bluuebunny/crossref_metadata_2025 huggingface dataset:
Neurotrophins in the brain of C57BL/6-Plautm1.1BugThisPlauGFDhu/GFDhu mice with B16/F10 melanoma growing with comorbid pathology.
Authors: Frantsiyants Elena M. , Kaplieva Irina V. , Bandovkina Valeria A. , Surikova Ekaterina I. , Neskubina Irina V. , Trepitaki Lidia K. , Cheryarina Natalia D. , Nemashkalova Ludmila A. , Lesovaya Natalia S. , Przhedetskiy Yuriy V. , Przhedetskaya Viktoria Yu. , Pozdnyakova Viktoria V. , Zakharova Natalia A. , Khokhlova Olga , Kit Oleg I. , Shikhlyarova Alla I. , Zhukova Galina V.
Published: June 2021

e21557

Background: 10% of cancer patients have comorbidities accompanied by chronic pain. Neurotrophins and fibrinolytic system are involved in carcinogenesis and pain pathogenesis. The purpose of the study was to measure levels of neurotrophins in white matter of the brain of urokinase-deficient (uPA–) mice with B16/F10 melanoma growing in presence of chronic neuropathic pain (CNP). Methods: The study included female mice С57ВL/6 (normal genome uPA+, n = 40) and C57BL/6-Plautm1.1BugThisPlauGFDhu/GFDhu (urokinase gene-knockout uPA–, n = 28) with B16/F10 melanoma (M) implanted subcutaneously 2 weeks after bilateral sciatic nerve ligation (CNP model). Intact mice (I) were controls. Levels of brain-derived neurotrophic factor BDNF, nerve growth factor NGF-β and neurotrophins 3 and 4 (NT3, NT4) were measured by ELISA in white matter of the brain after 3 weeks of tumor growth in presence of CNP. Results: Tumor volume in (uPA–) females by week 3 of carcinogenesis was 0.04 cm3, which was 70 times smaller than in (uPA+) females. Tumor volume in (uPA–) females with CNP was 5.76 cm3, which was 144 times larger than in (uPA–) females without CNP, and in (uPA+) females – 2.5 cm3. The brain of I (uPA–) showed higher levels of NT3 (by 1.3 times, p < 0.05), NT4 (by 2.6 times) and NGF-β (by 1.9 times, p < 0.05) and lower BDNF (by 1.7 times, p < 0.05), compared to I (uPA+). Both strains of mice with M or CNP demonstrated decreased levels of NGF-β, more pronounced in animals with a combination of these factors. (uPA–) females with CNP+M showed a decrease of NT3 and BDNF by 2 times, with NGF-β 2.2 times higher than in (uPA+) mice. Conclusions: The study revealed underlying differences in levels of neurotrophins in the brain of (uPA–) females which could contribute to the creation of conditions for the inhibition of tumor growth. Changes in the levels of NGF-β in mice with melanoma or CNP were nonspecific. Changes in the BDNF, NT3 and NGF-β balance in the brain of (uPA–) mice may be part of the mechanism of greater stimulation of melanoma growth under the influence of CNP.
Circulating tumor DNA mutation as a prognostic marker in melanoma with brain metastasis.
Authors: Behera Tapas Ranjan , Song Jung Min , Eicher Donald Matthew , Gastman Brian , Farkas Daniel H. , Funchain Pauline
Published: June 2021

e21560

Background: Prognosis in melanoma with brain metastasis is poor with a median survival of four months and a one-year survival rate of 10–20%. There is an unmet need for surveillance methods that can supplement imaging at regular intervals. Serial analysis of circulating tumor DNA (ctDNA) may aid surveillance and prognostication. A PCR-based, “specimen in/result out” testing device was employed to detect BRAF variants in plasma-derived ctDNA to evaluate the utility of rapid biomarker detection in the management of melanoma with brain metastasis. Methods: Serial blood samples from patients diagnosed with BRAF mutation-positive metastatic melanoma were collected at regular intervals. We employed a real-time PCR-based automated mutation detection system (Idylla; Biocartis, Belgium) to interrogate the plasma samples. The ctDNA mutation detection trend was analyzed relative to disease progression. Results: 39 patients with BRAF mutation positive melanoma were enrolled. 29 patients were treated in the metastatic setting, 10 in the adjuvant setting. 18 of the 29 patients with metastatic disease (62%) had brain metastases. Circulating BRAF mutation was detected in 17 of the 29 (59%) patients with metastatic disease, and was not detected in any patients treated adjuvantly. In the group with metastatic disease, this circulating biomarker changed from undetectable to detectable in eight (28%) and detectable to undetectable in three (10%). No change in circulating mutation status occurred in 18 (62%). In the eight patients who had an initial negative test that later became positive, seven (87%) had brain metastases. In three patients, ctDNA mutation detection occurred before the diagnosis of brain metastases on imaging, with a median lead time of five weeks (range, 3-12 weeks). In one patient with de novo metastatic disease admitted to the ICU, tissue was unavailable for BRAF testing but plasma was found to be positive for ctDNA BRAF detection. BRAF/MEK targeted therapy resulted in a sustained objective response. Five of six (83%) patients that had persistent ctDNA positivity had brain metastases. Among patients with brain metastases, median overall survival (mOS) of patients demonstrating >50% test positivity was numerically longer than those with <50% positivity (mOS 12.3 vs 53.5 months; p = 0.133). Conclusions: Plasma-based, rapid ctDNA testing may be useful as an aid in detecting progression and gauging prognosis in patients with melanoma treated in the metastatic setting. The dynamics of ctDNA test positivity may indicate a need for more urgent imaging, particularly of the brain. Blood-based, semi-automated ctDNA detection may serve as an attractive adjunct to scheduled imaging surveillance in melanoma.
Antimetastatic effect of organotin compounds on the model of melanoma B16 in the experiment.
Authors: Dodokhova Margarita Avdeevna , Kotieva Inga Movlievna , Shpakovsky Dmitriy Borisovich , Safronenko Andrej Vladimirovich , Komarova Ekaterina Fedorovna , Alkhuseyn-Kulyaginova Margarita Stefanovna , Milaeva Elena Rudolfovna , Shtil Alexander Albertovich
Published: June 2021

e21564

Background: Melanoma is an extremely malignant tumor. The unfavorable prognosis in the treatment of patients is mainly due to aggressive metastasis of the tumor in various ways: hematogenic, lymphogenic and lymphohematogenic. Metastatic melanoma cells are relatively drug - resistant. Despite some successes in the treatment of melanoma, the search for new antimetastatic substances remains an urgent task of experimental pharmacology and oncology. Organotin compounds were studied by us as promising candidates for antimetastatic agents. Methods: The study was conducted on experimental C57BL/6 mice (n =72, each cohort contained 12 mice) with B16 melanoma (subcutaneous transplantation) to determine the intensity of metastasis in the presence of the cytotoxic organotin compound dimethyltin bis (3,5-di-tert-butyl-4-hydroxyphenylthiolate) [1-3] (Me3). All manipulations were carried out in accordance with the European Convention for the Protection of Vertebrates Used for Experimental and Other Scientific Purposes (ETS 123). Female mice (8 weeks of age, weighing 21-22 g) were administered intraperitoneal 1% aqueous gelatin solution of organotin Me3 daily for 5 days. The total doses in the first series of the experiment were 150, 250, 375 mg/kg (I, II, III cohorts and IV control group), which allowed us to choose the most effective dose of Me3. After that, in the second series of experiments, the metastasis inhibition index was evaluated in group V (total dose 375 mg/kg) and control group VI. The animals were euthanized on the 18th day after the tumor was inoculated. Results: It was shown that when administered intraperitoneal to mice, Me3 did not inhibit the growth of B16 melanoma in any of the groups. The results showed that the average life expectancy of animals in the experimental group III with the introduction of Me3 at a dose of 375 mg/kg significantly increased and amounted to 30.1±2.5 days, in control mice of group IV-21.8±2.6 days. In the second series of the experiment, after 18 days, the index of metastasis inhibition was almost twice lower (54%) in group V than in the control group (VI). Conclusions: It is concluded that the overall result of this study clearly demonstrates that the organotin compound dimethyltin bis (3,5-di-tert-butyl-4-hydroxyphenylthiolate) (Me3) is an effective antimetastatic agent in transplanted experimental mouse melanoma B16 at a total dose of 375 mg/kg.
Is CTLA4 targeting the Achilles’ heel of Merkel cell carcinoma?
Authors: Wu Richard Cheng Han , Kendra Kari Lynn , Blakaj Dukagjin , Shah Hiral A. , Jeter Joanne M. , Verschraegen Claire F.
Published: June 2021

e21567

Background: Merkel Cell Carcinoma (MCC) is a cutaneous malignancy with neuroendocrine differentiation, linked to infection with polyomavirus (MCPyV) in 80% of cases. PD1 inhibitors have recently been approved for this indication with ORR, 33-56%; CR, 11-24%; PFS, about 17 months; OS, about 12 months. Nivolumab was tested in the neoadjuvant setting with similar responses with pathological CR, 47%. Methods: Adjuvant pilot study (NCT03798639) with two immunotherapy regimens administered for one year to patients with completely resected MCC at high risk of recurrence (primary lesion of 2 cm or greater, positive or close margins ( < 2 cm), perineural or lymphovascular invasion, mitotic index ≥ 20 mitotic figures per mm2, lymph node involvement (stage pIIIA or pIIIB) with or without extracapsular extension, or completely resected stage IV disease). Arm 1, nivolumab 480 mg q 4 wks and radiation therapy (RT) 50-60 Gy in 25-30 fractions, per standard of care. Arm 2, nivolumab 240 mg q 2 wks and ipilimumab 1 mg/kg q 6 wks. Primary objective was feasibility and completion of treatment in this population. Safety profile (CTCAE v5.0) and recurrence-free survival (RFS) after 18 months were secondary endpoints. Patients were randomly allocated 1:1. Results: Ten patients were screened from January 2019 until April 2020, when COVID put the study on hold and the sponsor discontinued the free drug supply. Seven were enrolled. Four were allocated to Arm 1 and three to Arm 2. Patient characteristics in Table. All patients have completed treatment and are in follow-up. Arm 1: all four patients completed radiation therapy and immunotherapy with no dose modifications or delays. Arm 2: one patient had nivolumab delayed 2 weeks for cellulitis, and another missed the last four last doses of nivolumab for cholecystitis and pancreatitis requiring surgery, unrelated to the immunotherapy. Adverse events (AE) were as expected. Arm1 caused more grade 2 and 3 AEs then Arm2 (no grade 3). One patient each discontinued treatment, in Arm 1 for progression and Arm 2 for immunotoxicity (temporal arteritis grade 2). One recurrence was observed in Arm 1 and none in Arm 2. Conclusions: The number of patients expected to recur at 1 year is 20%. Our observed data is insufficient to establish efficacy. However with no patient recurring in the ipilimumab arm after 18 months of follow-up and lower observed side effects, we would favor this regimen for the next trial. Clinical trial information: NCT03798639. [Table: see text]
FDG-PET/CT response and outcome of neoadjuvant immunotherapy for clinical stage III melanoma.
Authors: De Barros E. Silva Milton Jose , Liz Caio Dabbous , Teixeira Marcos Rezende , Rinck José Augusto , Tavares Monique Celeste , Garcia Daniel , Lima Joao Paulo S. N. , Lobo Matheus , Pinto Clovis , Cavicchioli Marcelo , Lima Eduardo , Bertolli Eduardo , Molina Andre , Gollob Kenneth , Figueiredo Amanda , Duprat Joao
Published: June 2021

e21569

Background: Neoadjuvant immunotherapy with nivolumab 3mg/kg and ipilimumab 1mg/kg for two cycles(N3+I1) or anti-PD1 for 3-8 weeks for clinical stage III melanoma have shown rates of pCR/near-pCR about 60% or 30%, respectively. The prognosis of this group seems to be excellent so far. On the other hand, patients classified as pathological non-response have a worse outcome and early identification of this group may allow us to tailor treatment before surgery. Methods: We conducted a retrospective analysis of patients with clinical stage III melanoma treated with neoadjuvant immune checkpoint blockade who did baseline and pre-operative FDG-PET/CT. The total number of FGD avid lesions and the percentual difference between the maximum SUV per lesion was calculated. The pathological results were correlated to FGD-PET/CT findings. Results: Between January 2019 and January 2021, nine patients with clinical stage III melanoma were identified. Six patients received Nivolumab 3m/kg and Ipilimumab 1mg/kg for two cycles and 3 received anti-PD1 for 60 days. Baseline FDG-PET/CT showed just one avid lesion in 7 patients, 2 avid lesions in one patient and 3 avid lesions in one patient. All known lesions identified by CT scan were also captured by FGD-PET/CT. After the neoadjuvant treatment, 4 patients achieved pCR/near-pCR. All of them were treated with N3+I1. Two of them had metabolic complete response (including the one with 3 PET- avid lesions) and 2 had reduction on FDG concentration (-31% and – 76%). Three patients had absence of response: 100% of viable tumor cells (VTC), all of them with increase in FDG concentration (+12% to + 307%) and appearance of a new lesion in one case. Two out of them were treated with anti-PD1. One patient had partial response (40% of VTC). Interestingly, this patient developed sarcoidosis-like reaction with increase of SUV in the index lesion (+68%) and appearance of mediastinal lymph-nodes. One patient, who had two lesions, presented a mixed response: complete response in one and 90% of VTC in the other. FDG-PET/CT was able to detect both responses (metabolic complete response and increase of FGD concentration of 17%, respectively). Conclusions: Reduction in FGD-PET/CT concentration with no appearance of new lesion(s) is associated with significant pathological response. An increase of SUV or appearance of new lesion(s) should be carefully interpreted.
Joint application of a new rotavirus group from reoviridae family and PD-1 inhibitor on the growth of melanoma В16/F10.
Authors: Kolpakov Sergey A. , Kolpakova Elena P. , Zlatnik Elena Yu. , Shulgina Oksana G. , Triandafilidi Elena I. , Bykadorova Oksana V.
Published: June 2021

e21573

Background: The purpose of the study was to assess the possible synergism of strains of a new rotavirus group (Reoviridae family) and PD-1 inhibitor pembrolizumab (P) on the growth of murine transplantable melanoma В16/F10. Methods: The study was performed using a strains 228 and 100 of a new group of rotaviruses (working title «group K», RVK) ( http://jbks.ru/archive/issue-10/article-6 ). RVK is a live attenuated and apathogenic strain growing on the PEKC culture (pig embryo kidney cells) with 5·109 viral particles/mL. Melanoma B16/F10 was transplanted subcutaneously (2x106 living tumor cells/mL) to 40 female mice C57/Bl6. RVK strains (0.3 ml of a virus-containing fluid) were injected intramuscularly once a week during 5 weeks before tumor transplantation and P was administrated intramuscularly (0,04 µg once a week during the life span of the mice) after formation of the visible tumor. The 1 experimental group received RVK 228+P, the 2 – RVK 100+P, the 3 – only P, the 4 group was tumor-bearing control; n was 10 in each group. Results: 1 week after melanoma transplantation tumor was visible and palpable in all the mice except those of the 1 group; 10 days after transplantation tumor size was 0.028±0.0046 cm3 in the 1 group, 0.14±0.055 in the 2 group, 0.24±0.05 in the 3 group, 0.21±0.042 in the control group. A week later these parameters were 0.6±0.24, 0.99±0.3, 1.3±0.25, и 2.1±0.3 сm3 respectively, i.e. in all the experimental groups they were decreased vs control (р < 0.05). 3 weeks after transplantation the melanoma size became equal in the 3 and 4 groups (2.0±0.38 и 2.43±0.38 сm3 respectively) while in mice of the 1 group it remained decreased (1.17±0.26 сm3; р < 0.05). 1 month after transplantation the minimal tumor size was observed in mice of the 2 group (1.9±0.6 cm3), in the 1 group it was 2.6±0.17 сm3. By this time only 1 mouse survived in control group while 5 mice survived in the 3 and 1 groups, 6 mice in the 2 group. So in both of the groups vaccinated with RVK before P tumor burden was less than in controls and in mice with only P. The life span of all the experimental groups was similar and significantly higher than in controls. Conclusions: Application of RVK strains №228 and №100 in vaccination mode enhanced the antitumor effect of PD-1 inhibitor pembrolizumab on B16/F10 growth; this defines a solid rationale for their joint use. Strain 228 demonstrates the result in early and strain 100 – in later term of tumor growth.
Impact of the azoximer bromide concomitant therapy on patient outcomes in patients with melanoma.
Authors: Shendaleva Natalya , Novik Aleksei Viktorovich , Zozulya Anton , Nekhaeva Tatyana Leonidovna , Semenova Anna , Teletaeva Gulfiya Midhatovna , Latipova Dilorom Khamidovna , Semiglazova Tatiana , Protsenko Svetlana , Baldueva Irina Alexandrovna
Published: June 2021

e21574

Background: Immunomodulators are used in the treatment of patients with melanoma. However, their role as anticancer therapeutic agents requires further investigation. Azoximer bromide (AB) is a well-tolerated immunomodulator that has been used in cases of melanoma. We investigated the impact of AB when used concomitantly with other melanoma treatment modalities on the overall survival (OS) and time to progression (TTP). Methods: We reviewed per protocol, a single-center real practice database that included 1,391 patients. Forty-two patients had received AB as a concomitant therapeutic agent. Concomitant medications included immune checkpoint inhibitors, cytokines, vaccines, targeted therapy and surgery alone in the adjuvant or metastatic setting. We built Cox proportional-hazards models for OS and TTP stratified by stage in SPSS v19. All known prognostic factors (LDH, TNM stage and sub-stage, mutations, sex, age, therapy by type, and by immunologic action) were included in the model along with AB therapy. Known factors were separated from unknown (AB therapy) by different variable blocks. A step forward method was used for model construction. Results: Significant (p < 0.05) factors to emerge in the OS model were LDH (Hazards ration [HR]: 1.458 for high LDH), sub-stage (HR: 1.718 for M1b-d sub-stage), BRAF mutation (HR: 0.698 if present), current therapy type (HR: 0.501 for immune checkpoint inhibitors (ICI), HR: 0.656 for targeted therapy (TT), HR: 1.275 for systemic immunotherapy, HR: 0.825 per added method for complex treatment, HR: 0.605 for surgery), previous treatment (HR: 0.778 for ICI, HR: 1.207 for single-agent chemotherapy, HR 1.176 for targeted or local treatment, HR: 1.315 for combination chemotherapy, HR: 2.039 for immunosuppressive factors reduction methods), male sex (HR: 1.204) and AB therapy (HR: 0.475). Significant factors in the TTP model were LDH (HR: 1.348 for high LDH), sub-stage (HR: 1.434 for B-D sub-stage), current therapy type (HR: 0.432 for (ICI), HR: 0.541 for TT, HR: 0.692 per added method for complex therapy HR: 0.705 for surgery), previous therapy (HR: 0.789 for ICI), male sex (HR: 1.167) and AB therapy (HR: 0.478). Conclusions: The addition of AB to standard therapy in melanoma appears to be an independent favorable prognostic factor. Prospective, randomized, clinical trials are needed to investigate these findings further.
The clinicopathological and survival analysis of urological mucosal melanoma: A single-center retrospective observational study.
Authors: Tang Bixia , Yan Xieqiao , Chi Zhihong , Li Siming , Cui Chuanliang , Lian Bin , Si Lu , Mao Lili , Wang Xuan , Bai Xue , Zhou Li , Duan Rong , Xu Huayan , Li Caili , Guo Jun , Sheng Xinan
Published: June 2021

e21588

Background: Primary mucosal melanoma arising in the urinary tract is rare and poorly characterized. Methods: The records of patients with urological mucosal melanoma who presented to the department of Renal Cancer and Melanoma of Peking University Cancer Hospital between September, 2004 and April, 2019 were reviewed. Available clinicopathological and molecular characteristics were summarized, including pathological parameters, gene mutation, primary surgical intervention, systemic treatment and clinical course. The rates of local recurrence rate, loco-regional lymph node metastasis and distant metastasis were assessed. American Joint Committee on Cancer (AJCC) TNM Staging System for bladder cancer/renal pelvis and ureter cancer/urethral carcinoma (8th ed., 2017) were adopted for staging. Results: Fifty-eight patients were involved in the study with a median age of 62.5 years (range: 32-82). The anatomic sites of the primary urological mucosal melanomas were from the urethra (89.7%), bladder (6.9%), ureter (0%) and kidney (0%), and the left (4.4%) were from multiple loci. At initial diagnosis, 75.9% (n=44) were stage I/II disease, 1.7% (n=1) stage III, and 22.4% (n=13) stage IV. There was 3.4% incidence of CKIT mutation and 1.7% of BRAF mutation. After median follow-up of 22.6 mo, 31.4% (16/51) relapsed locally after organ-preserved surgery. 21.6% (11/51) and 39.2% (20/51) developed metastases to reginal lymph nodes and distance, respectively. The median relapse free survival and median overall survival were 12.2 (95%CI: 7.9-16.4) mo and 33.9 (95%CI: 19.2-48.6) mo, respectively. Univariate Cox analysis showed that TNM stage and systemic adjuvant therapy were the prognostic factors of OS, while no association was found with Breslow thickness, miotic rate, ulceration and gender. Conclusions: Urological mucosal melanoma predominantly arises from lower urinary tract with rare BRAF and CKIT mutation. AJCC TNM Staging System for urothelial carcinoma is proved practical for urothelial melanoma, which should be validated in larger population. Future research is required to identify adjuvant treatment approaches to improve disease outcomes.
Hospital admissions and subsequent outcomes from immune-related adverse events.
Authors: Ho Hui Jan , Arneil Melissa , Xu Wen , Atkinson Victoria
Published: June 2021

e21590

Background: Checkpoint inhibitor (CPI) use has been increasing in recent years. Immune related adverse events (irAEs) are a known complication of CPIs, particularly with the concurrent use of PD-1 and CTLA-4 inhibitors (combination therapy). IrAEs are associated with increased hospital resource utilisation including admissions and immunomodulator therapy. This is a retrospective analysis of patients receiving CPI therapy for metastatic melanoma. Methods: Data was collected from a Queensland Health centre using electronic medical records and immunotherapy prescribing software. Patient demographics, CPIs, irAEs, admissions, and outcomes were recorded from 2015-2019. All patients had metastatic disease; they either received single agent or combination CPI as first line metastatic treatment or received single agent CPI as adjuvant therapy. Patients admitted to hospitals without electronic medical records were not included. Results: 51 out of 343 patients were eligible for analysis, indicating 15% of patients receiving CPI required hospital admissions due to irAEs. The mean age was 64.7 years, with 64.7% male patients. The commonest BRAF status was wild type (60.8%, n = 31). 54.9% (n = 28) of patients received combination therapy, 39.2% (n = 20) received PD-1 inhibitors, and 5.9% (n = 3) received CTLA-4 inhibitors. 24% (n = 12) of patients experienced early toxicity, defined as hospital admission after one dose. The commonest early toxicity was pneumonitis; all had received PD-1 inhibitors. In the rest of the cohort, the most frequent irAE was colitis (35.3%, n = 18). Regardless of CPI, average length of admission was 6-7 days. 17.6% (n = 9) patients had greater than one admission. Rescue immunomodulators were required in eight patients (15.7%), seven of whom had received combination therapy. Of patients with irAE from combination therapy, 28.7% (n = 8) were palliated due to progressive disease (PD), and 25% (n = 7) continued on single agent PD-1 inhibitor. In patients with irAE from PD-1 inhibitors, the majority (70%, n = 14) ceased treatment; of these, 8 had stable disease and 6 developed PD and were subsequently palliated. Conclusions: IrAEs are a well-documented complication of CPIs. Important considerations for CPI use include severe irAEs requiring admission and subsequent hospital resource utilisation. This occurs not infrequently, as demonstrated in this analysis. It is important to consider individual patient risks and benefits prior to commencement of treatment.
Clinical significance of next-generation sequencing in Chinese patients with relapsed/refractory Wilm’s tumor.
Authors: Wang Juan , Sun Fei-fei , Hu Wanming , Zhang Lian , WANG Qing , Zhen Zijun , Zhu Jia , Lu Suying , Huang Junting , Que Yi , Sun Xiaofei , Zhang Yizhuo
Published: June 2021

e22003

Background: Medical advances have been greatly improved in the survival rate for Wilms’ tumor, but the survival is still dismal for relapsed/refractory (R/R) patients. In the present study, we aimed to investigated the genomic profiling and the incidence of germline cancer susceptibility mutations of Chinese patients with R/R WT. Methods: From Jun 18, 2020 to Dec 22, 2020, the tumor specimens with matched blood samples obtained from R/R pediatric WT in Sun Yat-Sen University Cancer Center were performed next-generation sequencing (NGS) using a 539 cancer-related gene panel in a CAP-certified laboratory (Simcere Diagnostic Co, Ltd). Clinical information including age, gender and tumor histology were collected. Somatic and germline variations including single nucleotide variants (SNV), insertion-deletion variants (Indels), copy number variations (CNVs) and fusion, as well as tumor mutational burden (TMB)/microsatellite instability (MSI) were analyzed. IHC staining for PD-L1 expression was performed by FDA-approved VENTANA PD-L1(SP263) assay. Results: Eight patients with R/R WT were enrolled in this study, including 5 males and 3 females, with a median age of 6 years old (range, 3-14). All of the pathology was identified as favorable histology WT (FHWT). Of the specimens, 8 were from pulmonary and 1from peritoneum. We identified 152 reportable molecular aberrations, with a median of 19 (0-24). CNVs accounted for the majority of the total somatic aberrations, followed by SNVs, the percentage was 77% and 22%, respectively. Genes with either CNVs or SNVs were detected in FGFR1 (n=4), ERBB2(n=3), MYCN(n=4), MET(n=2), CDK4/6(n=2), TP53(n=2), CTNNB1(n=2), MYC(n=2), NF1(n=2), MDM4(n=2), CHEK2(n=1), FBXW7(n=1), EGFR(n=1). Notable cancer driver mutations were also characterized, such as the amplifications of ERBB2/MET/EGFR/FGFR1, and the point variations of CHEK2/FBXW7/NF1. Besides, a novel ASB12 intergenic region- AMER1 fusion was identified. Both of the patients available for PD-L1 evaluation showed negative PD-L1 expression on tumor cells. The median TMB was 1.47 (range, 0-7.8). All patients were microsatellite stabilization (MSS). A 4-year-old patient suffering peritoneal relapse harbored a germline pathogenic mutation in FANCA (c.1777-1G>C, intron 19), this locus has never been reported in WT before. Conclusions: We discovered some driver genes mutations which potentially sensitive to the corresponding targeted drugs in Chinese R/R WT patients. Large sample size was needed to provide a better understanding of molecular features in R/R WT patients to achieve precision medicine.
The efficacy and safety of irinotecan plus doxorubicin liposome in relapsed/refractory Wilms’ tumors: A retrospective study.
Authors: Wang Juan , Zhang Lian , Que Yi , Zhen Zijun , Zhu Jia , Sun Feifei , Lu Suying , Huang Junting , Wu Liuhong , Cai Ruiqing , Zhang Yizhuo , Sun Xiaofei
Published: June 2021

e22007

Background: To evaluate the efficacy of the regimen of combination of irinotecan and doxorubicin hydrochloride liposome in relapsed/refractory pediatric Wilms’ tumor. Life quality and toxicity are seriously considered and assessed. Methods: The project stipulated 5-day course of irinotecan 50 mg/m2 (90-minute infusion) and doxorubicin hydrochloride liposome 40mg/m2 every 3 weeks. Granulocyte colony-stimulating factor was applied when the number of neutrophil count was lower than 1,000/ L. Results: 16 patients received 1to 8 courses (median, 3 courses) of this regimen, including 8 males and 8 females, with a median age of 4.2 years old (range, 0.5-11) . 2 patients were not assessable for response (1were treated in third CR, and 1with refractory WT received only one course as part of complex salvage regimens). Of 14 patients treated for relapsed or refractory Wilms’ tumor and accessed for response, 2 patients had complete responses (CR), 5 patients had partial responses (PR). Of 2 patients had stable diseases (SD), including 1 patient showed objective response on pulmonary lesion. The disease control rate was 64% (2 CR, 5 PR, and 2 SD), and the objective response rate was 50% (2 CR, 5 PR). The median progression-free survival was 3.5 months (range 0.5-12), and the median survival duration was 8 months (range 1-28). Myelosuppressive and gastrointestinal adverse effects were self-limited and clinically controllable with routinely intervention, and this therapeutic regimen was generally continued without delayed therapy. Multiple courses of this regimen had no cumulative toxicity and achieved disease control in relapsed or refractory Wilms’ tumor. Conclusions: The regimen of combination of irinotecan and doxorubicin hydrochloride liposome has positive effect on relapsed/refractory Wilms’ tumor with gentle toxicity without reducing the efficacy, and achieves good quality of life.
Evaluation of the relationship between antenatal and postnatal tobacco smoke exposure and childhood cancers.
Authors: Tacyildiz Nurdan , Güzel Adil , Bakar Ateş Filiz , Özyörük Derya , Unal Emel Cabi , Dincaslan Handan
Published: June 2021

e22011

Background: The incidence of childhood cancers increased by 1 % per year over the last three decades. Life style changes and increased variety of environmental exposures are accused of this trend. One of these environmental factors is cigarette smoking and parental smoking is the main source of tobacco smoke exposure of children. There are strong reasons for considering parental smoking behaviour as a risk factor for childhood cancers. Many tobacco related compounds are detected in fetal tissues, breast milk and tissues of children of smoking parents. However, it is hard to make causal relationship between parental smoking and childhood cancers. One of the reasons is the difficulty to detect tobacco smoke exposure. Questionnaires, commonly used method to detect tobacco smoke exposure, are prone to biases. Cotinine is the main metabolite of nicotine which is the abundant organic compound in tobacco and a good biomarker to detect tobacco smoke exposure. Methods: 104 newly diagnosed, 0-18 years aged pediatric cancer patients from two pediatric oncology centers ( Ankara University Children’s Hospital and Ankara City Hospital) and 99 healthy children aged 0-18 applied to the Ankara University Children’s Hospital participated our study. Parental smoking behaviours (preconceptional, during pregnancy and current smoking) and environmental tobacco smoke exposures (ETS) of children were compared between two groups. ETS exposures of cancer patients and healthy children were evaluated by hair cotinine ELISA analysis and questionnaire. For hair cotinine analysis, 30 mg of hair samples were taken from occipital part of scalp by a stainless scissors. Samples were processed according to manufacturer's instructions. Parents of two groups were surveyed about their smoking behaviours and ETS exposures of their children. Results: We found no differences between two groups by means of maternal preconceptional smoking, smoking during pregnancy and current smoking behaviours. Paternal preconceptional smoking and smoking during pregnancy rates were significantly low in cancer patients (p < 0,05) according to questionnaire. Environmental tobacco smoke exposures were found statistically low in cancer patients according to questionnaire (p < 0,05). However, quantitative exposure assessment by hair cotinine analysis revealed that cancer patients are exposed to tobacco smoke more than healthy children (p < 0,001). Conclusions: Our findings support that smoking could be a risk factor for childhood cancers. This study also revealed that questionnaires could cause biases. We thought, social desirability bias of father of cancer patients could be a reason of their low smoking rates according to questionnaire. We suggest that cotinine analysis along with validated questionnaires can be used to prevent biases in studies of tobacco smoke in the etiology of childhood cancers.
Associations between diet and chronic disease burden in adult survivors of childhood cancer in the St. Jude Lifetime Cohort (SJLIFE) study.
Authors: Foley Elizabeth M. , Hyun Geehong , Zhang Fang Fang , Krull Kevin R. , Bhakta Nickhill , Ehrhardt Matthew J. , Brinkman Tara M. , Lanctot Jennifer Q. , Robison Leslie L. , Hudson Melissa M. , Ness Kirsten K.
Published: June 2021

e22017

Background: Nutritional intake can impact health. Data describing associations between diet or specific dietary components and chronic health conditions in long-term survivors of childhood cancer are limited. This study evaluated the associations between specific components of diet and chronic disease burden in childhood cancer survivors. Methods: Adult survivors (≥5 years) of childhood cancer participating in SJLIFE (n = 2822), who completed a clinical evaluation and the Block Food Frequency Questionnaire were included. 168 chronic conditions were graded using a modified Common Terminology for Adverse Events. Conditions were summed within grade category, multiplied by weights (1, 2, 3, and 8 for grades 1-4, respectively) and standardized (z-scores) with higher scores indicating more disease burden. Adherence to the 2015 Dietary Guidelines for Americans was scored with the Healthy Eating Index-15 (HEI). Intake of key food groups and nutrients was estimated and divided into quartiles for analysis. Multivariable logistic regression, adjusted for sex, age, and race was used to compare dietary intake and higher disease burden (defined as a z-score > 0). Results: Survivors (median [range] survival time 23 [10-49] years, diagnosis age 7 [0-24] years, 47.6% female, 16.9% non-white, 38.0% leukemia, 19.5% lymphoma, 10.3% CNS tumor, 32.2% other solid tumor) had an average of 10.0 (95% CI 9.7-10.3) conditions by 30 years of age and had a mean score on the HEI of 57.9±12.2 (out of 100 where the population average is 59). Scores on the HEI were not associated with disease burden z-score. Compared to those in the lowest quartile, survivors who consumed in the highest quartile of dark green vegetables (OR 0.77, 95% CI 0.61-0.97), legumes (OR 0.74, 95% CI 0.59-0.92), and whole grains (OR 0.75, 95% CI 0.60-0.95) were less likely to have a disease burden z-score > 0, whereas those who consumed in the highest quartile of white potatoes (OR 1.31, 95% CI 1.05-1.64), refined grains (OR 1.26, 95% CI 1.01-1.58), and added sugars (OR: 1.27, 95% CI 1.01-1.56) were more likely to have a disease burden z-score > 0. Conclusions: Specific components of diet are associated with chronic disease burden in long term survivors of cancer. Dietary interventions may have potential to decrease chronic disease burden in this population.
The real-world BRCA1/2 germline mutations in Chinese solid tumors.
Authors: Chen Jian , Gong Zhaohua , Sun Dengjun , Song Shujie , Zhang Weiwei , Luo Ningning , Zhang Qin , Lu Guanghua , Qi Yingxue , Wu Yaqing
Published: June 2021

e22500

Background: Breast cancer susceptibility genes BRCA1 and 2 are tumor suppressor genes and they play an important role in DNA damage response and repair during homologous recombination. Hereditary breast and ovarian cancer (HBOC) syndrome is an autosomal dominant disease due to BRCA1 and 2 germline mutation. Germline mutations of BRCA1 and 2 genes significantly increase the risk of developing breast cancer, ovarian cancer, prostate cancer and a broad range of cancers. PARP inhibitor (PARPi) monotherapy and combinations have shown promising efficacy against a variety of cancer types with BRCA mutations. Nevertheless, the knowledge of incidence of BRCA1 and 2 germline mutations in solid tumor remains poorly understood. Herein, next generation sequencing of 539-gene profiling was performed to explore the incidence of BRCA1 and 2 germline mutations in Chinese solid tumors. Methods: We retrospectively analyzed the BRCA1 and BRCA2 germline mutations from a comprehensive 539-gene profiling of 8535 Chinese patients with pan-cancer. 539-gene profiling contains the somatic mutations in tumor tissue or blood ctDNA and the germline mutations in blood leukocyte. We screened out the pathogenic and likely pathogenic mutations in BRCA germline mutations, and calculated the mutation frequency and the median age in every cancer type. Results: In 8535 patients with pan-cancer, 110 patients were found pathogenic or likely pathogenic germline mutations in BRCA gene and the mutation frequency was 1.29%, of which 40 BRCA1 mutations and 70 BRCA2 mutations were found in patients, respectively. The total median age was 58.15. Eliminated a few types of cancers that had a smaller number (less than 50), the higher frequency of mutations contained ovarian cancer (14.78%, media age 58), prostatic cancer (6%, media age 58.33), breast cancer (5.2% media age 57.33). The details of the top 8 cancer types with mutation frequency and media age were shown in Table. Conclusions: This was the first report of the incidence of BRCA1 and 2 germline mutations in Chinese solid tumors, which expanded the understanding of BRCA1/2 and provided a direction for clinical trial design of PARPi monotherapy and combinations.[Table: see text]
Final report from a registry study of patients with active cancer undergoing ecological staging.
Authors: Cunningham James R. , Dodd Cheryl , Rittenbach Jon , Clemens Mitch
Published: June 2021

e22501

Background: The host-cancer relationship can be viewed as a set of tumor supportive and inhibitory interactions, that is as an ecosystem. An advantage of such a perspective might include a more dynamic understanding of the selection pressures affecting tumor evolution. If so then a means of detecting and measuring those forces would be of help in understanding that drive and point to potential therapeutic clinical interventions. Towards this goal a registry study of patients with invasive cancer was conducted to examine readily available clinical measures to inform an ecological staging system. Methods: Eligibility for registry participation included age of 18 years or older, active cancer requiring treatment, life expectancy estimated to be at least six months and willingness to provide informed consent for this IRB-approved study. Ecological staging was then conducted at entry assessing 22 separate clinical parameters from history, physical exam and laboratory known to effect tumor biology, grouped into eight profiles and scored using a trichotomization of data, increasing score corresponding to an increase in positive tumor selection. To aggregate data from the profiles, a geometric figure, an octamer, or ecogram, was constructed, vertices representing the net score of each of the eight profiles. We hypothesize that the area bounded by the polygon, ecogram area (EA) would reflect an index of adverse, tumor-supporting ecological influence. Overall survival was determined from time of diagnosis of cancer until time of registry closure. Results: 15 subjects, eight female, seven male, ages 53-84 (median 64) participated in the registry. Complete ecological staging was obtained from all participating subjects, an indication of feasibility for collection of such data in the clinic. Resulting EA ranged 12-fold (0-12.1) across subjects suggesting sensitivity of EA to differences in selection pressures among the participants; ecogram morphology from individual subjects demonstrated unique shapes, an indication of specificity for character of individual tumor ecological landscape. Mean overall survival for participants from time of cancer diagnosis was 265 weeks. For 12 subjects with advanced stage disease, overall survival was inversely related to ecogram area (r = -.45). Conclusions: Ecological staging of cancer from clinical parameters proved feasible in this registry study of patients with active cancer. Ecological information from those parameters when aggregated using a geometric figure, an ecogram, demonstrated both sensitivity and specificity for differences among participants. For those subjects with advanced stage disease, ecogram area was inversely related to overall cancer survival. Ecological staging may be a useful tool in gauging selection pressures affecting cancer evolutionary tendency and of potential benefit to oncologists in forecasting such development.
Hereditary breast cancer associated with the CHEK2 gene: Study through NGS in a Spanish cohort.
Authors: Alonso Marin Natalia , Ocáriz Maitane , Gascon Ruiz Marta , Sesma Goñi Andrea , Zurera Berjaga Maria , Zapata-Garcia Maria , Ruiz Moreno Ines , Moratiel Pellitero Alba , Marti Pi Maria , Goas Gomez Ana , Cruellas Mara , Alvarez Maria , Andrés Raquel , Isla Dolores , Lastra Rodrigo
Published: June 2021

e22502

Background: Inherited mutations in the CHEK2 gene have been associated with an increased lifetimerisk of develop breast cancer (BC). The main objective of the study is to identify in our population the prevalence of mutations in the CHEK2 gene in diagnosed BC patients, as well as to evaluate the phenotypic characteristics of the tumour and family history. Methods: A genetic study was performed in 396 patients diagnosed of BC at the University Hospital Lozano Blesa of Zaragoza (Spain). We selected 9 patients with genetic variants in the CHEK2 gene and performed a descriptive analysis of the clinical variables, a bibliographic review of the genetic variants and a co-segregation study. Results: We identified 2 pathogenic variants ( CHEK2 c.349 A>G and c.507delT) and 6 variants of uncertain significance (VUS). The genotypic characteristics of the VUS are summarized in the table. In all cases there was a family history of BC in first and /or second degree relatives. The variant cosegregated with the disease in one of the families. Conclusions: The pathogenic missense variant c.349A>G was found in two families. This is a rare missense variant. Studies have shown that this variant had a significant impact on the protein based on in silico prediction and has been associated with BC. In our study, this variant was found in a patient with renal carcinoma and was identified in a proband with a strong family history of pancreatic and ovarian cancer (OC). However, there aren’t exist data about the risk of developing other cancer, different of BC, with this specific mutation. The other pathogenic variant detected was CHEK2 c.507delT in a family with history of BC and OC. This variant is a frameshift mutation, predicted to cause loss of normal protein function. CHEK2 507delT was reported in one of 12 BC families in one series and is possible its relation with OC. With regard to the VUS the cosegregation analysis in selected families may help understand if a variant could have played a role in developing cancer. In conclusion, CHEK2 mutations have been associated with increased risk for BC. However, the frequency of carriers may vary depending on the population, and different mutations may be associated with different cancer risks. More studies are needed to establish a complete range of risks associated with CHEK2 mutations. [Table: see text]
SARS-CoV2 infection rate in patients and health care personnel in a chemoradiotherapy unit: A prospective cohort in Mexico.
Authors: Meneses Medina Mónica Isabel , Hernandez-Felix Jorge Humberto , Camargo Vanessa Rosas Rosas , Valenzuela Ana Karen , Cedro-Tanda Alberto , Martos Armendariz Edgar Omar , Anaya Sánchez Luis Guillermo , Torres Valdiviezo Lucero Itzel , Galindo Fraga Arturo , Herrera Montalvo Luis A. , Hidalgo Alfredo , Huitzil Melendez Fidel David
Published: June 2021

e22521

Background: Cancer treatment during the COVID-19 pandemic represents a challenge. Increased hospital visits to receive treatment as well as interaction with healthcare personnel (HCP), represent a potential risk factor for acquiring COVID-19. Our objective was to analyze the SARS-CoV-2 infection rate in patients (pts) with cancer and HCP of a chemoradiotherapy unit localized in a center designated as a COVID-19 priority facility in Mexico City. Methods: We invited HCP and pts with solid tumors attending the chemoradiotherapy unit to participate in a prospective follow-up cohort to early detect asymptomatic COVID-19 infection. Only participants who gave informed consent were included. A RT-PCR test for SARS-COV-2 from nasopharyngeal swab samples was performed every 2 weeks, and daily electronic clinical questionnaires were sent. Recruitment started on June 12, 2020. Participants entered the study in different moments and they were followed until a positive test for COVID-19 was found, or pts finished treatment or, HCP changed work area or, withdrawal of inform consent, or follow up completion, which ever occurred first. The last day of follow up was September 30, 2020. The general infection rate during all the period of follow-up was calculated, as well as the infection rate per month. Results: We included 130 asymptomatic participants, 44.6% (n = 58) were HCP and 55.4% (n = 72) were cancer pts, 45.9% (n = 61) were men, and 54.1% (n = 72) were women. During a median follow-up of 85 days (IQR 48-103) we performed 634 nasopharyngeal swabs for SARS-CoV-2 RT-PCR, with a median number per participant of 5 (IQR 3-7). Within this period, 18 (13.5%) participants tested positive for SARS-CoV-2 infection. 12 were asymptomatic and 6 developed symptoms. None of them had a severe form of COVID-19 and we did not register any death associated to COVID-19. Table shows the infection rate per month. Conclusions: In our center, during the time period of follow up, the overall rate of COVID-19 infection was higher than that reported in a study from asymptomatic HCP and office workers in Mexico City (13.5 vs 8.4%). We also observed a monthly variation that was consistent with the months with the highest number of cases detected in Mexico City during the first wave. With careful implementation, it is feasible to continue to safely deliver systemic oncologic treatments during the COVID-19 pandemic.[Table: see text]