bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical outcomes of extramammary Paget’s disease in Korea: A multicenter, retrospective study.
Authors: Sohn Byeong Seok , Kim Jeong Eun , Kim Miso , Hong Jung Yong , Lee Jieun , Park Song Ee , Kim Hyojeong , Lee Hyo Jin , Kang Eun Joo , Lee Soon Il , Lee In Hee , Huh Seok Jae , Jo Jeong Min , Lim Sung-nam , Kim Ho Young 
Published: June 2023

e21599 Background: Extramammary Paget’s disease (EMPD) is very rare disease. Due to its rarity, there have been few clinical trials and no standard therapy to date. In this multicenter retrospective study, we investigated the treatment patterns and outcomes of Korean patients with advanced/metastatic extramammary Paget’s disease. Methods: As a retrospective multicenter study, we searched the medical record from 15 centers participating Rare Cancer Committee in Korean Cancer Study Group (KCSG). Results: A total of 54 patients were identified, and 11 patients who refused or did not receive treatments were excluded. In remaining 43 patients, 9 patients received locoregional therapy as first-line treatment and 34 patients initially received systemic chemotherapy. In 34 patients who received systemic chemotherapy as first-line treatment, cisplatin plus 5-fluorouracil was the most frequently used chemotherapy regimen (n = 19). Cisplatin plus 5-fluorouracil regimen achieved an objective response rate of 42.1% and a median PFS of 7.9 months. The next frequently used chemotherapy regimen was docetaxel monotherapy (n = 6). Docetaxel monotherapy achieved an objective response rate of 50.0% and a median PFS of 8.5 months. There was no statistical difference between the two treatments (p = 0.29). Two patients received trastuzumab plus paclitaxel regimen as first-line therapy. Both obtained partial response, with PFS of 13.0+ and 8.2+ months respectively. Seventeen patients received second-line chemotherapy for disease progression. In 17 patients who received systemic chemotherapy as second-line treatment, docetaxel monotherapy was the most frequently used chemotherapy regimen (n = 6). Docetaxel monotherapy achieved an objective response rate of 50.0% and a median PFS of 4.5 months. Two patients received trastuzumab plus paclitaxel regimen as second-line therapy. Both obtained partial response, with PFS of 8.7 and 12.7 months respectively. In 4 patients received trastuzumab plus paclitaxel during first- and second-line chemotherapy, trastuzumab plus paclitaxel achieved an objective response rate of 100% and a median PFS of 10.7+ months. Overall, most patients with advanced/metastatic extramammary Paget’s disease could receive up to median two lines of chemotherapy and obtained median overall survival of 20.8 months. Conclusions: Due to its rarity, advanced or metastatic EMPD still has no established standard treatment. Results of our study indicate that there is no significant difference between cisplatin plus 5-fluorouracil and docetaxel treatment in the first-line treatment. The combination of trastuzumab with paclitaxel has longer survival than conventional cytotoxic chemotherapy only.
Synergistic activity of JAK2 and BCL-2 inhibition against B-cell acute lymphoblastic leukemia.
Authors: Rinella Sean , Hess Nicholas , Bell Haley , Shi Lei , Rui Lixin , Capitini Christian 
Published: June 2023

e22002 Background: Treatment of relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL) remains a challenge particularly in patients who do not respond to traditional chemotherapy. The objective of this study was to assess the efficacy of fedratinib, a semi selective JAK2 inhibitor and venetoclax, a selective BCL-2 inhibitor, on a model of B-ALL using the human cell line RS4;11 in vitro and in vivo. While select studies have examined the efficacy of these drugs on hematologic disorders as single agents, data is lacking on whether these drugs work optimally as single agents or in combination. Methods: RS4;11 cells were treated with either vehicle (DMSO), single agent fedratinib or venetoclax, or the combination of both inhibitors for 48 and 72 hours. Live/dead discrimination was performed using flow cytometry and a 72-hour MTS assay to assess proliferation. Drug synergy was calculated using CompuSyn software to generate combination index (CI) scores, with a CI score less than 1 reflecting synergy. RS4;11 was then used in a cell line derived xenograft model using NSG mice. Peripheral blood was obtained via retroorbital bleeds on days +10 (engraftment), +21 (treatment start), and +35 (post treatment) to assess B-ALL disease burden. Mice were randomized to one of the following groups: untreated, single agent venetoclax, fedratinib, or combination therapy. Mice were treated for 14 days with 6.25 mg/kg venetoclax IP and 100 mg/kg fedratinib via gavage. Results: In vitro, the combination of 7.5 nM venetoclax and 700 nM fedratinib significantly increased cell death compared to single agent venetoclax (p = 0.0186) and fedratinib (p = 0.0035). Furthermore, the combination significantly decreased leukemia cell proliferation compared to single agent venetoclax (p = 0.0183) and fedratinib (p = < 0.0001). Synergy between venetoclax and fedratinib was seen in combination (CI = 0.40517). In vivo, peripheral blood counts post treatment showed a significant decrease in leukemic burden in combination compared to both single agent venetoclax (p = 0.016770) and fedratinib (p = 0.00002). Flow cytometry analysis of peripheral blood also showed a significant increase in CD19 MFI expression in samples from mice that received either venetoclax or combination therapy. Conclusions: The combination of fedratinib and venetoclax synergistically combined to treat B-ALL in vitro. The combination also was effective at significantly reducing leukemic disease burden in a cell line derived xenograft model. Finally, the significant increase in CD19 MFI expression post treatment suggests this combination therapy may be useful as a bridge to other CD19 targeted cell therapies.
Novel biomarkers to predict chronic kidney disease and hypertension at 3 and 12 months post-cisplatin.
Authors: Huang Ryan S T , McMahon Kelly , Wang Stella , Chui Hayton , Lebel Asaf , Lee Jasmine , Cockovski Vedran , Rassekh Shahrad Rod , Schultz Kirk R. , Blydt-Hansen Tom D. , Cuvelier Geoffrey D. E , Mammen Cherry , Pinsk Maury , Carleton Bruce C. , Tsuyuki Ross T. , Ross Colin , Palijan Ana , Zappitelli Michael 
Published: June 2023

e22003 Background: Urine kidney injury biomarkers measured during cisplatin therapy may help identify patients at risk for adverse long-term kidney outcomes. In children treated for cancer, we examined associations of urine tubular injury biomarkers collected during two cisplatin cycles, with chronic kidney disease (CKD) and hypertension at 3 and 12 months post-cisplatin. Methods: We analyzed data from the Applying Biomarkers to Minimize Long-Term Effects of Childhood/Adolescent Cancer Treatment (ABLE) Nephrotoxicity Study: a twelve-center prospective cohort of 159 children receiving cisplatin. Urine tubular injury biomarkers (by ELISA: neutrophil gelatinase-associated lipocalin [NGAL]; kidney injury molecule-1 [KIM-1]; tissue inhibitor of metalloproteinase-2 [TIMP-2]; insulin-like growth factor-binding protein-7 [IGFBP-7]) were measured at three timepoints (pre-infusion; 12-24 hours post-infusion; discharge after cisplatin cycle) during an early cisplatin cycle (EarlyCisP: first or second cycle of therapy) and a later cycle (LateCisP: last or second-to-last cycle). Area under the curve (AUC) for biomarkers to predict CKD (estimated glomerular filtration rate below normal or urine albumin/creatinine above normal for age, per international definition) and hypertension (3 blood pressures; per American Academy of Pediatrics guidelines) at 3 and 12 months post-cisplatin was calculated. AUC change from adding biomarkers to a published clinical prediction model for 3-month outcomes was evaluated (DeLong method). Results: 156 patients were available for analysis (mainly solid tumors). 3-month (median 90 days) outcomes were 52/118 (44%) CKD; 17/125 (14%) hypertension. 12-month (median 335 days) outcomes were 47/118 (40%) CKD; 15/125 (12%) hypertension. AUCs for all biomarkers to predict 3 and 12-month CKD and hypertension were poor to modest (best AUC = 0.70, 95% CI 0.60-0.80 for pre-infusion EarlyCisP TIMP-2*IGFBP-7 to predict 3-month hypertension). Biomarkers did not improve the clinical prediction model for 3-month CKD (AUC change not statistically significant with vs. without biomarkers). Adding pre-infusion EarlyCisP NGAL and TIMP-2*IGFBP-7 to the clinical prediction model for 3-month hypertension led to AUC change from 0.81 (0.72-0.91) to 0.89 (0.83-0.95) (p < 0.05). Conclusions: Tubular injury biomarkers we studied were individually not strong predictors of 3 or 12-month post-cisplatin kidney outcomes. Adding biomarkers to existing clinical prediction models may help predict post-therapy hypertension development or identify higher kidney-risk patients.
Recursive partitioning analysis to identify risk stratification for pediatric rhabdomyosarcoma: A real-world data retrospective cohort study based on the SEER database.
Authors: Lin Zhuangbin , Qiu Shuping , Li Xiaobo , Song Jianyuan , Li Anchuan , Xu Benhua 
Published: June 2023

e22005 Background: For pediatric rhabdomyosarcoma (RMS), IRSG risk stratification is based on two distinct staging systems that differ according to whether surgery is performed. Its complexity hinders its effective clinical application to a certain extent. We aimed to develop a simple, practical, and reproducible risk stratification model to offer treatment guidance for RMS. Methods: We conducted a retrospective study based on the Surveillance, Epidemiology, and End Results (SEER) database obtained from SEER*Stat software, version 8.4.0. Multivariate Cox regression analysis was used to identify independent prognostic factors in RMS. Later, prognostic factors were integrated to construct an OS prediction nomogram. Recursive partitioning analysis (RPA) was performed to stratify the risk of the patients. Results: A total of 223 patients with pediatric RMS were ultimately included in this study. All patients received chemotherapy, and most received radiotherapy (98.2%). The median follow-up time was 93.0 months, and the overall median survival time was not reached. Multivariate Cox analysis revealed that histology (hazard ratio [HR] = 2.2374, P = 0.031), tumor size (HR = 3.403, P = 0.008), and M classification (HR = 2.060, P = 0.028) were independent factors for OS in RMS. A nomogram was constructed to predict accuracy toward individual OS with a training C-index of 0.698 and a validation C-index of 0.781. Compared to the IRSG risk stratification, the risk groups stratified by RPA allowed for significant distinction between survival curves in our cohort (for 3-y OS, IDI = 0.04454772, P = 0.022; for 5-y OS, IDI = 0.05452665, P = 0.015). Conclusions: The risk stratification model constructed by RPA could help clinicians to identify patients with poor outcomes and assist them in making treatment and surveillance decisions.
Deep multi-omic analyses to identify targetable pathways in desmoplastic small round cell tumor (DSRCT) with opportunities for clinical intervention.
Authors: Zhu Limin , Keck Jamie , Stommel Jayne , Johnson Brett , Corless Christopher L. , Ryan Christopher W. , Mills Gordon B. , Davis Lara E. 
Published: June 2023

e22006 Background: DSRCT is an extremely rare and highly aggressive soft-tissue sarcoma affecting adolescents and young adults with male predominance. The 5-year overall survival is < 25% despite intensive multi-modality treatment including aggressive surgical resection, radiotherapy, chemotherapy, and targeted therapy. Therefore, more effective and innovative therapeutic options are urgently needed. Recent advances in genomic, epigenomic, proteomic, and immune profiling have uncovered a large number of therapeutic targets that are transforming the field of cancer medicine. This study aimed to identify novel targetable pathways in DSRCT using a deep multi-omics-based platform. Methods: Three patients with biopsy proven metastatic DSRCT were enrolled under an IRB-approved observational study within the “Serial Measurements of Molecular and Architectural Responses to Therapy” (SMMART) program at OHSU. Biopsies taken at enrollment were analyzed with targeted DNA sequencing, whole transcriptome sequencing, immunohistochemistry (IHC), NanoString GeoMx digital spatial profiling (DSP) multiplexed proteomics, single cell cyclic immunofluorescence (Cyc-IF), and reverse phase protein array (RPPA). Results: Multiple clinically relevant targets were identified, including HER2, androgen receptor (AR), elevated DNA damage response, and MAPK and mTOR signaling pathways. All three DSRCTs expressed HER2: clinical IHC identified HER2 low (1+) to HER2 equivocal (2+) expression; DSP analysis showed high HER2 and phospho-HER2 expression; and HER2 RNA expression was elevated compared to the TCGA sarcoma cohort. Two of the three patients displayed high AR protein expression, assessed by clinical IHC (90-100% positive cells) and DSP (top quartile compared to a 20 mixed-subtype breast cancer cohort). Strong evidence of DNA damage response was demonstrated at both RNA and protein levels, and RPPA revealed high PARP1, PAR, p-ATM, p-RPA32, and RAD51. Within cell signaling pathways, one DSRCT exhibited high total and phospho-ERK1/2 protein across all clinical and exploratory assays, while another patient displayed evidence of elevated mTOR pathway signaling by RPPA. Conclusions: Overall, this multi-omic analysis provided new insights into possible therapeutic targets for this rare and difficult to treat sarcoma subtype. Results from this study will be further validated in vivo using patient-derived xenograft (PDX) models, providing support for development of multiple early phase trials.
Clinical trends of children with primary cardiac tumors: 15-year experience from a single center.
Authors: Patel Nishant , Dong Dan , Ding Peicheng , Wu Kede , Yang Zhaocong , Mo Xuming 
Published: June 2023

e22008 Background: Clinical presentation of pediatric primary cardiac tumors is exceptionally rare throughout the world. The purpose of our study is to evaluate clinical intervention by following up on children with primary cardiac tumors. Methods: Our study retrospectively enrolled 97 children diagnosed with primary cardiac tumors from Jan 2005 to Dec 2020 in a single center, Children’s Hospital of Nanjing Medical University by confirming with clinicoradiological and non-invasive diagnostic procedures. Primary outcome was to measure clinical trends and interventions while secondary was to analyze survival of 26 (26.80%) operative and 71 (73.19%) non-operative patients. Surgical intervention patients were followed for 6 Mo in the first postoperative year, then every year. Meanwhile, non-serious, asymptomatic, and no hemodynamic changes patients were treated non-operatively and followed up every year regularly. Results: In primary outcome, median age of children was 4.72±4.10 years (1d~16y), and median follow-up was 5.60±4.97 years (1m~15y). Most enrolled children were younger than 1 year old at the time of diagnosis. Primary cardiac tumors patients consisting of 60 rhabdomyoma (61.85%), 11 myxomas (11.34%), 7 fibromas (7.21%), 3 lymphangiomas (3.09%), 2 lipomas (2.06%), 9 unclassified tumors (9.27%) and 5 malignant tumors (5.15%) were retrospectively analyzed. Major 75 patients (77.31%) were diagnosed during various treatments of clinical symptoms, whereas 18 (18.55%) were diagnosed with routine investigation and 14 (14.43%) were diagnosed by prenatal fetal echocardiography. Herein, 26 children with critical symptoms and serious hemodynamic alteration had undergone surgical intervention in our hospital. Among them, 6 (23.07%) patients had postoperative complications; 2 (7.7%) patients were unable to survive due to post-operative arrhythmia and low cardiac output syndrome; While 2 (7.7%) patients with myxomas had a reoccurrence, and 2 (7.7%) patients had been diagnosed with another rhabdomyoma after intervention, others recovered well. Meanwhile, 71 children had non-surgical management, where 8 (11.26%) were lost to follow-up; 3 (4.22%) patients with malignant tumors were unable to survive after discharge due to unknown causes, and other patients had no serious symptoms or growth of tumors during follow-up. In secondary outcome, survival between operative and non-operative patients had no significant difference ( P > 0.05). Conclusions: Clinical intervention of pediatric primary cardiac tumors may be performed one-on-one by accounting presentations, symptoms, and emergence even though majority of primary cardiac tumors in children are benign in nature, and postoperative reoccurrence is feasible, particularly for rhabdomyoma. Meanwhile, the primary goal of surgical intervention is to reinstate normal hemodynamics, and preserve significant structures and cardiac tissues.
Pelvic Ewing sarcoma in children: Multimodal treatment, long term outcome and prognostic factors.
Authors: Kebudi Rejin , Yildirim Ulku Miray Miray , Iribas Ayca , Salduz Ahmet , Zulfikar Bulent , Bilgiç Bilge 
Published: June 2023

e22010 Background: The pelvis is one of the primary sites of Ewing sarcoma (ES) and is associated with a higher rate of local recurrence and poorer prognosis, compared with nonpelvic sites. Due to the rarity of this disease and limited data available, the prognostic factors of pelvic ES remain controversial. This study aims to assess the demographic, clinical features, treatment approach, outcome and prognostic factors in children with pelvic Ewing Sarcoma. Methods: Files of 264 children and adolescents with Ewing sarcoma diagnosed and treated between 1990-2022 in our center were retrospectively reviewed, of these 42 (15.9 %) were located in the pelvis. All recieved a COG modified chemotherapy regimen of ifosfamide-etoposide, alternating with vincristin, adriamisin/actinomycinD and cyclophosphamide (IE/VAC) every three weeks (every two weeks since 2012). Local treatment was discussed in each patient in the tumor board. Variables including age, gender, tumor stage, local and systemic treatment, outcome were analyzed using the Kaplan-Meier method and log rank test. Results: The median age of the 42 (23 male, 19 female) patients was 12.5 (2-16) years. The median time to diagnosis was 4 (0.25-12) months. The primary site was skeletal in 37 and extraskeletal in 5 patients. Seventeen (%40) had metastasis at diagnosis (lung, bone, bone marrow). Radiotherapy (RT) was given to 36 patients (10 preoperatively, 5 postoperatively, 21 definitive RT), 19 underwent surgery (4 at diagnosis, 14 had additional RT ). Surgical margins were positive in 6 and negative in 13. The histopathological necrosis was <90% in 6 and ≥ 90% in 9. The median follow-up was 56 (10-370) months. At a median of 13 months (3-115), 22 patients had recurrence(9) /progression (13). The 3-year event free survival (EFS) and overall survival (OS) were 50.1% and 62.6%; in all; 62.2 and 75.3% in nonmetastatic; 31.9% ve %42.9% in metastatic patients ( p=0.048, p= 0.028) respectively. The 3-year EFS and OS were significantly higher in patients with negative surgical margins compared to ones with positive margins [(%83.9 vs 0 % (p=0.0001) and %91.7 vs %16.7 (p=0.001) respectively] . The 3-year EFS and overall survival OS were higher in patients with ≥90% necrosis [76.2 vs 33.3 % ( p=0.029); 87.5 vs 50% (p=0.13)respectively]. Age, gender, the mode of local therapy (surgery/RT/RT+surgery) was not prognostic. One patient who had recieved oral etoposide and RT at recurrence and who achieved a complete response, developed acute myeloid leukemia (AML), M5 myelomonocytic subtype, 20 months after relapse, and died. Conclusions: In our cohort of patients with pelvic Ewing sarcoma, 40% had metastasis at diagnosis. Metastasis, positive surgical margins, poor necrosois rate <90% after neoadjuvant chemotherapy were found to be poor prognostic factors for outcome. Patients with localized pelvic Ewing sarcoma had a successful outcome with multidisciplinary treatment approach.
Safety and efficacy of naxitamab plus modified dosing of GM-CSF for patients with high-risk neuroblastoma (HR-NB) in first complete remission (CR) or with primary refractory disease.
Authors: Kushner Brian H. , Modak Shakeel , Basu Ellen M. , Iglesias Cardenas Fiorella , Kramer Kim , Roberts Stephen S. , Cheung Nai-Kong V. 
Published: June 2023

e22012 Background: In an international trial, the humanized anti-GD2 antibody naxitamab+GM-CSF was effective against chemo-resistant HR-NB, leading to approval by the Food and Drug Administration. We subsequently modified GM-CSF dosing based on a shortened priming period and pharmacokinetics showing prolonged T½ of naxitamab. We investigated safety and efficacy of naxitamab plus GM-CSF administered by a novel schedule in HR-NB patients treated in 1st CR (Group 1) or with primary refractory disease in bones and/or bone marrow (BM) (Group 2). Methods: Immunotherapy was administered q1-2 months up to 5 cycles in Group 1 and ≥5 cycles after major responses in Group 2. Naxitamab was infused intravenously (30-90”) on days 1/Monday-3/Wednesday-5/Friday (i.e., 3 doses/cycle), 3mg/kg/infusion (9mg/kg/cycle, i.e., ~270mg/m2/cycle). Previously, priming doses of GM-CSF 250µg/m2/day were subcutaneously-administered x5 (days -4 to 0), followed by a step-up to 500µg/m2/day x5 (days 1-to-5), but now priming doses were x3 days (days -2 to 0 [Friday-Saturday-Sunday]) and stepped-up dosing was x7 (days 1-to-7 [Monday-to-Sunday]), i.e., through 2 days after the last dose of naxitamab. Patients did not receive isotretinoin. Follow-up was from start of naxitamab through 1/15/23. Results: From 2/22/2021-to-12/15/22, 59 patients (32 Group 1, 27 Group 2) received 1-10 (median 5) cycles, total 250. No unexpected toxicities occurred. No patient had to discontinue GM-CSF. Treatment was outpatient, except 3 patients with hypertension. Cycles were aborted because of viral symptoms (n=3), suspected small bowel obstruction (n=3), hypoxia (n=2), and hyperbilirubinemia (n=1). Four patients received only ½ of dose 1 in cycle 1 because of agitation or hypotension. In Group 1, 4/32 patients relapsed at 4-5 months while 28 patients remain in CR at 1+-to-22+ (median 15+) months. In Group 2, disease sites and responses were: BM alone (n=7): CR in 6 (1 later relapsed); MIBG alone (Curie scores 1-11) (n=8): 1 partial response, 1 progressive disease, 2 stable (1 later relapsed), 4 non-evaluable because of radiotherapy; MIBG (Curie scores 1-26) and BM(+) (n=12): 7 CR (3 later relapsed), 4 PR, 1 stable disease (subsequently progressed). Conclusions: This large experience confirms that the new schedule is safe and, despite short follow-up, appears as effective as the prior schedule.