bluuebunny/crossref_metadata_2025_split huggingface dataset:
Single agent high-dose ifosfamide in refractory or relapsed osteosarcoma.
Authors: Jiwani Zahra Merchant , Ramiz Sarah Watheq Shakir 
Published: June 2021

e22006 Background: Osteosarcoma (OS) is the most common primary malignant neoplasm of the bone in children and adolescents, typically occurring in the metaphysis of long bones. Historically, patients were treated with surgical resection, but the addition of neoadjuvant chemotherapy over the last 50 years has greatly improved prognosis, with survival rates increasing from 20% to almost 70% for non-metastatic tumors. However, prognosis remains poor for patients with refractory or recurrent disease, and Ifosfamide containing regimens are the standard 2nd line chemotherapy. Ifosfamide has been utilized in various combinations with other chemotherapeutic agents including methotrexate, cisplatin and epirubicin with variable reported results. Alternatively, it has been used as a single agent at an escalated dose of 12-14 gm/m2 with improved response. However, high dose Ifosfamide (HDI) is associated with nephrotoxicity. We aim to evaluate our institution’s experience with single agent HDI in terms of both outcome and safety. Methods: This is a single institutional retrospective study conducted at the Children’s Hospital of Michigan. All pediatric patients up to age 21 years with refractory or relapsed osteosarcoma who received at least 2 cycles of HDI therapy after MAP over the course of 20 years were included. Progression free and event free survival were calculated. Nephrotoxicity was documented as per common terminology criteria for adverse events (CTCAE) v.50 grading. Results: A total of 46 charts were screened, 19 patients were found to have recurrent or refractory OS. 3 patients were only treated surgically. 16 patients received 2nd line chemotherapy with/without surgical resection. 13 patients received single agent HDI and were included in our analysis. The mean age at diagnosis was 13.78, with 6 recurrent and 7 refractory patients. Patients received an average of 5 cycles of HDI. At end of therapy, objective response rate was 46% and disease control rate was 61%. 5 patients in our analysis had reported nephrotoxicity, with 3 patients having transient grade 1 elevations in creatinine that improved while remaining on chemotherapy. 2 patients developed persistent grade I elevation of creatinine, both developed this nephrotoxicity after being off therapy for more than 1 year. Nephrotoxicity was associated with higher number of cycles of HDI, with these patients receiving at least 4 cycles. At this point of follow up, 3 patients are alive without evidence of disease at least 2 years after completion of chemotherapy. Conclusions: Our experience is consistent with prior reports that HDI is efficacious as single agent therapy for patients with osteosarcoma that is refractory or recurrent with acceptable nephrotoxicity. In our experience, nephrotoxicity occasionally developed months after the cessation of therapy. As such, long term follow up of survivors is necessary.
Vincristine, irinotecan, and temozolomide in patients with relapsed and refractory neuroblastoma.
Authors: Zhu Jia , Zhen Zijun , Wang Juan , Chen Tingting , Lu Suying , Sun Feifei , Huang Junting , Que Yi , Zhang Lian , Zhang Yizhuo , Sun Xiaofei 
Published: June 2021

e22009 Background: The combination of irinotecan, temozolomide and vincristine has been proposed as an effective salvage regimen for some pediatric malignancies. Thus, we sought to evaluate this combination for patients with relapsed or refractory neuroblastoma (NB). Methods: Forty-six patients with relapsed or refractory NB were treated with the combination of vincristine (1.5 mg/m2 i.v. day 1), irinotecan (50 mg/m2 /day i.v. days 1–5) and temozolomide (100 mg/m2 /day p.o. days 1–5) (VIT) during the period 2011–2019. All toxicities were documented. Results: A total of 251 cycles (median 6 cycles/patient) were administered. A complete response (CR) was achieved in 5 patients, partial response (PR) in 27 patients, stable disease (SD) in 8 patients, and progression disease (PD) in 6 patients, with an overall objective response rate (CR+PR) of 69.6%. Eighteen patients developed diarrhea with Grade III or less. Grade 1-2 hematologic toxicity occurred in 10 patients. Grade 3-4 hematologic toxicity developed in 32 patients. VIT was an effective regimen for different metastatic sites. Overall objective response rates to VIT combination for patients with mediastinum, bone marrow/bone, lymph node, abdomen and brain involvement were 100.0%, 80.0%, 77.8%, 50.0%, 42.9%, respectively. UGT1A*28 genotyping performed in 7 patients revealed wild type. Diarrhea occurred in 4 of them. Conclusions: The shorter, 5-day VIT regimen is an active and well-tolerated salvage regimen in relapse/refractory NB.[Table: see text]
Predictors of inpatient admission for pediatric cancer patients visiting the emergency department.
Authors: Lee Terrence C. , Qiao Edmund M. , Qian Alexander S. , Nalawade Vinit , Voora Rohith S. , Kotha Nikhil V. , Dameff Christian , Coyne Christopher John , Murphy James Don 
Published: June 2021

e22019 Background: Pediatric cancer patients represent a vulnerable cohort at risk of adverse outcomes after presenting to the emergency department (ED). Given the severity of cancer-related complications and uniqueness of this population, approaches to better risk stratify this cohort could potentially help define future interventions geared towards improving outcomes. We used a high-dimensional machine learning approach to help define the risk of hospitalization after an ED visit among pediatric patients with cancer. Methods: A cohort of cancer patients under 18 was identified from the Nationwide Emergency Department Sample (NEDS) between 2016-2018. We used a lasso regression model to predict inpatient admission after an ED visit. Model covariates included patient demographics, hospital characteristics, and International Classification of Diseases, version 10 (ICD-10) diagnosis codes. The data were split 75%/25% into training/testing data. The model was constructed with training data, and performance assessed on the test data using the area under the curve (AUC), with an AUC of 1.0 indicating perfect prediction. Results: We identified 129,631 pediatric cancer patients who visited the ED, of which 54.5% were subsequently admitted. The final predictive model included 150 variables, including 9 demographic, 6 hospital, and 135 unique ICD-10 codes. The model demonstrated excellent ability to predict hospitalization with an AUC of 0.96. The top 5 most important variables associated with inpatient admission were diagnoses of paralytic ileus/intestinal obstruction, neutropenia, sepsis, aplastic anemia/bone marrow failure, and bacterial infection. Conclusions: Pediatric cancer patients frequently present to the ED with complications of their cancer or their treatment, and over half of these patients are admitted. This study demonstrates the capacity of high-dimensional prediction models to help identify pediatric patients at risk of hospitalization. Additional research is needed to determine how to implement these predictive models in clinical practice.
Improved universal tumor screening program with paired testing: Experience at a large community-based teaching hospital.
Authors: Majmudar Gnyapti , Ivan Kristina , Rangarajan Tara , Zakalik Dana 
Published: June 2021

e22505 Background: Lynch syndrome (LS) is the most common cause of hereditary predisposition to colon, endometrial, and other cancers. The universal tumor screening program for LS at Beaumont Health (BH) utilizes immunohistochemistry (IHC) of the mismatch repair (MMR) proteins to identify patients for genetics evaluation. We present the 8-year experience of the program at a large community-based teaching hospital. Methods: The MMR IHC results for all colorectal cancer (CRC) resection specimens screened from August 2012 to September 2020 were reviewed. Specimens with absent MLH1 and PMS2 were evaluated for MLH1 promoter hypermethylation with reflex to BRAF V600E mutation analysis. All abnormal results were referred for cancer genetics evaluation. The distribution of abnormal MMR and germline genetic testing results was analyzed. Results: Specimens from 2361 CRC resections were screened, and 511 specimens had abnormal MMR IHC (22%). Most cases of absent MLH1 and PMS2 were explained by hypermethylation or BRAF analysis (n = 338, 66% of all abnormal, 89% of MLH1 and PMS2). Of the remaining cases showing MMR deficiency (n = 173), the most common result was absence of MSH2 and MSH6 (n = 67), followed by absence of MLH1 and PMS2 (n=41, see table). Germline genetic testing of 83 individuals with abnormal MMR IHC revealed 49 cases of Lynch syndrome [MLH1 (n=9), MSH2 (n= 25), MSH6 (n=7), PMS2 (n=7), EPCAM (n=1)]. A significant proportion of cases (n=34, 40%) had negative germline testing, and had unexplained MMR deficiency. Paired germline/tumor testing was implemented in 2017, and 14 patients had this analysis. Using this approach, 5 individuals were identified to have somatic mutations explaining their result, and the proportion of unexplained cases was reduced to 29% (n = 4). Conclusions: Recent advances in cancer screening and therapeutics have underscored the importance of analyzing tumors for mismatch repair deficiency (dMMR), with known challenges to implementation and interpretation of results. The BH cancer genetics program has demonstrated successful growth of a universal tumor screening program over 8 years. This has led to the identification of a large number of dMMR tumors (22% of all CRC resections) and LS cases (2% of all CRC resections), which impacts management for patients and their families. Recent implementation of paired germline/tumor testing has improved the testing algorithm, and resulted in more accurate interpretation of a greater proportion of abnormal IHC results. This combined approach allows for focused high-risk screening for LS patients, access to novel therapeutic interventions including immune therapies for patients with dMMR tumors, and future precision oncology approaches.[Table: see text]
Prevalence of pathogenic mutations and variants of uncertain significance in patients undergoing hereditary cancer genetic testing in Cambridge, MA.
Authors: Jani Chinmay , Rupal Arashdeep , Al Omari Omar , Agarwal Lipisha , Stafford Katherine A. , Singh Harpreet , Dar Abdul Qadir , Lotz Margaret , Dangelo Abby , Lam Prudence B. 
Published: June 2021

e22506 Background: Genetic testing allows for enhanced prognostication and early intervention in patients with high risk of developing cancer. Genetic testing often reveals variants of uncertain significance (VUS), for which association with disease risk is unclear. The ambiguity of this finding creates a dilemma for patients and providers and has been associated with significant communication error and distress. In this retrospective observational study, we seek to characterize the indications, outcomes, and trends in patients undergoing genetic testing in a community hospital in Cambridge, MA. As our study spanned the beginning of the COVID-19 pandemic, we also assessed its impact on care accessibility. Methods: We included patients undergoing genetic testing at our hospital between December 2019 and October 2020 (n=371). Medical charts were abstracted to identify patient characteristics, family history, indication for genetic testing, genetic findings, and subsequent management. Results: Our population had a mean age of 48 years (SD=15), was predominantly female (88.1%), and had a high proportion of Ashkenazi Jewish descent (15.3%). The vast majority (351, 94.6%) had a family history of cancer, while 123 (33.2%) had a personal history of cancer, most commonly breast (n=89). The most common indications for genetic testing were Hereditary Breast and Ovarian Cancer (HBOC in 280, 75%), Lynch Syndrome (LS in 22, 5.9%), and Familial Adenomatous Polyposis (FAP in 7, 2%). Of patients who met HBOC, LS, or FAP criteria for genetic testing, pathogenic mutations were identified in 9.5% and VUS in 28.6%. Out of total 35 (9.4%) pathogenic mutations found in our entire study population, the most common were in BRCA (9, 25.7%), MUTYH (5, 14.2%), and Lynch genes (3, 8.6%). Out of 103 patients with VUS (27.8%), the most common sites were APC (14) and MSH3 (9). We found no significant trend in genetic counseling consultations over our 11 months study period despite the COVID-19 pandemic (R2 = 0.006). Conclusions: Among patients who met criteria for genetic cancer screening at a community hospital, 9.5% were found to have a pathogenic mutation while 28.6% were found to have VUS. These numbers are comparable to previously published estimates. Despite advances in our understanding of genetic colon and gynecological cancers, the majority of patients presenting for genetic cancer counseling continue to do so due to breast cancer concerns. Lastly, we noted high efficacy in our conversion of in-person genetics consultations to telemedicine during the COVID-19 pandemic, suggesting telemedicine is a robust format for genetic counselling. Mutations (N): BRCA1 (3), BRCA2 (6); MUTHY (5); MSH2 (2), MSH6 (1); ATM (2), and one each in PALB2, RAD50, RAD51C, RAD51D, Tp53, CDKN2A, APC, F2, SDHA, SDHB, VHL. FANCL, NTHL1.
Systematic review of family studies of heritable breast cancer in Africa.
Authors: Dhahri Amina , Adebamowo Sally Nneoma , Adebamowo Clement Adebayo 
Published: June 2021

e22508 Background: The incidence of breast cancer (BC) in Africa (40.4 per 100,000) is 49% that of Europe and North America (81.9 per 100,000) but the mortality rate is 42% higher (19.4 versus 13.7 per 100,000). The high mortality is due to lack of screening. However, more targeted screening based on genomic risks are also missed because of stigmatization, poor family history, and limited information on BC susceptibility gene mutations. Internationally based family members are influencing cultural attitudes to BC in Africa leading to reduced stigmatization, increased better family history and uptake of genomic screening. Family-based studies of BC in Africa would provide useful information on prevalence of mutations that can inform genomic screening panels. We conducted systemic review of all family-based studies of BC in Africa to document state of the art, identify barriers and facilitators of this research method and methods of advancing the science. Methods: Using a comprehensive research strategy, we reviewed articles indexed in PubMed and African Journals Online (AJOL) to identify studies of familial BC in Africa. Specifically, we searched for family-based, study design papers on BC in each country in Africa using the following keywords: breast cancer, family-studies, hereditary, genetic, gene, mutations, and Africa. We excluded case-control, and registry studies, and clinical trials. We extracted relevant information from each study using standardized criteria: number of first- and second-degree relatives affected by BC, mutations, genetic variations, and polymorphisms. Results: A total of 12 out of 727 studies met our inclusion criteria. 80% of these studies were published after the year 2010. There were 9 publications from North Africa evaluating 191 families in total. One study reported novel breast cancer candidate genes: MMS19, DNAH3, POLK and KATB6 and nine publications investigated the mutation spectrum of BRCA genes. One publication from West Africa and one publication from Southern Africa included 1 and 219 families, respectively. All the studies done in these two regions reported targeted genomic screening for only BRCA genes. No study was done in Central and East Africa. Conclusions: There is paucity of family-based studies of breast cancer in Africa. Given the high level of heterogeneity in African genomes, these types of studies may be needed to identify high penetrance, germline mutations to better understand hereditary BC risk and ultimately develop a multigene panel testing to for diagnosis of heritable BC in this population.
Factors associated with cancer screening adherence amongst Latinos in Indiana: Results of an electronic survey.
Authors: Espinoza Gutarra Manuel Ricardo , Rawl Susan M , Valenzuela Robin E. , Parker Erik , Golzarri-Arroyo Lilian , Caeli Malloy L. , Reid Tisha R. , Haunert Laura A. , O'Leary Heather A. , Maupome Gerardo , Haggstrom David A. 
Published: June 2021

e22513 Background: Latinos are the fastest growing ethnic group in the US: cancer is the leading cause of death. Cancer screening is designed to decrease cancer-specific mortality among age- and gender-appropriate populations, but is implemented less frequently among Latino populations. Barriers to screening among Latinos are less well understood. Methods: A cross-sectional, online survey was used to assess perspective on cancer information-seeking behavior, demographic, economic, healthcare access and COVID-related factors among Latino adults (>18) living in Indiana able to read and write in Spanish or English. Respondents were recruited using Facebook targeted advertisement and data were collected through Qualtrics. USPSTF recommendations for breast (BC), cervical (CC) and colorectal cancer (CRC) screening were used to evaluate screening adherence. The influence of explanatory variables on cancer-related outcomes was analyzed using univariate chi-squared tests for categorical variables and t-test for scale variables. Following this, significantly influential factors (p < 0.05) were included in multivariate logistic regression models for each response variable. Model selection was performed using stepwise regression. Results: A total of 1624 respondents participated, with 832 (51.2%) completing the survey in Spanish. Median age was 52 years old (range 18-71) for English and 54 (18-77) for Spanish respondents. 80% of respondents were located in urban areas. Cancer screening adherence rates were 45.2% for BC, 61.8% for CC and 68.0% for CRC. The main factor associated with screening adherence across all malignancies (Table) was white self-identification, other factors included having children (OR: 1.79) and having received a COVID test (OR: 1.91) for CRC, having Spanish as chosen language for the survey for CC and BC respectively. Having higher income was associated with less adherence in CRC (OR: 0.50 when expressed as subjective income adequacy, compared with people finding difficult on present income) and CC (OR: 0.18 when expressed as > 75,000 USD annual income, compared with 0-35,000 USD annual income). Conclusions: In this interim analysis of the largest Latino survey in Indiana, our findings were counter-intuitive regarding the association of income and language with cancer screening adherence. For income, these findings may have been due to lower out-of-pocket costs among vulnerable populations covered by Medicaid or Medicare insurance. For Spanish differences may be explained by increased language specific outreach for certain screening tests but not for others. Overall, these results highlight the necessity for targeted awareness campaigns for the Latino population in Indiana.[Table: see text]
Chromosomal instability associated with pathogenesis in adenomyosis.
Authors: Chao Xiaopei , Wu Wendy , Li Lei , Li Hui , Li Zhenzhen 
Published: June 2021

e22517 Background: Uterine adenomyosis is a benign condition in which endometrium-like epithelial and stromal tissue appear in the myometrium, but easily concurrent with uterine cancer and other diseases. To date, few investigations have explored the molecular mechanism of adenomyosis. This research is the first report that found the association between chromosomal instability and pathogenesis in adenomyosis. Methods: Whole exome (̃39Mb CDS of over 18,000 genes; WES) and RNA sequencing were conducted on a total of 57 adenomyosis patients enrolled in this study from 2018 to 2020, including 57 normal endometrium (EN), 57 adenomyosis (AM) and 11 endometrioses (EMT) samples. Genomic test results including somatic SNVs and CNVs as well as the whole genome duplication status were determined, which were all analyzed correlated with clinical factors. Results: We identified the presence of whole genome doubling event in 19 specimens from 16 adenomyosis patients (grouped as WGD, the other 41 patients grouped as noWGD), related to 7 normal endometrium (EN), 9 adenomyosis (AM) and 3 endometriosis (EMT) samples, which was significant with p value of 4.5e-12 by means of Wilcoxon rank sum test. Disease Free Survival (DFS) of WGD patients was significantly shorter than noWGD patients (Wilcoxon rank sum test: P = 2.42e-04), which indicated that WGD group has early on-set in adenomyosis. Estrogen therapy was applied to 31 patients before uterectomy (11 in WGD group and 20 in noWGD group), and the effectiveness of the treatment was significantly higher in WGD patients (Fisher’s exact test: P = 0.02). We found that one third adenomyosis performed whole genome doubling events, which leaded to the early on-set of this disease and significantly sensitive to estrogen therapy. Cellular stressors are extensive correlated with the generation of polyploid cells in a diploid organism form by cell proliferation progress. Compared with the normal and energy-intensive cell differentiation process, cell proliferation offers a “fast but cheap” solution under stress. Our results suggested that when cell differentiation in uterine could not be carried out properly, cell proliferation would have performed instead and produced more polyploid cells, shown as whole genome doubling events. While this circumstance would have been relieved when easing the metabolic stress with estrogen treatment. Conclusions: Our results explored the strong association between chromosomal instability and pathogenesis of adenomyosis and assumed that polyploidy caused by abnormal cell proliferation might be the molecular mechanism of uterine adenomyosis. More accurate verdict could be concluded through larger scale cohort study.