8.6) for DIPG with a 1-year PFS±SE of 24±10% and 25%±10% respectively. The median OS for HGA was 17.7 months (95% CI: 14.1-18.0) and 11.5 months (8.8-14.2) for DIPG. Biological correlative studies will be presented. Conclusions: Cetuximab and radiation therapy followed by cetuximab and irinotecan is well tolerated in children. Based on the 1-year PFS, this regimen may deserve further investigation in patients with DIPG. Biological correlative studies will delineate the mechanisms of the rash and possible implications for EGFR-targeted therapeutics in such patients. Clinical trial information: NCT01012609.
Investigating the pharmacokinetics and dosing of anticancer drugs in infants and young children.
Authors: Veal Gareth J , Errington Julie , Malik Ghada , Hill Christopher R , Boddy Alan V
Published: March 2020

10033

Background: Dosing regimens for anticancer drugs administered to infants and young children frequently differ between tumour types and protocols, with dosing based on body weight commonly implicated. We have recently highlighted a reduced exposure to 13-cis-retinoic acid in neuroblastoma patients <12kg dosed on body weight (Clin Cancer Res19:469-79,2013). Given the toxicity observed with many chemotherapeutics, it is appropriate to establish a pharmacological basis for dose adjustments implemented in younger patients. Methods: The pharmacokinetics of cyclophosphamide (CPA), actinomycin D (Act D), carboplatin and etoposide were investigated in children aged 0-6, 6-12 and 12-24 months. CPA was administered i.v. at a dose of 100-1,500 mg/m2, with infusion times up to 1.5h, Act D as a bolus i.v. infusion of 0.4-1.5mg/m2, carboplatin as an i.v. dose of 3.8-30mg/kg over 1-4h and etoposide as an i.v. dose of 3.5-14mg/kg over 1-6h. Eighty-six children were studied at 14 centres, with PK sampling carried out over 24h for CPA and Act D, 3h for carboplatin and up to 6h for etoposide. Plasma concentrations of CPA, Act D and etoposide were determined by LC-MS analysis, with carboplatin concentrations determined in plasma ultrafiltrate by AAS. PK parameters were calculated using WinNonlin or previously used PK models as appropriate. Results: Clearance values normalized to body weight ranged from 0.5-7.7 ml/min/kg for CPA, 1.7-17.4 for Act D, 1.6-10.5 for carboplatin and 0.2-1.7 for etoposide. No significant differences in normalized clearance were observed between the defined age cohorts of 0-6, 6-12 and 12-24 months and the data do not indicate clear differences in drug handling in infants and young children. However, when normalized clearance values were compared to data from older children, a greater degree of inter-patient variation was observed in patients <2 years than in children >2 years for all drugs. Conclusions: While normalized clearance values for the drugs studied do not support reduced dosing approaches, data suggest that individual drug clearance values may be more difficult to predict in younger patients. Further studies involving additional anticancer drugs may allow more rationale approaches to dosing. Clinical trial information: NCT00897871.
Computerized intervention for amelioration of cognitive late effects among childhood cancer survivors.
Authors: Conklin Heather M. , Ashford Jason M. , Clark Kellie N. , Martin-Elbahesh Karen , Hardy Kristina K. , Merchant Thomas E. , Ogg Robert J. , Jeha Sima , Wu Shengjie , Zhang Hui
Published: March 2020

10034

Background: Children treated for cancer with CNS-directed therapy are at significant risk for attention and working memory (WM) problems. There is empirical support for pharmacotherapy and therapist-delivered cognitive rehabilitation; yet, the reach of these approaches is limited by medical contraindications, need for facility proximity and high resource utilization. A computer-based WM intervention has demonstrated efficacy for healthy individuals with attention disorders. We investigated this approach with childhood cancer survivors. Methods: Sixty-eight survivors of childhood acute lymphoblastic leukemia (ALL) or brain tumor (BT) with identified WM deficits were randomly assigned to a computerized WM intervention (18 males/16 females, 23 ALL/11 BT, age= 12.21±2.47) or a wait-list control group (18 males/16 females, 24 ALL/10 BT, age= 11.82±2.42). Participants in the intervention group were asked to complete 25 training sessions at home with weekly, phone-based coaching support. Cognitive assessments were completed pre- and post-intervention. Results: Among 34 participants randomized to intervention, 30 (88%) were adherent while 4 were removed from intervention because they failed to complete training in the allotted time. Survivors who completed the intervention demonstrated significantly greater improvements than controls on measures of attention (e.g., WISC-IV Spatial Span Forward 3.30±3.87 vs 1.33±2.20, p= .02, ES= .63), WM (e.g., WISC-IV Spatial Span Backward 3.13±3.19 vs 0.80±2.46, p= .002, ES= .82) and processing speed (e.g., Conners’ CPT Hit Reaction Time -2.10±8.04 vs 2.36±6.68, p= .02, ES=.60), and showed greater reductions in parent reported executive dysfunction (e.g., Conners’ Parent Rating Scale, III -6.73±8.25 vs .13±8.86, p= .003, ES= .80). No group differences in academic fluency were found (e.g., Woodcock Johnson III Math Fluency 0.90±4.59 vs 1.90±7.18, p= .52, ES= .17). Conclusions: Study results suggest computerized intervention is feasible and efficacious for childhood cancer survivors, with some evidence for generalized benefits. Computerized training may offer a safer, less time intensive and more portable alternative to existing interventions. Clinical trial information: NCT01217996.
Non-Hodgkin lymphoma in children: Is 1 g/m2 methotrexate as effective as 5 g/m2 in advanced-stage nonlymphoblastic non-Hodgkin lymphoma?
Authors: Kebudi Rejin , Zulfikar Bulent , Cakır F Betul , Gorgun Omer , Ayan Inci , Dogan Oner
Published: March 2020

10043

Background: Survival rates in non-Hodgkin lymphoma (NHL) have increased significantly in the last decades. This study aims to assess the demographic data and treatment results of children with nonlymphoblastic NHL treated in a single institution. Methods: 106 children (74 male, 32 female), treated in Istanbul University, Oncology Institute, between 9/1989-12/2012 were evaluated retrospectively. Nonlymphoblastic NHL received COMP until 1991. After then, all received BFM protocols. They received BFM 90 protocol with 5 g/m2 methotrexate (MTX) until 1995 and modified BFM protocol with 1 g/m2 MTX thereafter. Results:The median age was 8(2-19) years. Histopathologic subtypes: 81 Burkitt, 25 large cell. The primary location was abdomen in 51, mediastinum 4, head/neck 31, 20 other (bone 8, breast 2, ovaries 2, skin 2, paravertebral 2, other 4). Bone marrow was involved in 10, CNS in 2. 40 patients had stage I+II, 44 stage III, and 22 stage IV disease. 23 patients died, 7 due to toxicity, 2 with second malignancies (AML,GBM). 10 year survival and EFS in the whole group was 76 and 76 % respectively. 10 year survival was 100, 94.3, 71.3 and 50% in stage I, II, III, and IV. In advanced stage nonlymphoblastic NHL patients, 10 year survival was significantly higher in patients receiving BFM regimen with 1 g/m2 MTX, than in ones receiving COMP or BFM protocol with 5 g/m2 MTX (10 year S, 81%, 46.7%, 44.4% respectively). These results were also compared with 47 advanced stage nonlymphoblastic NHL patients treated with 5 g/m2 BFM protocol in another center in the same university in the same time period (5 year S 78 %). Conclusions: Survival rates in the whole group are in parallel with advances attained in the world in NHL. The significantly higher survival rates achieved in patients with advanced stage non-lymphoblastic patients receiving modified BFM (1g/m2MTX) may be due to the decreased toxicity seen in this group and to the advances in supportive care in the last decade. In another major center in the same university that used the same protocol with 5 g/m2 MTX in the same time period, similar survival rates suggest that 1 g/m2 MTX which is cheaper and less toxic is also as effective as 5 gr/m2 in these patients.
Is magnetic resonance useful predicting neoadjuvant response in children with osteosarcoma?
Authors: Zapata-Tarres Marta , Castellanos-Toledo Araceli , Elizalde-Velazquez Susana , Deuña-Flores Armando , Peña-del-Castillo Humberto , Figueroa Carbajal Jose de Jesus
Published: March 2020

10056

Background: Few prognostic factors had been described for pediatric high-grade osteosarcoma (HGO). Primary tumor necrosis percentage after neoadjuvant chemotherapy, analyzed by pathologists, remains as an important prognostic factor. Magnetic resonance imaging (MRI) has been postulated to predict necrosis in adults. Our aim was therefore to calculate the diagnostic utility of MRI in children. Methods: Prospective, longitudinal and clinical study was performed from September 2011 to January 2012. Twenty two patients (< 18 years), with extremity HGO and no prior chemotherapy treatment were included. All had MRI from diagnosis and just before surgery. We performed a sensibility-specificity analysis comparing percentage of necrosis by MRI vs histological Rosen grades (grades I and II were classified as bad responders; III and IV as good responders). Cut off value for MRI was 90%. Agreement between radiologists was calculated by Cohen´s Kappa coefficient. Results: Average age was 11.7 ± 3.04 (SD), 54.5% were women. All patients received neoadyuvant chemotherapy (cisplatin 120mg/m2 and adriamicin 75mg/m2). Nine patients had limb-sparing surgery, 8 limb disarticulation and 5 amputations; 72.8% were classified as bad responders by histology. MRI sensibility was 25%, specificity 86.6%, positive predictive value 50% and negative predictive value 68.4%. Kappa correlation coefficient between radiologists was 0,229. Conclusions: Diagnostic utility values in this study were lower than those reported previously. Torricelli, Dyke and Guo reported MRI sensibility of over 70% and specificity ranging from 37% to 87% (similar number of patients). Predictive values were also higher (> 80%). Differences are likely explained by the lack of correlation between radiologists. Our results support the need to establish systematized criteria to measure necrosis by MRI. In order to predict clinical response to chemotherapy in HGO, it is necessary to establish areas and cut off percentages of necrosis for appropriate clinical decision making.
Risk factors for underlying vitamin D deficiency in children with cancer at their diagnosis for cancer.
Authors: Tacyildiz Nurdan , Oktay Tanyildiz Gulsah , Yavuz Gulsan , Unal Emel , Dincaslan Handan , Gordu Zulfukar , Ozyoruk Derya , Oztuna Derya Gokmen , Biyikli Zeynep
Published: March 2020

10068

Background: There is increasing interest in the possible association between cancer incidence and vitamin D. Our recent study showed a prominent Vit D deficiency in our pediatric cancer patients during their admition. Methods: Seventy newly diagnosed Pediatric cancer patients that have been defined as Vit D deficiency at our clinic, enrolled the study between 2010-2013. A questionare with 32 questiones has been performed to each patient’s family. Questiones are designed to determine risk factors for Vit D deficiency like; daily sun light exposure, consumption of food that known as source of the Vit D, suplementation during pregnancy, lactation and during infancy,etc.SPSS 11.5 program used for istatistical analyses Results: This study has been designed as a questionare based research to find out possible risk factors for Vit D deficiency in our patients. Seventy patients with leukemias , lymphomas and solid tumors were included in the study. Fourtysix boys (66%) and 24 girls ( 34%) were between 2 months to 18 years old (median: 9 years). Almost 60 % of the patients have been borned during autumn or winter. Education level : 8 % of the fathers and 19 % of the mothers were not received any education at school. During pregnancy 64% and during lactation 83% of the mothers have not been supplemented with Vit D. Seventy four percent of the mothers did not have any knowledge about importance of the Vit D. Supplementation of the Vit D during infancy was not avaliable for 58% of the patients. Daily exposure to the sun light was between 0 to 6 hours (median:2.2 hours/day). Monthly consumption of fish and egg was between 0 to 5 times (median: 1.3 time/month) for fish and between 0 to 45 eggs (median 13.9 eggs/ month ) respectively. Daily consumption of the milk was between 0 to 2 glases (median: 1 glass/day) . Conclusions: Famillies are not aware of the importance of Vit D. Consumption of Vit D containing foods are much lover than recomended nutrition facts.A special attention has to be given for education of parents for vit D supplementation during pregnancy, lactation and infancy. Besides, it should be started to educate peopele beginning from their childhood to have enough daily sun light exposure and Vit D containing foods as a part of their healthy life style.
The presence and extent of extracapsular extension (ECE) and the need for axillary lymph node dissection (ALND) in patients who meet ACOSOG Z11 eligibility criteria.
Authors: Dengel Lynn , Cody Hiram S. , King Tari A. , Van Zee Kimberly J. , Patil Sujata , Corben Adriana , El-Tamer Mahmoud , Stempel Michelle , Sclafani Lisa M. , Heerdt Alexandra S. , Gemignani Mary , Capko Deborah , Sacchini Virgilio , Plitas George , Morrow Monica
Published: March 2020

1019

Background: Whether ECE mandates ALND in patients with ≤2 positive sentinel nodes (SN) is controversial. ACOSOG Z11 excluded patients with matted nodes, but did not comment on microscopic ECE. In a prospective, consecutive series of patients, we sought to determine if ECE correlates with the number of positive axillary lymph nodes (LN) and if ECE ≤2mm clinically differs from ECE >2mm. Methods: In 8/2010 an institutional treatment algorithm based on the Z11 results was prospectively applied to consecutive patients having BCS. ALND was performed for ≥3 +SNs. The approach to ECE was not specified. Characteristics of patients with and without ECE were compared with Fisher’s exact test and the Wilcoxon rank sum test. Results: From 8/10-11/12, 2157 invasive breast cancer patients had BCS; 381 had LN metastasis, 287 met Z11 selection criteria, and ALND was avoided in 242 (84%). ECE was present in 111 (39%), of whom 23% had ≥3 +SNs (vs 2% without ECE; p<0.0001) and 35% had ALND (vs 3% without ECE; p<0.0001). The presence of ECE was associated with tumor size (1.9cm vs 1.6; p=.01) but not with age, grade, or receptor status. The degree of ECE was associated with age, grade, number of +SNs, and performance of ALND (Table). In 45 cases, ALND was advised for ≥3 +SNs (n=29) or <3 +SNs with ECE (n=16). 39 patients had ALND and 34 of these had ECE. Additional +LNs were seen in 5/9 patients with ≤2mm ECE and 20/25 with >2mm ECE; median of 1 additional +LN in each group. Seven or more additional +LNs were seen in 6 patients with >2mm ECE; 1 patient with ≤2mm ECE had 6 additional +LNs, the remainder had ≤3. Conclusions: The presence of ECE was associated with ≥3 +SNs and the need for ALND. Only a minority of patients with ≤2mm of ECE had ≥3 +SNs, and nodal disease at ALND in this group was limited, suggesting that ≤2mm ECE may not be an indication for ALND. [Table: see text]
Predicting nonsentinel lymph node metastases using established nomograms among patients with breast cancer after primary systemic therapy (PST): The transSENTINA substudy.
Authors: Liedtke Cornelia , Goerlich Dennis , Van Zee Kimberly J. , Korndoerfer Jelka , Bauerfeind Ingo , Fehm Tanja N , Fleige Barbara , Helms Gisela , Lebeau Annette , Mai Marion , Staebler Annette , Von Minckwitz Gunter , Untch Michael , Kühn Thorsten
Published: March 2020

1020

Background: Recent studies such as the SENTINA trial suggest that performing SLNB in patients with a cN1 status before but converting to a ycN0 status through PST result more often in a false-negative evaluation of LN status compared to SLNB at primary surgery. Therefore, there is a need to predict non-SLN status after PST and tailor axillary staging procedures. We investigated the accuracy of established nomograms to predict non-SLN metastases at primary surgery in patients after PST. Methods: The SENTINA trial is a 4-arm prospective multicenter cohort study evaluating an algorithm for the timing of a standardized SLNB in patients undergoing PST. 1,737 pts. from 104 institutions were categorized into four treatment arms according to the clinical axillary staging (including ultrasound examination) before and after chemotherapy. Patients in arm C with a cN1 status prior to PST converting to a ycN0 status but found to have a histologically positive SLN after PST were included. Several published nomograms predicting non-SLN status in patients with a positive SLN at primary surgery were applied (including the MSKCC-, Mayo-, Cambridge-, and Stanford-Nomogram, MDA-Score and Tenon-Score) and Area-under-the-Curve-(AUC)-values were calculated. Results:This subgroup comprised 592 patients. Among these, 74 patients had a positive SLN after PST and had all available data to run the nomograms. AUC-values were: MSKCC: 82.3 (95% confidence interval (95%CI) 72.6-91.9), Mayo: 71.8 (95%CI 60.1-83.5), Cambridge: 71.5 (95%CI 59.7-83.2), Stanford 70.6 (95%CI 59.7-83.2), MDA 70.7 (95%CI 59.0-82.5), and Tenon 73.1 (61.5-84.7). Conclusions: Analysis of the above nomograms in the post-neoadjuvant setting yielded AUC values comparable to those in the setting of primary surgery. Our results suggest that nomograms predicting non-SLN status in the setting of primary surgery (and particularly the MSKCC nomogram) may be used to avoid full axillary dissection in patients after PST.
A randomized controlled trial comparing zoledronic acid plus chemotherapy with chemotherapy alone as a neoadjuvant treatment in patients with HER2-negative primary breast cancer.
Authors: Horiguchi Jun , Hasegawa Yoshie , Miura Daishu , Ishikawa Takashi , Hayashi Mitsuhiro , Takao Shintaro , Kim Seung Jin , Tanino Hirokazu , Miyashita Masaru , Konishi Muneharu , Shigeoka Yasushi , Yamagami Kazuhiko , Akazawa Kohei , Kohno Norio
Published: March 2020

1029

Background: Zoledronic acid (ZOL) has been found to have a synergistic anti-proliferative effect when used in combination with antitumor drugs. We investigated the synergistic effect of ZOL, assessed by pathological complete response (pCR) rate, when added to neoadjuvant chemotherapy (CT) in the primary tumor. Methods: Women with resectable invasive Stage IIA-IIIB breast cancer who are HER2-negative, between 20 and 70 years of age, and ECOG PS 0-1 were eligible. CT regimen was FEC100 q3w × 4 cycles followed by weekly paclitaxel for 12 cycles. ZOL 4mg was administered every 3-4 weeks, a total of 7 times. Patients were randomized 1:1 to the ZOL group or CT group, according to the presence or absence of lymph node metastasis, estrogen receptor (ER) status, and menopausal status. The primary endpoint was the rate of pCR defined as absence of invasive disease in the breast at surgery. The planned sample size was 180 patients. Results: 188 patients were recruited between March 2010 and April 2012; however 10 patients were excluded from the primary assessment. The overall pCR rate was 14.8% and 7.8% in the ZOL and CT groups, respectively (p=0.160). In the postmenopausal patients, pCR rate was 18.4% and 5.4% in the ZOL and CT groups, respectively (p=0.153). In the triple-negative patients, pCR rate was 35.3% and 11.8% in the ZOL and CT groups, respectively (p=0.225). In the postmenopausal and triple-negative patients, pCR rate was 50.0% and 0% in the ZOL and CT groups, respectively (p=0.077). There was no significant difference in severe toxicity between the two groups. Conclusions: The results of this trial suggest that the addition of ZOL to neoadjuvant CT has potential anti-cancer benefit in patients with postmenopausal and triple-negative breast cancer. Further investigation will be warranted. Clinical trial information: 000003261.
A retrospective comparison of the characteristics and recurrence outcome of triple-negative and triple-positive breast cancer.
Authors: Randhawa Jaskirat Singh , Alva Venur Vyshak , Kawsar Hameem , Spiro Timothy Peter , Haddad Abdo S. , Bagai Rajesh Kumar , Daw Hamed
Published: March 2020

1038

Background: Triple-negative (estrogen/progesterone-receptors negative and HER2-negative; TNBC) and Triple-positive (estrogen/progesterone-receptors positive and HER2-positive; TPBC) breast cancers are very distinctive in terms of tumor behavior as well as disease management. Due to lack of an effective targeted therapy, the treatment options are limited for TNBC. We conducted a retrospective review to compare various characteristics and recurrence outcome in TNBC and TPBC. Methods: Over 3000 non-consecutive female breast cancer patients (diagnosed between 2000-2012) were reviewed. Of these, 406 patients (206 TNBC, 200 TPBC) were included. The following data at diagnosis were studied: age, tumor size, stage, grade, lymph node involvement, distant metastases and smoking history. Analyses are performed using R statistical software (Version 2.15.2). Numeric data are summarized by median and quartile with comparisons between groups performed by Wilcoxon Rank Sum Tests. Categorical data are summarized by frequency and percentage and comparisons between groups are performed by chi-square tests. Statistical significance is determined by a p-value ≤ 0.05. Results: Both TNBC and TPBC were diagnosed at similar median ages of 56.5 and 55 years respectively (p= 0.059). TNBC were more likely to have poorly differentiated histology (75.63%) whereas TPBC were more often moderately differentiated (54.79%) (p< 0.001). At diagnosis, Triple-Positive (TP) tumors were larger (median 2.4 cm) compared to Triple-Negative (TN) tumors (median 2 cm) (p= 0.013). However, there were no significant differences with respect to lymph node involvement and distant metastases in the two groups. Importantly, recurrences were more common in TNBC 33.85% (65/192) compared to TPBC 4.21% (8/190) (p < 0.001) and there was no association found with smoking history or active smoking status. Conclusions: TN tumors although smaller in size compared to TP were more likely to have poorly differentiated histology, showed higher recurrence rates and therefore were more aggressive in behavior. Both TNBC and TPBC were diagnosed at similar median age and exhibited no recurrence association with smoking history.
Use of adjuvant chemotherapy and outcomes in women age 70 and older with HER2-positive (HER2+) or triple-negative (TN) breast cancer (BC).
Authors: Hsu Tina , Speers Caroline , Tyldesley Scott , Chia Stephen K. L.
Published: March 2020

1044

Background: Chemotherapy use decreases with increasing age. There is a stronger rationale for adjuvant chemotherapy in HER2+ and TN BC due to a higher risk of recurrence, known benefit of trastuzumab with chemotherapy and lack of other systemic options. Aims: 1) Characterize and compare outcomes of resected HER2+/TN BC in older women (age ≥70) (OW) vs. younger women (age 50-69) (YW) 2) Determine chemotherapy use in OW vs. YW 3) Compare outcomes in OW based on receipt of chemotherapy. Methods: Women ≥ 50 years old with newly diagnosed resected HER2+ or TN stage I-III BC in British Columbia between 2003 and 2006 were included. Demographic, prognostic and treatment characteristics were compared in OW vs. YW using Chi-Square and t-tests. Kaplan-Meier curves for relapse-free survival (RFS), breast cancer-specific survival (BCSS) and overall survival (OS) were calculated in the various cohorts. Results: OW (n=292) had larger tumors (p=0.002), more often had mastectomy and less often had adjuvant radiation (p<0.001) than YW (n=946). There were no differences in nodal or receptor status. OW vs. YW were less likely to receive chemotherapy (28.1 vs. 81.3%, p<0.001); odds decreased with increasing age (OR 15.9 and 7.4 for women age 50-59 and 60-69 vs. ≥70, p<0.001). OW had worse 5-year RFS (75.4 vs. 83.2%, p=0.002), local RFS (93.2 vs. 95.5%, p=0.05) and distant RFS (77.5 vs. 85.5%, p=0.001). Both 5-year BCSS (79.5 vs. 88.1%, p<0.001) and OS (63.7 vs. 85.8%, p<0.001) were worse in OW vs. YW. OS, but not BC-specific outcomes (RFS, BCSS), was significantly better in those who received chemotherapy compared to those who did not (Table). Conclusions: OW with HER2+ and TN BC are less likely to receive adjuvant chemotherapy than YW. No difference in BCSS was noted in OW based on receipt of chemotherapy, possibly due to a small sample size. Differences in OS based on receipt of adjuvant chemotherapy suggest that oncologists in British Columbia are accurately identifying women with limited life expectancy less likely to benefit from chemotherapy. [Table: see text]
Use of ponatinib to inhibit kinase mutations associated with drug-resistant gastrointestinal stromal tumors (GIST).
Authors: Heinrich Michael C. , Fletcher Jonathan A. , Anjum Rana , Serrano-Garcia Cesar , Vodala Sadanand , Bauer Sebastian , Town Ajia , Zhu Meijun , Ning Yaoyu , Eilers Grant , Griffith Diana , Patterson Janice , McKinley Arin , Wang Frank Y , Garner Andrew P , Rivera Victor M.
Published: March 2020

10509

Background: Ponatinib (PO) is a multi-targeted tyrosine kinase inhibitor with potent pan-BCR-ABL activity that has recently been approved for treatment of CML and Ph+ ALL. PO also inhibits the kinase activity of KIT. Approximately 80% of gastrointestinal stromal tumors (GIST) contain primary activating KIT mutations, the majority of which cluster in exon 11. Imatinib (IM) is approved for the 1st line treatment of GIST; however, patients frequently relapse due to the acquisition of secondary resistance mutations located in either the KIT ATP-binding pocket or the activation (A) loop. Sunitinib (SU) is approved for 2nd line treatment of GIST but does not effectively inhibit A-loop mutants. Here we explored the activity of PO against major primary and secondary KIT mutants found in GIST. Methods: The drug sensitivity of KIT mutants was determined using engineered Ba/F3 cells harboring mutant forms of KIT exon 11 with or without ATP binding pocket or A-loop mutations. The abilities of PO, IM, SU, and regorafenib (RE) to inhibit viability and/or KIT kinase activity were compared using this system as well as an isogenic CHO cell system. We also profiled these same drugs using a panel of GIST cell lines, including cell lines with IM-resistant secondary KIT mutations. Results: In all in vitro systems, PO potently inhibited KIT exon 11 mutant kinases, with an IC50 of < 30 nM. PO also potently inhibited a range of secondary KIT mutants, including multiple A-loop mutant kinases. PO induced substantial tumor regression in Ba/F3 tumor models expressing a KIT exon 11 mutant with or without an A-loop mutation (D816H). Using GIST cell lines, PO inhibited the viability of those harboring primary KIT exon 11 and secondary resistance mutations more effectively than IM, SU, and RE. Importantly, in patients dosed once daily with 45 mg ponatinib, plasma concentrations achieved are predicted to lead to inhibition of all KIT mutants tested with the possible exception of V654A. Conclusions: PO potently inhibits the majority of clinically relevant KIT mutant kinases and has a broader spectrum of activity compared to IM, SU, or RE. Based on these data, a phase 2 study of PO in drug-resistant GIST is being initiated.
Prolonged survival and disease control in the academic phase II trial of regorafenib in GIST: Response based on genotype.
Authors: George Suzanne , Feng Yang , von Mehren Margaret , Choy Edwin , Corless Christopher L. , Hornick Jason L. , Butrynski James E. , Wagner Andrew J. , Solomon Sarah , Morgan Jeffrey A. , Heinrich Michael C. , Demetri George D.
Published: March 2020

10511

Background: Regorafenib (REGO) is a broad spectrum tyrosine kinase inhibitor with activity against KIT, PDGFR, VEGFR, and FGFR. Phase II and III trials demonstrated significant activity in patients (pts) with advanced GIST following failure of at least imatinib and sunitinib. Pts have continued on the Phase II trial, and we now report longer-term follow-up as related to primary and secondary tumor genotype (KIT, PDGFRA) and SDH expression. Methods: This multicenter Phase II study of RE in GIST enrolled 33 pts with metastatic GIST. REGO was started at a dose of 160mg per day, d1-21 of each 28d cycle. Anatomic restaging was performed every 2 cycles. Clinical benefit rate (CBR) was defined as CR, PR or prolonged SD (>16 wks) per RECIST 1.1. KIT genotype was determined for tumors with adequate tissue available. SDHB staining was performed on a subset of patients whose tumors lacked activating mutations in KIT or PDGFRA. Response, progression free survival (PFS), and overall survival (OS) were determined for the entire cohort and for subsets based on KIT genotype and SDHB immunohistochemical status. Results: Median followup as of 20Jan2013 was 20 mos. Four pts remain on REGO without progression. CBR for the entire cohort was 81%, with 9% PR (n=3). Median PFS for the entire cohort was 13 mos (95%CI 9-18). Median OS was 27 mos (95%CI 16-NR). Tumor primary KIT mutations and associated median PFS are as follows: exon 11(n=19), 13 mos (95%CI 10-21); exon 9(n=3), 6 mos (95%CI 2-NR) (log-rank p-value=0.93). 6 pts had SDH-deficient GIST, 2 of whom experienced PR. Median PFS of pts with SDH-deficient GIST was 12 mos (95%CI 7-NR). Secondary KITmutations in a GIST lesion were identified prior to enrollment in 9 pts : exon 17 (n=7); one each in exon 13 and exon 18. Median PFS for pts with a documented exon 17 mutation was 18 mos (95%CI 6-NR). Conclusions: REGO is an active agent in advanced GIST. Prolonged disease control and OS is demonstrated in heavily pre-treated pts with KIT exon 11-mutant GIST; although with small sample size, there is no statistical significance in outcomes between genotypes. Objective responses were seen in 2 of 6 of pts with SDHB-deficient GIST. Other biomarkers of response and benefit are under active investigation. Clinical trial information: NCT01068769.
Reversing the oncogenic roles of misdirected chromatin remodeling: Mechanistic insights into the SS18-SSX fusion protein in synovial sarcoma.
Authors: Kadoch Cigall , Crabtree Gerald R.
Published: March 2020

10515

Background: Synovial sarcoma (SS) accounts for ~10% of soft-tissue malignancies and is generally resistant to chemotherapy-based approaches, underscoring the need for a mechanistic understanding of its pathogenesis and the development of disease-specific biologic agents. The hallmark molecular feature is a precise and uniform translocation, t(X;18), which results in the fusion of exactly 78 amino acids of SSX to the SS18 C-terminus. Because the SS18-SSX genetic lesion is observed in 100% of cases, it is likely the driving oncogenic event in these tumors; however, the molecular basis for its role in oncogenesis is undefined. Methods: We performed an affinity purification-/mass spectrometry-based analysis of endogenous mSWI/SNF (BAF) chromatin remodeling complexes in several primary cell types. Using these data in combination with protein biochemical methods, we discovered that SS18 is a dedicated, non-exchangeable subunit of these complexes with a binding affinity comparable to that of ribosomal subunits. Subsequent biochemical and functional investigations were performed to assess the oncogenic consequences of addition of 78aa of SSX to the SS18 subunit in SS. Results: We demonstrate that the SS18-SSX fusion incorporates into BAF complexes, evicting both wild-type (WT) SS18 and the tumor suppressor subunit, hSNF5 (BAF47), known to be biallelically inactivated in pediatric malignant rhabdoid tumors (MRTs). The altered complex binds the Sox2 locus, reversing polycomb-mediated repression and activating Sox2. Sox2, a pro-pluripotency transcription factor, is uniformly expressed in SS tumors and is essential for proliferation. Remarkably, increasing the concentration of WT SS18 leads to reassembly of WT complexes, retargeting of BAF complexes, returned polycomb-mediated repression at the Sox2 locus and cessation of SS cell proliferation. This mechanism of transformation depends on a region of only two amino acids of SSX, and hence provides a strong foundation for therapeutic intervention. Conclusions: These studies provide a novel oncogenic mechanism for SS tumors and inform strategies for therapeutic development in this intractable cancer.
An open-label international multicentric phase II study of nilotinib in progressive pigmented villo-nodular synovitis (PVNS) not amenable to a conservative surgical treatment.
Authors: Gelderblom Hans , Pérol David , Chevreau Christine , Tattersall Martin HN , Stacchiotti Silvia , Casali Paolo Giovanni , Cropet Claire , Piperno-Neumann Sophie , Le Cesne Axel , Italiano Antoine , Ferraresi Virginia , Duffaud Florence , Penel Nicolas , Dileo Palma , Bertucci François , Hassan Andrew Bassim , Kroep Judith R. , Denizot-Guillemaut Severine , Blay Jean-Yves
Published: March 2020

10516

Background: PVNS, also known as tenosynovial giant cell tumor (TGCT), is a rare pathological entity affecting the synovium in young adults. This neoplastic disease is driven by a t(1;2) translocation resulting in the fusion of COL6A3 and M-CSF genes. Nilotinib has inhibitory properties on M-CSF receptor pathway which could be of therapeutic interest in patient (pts) with non resectable PVNS. Methods: In this open-label international, multicentric, non-randomized, phase II study the primary objective is to evaluate the efficacy of nilotinib treatment (800 mg/day) in pts with progressive or relapsing PVNS not amenable to surgery or in whom surgery would be mutilating, as measured by the 12-week progression-free rate (12-w PFR) validated by an independent committee. Using a Bayesian design with a futility stopping rule and a maximum sample size set to 50 evaluable pts, interim analyses (IA) were planned after the inclusion of 10 and then every 5 pts. Results: From December 2010 to September 2012, 56 pts with progressive disease were enrolled by 17 institutions from Europe and Australia. Successive previous IA led to positive results in favour of the study continuation. 47 pts (median age 37 y (range: 18-74), 51% of males) were evaluable at the time of the last IA, with a median follow-up of 11.2 months (range: 0.6-12.7). Median time since diagnosis was 2.5 years (range: 0.02-26). Primary tumour was mainly located on knee (25 pts, 53%), hip (6 pts, 13%), ankle (6 pts, 13%). 4 pts had already received imatinib, 76% of pts had undergone a previous surgery. The 12-w PFR was 93.6% (95%CI, 82.5%-98.7%), without any OR. PR were observed later (2 at w-24 and 1 at w-48). Nilotinib was well tolerated, with only 4 pts experiencing grade 3 adverse events (anorexia: 1 pt; prurit: 1 pt; diarrhea: 1 pt; hepatic failure: 1 pt). 8 pts (17%) had a dose reduction and/or temporary discontinuation of nilotinib due to toxicity. Final results will be further presented. Conclusions: Nilotinib treatment induces disease stabilisation in a large proportion of PVNS patients with non resectable disease or in whom resection would be mutilating. Clinical trial information: NCT01261429.
Preoperative chemoradiation therapy for localized retroperitoneal sarcoma (RPS): Final results of a phase II study from the Italian Sarcoma Group.
Authors: Gronchi Alessandro , De Paoli Antonino , Dani Carla , Merlo Domenico Franco , Quagliuolo Vittorio , Grignani Giovanni , Bertola Giulio , Navarria Piera , Sangalli Claudia , Dei Tos Angelo Paolo , Fiore Marco , Casali Paolo Giovanni
Published: March 2020

10519

Background: To study the feasibility, safety and activity of the combination of high dose long-infusion Ifosfamide (HLI) and radiation therapy (RT) as preoperative treatment for resectable localized RPS. Methods: Patients received 3 cycles of HLI (14 g/m2). RT was started in combination with the onset of the 2nd cycle and administered up to a total dose of 50.4 Gy. Surgery was scheduled 4-6 weeks after the end of RT. Primary end-point was 3-yr relapse free survival (RFS). The expected 3-yr RFS in the study population treated with surgery alone was 40%. The experimental treatment was aimed at achieving a relative reduction in relapses of at least 1/3, corresponding to a 3-yrs RFS of 55%. With 60 enrolled patients, the study would have had a 90% power to discriminate between the hypotheses of 3-yrs RFS of 40% (H0) and 55% (H1), using a 1-sided 10% level of significance. Results: Between December 2003 and 2010, 86 patients were recruited. 3 patients were ineligible after central pathological review. 63 were affected by primary tumor and 20 by local recurrence. The 3 main histological subtypes were well differentiated liposarcoma (19/83, 23%), dedifferentiated liposarcoma (26/83, 31%) and leiomyosarcoma (14/83, 17%). Median tumor size was 120 mm (IQ range= 82-160). The overall preoperative treatment was completed in 60 patients. CT was completed in 65 patients, while RT in 73. Five patients had progression before surgery (3 distant and 2 local) and were not operated. 78 patients underwent surgery. At a median follow-up of 4.8 years (IQ range=3-6.1), 23 and 15 patients developed local recurrence (LR) and distant metastases (DM) respectively; 30 patients died of disease. 3-yr and 5-yr RFS and overall survival were 56% and 44%, and 74% and 59%, respectively. Crude cumulative incidence of LR and DM at 5 yrs were 37% and 26%, respectively. Conclusions: The combination of preoperative HLI and RT was feasible in two thirds of patients, while pre-operative RT could be completed in most (73/83). The primary endpoint of the study was met. Although a systemic coverage can be added to RT when this is felt to be appropriate, the ongoing international Phase III trial is exploring the role of RT alone. Clinical trial information: ITASARC_*II_2004_003.
Using pegylated arginine deiminase (ADI-PEG20) for the treatment of sarcomas that lack argininosuccinate synthesase 1 expression.
Authors: Van Tine Brian Andrew , Bean Gregory R , Boone Phillip , Tanas Munir , Schulze Matthew B , Chen David Y , Bomalaski John S. , Rubin Brian
Published: March 2020

10526

Background: To better understand the metabolism of sarcomas, we explored the role of argininosuccinate synthase 1 (ASS1), the rate-limiting enzyme in the conversion of citrulline to arginine in the urea cycle. When ASS1 is not expressed the amino acid arginine becomes an essential amino acid that must be delivered from the diet. The potential for therapeutic manipulation of this pathway with pegylated arginine deiminase (ADI-PEG20) was explored using metabolomic mass spectroscopy. Methods: Immunohistochemistry (IHC) of ASS1 expression on 701 patient specimens representing 45 subtypes of sarcoma was performed. Proliferation and cell death were analyzed in a panel of cell lines. Clonogenic assays were performed using ADI-PEG20 and chloroquine. Autophagy induction and inhibition was assessed. Xenograft models were tested. Metabolomic mass spectroscopy was performed in the presence and absence of ADI-PEG20. Results: lHC analysis demonstrated that ASS1 is not expressed in over 85% of sarcomas (619 of 701 patient samples). Treatment of a panel of LMS, synovial, ASPS, GIST, MPNST, chondrosarcoma, osteosarcoma, and Ewings sarcoma cell lines with ADI-PEG20 resulted in cell cycle arrest but not apoptosis when ASS1 expression was low (13/15 lines). Xenografts of the ASS1 low MNNG/HOS cells and SKLMS1 cells into nude mice followed by treatment with ADI-PEG20 +/- chloroquine demonstrated significantly slower tumor growth as compared to PBS or chloroquine treated controls. Treatment of sarcomas that lack ASS1 with ADI-PEG20 induced autophagy. Global analysis of metabolomic mass spectroscopy demonstrated alterations in PKM2, glutamine dependence, the Warburg effect, the TCA cycle and glutathione biology. Conclusions: This suggests that sarcomas may be sensitive to the arginine depletion therapy using ADI-PEG20. Autophagy induction has global metabolic consequences for sarcoma. Successful control of tumor burden by using arginine deprivation therapy and autophagy inhibition in our preclinical studies will help to orient clinical trials for this innovative treatment in patients with sarcoma that lack ASS1 expression.
Outcome and prognostic factors in localized primitive neuroectodermal tumors with uniform chemotherapy protocol: A single center experience of 224 cases.
Authors: Biswas Bivas , Rastogi Shishir , Khan Shah Alam , Agarwala Sandeep , Mohanti B. K. , Shukla N. K. , Deo S. V. S. , Sharma Dayanand , Sharma Mehar C , Vishnubhatla Sreenivas , Bakhshi Sameer
Published: March 2020

10527

Background: Data on localized PNET with uniform protocol is minimal. Methods: This is single institutional patient review treated between June 2003-Nov 2011, and evaluated on intent-to-treat analysis. All patients received uniform chemotherapy (VAC/IE) as follows: neo-adjuvant chemotherapy (NACT), surgery and/or radiotherapy as local treatment followed by ACT. Results: 224/374 (60%) PNET patients were localized with median age 15 years (range: 0.1–55), tumor diameter 8 cm (range: 1.6-25) and symptom duration 4 months (range: 0.5-30). Regions were extremities 40%, thorax 25% and head & neck 14%. Post-NACT, CR was 32(14%); PR 152(68%) with ORR 82%. Ninety-nine patients underwent surgery (50/99 received adjuvant radiotherapy); 80 received radical radiotherapy as local therapy. There were no adverse tumor characteristics or poor NACT response in radical radiotherapy group versus surgery group. At median follow-up of 31.1 months (range: 1.3–113.4), 5-year EFS, OS and local control rate (LCR) were 34±3.5%, 52.5±4.7% and 59.5±4.8%, respectively. Multivariate analysis of prognostic factors is shown in the Table. Conclusions: This is largest data of localized PNET from Asia which identified unique prognostic factors. Localized PNET constituted 60% of entire cohort with delayed presentation. High WBC may be a marker of micrometastatic disease or an adverse paraneoplastic response. Skeletal primary and tumor diameter >8 cm predicted inferior OS and LCR; additionally radical radiotherapy predicted inferior LCR. All efforts should be made to resect primary tumor post-NACT as radical radiotherapy alone despite good NACT response results in inferior LCR. [Table: see text]