bluuebunny/crossref_metadata_2025 huggingface dataset:
Toxicities with combination BRAF and MEK inhibition in resected stage III melanoma.
Authors: Warrier Govind , Homan Morgan , Lao Christopher D. , Yentz Sarah Elizabeth , Kraft Shawna , Fecher Leslie Anne
Published: May 2020

e22086

Background: Patients with stage III melanoma are at high risk for recurrence after resection of the primary lesion. The Combi-AD study showed adjuvant therapy with BRAF inhibitor, dabrafenib (D), and MEK inhibitor, trametinib (T), in patients with resected stage III BRAF mutant melanoma offers recurrence free survival benefit at 3 and 4 years compared to placebo. In this study, adverse events led to dose interruption in 66% of patients, dose reduction in 38% of patients, and permanent discontinuation in 26% of patients. This is a retrospective case series of patients with resected stage III melanoma treated with adjuvant BRAF and MEK inhibition reporting toxicities in a real-world population. Methods: Medical records of all patients with resected Stage III melanoma treated with adjuvant D+T by multiple, independent oncologists at our institution between November 2017 and December 2019 were reviewed. Planned treatment was dabrafenib 150 mg bid and trametinib 2 mg daily for 1 year. Primary outcome of interest was development of toxicities. Secondary outcomes included number of treatment interruptions, dose reductions, and total time on combination therapy. Results: Twenty patients were treated with adjuvant D+T during the study period. Eighteen patients (90%) required at least 1 treatment interruption due to adverse events. Eleven patients (55%) required a dose reduction and 14 (70%) permanently discontinued therapy due to an adverse event. The 9 patients who did not require dose reduction had been initiated on a lower dose of dabrafenib (75 mg BID) due to physician experience with toxicities in prior patients. The most common treatment-limiting adverse events were recurrent pyrexia (85%) and liver laboratory abnormalities (50%). Permanent discontinuation was secondary to recurrent pyrexia in 9 patients (45%) and liver laboratory abnormalities in 5 patients (25%). For the 16 patients who completed or discontinued therapy, the median total time on therapy was 76 days, 20.8% of the intended duration. The majority of these patients never reached the FDA labeled combination dose. Conclusions: We report our findings of the side effects of adjuvant D+T to demonstrate the frequency and severity of treatment limiting toxicities in a real-world population, which exceeds what has been reported in clinical trials. Adjuvant D+T is an approved treatment for resected stage III melanoma but requires diligent toxicity assessment and management.
Predictors of extensive subclinical spread in squamous cell carcinoma.
Authors: Eversman Anna , Tracey Elizabeth , Michalik Daniel , Rodriguez Marla , Briskin Isaac , Poblete-Lopez Christine
Published: May 2020

e22093

Background: Extensive spread of squamous cell carcinoma (SCC) is often clinically imperceptible but has a profound impact on risk of recurrence and metastasis. Accurate identification of high-risk SCC enables educated choices in treatment modality and appropriate referrals for Mohs micrographic surgery (MMS). Methods: We conducted a retrospective cohort study of 1,019 patients with SCC removal by MMS at the Cleveland Clinic. We analyzed the relationship between various patient and tumor characteristics to aggressive subclinical extension (ASE), defined as tumors requiring >3 Mohs layers to obtain clear margins. Tumor locations were grouped into zones according to the American Academy of DermatologyÕs appropriate use criteria (AUC). Results: 67 of 1,149 tumors required >3 Mohs layers for removal. Tumor grade was the only statistically significant variable, with moderately-differentiated tumors having 1.828 times the odds of ASE compared to well-differentiated tumors (95% CI = [1.026, 3.255], p = 0.041). Poorly-differentiated tumors had 4.273 times the odds of ASE compared to well-differentiated tumors (95% CI = [1.755, 10.4], p = 0.001). Conclusions: Current treatment guidelines for SCC are largely derived from data on all non-melanoma skin cancers. SCC is associated with higher metastatic potential than basal cell carcinoma (BCC), emphasizing the importance of independent analysis of SCC. The power of this study was limited by the small number of extensively spread tumors. Despite this limitation, our analysis shows poorly and moderately-differentiated tumors are correlated with a higher rate of ASE compared to well-differentiated tumors. Moderately-differentiated tumor grade is not included in the AUC, however treatment of these tumors with MMS might improve patient outcomes and minimize costs associated with recurrence. Our results show risk stratification by zone has minimal utility in identifying ASE-SCC. Improved understanding of location-based differences in tumor behavior could reveal discrepancies between SCC and BCC, enabling revised zones specific to SCC. [Table: see text]
Quantifying the additional prognostic value of sentinel lymph node status over established clinicopathologic primary tumor features for predicting survival outcomes in melanoma patients.
Authors: Lo Serigne , El Sharouni Mary-Ann , Suijkerbuijk Karijn , Ahmed Tasnia , Arjen Witkamp , Cust Anne E. , Sigurdsson Vigfús , van Diest Paul J. , Scolyer Richard A. , Van Gils Carla , Thompson John F.
Published: May 2020

e22105

Background: Sentinel node (SN) staging not only provides important prognostic information for patients with primary cutaneous melanoma but it also assists in assessing eligibility for adjuvant systemic therapy and clinical trials. This study aimed to quantify the incremental value of SN status over established clinicopathologic prognostic factors in predicting survival outcomes. Methods: The training cohort (n = 9272) consisted of all Dutch melanoma patients who underwent SN biopsy (SNB) between 2004 and 2014. Melanoma patients having SNB during the same period were identified from the Melanoma Institute Australia (MIA) database as the validation cohort (n = 5644). Outcomes investigated included overall survival (OS), disease-free survival (DFS) and melanoma-specific survival (MSS, available for the MIA cohort only). Multivariable Cox proportional hazards analyses were performed with and without SN status and compared for each of the outcomes. The effect of adding SN status on the predictive performance of the models was quantified through discrimination index (Harrell’s C-statistic), calibration (plots) and reclassification (Net Reclassification Index (NRI)) at fixed follow-up time points. Results: In the Dutch cohort adding SN status to a model with Breslow thickness, ulceration, mitotic rate, age, gender, melanoma subtype, anatomic site and regression, improved the C-statistic from 0.72 (95% CI 0.70-0.73) to 0.76 (95% CI 0.75-0.77) for DFS and from 0.75 (95% CI 0.73-0.76) to 0.78 (95% CI 0.77-0.79) for OS. These findings were confirmed in the validation cohort, with the C-statistic increasing from 0.69 (95% CI 0.66-0.72) to 0.73 (95% CI 0.70-0.76) for DFS, 0.69 (95% CI 0.66-0.73) to 0.73 (95% CI 0.70-0.76) for OS and 0.71 (95% CI 0.69-0.73) to 0.76 (95% CI 0.74-0.78) for MSS. When setting 10% as the cut-off risk in NRI analysis, 54 Dutch and 26 MIA patients who experienced disease progression within the first 3 years after melanoma diagnosis, but were classified as low-risk patients, would have been reclassified as high-risk with addition of SN status. At the same time, 209 Dutch and 230 MIA patients who were disease-free within the first 3 years, but classified as high-risk would have been reclassified as low-risk with addition of SN status. Conclusions: Adding SN status significantly improved the predictive accuracy for OS, DFS and MSS models in melanoma patients.
Clinicopathological demographics of malignant melanoma of the vulva and vagina in Japan: Japanese Gynecologic Oncology Group (JGOG)/Japanese Skin Cancer Society (JSCS)—Intergroup Study.
Authors: Nishio Shin , Ogata Dai , Kiyohara Yoshio , Takekuma Munetaka , Mikami Mikio , Usami Tomoka , Kanao Hiroyuki , Kobayashi Eiji , Kondo Eiji , Nishino Koji , Miyamoto Yuichiro , Furusawa Akiko , Fujisawa Yasuhiro , Yamamoto Yuki , Kaji Tatsuya , Ihn Hironobu , Enomoto Takayuki
Published: May 2020

e22106

Background: Malignant melanomas of the vulva (VuM) and vagina (VaM) represent a unique subgroup of malignant melanomas with important differences in biological properties and treatment. In Japan adequate surveys have not been performed.The objective of this study was to elucidate the clinicopathological demographics and outcomes of VuM and VaM in Japan. Methods: Women with invasive VuM or VaM were identified from a medical records. Data on clinician (Gynecologist or Dermatologist), age, location, node status, ulceration, mitotic count, histologic subtype, American Joint Committee on Cancer (AJCC) stage, primary surgery, and surgical margin were collected. The Kaplan-Meier method was used to analyze progression free survival (PFS) and overall survival (OS). Univariate and multivariate regression models were used to identify factors significantly related to survival. Results: A total of 217 patients (pts) were identified; 109 (50.2%) had VuM and 108 (49.8%) had VaM. The median age of the subjects was 67 years (range [R], 29-96 years). Surgery was performed in 84.3% of the women with VuM and 83.3% of those with VaM. The median depth of invasion was 4.5 mm (R, 0.1-12 mm). Ulceration was documented in 47.9% (104/217) of the lesions. Nodal status was positive in 60 pts (27.6%), negative in 149 pts (68.7%), and unknown in 8 (3.7%) pts. The AJCC stage was stage I in 37 pts (17.1%), II in 106 pts (48.8%), III in 46 pts (21.2%), and IV in 28 pts (12.9%). Nodular melanoma was the most common subtype (48.8%). The median PFS was 16.8 months in pts with VuM (95% confidence interval [CI] 23.1-87.7) and 15.6 months in pts with VaM (95% CI 8.4-12.6). The median OS was 43.9 months (95% CI 60-138) in pts with VuM and 31.1 months (95% CI 24.8-45.3) in pts with VaM. Univariate analysis showed that vaginal location, nodal metastases, stage, surgery, and surgical margin were associated with poorer PFS, whereas nodal status, histologic subtype, stage, surgery, and surgical margin were associated with poorer OS. Multivariate analysis showed that only disease stage (hazard ratio [HR] = 3.09; 95% CI = 1.73-5.49) was associated with poorer PFS. Surgical margin was the only independent factor influencing OS (HR = 2.39; 95% CI = 1.48-3.80). Conclusions: The overall outcomes of VuM and VaM remain poor in Japan. In particular, the outcomes of VaM are worse than those reported previously. AJCC stage and surgical margin are important predictors of survival. Regardless of disease stage, suitable surgical resection is required. Clinical trial information: UMIN000025968.
Influence of urokinase gene knockout on tissue levels of biogenic amines in mice with melanoma.
Authors: Kaplieva Irina V. , Frantsiyants Elena M. , Surikova Ekaterina I. , Neskubina Irina V. , Bandovkina Valeria A. , Trepitaki Lidia K. , Nemashkalova Ludmila A. , Pozdnyakova Viktoria V. , Przhedetskiy Yuriy V. , Zakharova Natalia A. , Khokhlova Olga V. , Przhedetskaya Viktoria Yu. , Kit Oleg I.
Published: May 2020

e22109

Background: The plasminogen activation system and biogenic amines are involved in melanoma pathogenesis, but currently, the mutual influence of the components of these systems on each other is unknown. The purpose of the study was to reveal the dynamics of biogenic amines in the brain and intact and tumorous skin (B16/F10 melanoma) in C57BL/6-PlautmI.IBug-ThisPlau6FDhu/GFDhu mice with uPA gene knockout. Methods: The study included male and female C57BL/6-PlautmI.IBug-This Plau6FDhu/GFDhu mice, n = 38; the comparison group included C57BL/6 mice without uPA gene knockout, n = 61. Melanoma was transplanted under the skin of the back. Levels of biogenic amines were measured in tissues taken in week 3 of carcinogenesis by ELISA using standard test systems (Cusabio, China). Results: The total content of biogenic amines was elevated in tissues of intact C57BL/6-PlautmI.IBug-ThisPlau6FDhu/GFDhu mice: in the skin – due to the noradrenaline (NA) rise by 4.8 times in males and by 4.9 times in females, histamine (H) – by 3.6 times in males and 1.6 times (p < 0.05) in females, serotonin (5HT) by 3.4 times in males and 8.3 times in females; in the brain – due to the NA rise by 3.5 times in males and 3.2 times in females, dophamine by 2.1 times in males and 2.9 times in females, while H levels declined. Distinctive features of the melanoma development in C57BL/6-PlautmI.IBug-ThisPlau6FDhu/GFDhu mice included: lower levels of adrenaline with high NA concentrations and an enhanced synthesis and inactivation of 5HTin the brain. The content of catecholamines in the tumor nodes was the same as in C57BL/6 mice, with a high concentration of H recorded in the tumor and skin, together with a high 5HT level in the skin. Conclusions: The uPA gene knockout limits the development of stress at the central regulatory and peripheral effector levels, and modulates the immune antitumor response by increasing serotonergic mediation in the brain and increasing serotonin and histamine levels in the skin of mice with B16/F10 melanoma.
A single-center, open-label clinical study to evaluate pharmacokinetics and pharmacodynamics of pegylated recombinant human granulocyte stimulating factor in pediatric patients with acute lymphoblastic leukemia.
Authors: Yang Wenyu , Liu Tianfeng , Chen Xiaojuan , Guo Ye , Li Ting , Qi Benquan , Liu Fang , Chang Lixian , Ruan Min , Liu Xiaoming , Zhang Li , Zou Yao , Chen Yumei , Zhu Xiaofan
Published: May 2020

e22501

Background: The aims of the study were to investigate the pharmacokinetics and pharmacodynamics of pegylated recombinant human granulocyte colony stimulating factor(PEG-rhG-CSF) in pediatric patients with acute lymphoblastic leukemia(ALL), and compare the efficacy and safety of PEG-rhG-CSF (brand name:jinyouli) and rhG-CSF. Methods: Pediatric patients with newly diagnosed ALL who planned to use CAM (cyclophosphamide, cytarabine, 6-mercaptopurine) for chemotherapy were assigned to PEG-rhG-CSF group or rhG-CSF group. In the PEG-rhG-CSF group, PEG-rhG-CSF (100ug/kg) was injected subcutaneously once 48 hours after chemotherapy. In the rhG-CSF group, rhG-CSF (150ug/d) was injected subcutaneously daily from 48 hours after chemotherapy until the absolute neutrophil count (ANC) was≥1.0×109/L. The serum concentration of PEG-rhG-CSF was detected by enzyme-linked immunosorbent assay (ELISA). Safety and efficacy of the two groups were evaluated. Results: Between November 2015 to April 2016, 17 pediatric patients were assigned to PEG-rhG-CSF(n = 9) or rhG-CSF(n = 8) groups. The main pharmacokinetic parameters (mean±SD) of PEG-rhG-CSF group were as follows: Cmax was 353.50±136.3 ng/ml, Tmax was 44.00±20.8 h, t1/2 was 14.58± 2.2h. The PEG-rhG-CSF serum concentration and ANC curve were consistent with the mechanism of neutrophil mediated clearance. The average value of ANC nadir in PEG-rhG-CSF group was 0.18 (±0.32)×109/L, and the rhG-CSF group was 0.08 (±0.09)×109/L, there was no significant difference between the two groups ( P = 0.469). Compared with rhG-CSF, the average time of ANC recovery in PEG-rhG-CSF group was earlier (18.33±2.18 vs. 21.50±2.33, P = 0.021). There were no significant differences in the incidence of FN and infection, the duration of grade Ⅳ neutropenia and hospitalization, and the safety of the two groups. Conclusions: PEG-rhG-CSF had favorable efficacy in pediatric patients with ALL receiving chemotherapy, and there was no serious adverse event. Compared with rhG-CSF, PEG-rhG-CSF needed only once in each chemotherapy cycle, which is more suitable for pediatric patients. Clinical trial information: NCT02953730.
Body composition and treatment-related toxicity in pediatric lymphoma.
Authors: Wadhwa Aman , Barnett Kandice , Dai Chen , Richman Joshua , McDonald Andrew Michael , Williams Grant R. , Bhatia Smita
Published: May 2020

e22503

Background: Body composition is an emerging predictor of toxicity and survival in older adults with cancer ( Shachar, Eur J Can, 2016); however, its role in pediatric cancer is not known. We examined body composition (using computed-tomography [CT] scans at the 3rd lumbar level) in children with lymphoma (Hodgkin [HL] and non-Hodgkin [NHL]) at cancer diagnosis and examined its association with treatment-related toxicities. Methods: We constructed a retrospective cohort of 87 consecutive children (HL: n = 45; NHL: n = 42) diagnosed between 2000 and 2015 (2-21y at diagnosis) with pretreatment abdominal CT scans. Body composition was assessed using sliceOmatic (TomoVision) and included skeletal muscle index (SMI, cm2/m2), skeletal muscle density (SMD: Hounsfield units [HU]), and height-adjusted total adipose tissue (hTAT: sum of visceral, intramuscular and subcutaneous adipose tissue, cm2/m2). For the analysis, we used skeletal muscle gauge (SMG = SMI x SMD, expressed per 1000 in arbitrary units [AU]) and hTAT. Sociodemographics, disease and treatment details, as well as toxicities (CTCAE v5) were abstracted from medical records. Proportion of chemotherapy cycles with grade 4 hematologic or grade 3-4 non-hematologic toxicities were calculated (percent toxicity). Generalized linear regression models were constructed to examine associations between body composition metrics and toxicities, adjusting for age at diagnosis, gender, race/ethnicity and lymphoma subtype. Results: Median age at diagnosis was 12.9y (range, 2-18.5y); 60.9% males; 60.4% non-Hispanic white. Median BMI%ile was 62 (0-99), median SMG was 2.2AU (0.9-3.7) and median hTAT was 20.1 cm2/m2 (0.04-226.7). Overall, the mean percent toxicity for grade 4 hematologic and grade 3-4 non-hematologic toxicity was 38.9% (±32.6) and 31.4% (±32.6) respectively. Correlation was poor between SMG and BMI%ile ( R2= 0.04), SMG and hTAT ( R2= -0.01) and moderate between hTAT and BMI%ile ( R2= 0.4). SMG was significantly associated with grade 4 hematologic percent toxicity ( β= -18, P= 0.007) after adjusting for hTAT and cancer type. BMI%ile was not associated with grade 4 hematologic percent toxicity ( β= -0.09, P= 0.5). Non-hematologic percent toxicity was not associated with BMI%ile, hTAT or SMG. Conclusions: In this first study of its kind, we find that children with poorer muscle quality are more likely to experience grade 4 hematologic toxicities. These findings form the basis for larger studies to incorporate body composition when developing prediction models for chemotherapy-related toxicity and disease outcomes.
Bianca: Phase II, single-arm, global trial to determine efficacy and safety of tisagenlecleucel in pediatric/young adult (YA) patients (Pts) with relapsed/refractory B-cell non-Hodgkin lymphoma (R/R B-NHL).
Authors: Minard Veronique , Maude Shannon L. , Buechner Jochen , Krueger Joerg , Locatelli Franco , Attarbaschi Andishe , Laetsch Theodore Willis , González Martínez Berta , Diaz de Heredia Rubio Cristina , Awasthi Rakesh , Newsome Simon , Davis Jaclyn , Bubuteishvili-Pacaud Lida , Burkhardt Birgit
Published: May 2020

e22504

Background: Pediatric/YA pts with r/r B-NHL are rare and have heterogenous, aggressive histology and poor prognosis. We report early results for tisagenlecleucel (anti-CD19 CAR-T cell therapy) in pediatric/YA pts with r/r B-NHL. Methods: BIANCA (NCT03610724) is a phase 2, single-arm, global, open-label trial of tisagenlecleucel in pediatric/YA pts with CD19+ r/r B-NHL. Pts must have confirmed mature B-NHL r/r to ≥1 prior lines of therapy and no active CNS involvement. Primary endpoint is ORR. Secondary outcomes include DOR, EFS, safety and pharmacokinetics. Results: As of Nov 4, 2019, 8 pts were enrolled, of whom 4 had large B-cell lymphoma (LBCL), 3 Burkitt lymphoma (BL), and 1 gray zone lymphoma (GZL) (Table). Five pts had ≥2 lines of prior therapy. Suitable apheresis product was harvested in all 8 pts. Five pts were infused and 3 were pending infusion at data cut off. Product was successfully manufactured within specifications for all infused pts. Median time from enrollment to infusion was 33 days (range 30-67). All 5 pts have ≥28 days follow up; 2 pts have ≥3 months follow up (median [range] 85 days [69-97]). All 8 pts received bridging chemotherapy (including 1 pt who also had surgery and 1 who also had radiotherapy). Tisagenlecleucel dose range was 0.3-1.1 × 108 CAR+ viable T cells (weight-based: 0.9-1.7 × 106 CAR+ viable T cells/kg). Cmax (range: Cmax= 8520-14,200 copies/µg; time to Cmax= 2-21 days; n = 4) was within range of expansion observed in pediatric/YA acute lymphoblastic leukemia and adult diffuse LBCL. All 5 pts had CRS; no grade ≥3 CRS was recorded. Three pts had neurologic events, including 2 grade 3/4 events. One pt died due to disease progression. Conclusions: Pediatric/YA pts with r/r B-NHL (including BL) were successfully infused with tisagenlecleucel in the BIANCA trial with a manageable safety profile. Apheresis/manufacturing were feasible in this cohort of rapidly progressing disorders. Tisagenlecleucel was shown to expand in vivo. BIANCA provides the first systematic data on CAR-T cell therapy in highly aggressive, pediatric/YA B-NHL. Planned enrollment is 35 pts (26 infused and evaluable). Clinical trial information: NCT03610724. [Table: see text]
Pediatric cancer registry in Turkey 2009-2019 (TPOG & TPHD).
Authors: Kutluk M. Tezer , Yeşilipek Akif
Published: May 2020

e22513

Background: The pediatric cancer registry is an essential element of pediatric cancer control. More than 200000 pediatric cancer cases annually are expected in children and adolescents aged 0-14 globally. The current efforts are focusing to improve the survival rates for children and adolescents in LMICs since the survival has already exceeded 80% in most of the high income countries. Here we present the most updated results of the pediatric cancer registry in Turkey. Methods: Pediatric cancer registry has been established by theTurkish Pediatric Oncology Group and Turkish Pediatric Hematology Association in 2002. The childhood cancer cases registered between 2009-2019 was included in this analysis. International Childhood Cancer Classification System was used for the classification. Essential demographic findings, ICD-O-3 morphology and topography codes were recorded for each case. Results: During the 11 years from 2009 to 2019, 17770 cases were registered. For all cases, median age was 6.8 year (0-17; M/F 9973/7789, 3 hermaphrodite, 5 unknown). Age distribution was 0-4 yrs, 40.3%; 5-9 yrs, 24.0%; 10-14 yrs, 23.6%; 15-19 yrs, 12.1%) The distribution of the tumor types were [number of cases, percentage of total, median age yrs, M/F]: Leukemia (4570, 25.7%, 5.5, 2633/1937); Lymphoma & other RES tumors (3477, 19.6%, 9.9, 2324/1150, 1 hermaphrodite & 2 unknown); CNS [brain & spinal] (2493, 14.0%, 6.9, 1363/1129, 1 unkown); Symphatetic system (1426, 8.0%, 2.4, 743/683); Retinoblastoma (348, 2.0%, 1.5, 204/144); Renal (905, 5.1%, 3.2, 435/469, 1 unknown); Liver (304, 1.7%, 1.8, 172/132); Malignant bone (1209, 6.8%, 12.6, 658/551); Soft tissue sarcomas (1221, 6.9%, 7.5, 703/518); Germ cell (1165, 6.6%, 8.8, 426/736, 2 hermaphrodite, 1 unknown); Carcinoma & other malignant epithelial (533, 3.0%, 13.8, 254/279); Other/non-specific malignant (119, 0.7%, 8.5, 58/61). Five year survival rate was found as 71.9%. Conclusions: The data is the most essential part of the cancer control.This registry has been used widely among professionals since its establishment in 2002. Survival rates for children and adolescents has been improved to 70%. This is at the acceptable level for the income level of Turkey which is classified as an upper middle income country. The registry is a useful source for investigators and decision makers at national and international level.
Modulation of radiation biomarkers in a randomized phase II study of 131I-MIBG with or without radiation sensitizers for resistant/relapsed neuroblastoma.
Authors: Campbell Kevin M. , Groshen Susan , Marachelian Araz , Pal Sharmistha , Haas-Kogan Daphne A. , Kellogg Mark , Evans Angela Clare , Coleman Matthew A. , Park Julie R. , Granger Meaghan , Matthay Katherine K. , DuBois Steven G.
Published: May 2020

e22514

Background: 131I-metaiodobenzylguanidine (MIBG), a radiopharmaceutical agent, has demonstrated efficacy as a single agent for patients with neuroblastoma. Recently, trials have focused on MIBG combination strategies, though little is known about impact of combination agents on markers of radiation exposure. Methods: NANT11-01 (NCT02035137) was a multicenter, open label, randomized phase II clinical trial that evaluated MIBG therapy alone (Arm A) or in combination with vincristine/irinotecan (Arm B) or vorinostat (Arm C) for patients with resistant/relapsed neuroblastoma. We collected blood samples at baseline and 72 hours after MIBG infusion and determined plasma flt3 ligand, serum amylase, gamma-H2AX levels, and gene expression for key transcripts. We plotted relative change from baseline and evaluated association of marker modulation by treatment arm and clinical response using NANT response criteria. Results: The cohort included 65 patients who had at least one biomarker available for analysis (19 Arm A; 24 Arm B; 22 Arm C). Across all arms, plasma flt3 ligand and serum amylase were significantly positively modulated while BCLXL/BCL2L1 and BCL2 gene expression demonstrated significant negative modulation by 72 hours after MIBG infusion compared to baseline (p < 0.001 for all markers). For patients randomized to Arm B, we observed significantly greater positive modulation of Flt3 ligand (geometric mean fold change 4.21 for Arm B vs. 2.22 and 2.08 for Arms A and C, respectively; p < 0.001) and significantly greater negative modulation of BCLXL/BCL2L1 (geometric mean fold change 0.11 for Arm B vs. 0.55 and 0.43 for Arms A and C, respectively; p < 0.001). There were no statistically significant associations of differential modulation of a specific biomarker with higher likelihood of response (partial response or better), though there was a trend to suggest that responders had greater gamma-H2AX modulation (p = 0.053). Conclusions: Peripheral blood biomarkers relevant to radiation exposure demonstrate significant modulation after MIBG treatment, with differential modulation when chemotherapy is combined with MIBG. Analysis of additional markers and additional samples is ongoing. Clinical trial information: NCT02035137.
Female genital tract rhabdomyosarcoma in childhood and adolescence: A single center experience.
Authors: Yaman Bajin Inci , Kutluk Tezer , Yildiz Ferah , Karnak İbrahim , Oğuz Berna , Orhan Diclehan , Elmali Aysenur , Gultekin Melis , Aydin Burca , Yalcin Bilgehan , Kurucu Nilgun , Varan Ali , Akyüz Canan
Published: May 2020

e22518

Background: Rhabdomyosarcoma is a rare tumor in children and adolescents, presenting 3% to 4% of all pediatric cancers. The female genital tract is considered as a favorable site of childhood RMS. The outcome has improved significantly during the last two decades, attributed to risk stratification and multimodality management of these challenging tumors. Here we present the clinical features and treatment results of girls with genital tract rhabdomyosarcoma to discuss. Methods: Fourteen girls with vaginal and uterine servical rhabdomyosarcoma younger than 18 years of age diagnosed and followed up between the years of 1995 and 2019 were included in this analysis. The clinical features and treatment results of patients were recorded from patient files and hospital information system retrospectively. Results: There were seven cases with vaginal and seven with uterin cervical carcinoma. All patients presented with polypoid masses protruding from the vagina. Median age of patients at diagnosis was 71 months (range 8-200 months). The IRS modified TNM staging was stage I for all the patients. All cases had embryonic type of RMS except one with alveolar type. All patients were treated with surgery and adjuvant chemotherapy, three received radiotherapy additionally. All achieved complete remission. Four patients experienced tumor relapse, 1 patient died with progressive disease. The median follow-up time was 75 months (7-271 months) for 13 patients who were alive with remission. Conclusions: Rhabdomyosarcoma is a rare sarcoma with a higher incidence in children and adolescents. With current treatment strategies, female genital tract rhabdomyosarcomas have a good prognosis. Favorable prognostic factors such as early stage at diagnosis and a favorable histology may contribute to the excellent observed survival. All parties who had involved on the care of these girls must be aware of the high survival with proper treatment to avoid treatment related morbidities and mortalities. Because of the rareness of the disease we wanted to share our experience.
Evaluation of the quality-of-life (QOL) and socio-demographic characteristics of patients with leukemia and lymphoma: Comparison with sibling and control group.
Authors: Tacyildiz Nurdan , Karakose Tugba , Unal Emel Cabi , Dincaslan Handan , Tanyildiz Gulsah , Çakmak Hatice Mine
Published: May 2020

e22524

Background: Pediatric cancer patients have increased survival rates with intensive and effective treatment methods which causing some chronic health problems and lower quality of life in long term follow up. In our study, patients in their active treatment period compared to patients who have completed their treatment in recent 5 years and more than 5 years groups, besides compared with their own siblings and healthy control group,evaluated in terms of quality of life ( QOL). Methods: This study has been daone in the Department of Pediatric Hematology-Oncology, Ankara University School of Medicine. A total of 191 children were included in the study, including 36 sibling, 76 children with leukemia (n:31) and lymphoma (n:45) besides 79 healthy children. The Turkish translation of the PedsQL questionnaire was used to evaluate the patients' quality of life. IBM SPSS-25 package program was used for statistical analysis. Results: When the sociodemographic characteristics of the patient, sibling and control group were examined; we determined that the patients, siblings and control groups were similar in age, age and gender. However, we found that the education level for the patient group was statisticaly signicantly lower then the siblings and the control group. In addition, physical and mental functionning and friendship capasity scores were lower in patient group than the other two groups. According to timing of the treatment; patients and parents quality of life scores were significantly lower than the patients that finished their treatment in recent 5 years or more than 5 years. QOL scores were higest in survivors and parents group that were in more than 5 years after completed the treatment. The risk of lower QOL in patients under treatment was 7.48 times higher than the children who had ≥5 years of treatment (OR = 7,48; p < 0,05), and 2.64 times higher than those who were treated < 5 years (OR = 2,64; p > 0,05). In this study, there were no independent variables that had an impact on QOL of the sibling group. Conclusions: The QOLof patients diagnosed with leukemia and lymphoma is significantly lower than siblings and healthy group. No statistically significant difference was found between the sibling group and the healthy control group. After the end of active treatment, the QOL of the patients was reflecting important increase by the time .
Screening practices for late effects in pediatric patients on tyrosine kinase inhibitors.
Authors: Smith Stephanie M , Sabnis Himalee S. , Williamson Lewis Rebecca , Effinger Karen Elizabeth , Bergsagel Daniel John , Patterson Briana , Mertens Ann C. , Sakamoto Kathleen , Schapira Lidia , Castellino Sharon M.
Published: May 2020

e22527

Background: BCR-ABL tyrosine kinase inhibitors (TKIs) have revolutionized treatment of Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ALL) and chronic myeloid leukemia (CML). The off-target effects of long-term TKI use in children are poorly understood. We evaluated institutional screening practices for cardiac and endocrine late effects in those who had received TKIs at two large pediatric cancer centers. Methods: This retrospective cohort included patients diagnosed with Ph+ALL (post completion of frontline therapy) or CML at age < 21 years with ≥1 years of follow-up. Patients were censored at stem cell transplant, blast crisis, secondary neoplasm, death, or last contact. Demographics, clinical features, and incidence of screening echocardiogram (ECHO), electrocardiogram (EKG), dual-energy x-ray absorptiometry (DXA), bone age, and thyroid function (TSH) were abstracted. Descriptive statistics and incidence of screening are presented by diagnosis. Results: The cohort (n = 68) was 50% female, 28% non-Hispanic white, 24% non-Hispanic black, 24% Asian, and 19% Hispanic. CML: Patients were diagnosed at 12.9±4.6 years of age and had 6.3 (0.9-15.6) years of TKI exposure and 6.3 (0.9-15.6) years of follow-up. Imatinib was most commonly used (80%) followed by dasatinib (59%); 48% were exposed to > 1 TKI. Excluding tests at diagnosis, 48% had an ECHO and 48% had an EKG during the follow-up period. TSH, DXA and bone age were measured in 50%, 9% and 11% patients, respectively. Ph+ALL: Patients were diagnosed at 10.8±5.1 years of age and had 2.8 (0.6-11.6) years of TKI exposure and 5.7 (2.1-11.8) years of follow-up. Dasatinib was most commonly used (73%) followed by imatinib (64%); 36% were exposed to > 1 TKI. All received anthracyclines and steroids. Excluding tests at diagnosis, 91% had an ECHO and 77% had an EKG. TSH, DXA and bone age were measured in 82%, 68% and 36% patients, respectively. Conclusions: We note inconsistent cardiac and endocrine screening in patients receiving TKIs for CML and Ph+ALL. Evidence-based guidelines for long-term follow-up and structured monitoring for potential off-target effects are needed. A prospective screening study is in progress and may enhance our understanding of the prevalence of late effects of TKIs. [Table: see text]
The role of peer support in psychosocial outcomes among adolescent and young adult (AYA) cancer survivors.
Authors: Matsui Motohiro , Taku Kanako , Tsutsumi Rina , Ueno Midori , Seto Mayuri , Makimoto Atsushi , Yuza Yuki
Published: May 2020

e22528

Background: Adolescents and young adults (AYA) who experienced cancer treatment sometimes show posttraumatic stress symptoms (PTSS) and yet report positive psychological changes, known as posttraumatic growth (PTG). Literature suggests PTSS and PTG are not on opposite ends of a single spectrum but rather coexist. It is expected to have distinct relationships with social support, and yet, the roles of peer support remain unknown. This study examines PTG and PTSS, and their correlates with peer support among AYA cancer survivors. Methods: A cross-sectional study was conducted using a questionnaire survey with AYA cancer survivors. A total of 212 AYA survivors were recruited from 11 cancer centers and 12 cancer patients’ communities. They completed a self-report measure of the PTG Inventory and the Impact of Event Scale revised (IES-R) to assess PTSS. Diagnosis, treatment, peer support (i.e., affiliation to AYA patients’ community and friendship with other AYA cancer patients), and social status information was also collected from questionnaires. A series of multiple regression analyses was used to identify significant correlates among peer support, PTG and PTSS. Results: PTG and PTSS were not significantly correlated with each other, being consistent with the previous studies. PTG was positively associated with male gender, years since diagnosis, good communication with others, and friendship with other AYA cancer patients. Friendship with other AYA cancer patients was positively associated with not just the overall PTG but all five domains of PTG. PTSS was associated with years since diagnosis, unemployed status, and symptom of late effects. PTSS was, however, unlike PTG, not related with friendship with other AYA cancer patients or affiliation to AYA patients’ community. Conclusions: Good communication and friendship with other AYA cancer patients is suggested to play an important role in PTG but not PTSS. Psychosocial intervention to facilitate peer support among AYA cancer patients would possibly contribute to revive their lives through PTG. Future studies should further investigate what factors would contribute to alleviation of PTSS and foster PTG. Clinical trial information: UMIN000035439.
Mutational analysis of radiation-induced subsequent thyroid cancers in pediatric patients.
Authors: Hess Jennifer , Walsh Alexandra Maria , Schafernak Kristian
Published: May 2020

e22531

Background: The genetic landscape of radiation induced pediatric thyroid cancers is unclear. Radiation (RT) induced thyroid cancers frequently demonstrate tumorigenesis driven by fusion oncogenes. However, data is limited to children exposed to radioactive contamination after the Chernobyl nuclear accident. Little is known about the genetic landscape of subsequent pediatric thyroid cancers after RT exposure for the treatment of a primary malignancy or conditioning regimens prior to bone marrow transplantation (BMT). The objective of this study was to assess the prevalence of different mutations in a small cohort of pediatric patients who developed a subsequent thyroid cancer after RT exposure for the treatment of a primary disease. Methods: This is a single-center retrospective study. Thyroid tissue blocks from 10 pediatric patients who underwent thyroidectomy between 2010 and 2019 for subsequent thyroid cancers after RT for treatment of a primary malignancy or BMT were analyzed for genetic alterations using targeted next-generation sequencing for alterations in 112 genes linked to thyroid cancer. Thyroid cancers included 7 papillary (PTC) and 3 follicular thyroid carcinomas (FTC). Results: Ten samples (6 females) were genotyped. The mean age at thyroid cancer diagnosis was 15.7 years (range 11–22 years) at a mean of 10.3 years (range 6 – 19 years) after RT exposure. The mean RT dose was 2618 cGy (range 400 – 10,080 cGy) delivered to the head, neck, and/or chest. Mutations were noted in 6/10 (60%) of patients. Mutations were detected in 6/7 (85.7%) of PTC cases: EMLA/NTRK in 2 cases, STRN/ALK in 2 cases, RET in 1 case, and CCDC30/ROS in 1 case. A DICER.1 c.5438A > C p.E1813A was also identified in a patient with an EMLA/NTRK fusion. Of 3 FTC patients, (2/3) 67% had copy number alterations, but no mutations were observed. BRAFV600E mutations were not present in any tissues analyzed. Conclusions: An exceedinlgy rare ROS fusion was identified. Multiple RT induced thyroid lesions were positive for classic therapeutic targets including NTRK3, ALK, ROS1, and RET fusions, demonstrating a potential role for tyrosine kinase inhibitor therapy for refractory, recurrent or metastatic disease. All cases were negative for mutant BRAFV600E consistent with the pathogenesis of RT induced thyroid cancers primarily activated by fusions rather than point mutations. Larger, pediatric cohorts with RT induced thyroid cancers followed long term will enable the genotypic variability, clinical presentation, and response to therapy to be better assessed.
Locally advanced GCTB recurrence after neoadjuvant denosumab use.
Authors: Taveira Gabriela Monte Tenorio , Marinho Felipe Da Silva , Souza Antonio Marcelo Gonçalves de , Carneiro Wagner cabral Gomes
Published: May 2020

e23507

Background: Giant Cell Tumor of Bone is a RANK/RANK-ligand (RANKL) positive, aggressive, locally destructive tumor leading to pain and impairment of movement and limb function. Even though surgery remains the standard treatment, the use of denosumab, monoclonal antibody RANK-L inhibitor is associated with tumor response and surgical morbidity, with downstaging benefit. Methods: All GCTB patients from 2005 to 2020 from Pernambuco Cancer Center Hospital were included in the study and followed up. All patients received Denosumab 120mg on D1, D8 and D15 (attack phase), and maintenance phase of 120mg monthly. Results: A total of Fifty GCTB Patients were included in the study, being mostly women (62%), between 21-40 yrs. old (56%), Capanacci III (72%), with tumors located in femur (41%), tibia (23%), and more rarely in talus or orbit. Denosumab neoadjuvant was prescribed to 40 patients, being 28 locally advanced disease and 12 irresectable or metastatic disease, with a median of 10 doses received. Among resectable Patients, after neoadjuvant denosumab, 25 were submitted to intralesional surgery (curettage/bone cement) and 3 to en-bloc surgery/prothesis. Overall recurrence after neoadjuvant denosumab was observed in 22% (9/40) and 32% (8/25) among Patients that received neoadjuvant denosumab and intralesional surgery. Denosumab was approved for irresectable GCTB, or when surgery may render high morbidity. Neoadjuvant Denosumab use has been related to lower recurrence rate, as well as reduction in invasive procedures morbidity and sequelae in motricity. In the present study, recurrence rate of 22%, regardless of the therapeutic modality applied, corroborates recurrence rates in published data (16-30%). Among locally advanced patients, even though recurrence rates are expectedly higher, there were lower rates of aggressive surgery and joint preservation. Motor sequelae was observed in 12,5% (5/40) of patients, with quality of life improvement and pain reduction after treatment. Conclusions: Neoadjuvant denosumab for GCTB provides promising results, with acceptable recurrence rates, as well as a less aggressive approach, with lower risk of morbidity or sequelae and excellent safety profile.
Staging work up in chondrosarcoma: Is a bone scan warranted for the metastatic workup of chondrosarcoma?
Authors: Gulia Ashish , Puri Ajay , Kurisunkal Vineet , Gupta Srinath
Published: May 2020

e23508

Background: To assess the value of a bone scan in the metastatic workup of a patient diagnosed with chondrosarcoma of bone. Methods: Retrospective analysis. 480 patients of extremity chondrosarcomas were identified with the help of nuclear imaging records and pathology department data base over a period of 12 years. Their clinical, radiological and histopathological details were retrieved from case files and electronic medical records. All cases were staged with a CT scan of thorax and bone scan or a whole body PET-CT. All reported and suspicious cases of metastasis were reviewed again by an experienced radiologist for this study. 53 patients had to be excluded from the study due to incomplete staging modalities. Results: 427 patients were available for final evaluation. Grade was not available for 3 patients. No grade I chondrosarcoma (53) had evidence of metastasis. In the remaining high grade chondrosarcomas (374), isolated lung metastasis was seen in 9% (35 cases) (grade II-31, grade III-4), combined lung and bone metastasis was seen in 0.5% (2 cases) (all grade II) and isolated bone metastasis was seen in 1 % (4 cases) (all grade II). Conclusions: The present study shows that the incidence of bony metastasis in extremity chondrosarcomas is extremely low. A non-contrast CT thorax would be adequate for staging in conventional chondrosarcomas. In light of the present results we feel bone scan may be omitted from the staging work up of conventional skeletal chondrosarcomas. It may be reserved for only symptomatic patients.
Clinical characteristics, treatment modalities, and oncological outcomes in patients with gastrointestinal stromal tumors in Mexico.
Authors: Anaya Sanchez Luis Guillermo , Soberanis Piña Pamela Denisse , Meneses Medina Mónica Isabel , Cedro-Tanda Alberto , Rosas Camargo Vanessa , Huitzil Melendez Fidel David
Published: May 2020

e23514

Background: In Mexico there is scarce information regarding treatment and outcomes of patients with gastrointestinal stromal tumors (GIST). Access to medical therapy in a country with limited resources may impact survival. We aim to report clinical characteristics, treatment modalities, and oncological outcomes in patients with GIST treated at our institution. Methods: Single-center retrospective review of patients with histologically confirmed diagnosis of GIST evaluated between Jan 2005 to Dec 2018. Overall survival (OS) was estimated by Kaplan-Meier curves and compared with log-rank rest. A p value < 0.05 was significant. Results: 90 cases were included with a median age of 57 years, 61% were women. Most common symptoms were gastrointestinal bleeding (68%), abdominal pain (58%) and anemic syndrome (54%). Primary tumor location was stomach (51%), small intestine (43%) and other locations (6%). 89% (n 80) were localized and 11% (n 10) metastatic. For localized tumors, Fletcher risk stratification was used to predict prognosis. We found 44% low, 29% intermediate and 27% high-risk. Treatment for localized patients was: initial surgery (95%, n76), neoadjuvant imatinib (5%, n4). Adjuvant imatinib was given to only 69% of patients that required it (31 of 45 patients with intermediate or high-risk), 12.5% (n12) of patients with localized disease had recurrence (2 of them did not receive adjuvant treatment). In the advanced seating (n10), most common site of metastasis was liver 70%. Initial treatment was surgery in 6 patients. Only 5 patients received imatinib (50% of those who required it). Only one patient had second line sunitinib. None had access to regorafenib, none had a molecular analysis performed. Survival outcomes are shown in table. Conclusions: Patients with localized GIST treated at our institution have good oncological outcomes and similar to those reported by other series. On the other hand, patients with advanced disease have inferior outcomes compared to those reported by other series possibly related to limited access to treatment. [Table: see text]
Modulation of YAP/ TAZ by statins to improve survival in epithelioid hemangioendothelioma (EHE).
Authors: Subramaniam Aparna , Zheng Jing , Yalamanchili Sudha , Conley Anthony Paul , Ratan Ravin , Somaiah Neeta , Livingston J Andrew , Zarzour Maria Alejandra , Araujo Dejka M. , Benjamin Robert S. , Patel Shreyaskumar , Ravi Vinod
Published: May 2020

e23527

Background: EHE is a rare soft tissue tumor of endothelial origin. It is distinguished by the pathognomonic WWTR1-CAMTA1 fusion (WWTR1 is the gene symbol for TAZ) seen in 90% of the tumors. YAP1-TFE3 fusion is less common and seen in 10% of the tumors. YAP and TAZ are critical downstream effectors of the Hippo pathway that regulate tumor development, progression, invasion and metastasis by modulating the expression of many Hippo pathway targets. Recent studies have shown that inhibition of HMG-CoA reductase, a key enzyme of the mevalonate pathway, can regulate YAP/ TAZ by preventing their nuclear accumulation and inhibiting their transcriptional activity. This has led to interest in the role of statins, which inhibit HMG-CoA reductase, as a modulator of YAP/ TAZ that could benefit patients with sarcoma, particularly EHE. Methods: A retrospective analysis was performed on patients with a diagnosis of EHE at M D Anderson Cancer Center. Patients were identified using the electronic database system and screened for statin use using EMRs. Demographic and clinical characteristics were tabulated. KM method was used to assess overall survival and log rank test was used to test survival differences between the statin use and non- statin use groups. All statistical analysis was performed using STATA 14. Results: 226 patients with EHE were identified. 27 of them had recorded statin use during the course of their disease. The median OS for the statin use group was not reached and the mean OS was 221 months. The median OS for the non- statin use group was 123.9 months, while the mean OS was 160 months. The difference in OS was not statistically significant between the two groups. The median follow-up time for our cohort was 36.6 months. Conclusions: Our findings indicate a trend towards improved survival for patients with EHE who have received statins over the course of their disease. Our study is limited by a small number of patients who received statins. Prospective studies are required to assess the therapeutic benefit of statins in EHE. [Table: see text]