tbuckley/cabot-search huggingface dataset:
Impact of Risk-Adapted Therapy for Pediatric Hodgkin Lymphoma on Risk of Long-Term Morbidity: A Report From the Childhood Cancer Survivor Study
Authors: Kevin C. Oeffinger, Kayla L. Stratton, Melissa M. Hudson, Wendy M. Leisenring, Tara O. Henderson, Rebecca M. Howell, Suzanne L. Wolden, Louis S. Constine, Lisa R. Diller, Charles A. Sklar, Paul C. Nathan, Sharon M. Castellino, Dana Barnea, Susan A. Smith, Raymond J. Hutchinson, Gregory T. Armstrong, Leslie L. Robison
Journal: Journal of Clinical Oncology (2021)

To determine the incidence of serious chronic health conditions among survivors of pediatric Hodgkin lymphoma (HL), compare by era of therapy and by selected cancer therapies, and provide estimates of risks associated with contemporary therapy.Assessing 2,996 5-year HL survivors in the Childhood Cancer Survivor Study diagnosed from 1970 to 1999, we examined the cumulative incidence of severe to fatal chronic conditions (grades 3-5) using self-report conditions, medically confirmed subsequent malignant neoplasms, and cause of death based on the National Death Index. We used multivariable regression models to estimate hazard ratios (HRs) per decade and by key treatment exposures.HL survivors were of a mean age of 35.6 years (range, 12-58 years). The cumulative incidence of any grade 3-5 condition by 35 years of age was 31.4% (95% CI, 29.2 to 33.5). Females were twice as likely (HR, 2.1; 95% CI, 1.8 to 2.4) to have a grade 3-5 condition compared with males. From the 1970s to the 1990s, there was a 20% reduction (HR, 0.8; 95% CI, 0.7 to 0.9) in decade-specific risk of a grade 3-5 condition (P trend = .002). In survivors who had a recurrence and/or hematopoietic cell transplant, the risk of a grade 3-5 condition was substantially elevated, similar to that of survivors treated with high-dose, extended-field radiotherapy (HR, 1.2; 95% CI, 0.9 to 1.5). Compared with survivors treated with chest radiotherapy ≥ 35 Gy in combination with an anthracycline or alkylator, a contemporary regimen for low-intermediate risk HL was estimated to lead to a 40% reduction in risk of a grade 3-5 condition (HR, 0.6; 95% CI, 0.4 to 0.8).This study demonstrates that risk-adapted therapy for pediatric HL has resulted in a significant reduction in serious long-term outcomes.
177Lu-PSMA Therapy for Metastatic Testicular Mixed Germ Cell Tumor
Authors: Duygu Has Simsek, Caner Civan, Meltem Ekenel, Serkan Kuyumcu, Yasemin Sanli
Journal: Clinical Nuclear Medicine (2021)

Prostate-specific membrane antigen (PSMA) overexpression in various tumors are demonstrated in both in vitro and in vivo studies. Prostate-specific membrane antigen-directed radionuclide therapies are generally used in prostate cancer and could be also useful in PSMA-avid other malignancies. Herein, we present a case of a 46-year-old male patient who had progressive metastatic testicular mixed germ cell tumor, despite repeated operations and treatments. 68Ga-PSMA PET/CT was performed to assess eligibility for 177Lu-PSMA therapy. Patient had intense PSMA uptake in metastatic lesions, and 177Lu-PSMA has been given to control of disease. However, α-fetoprotein level progressed, and mixed therapy response was detected in 68Ga-PSMA PET/CT.
Interaction between G ALNT12 and C1GALT1 Associates with Galactose-Deficient IgA1 and IgA Nephropathy
Authors: Yan-Na Wang, Xu-Jie Zhou, Pei Chen, Gui-Zhen Yu, Xue Zhang, Ping Hou, Li-Jun Liu, Su-Fang Shi, Ji-Cheng Lv, Hong Zhang
Journal: Journal of the American Society of Nephrology (2021)

Significance Statement Galactose-deficient IgA1 plays a key role in the pathogenesis of IgA nephropathy. Although variability in serum levels of galactose-deficient IgA1 has a strong genetic component, the genetic link between this molecule and IgA nephropathy has not yet been clearly determined. The authors performed a genome-wide association study of serum galactose-deficient IgA1 levels among 1127 patients with IgA nephropathy in a Chinese population, identifying two genome-wide significant loci, of which one is novel. They also observed potential associations between galactose-deficient IgA1 loci and susceptibility to IgA nephropathy. In addition, they found genetic interactions between the two loci associated with both serum levels of galactose-deficient IgA1 and susceptibility to developing IgA nephropathy. This study provides novel insights into the genetic link between galactose-deficient IgA1 and IgA nephropathy. Background Galactose-deficient IgA1 plays a key role in the pathogenesis of IgA nephropathy, the most common primary GN worldwide. Although serum levels of galactose-deficient IgA1 have a strong genetic component, the genetic link between this molecule and IgA nephropathy has not yet been clearly established. Methods To identify novel loci associated with galactose-deficient IgA1, we performed a quantitative genome-wide association study for serum galactose-deficient IgA1 levels, on the basis of two different genome-wide association study panels conducted in 1127 patients with IgA nephropathy. To test genetic associations with susceptibility to IgA nephropathy, we also enrolled 2352 patients with biopsy-diagnosed IgA nephropathy and 2632 healthy controls. Peripheral blood samples from 59 patients and 27 healthy controls were also collected for gene expression analysis. Results We discovered two loci, in C1GALT1 and GALNT12, that achieved genome-wide significance, explaining about 3.7% and 3.4% of variance in serum galactose-deficient IgA1 levels, respectively. We confirmed the previously reported association of C1GALT1 with serum galactose-deficient IgA1 levels, but with a different lead single-nucleotide polymorphism (rs10238682; β=0.26, P =1.20×10 −9 ); the locus we identified at GALNT12 (rs7856182; β=0.73, P =2.38×10 −9 ) was novel. Of more interest, we found that GALNT12 exhibits genetic interactions with C1GALT1 in both galactose-deficient IgA1 levels ( P =1.40×10 −2 ) and disease risk ( P =6.55×10 −3 ). GALNT12 mRNA expression in patients with IgA nephropathy was significantly lower compared with healthy controls. Conclusions Our data identify GALNT12 as a novel gene associated with galactose-deficient IgA1 and suggest novel genetic interactions. These findings support a key role of genetically conferred dysregulation of galactose-deficient IgA1 in the development of IgA nephropathy.
Abstract PS14-13: National comprehensive cancer network (NCCN) recommendations for drugs without US food and drug administration (FDA) approval in metastatic breast cancer: A cross-sectional study
Authors: Tal Etan, Eitan Amir, Adriana Tibau, Rinat Yerushalmi, Assaf Moore, Daniel Shepshelovich, Hadar Goldvaser
Journal: Cancer Research (2021)

Abstract Background: NCCN guidelines include recommendations not approved by the FDA. We aimed to compare the NCCN recommendations for metastatic breast cancer (MBC) with the FDA approved indications and to identify characteristics that are associated with NCCN recommendations for off-label treatment. Methods: All NCCN recommendations for MBC and their supporting data were identified. Drug labels were reviewed to determine whether recommendations are FDA approved indications. Odds ratio (OR) and 95% confidence interval (CI) were calculated to compare between FDA approved and off-label recommendations for pre-specified categories including drug type, tumor subtype, level of recommendation and line of therapy. Results: Of 124 recommendations identified, 68 (55%) were off-label. Chemotherapy and human epidermal growth factor receptor 2 (HER2) targeted drugs were associated with less frequent approved indications (OR=0.28, 95% CI 0.12-0.62, p=0.001 and OR=0.29, 95% CI 0.12-0.70, p=0.005, respectively). Recommendations for endocrine therapy (OR=3.44, 95% CI 1.32-9.09, p=0.009) and non-HER2 targeted treatment (OR=10.0, 95% CI 3.03-33.33, p&amp;lt;0.001) were associated with FDA approved indications. Compared to combination therapies, monotherapies were more likely to be FDA approved (OR=3.45, 95% CI 1.64-7.23, p=0.001). Category 1 (OR=7.63, 95% CI 2.19-26.55, p=0.001) and preferred NCCN recommendations (OR=5.49, 95% CI 2.36-12.77, p&amp;lt;0.001) were more likely to be FDA-approved indications. Compared to off-label recommendations, NCCN recommendations of approved drugs were based on significantly higher sample size (mean 477 vs. 342 patients, p=0.017) and were non- significantly associated with availability of randomized data (OR=1.92, 95% CI 0.87-4.24, p=0.10).Conclusion: More than half of all NCCN recommendations for MBC are off-label, mostly involving chemotherapy containing regimes for HER2 negative disease and combinations which include HER2 targeting drugs. The clarity of the NCCN guidelines can be improved by underlining the strength of the evidence supporting various recommendations for MBC and the hierarchy between various treatment options. Citation Format: Tal Etan, Eitan Amir, Adriana Tibau, Rinat Yerushalmi, Assaf Moore, Daniel Shepshelovich, Hadar Goldvaser. National comprehensive cancer network (NCCN) recommendations for drugs without US food and drug administration (FDA) approval in metastatic breast cancer: A cross-sectional study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS14-13.
Bisphenol S and Epidermal Growth Factor Receptor Signaling in Human Placental Cytotrophoblasts
Authors: Elvis Ticiani, Jeremy Gingrich, Yong Pu, Mathew Vettathu, Jacquelyn Davis, Denny Martin, Margaret G. Petroff, Almudena Veiga-Lopez
Journal: Environmental Health Perspectives (2021)

Bisphenol S (BPS) is an endocrine-disrupting chemical and the second most abundant bisphenol detected in humans. In vivo BPS exposure leads to reduced binucleate cell number in the ovine placenta. Binucleate cells form by cellular fusion, similar to the human placental syncytiotrophoblast layer. Given that human placental syncytialization can be stimulated through epidermal growth factor (EGF), we hypothesized that BPS would reduce human cytotrophoblast syncytialization through disruption of EGF receptor (EGFR) signaling.We tested whether BPS interferes EGFR signaling and disrupts human cytotrophoblast syncytialization.We first tested BPS competition for EGFR using an EGF/EGFR AlphaLISA assay. Using human primary term cytotrophoblast cells (hCTBs) and MDA-MD-231 cells, a breast cancer cell line with high EGFR expression, we evaluated EGFR downstream signaling and tested whether BPS could inhibit the EGF response by blocking EGFR activation. We also evaluated functional end points of EGFR signaling, including EGF endocytosis, cell proliferation, and syncytialization.BPS blocked EGF binding in a dose-dependent manner and reduced EGF-mediated phosphorylated EGFR in both cell types. We further confirmed that BPS acted as an EGFR antagonist as shown by a reduction in EGF internalization in both hCTBs and MDA-MD-231 cells. Finally, we demonstrated that BPS interfered with EGF-mediated cell processes, such as cell proliferation in MDA-MD-231 cells and syncytialization in hCTBs. EGF-mediated, but not spontaneous, hCTB syncytialization was fully blocked by BPS (200 ng/mL), a dose within urinary BPS concentrations detected in humans.Given the role of EGFR in trophoblast proliferation and differentiation during placental development, this study suggests that exposures to BPS at environmentally relevant concentrations may result in placenta dysfunction, affecting fetal growth and development. https://doi.org/10.1289/EHP7297.
Association between vision impairment and mortality: a systematic review and meta-analysis
Authors: Joshua R Ehrlich, Jacqueline Ramke, David Macleod, Helen Burn, Chan Ning Lee, Justine H Zhang, William Waldock, Bonnielin K Swenor, Iris Gordon, Nathan Congdon, Matthew Burton, Jennifer R Evans
Journal: The Lancet Global Health (2021)

The number of individuals with vision impairment worldwide is increasing because of an ageing population. We aimed to systematically identify studies describing the association between vision impairment and mortality, and to assess the association between vision impairment and all-cause mortality.
Abstract PS9-22: Supportive care needs and patient experience of women with metastatic breast cancer in a safety-net system
Authors: Ashley Buchanan, Ola El-Mubasher, Astrid Sarfo, Hoda Badr
Journal: Cancer Research (2021)

Abstract Background: Metastatic breast cancer (MBC) is an incurable, albeit treatable cancer affecting over 150,000 women in the US. Addressing supportive care needs has become increasingly important as women are living longer with MBC due to advances in treatment. However, most supportive care programs were developed for women with early stage breast cancer. The existing literature also offers limited understanding of the needs of patients receiving care in safety net settings, which are often under-resourced and treat medically underserved populations, who are more likely to be diagnosed with MBC. Methods: This study sought to understand the supportive care needs and experience of MBC patients receiving care in a safety net system. Semi-structured interviews were conducted with 11 patients (average age = 42.8 years, SD = 19.5) who were undergoing treatment for MBC. Questions centered on the diagnosis and treatment experience, patient-provider communication, and perceived barriers to care. Interviews were digitally audio-recorded, transcribed and coded using a Grounded Theory approach. Results: Patients noted that a lack of familiarity with medical terminology and insufficient medical knowledge made it difficult for them to evaluate treatment options, make treatment decisions, and communicate their supportive care needs. Half (n=5) did not feel their healthcare concerns were validated when expressed and some even went so far as to exaggerate reports of physical symptom severity in order to receive more timely and attentive care. Patients were dissatisfied with the timeliness of information delivery, scheduling delays, and long wait times. Some also felt that seeing different providers (e.g., residents, fellows) each time they came into the clinic interfered with the doctor-patient bond and continuity of care. Conclusion: This study identified patient, provider, and system-level factors affecting MBC patients’ experience of care in a safety-net system. Our findings indicate a strong need for support services including outreach to address health literacy issues, treatment decision making, and symptom management concerns. They also indicate a need for improved disease and treatment information exchange between patients and healthcare providers. Citation Format: Ashley Buchanan, Ola El-Mubasher, Astrid Sarfo, Hoda Badr. Supportive care needs and patient experience of women with metastatic breast cancer in a safety-net system [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS9-22.
Involvement of long non‐coding RNAs in the progression of esophageal cancer
Authors: Wenhua Xue, Yuanyuan Zheng, Zhibo Shen, Lifeng Li, Zhirui Fan, Wenbin Wang, Zijia Zhu, Yunkai Zhai, Jie Zhao, Quancheng Kan
Journal: Cancer Communications (2021)

Esophageal cancer (EC) is one of the most common malignant tumors of the digestive system with high incidence and mortality rate worldwide. Therefore, exploring the pathogenesis of EC and searching for new targeted therapies are the current research hotspot for EC treatment. Long non-coding RNAs (lncRNAs) are endogenous RNAs with more than 200 nucleotides, but without protein-coding function. In recent years, lncRNAs have gradually become the focuses in the field of non-coding RNA. Some lncRNAs have been proved to be closely related to the pathogenesis of EC. Many lncRNAs are abnormally expressed in EC and participate in many biological processes including cell proliferation, apoptosis, and metastasis by inhibiting or promoting target gene expression. LncRNAs can also regulate the progression of EC through epithelial-mesenchymal transformation (EMT), which is closely related to the occurrence, development, and prognosis of EC. In this article, we review and discuss the involvement of lncRNAs in the progression of EC.
99mTc-MDP 3-Phase Bone Imaging in 3 Cases of Pigmented Villonodular Synovitis
Authors: Tingting Hao, Xiaoliang Xiong, Libo Wang, Xue Shi, Yinlong Zhao
Journal: Clinical Nuclear Medicine (2021)

Pigmented villonodular synovitis (PVNS) is a rare proliferative synovial benign disorder, which is characterized by villonodular hyperplasia of joints, tendon sheath, and synovium; invasion of adjacent tissue; and sometimes visible hemosiderin deposition. Studies regarding bone scan findings of PVNS were relatively limited. Here, we report our findings on 99mTc-MDP 3-phase bone scan with SPECT/CT images on delayed phase in 3 patients with joint PVNS.
FAST: a randomised phase II study of zolbetuximab (IMAB362) plus EOX versus EOX alone for first-line treatment of advanced CLDN18.2-positive gastric and gastro-oesophageal adenocarcinoma
Authors: U. Sahin, Ö. Türeci, G. Manikhas, F. Lordick, A. Rusyn, I. Vynnychenko, A. Dudov, I. Bazin, I. Bondarenko, B. Melichar, K. Dhaene, K. Wiechen, C. Huber, D. Maurus, A. Arozullah, J.W. Park, M. Schuler, S.-E. Al-Batran
Journal: Annals of Oncology (2021)
Activated ALK Cooperates with N-Myc via Wnt/β-Catenin Signaling to Induce Neuroendocrine Prostate Cancer
Authors: Kenji Unno, Zachary R. Chalmers, Sahithi Pamarthy, Rajita Vatapalli, Yara Rodriguez, Barbara Lysy, Hanlin Mok, Vinay Sagar, Huiying Han, Young A. Yoo, Sheng-Yu Ku, Himisha Beltran, Yue Zhao, Sarki A. Abdulkadir
Journal: Cancer Research (2021)

Abstract Neuroendocrine prostate cancer (NEPC) is an aggressive subtype of prostate cancer with poor prognosis, and there is a critical need for novel therapeutic approaches. NEPC is associated with molecular perturbation of several pathways, including amplification of MYCN. Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase involved in the pathogenesis of neuroblastoma and other malignancies where it cooperates with N-Myc. We previously identified the first case of ALK F1174C-activating mutation in a patient with de novo NEPC who responded to the ALK inhibitor, alectinib. Here, we show that coactivation of ALK and N-Myc (ALK F1174C/N-Myc) is sufficient to transform mouse prostate basal stem cells into aggressive prostate cancer with neuroendocrine differentiation in a tissue recombination model. A novel gene signature from the ALK F1174C/N-Myc tumors was associated with poor outcome in multiple human prostate cancer datasets. ALK F1174C and ALK F1174C/N-Myc tumors displayed activation of the Wnt/β-catenin signaling pathway. Chemical and genetic ALK inhibition suppressed Wnt/β-catenin signaling and tumor growth in vitro in NEPC and neuroblastoma cells. ALK inhibition cooperated with Wnt inhibition to suppress NEPC and neuroblastoma proliferation in vitro and tumor growth and metastasis in vivo. These findings point to a role for ALK signaling in NEPC and the potential of cotargeting the ALK and Wnt/β-catenin pathways in ALK-driven tumors. Activated ALK and N-Myc are well known drivers in neuroblastoma development, suggesting potential similarities and opportunities to elucidate mechanisms and therapeutic targets in NEPC and vice versa. Significance: These findings demonstrate that coactivation of ALK and N-Myc induces NEPC by stimulating the Wnt/β-catenin pathway, which can be targeted therapeutically.
Common Fetal Hemoglobin Variants Modify Hematological Phenotypes in MDS/MPN/Myeloma Patients Receiving Cytotoxic Drugs
Authors: Norris E. Igbineweka, Adam Pilarski, Helen Rooks, Amandine Breton, Hannah Hall, Dilan D. Joshi, Daveena Meeks, Stephan Menzel, Timothy Chevassut, Swee Lay Thein
Journal: Blood (2017)
Incentive Payments and Research Related Risks—No Reason to Change
Authors: Søren Holm
Journal: The American Journal of Bioethics (2021)

Incentive payments and research related risks -No reason to changeThe paper by Fernandez Lynch et al argues that payments to research participants in biomedical research can be divided into three different categories, reimbursement, compensation, and incentive and that guidelines for each can be developed specifying what factors to take into account when deciding the amount to be paid to participants (Fernandez Lynch et al 2020).This comment focuses primarily on incentive payments and whether it is acceptable to incentivise healthy research participants to take on research related risks.It will show that the traditional position in research ethics that we should not offer risk payments is fully justified.This will further show that the current public health emergency created by the Covid-19 pandemic provides no reason to change that position.Covid-19 related research projects should, as Fernandez Lynch et al also argue be treated exactly as any other research projects involving the same procedures, risks and projected benefits.
Abstract PS16-21: Apc control of taxane resistance in breast cancer
Authors: Jeni Prosperi, Emily Astarita, Camden Hoover, Sara Maloney
Journal: Cancer Research (2021)

Abstract Adenomatous Polyposis Coli (APC) is a multi-domain tumor suppressor with multiple binding partners, including β-catenin, axin, and microtubules. APC is lost in many epithelial cancers, including up to 70% of sporadic breast cancers, with a tendency towards triple negative breast cancers (TNBCs). We previously demonstrated that APC knockdown in the human TNBC cell line, MDA-MB-157, resulted in resistance to Paclitaxel (PTX), a chemotherapeutic agent of the Taxane family that inhibits mitotic progression. Further studies have confirmed this finding in the MDA-MB-231 cells with CRISPR-mediated APC knockout. To understand the mechanism(s) by which APC controls response to PTX, we have taken two approaches. We first performed an unbiased analysis of transcriptomic changes downstream of APC loss to identify potential therapeutic targets to overcome PTX resistance. In this, a group of transcripts involved in regulation of the cell cycle were identified, including LBH, GLI1, RGS4, and NUPR1. These results have been validated by qRT-PCR and western blot, leading to studies in the laboratory to investigate their specific effects on the response to PTX in breast cancer. Along with the broad exploration studies, molecular studies have focused on whether APC controls expression of cell cycle proteins, leading to PTX resistance. While we observed changes in multiple cell cycle proteins, our focus was on the G2/M transition, given that both PTX and APC impact microtubule dynamics and the G2/M phase of the cell cycle. We examined the effect of APC loss on expression of G2/M proteins, identifying a significant upregulation of CDK1 in APCKD cells. Despite no changes in phosphorylation status of CDK1, we found that Cyclin B1 and CDK1 are only complexed in the APCKD cells, suggesting increased activation. Further studies showed that while the majority of CDK1 and Cyclin B1 are localized to the cytoplasm, there is a small amount in the nucleus. Based on these findings, we sought to investigate whether PTX sensitivity would be altered in response to CDK1 inhibitor, RO-3306. We have shown that PTX resistant APCKD cells are more sensitive (IC50 = 25.5uM) to RO-3306 compared the parental control (IC50 = 78uM). Future studies will use combination and sequential treatments to monitor PTX response in vitro and in vivo. Combined, these studies are elucidating the mechanisms by which loss of APC controls sensitivity to PTX in TNBC, with the long-term goal of designing treatment regimens to improve patient health and survival. Citation Format: Jeni Prosperi, Emily Astarita, Camden Hoover, Sara Maloney. Apc control of taxane resistance in breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS16-21.