tbuckley/cabot-search huggingface dataset:
Adult malignancy-associated hemophagocytic lymphohistiocytosis: Case series.
Authors: Inês Leão, Maria Eduarda Couto, Joana Catarina Lima Marinho, Isabel Oliveira, Ângelo Martins, Mário Mariz
Journal: Journal of Clinical Oncology (2021)

e19579 Background: Hemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening hyperinflammatory syndrome, with a challenging diagnosis (pediatric HLH-2004 criteria) and treatment (HLH-1994 protocol). Recently, HScore has adapted these diagnostic criteria to the adult population. Malignancy-associated HLH (M-HLH) can occur as the first manifestation of an unknown malignancy or after / during the treatment of a known cancer. This study evaluates features and outcomes of M-HLH in adult patients. Methods: Retrospective cohort study of all patients diagnosed with M-HLH in a single institution during 2013-2020. HLH-2004 and HScore criteria were used for diagnosis. Patients’ demographics, clinical and laboratory features, treatment and mortality were reviewed. Results: Eleven patients were analyzed. Ten fulfilled 5 of the HLH-2004 diagnostic criteria and one other had a HScore &gt; 190 (80% probability of M-HLH). Median age was 68 years (IQR 62-71), and 54.5% were females. The median time between hospital admission and M-HLH diagnosis was 9 days (IQR 7-16). The most common malignancy was diffuse large B-cell lymphoma (36.4%), followed by Hodgkin lymphoma (18.2%), multiple myeloma (18.2%), myelodysplastic syndrome, T-cell and follicular lymphoma (9.1% each). Malignancy and HLH diagnosis were simultaneous in 54.5% of the cases (4 newly diagnose, 2 disease-progression); the remaining 5 patients were in remission (median time from cancer diagnosis to HLH of 9.9 months (IQR 5.1–38.3)). One patient also had an autoimmune disorder. An infectious co-trigger was identified in 81.8% of patients (virus in 45.5%, fungous in 36.4%, bacteria in 27.3%). The triad of fever, splenomegaly and cytopenia was present in 36.4% of patients. All had increased sCD25 and ferritin, with a median concentration of 7612U/mL (IQR 2631–34161) and 13269µg/L (IQR 6381–17911), respectively. The ratio between sCD25 and ferritin was 1.09 (IQR 0.13–3.05). Morphological M-HLH was documented in 8 out of the 9 biopsied cases. The HLH-1994 protocol was prescribed in 54.5% of patients (including intrathecal methotrexate in 2 patients), steroids as monotherapy were used in 18.2% and malignancy-specific chemotherapy in 36.4%. All but one patient initiated broad spectrum antibiotics at hospital admission, with an antifungal in 45.5% and an antiviral (valganciclovir) in 27.3%. At the time of analysis 63.6% of patients had died (overall, 54.5% within 3 months since M-HLH diagnosis). Conclusions: Most symptoms of M-HLH are common and unspecific, demanding a clinical suspicion and an early evaluation of ferritin, sCD25, triglycerides and fibrinogen. Co-triggers are frequent and their treatment is advisable. The disease has an unfavorable prognosis in a short period of time. This rare case series increases awareness about M-HLH (urgent need of updated diagnostic criteria and more efficient adult-adapted treatment strategies).
ATRT-08. TARGETING THE TP53-MDM2 ENHANCES RADIATION SENSITIVITY IN ATRT
Authors: Irina Alimova, Etienne Danis, Dong Wang, Angela Pierce, Natalie Serkova, Sujatha Venkataraman, Rajeev Vibahakar
Journal: Neuro-Oncology (2021)

Abstract Atypical Teratoid Rhabdoid Tumor is a highly aggressive pediatric brain tumor. Despite radiation, aggressive chemotherapy and autologous stem cell rescue, the children usually have poor survival. A functional genomic screen identified the TP53-MDM2 axis as a therapeutic vulnerability in ATRT. Gene expression demonstrates that all ATRT sub-groups have high level of MDM2 a negative regulator of p53. We demonstrate that MDM2 inhibition by shRNA or with small-molecule drugs, Nutlin3 and Idasanutlin resulted in decreased ATRT cell growth, inhibition of clonogenic potential and induction of apoptosis in vitro and in vivo. MRI imaging of intracranial tumors shows that Apparent Diffusion Coefficient (ADC), a good marker for successful treatment, significantly increased with Idasanutlin treatment showing tumor necrosis. Moreover, Idasanutlin significantly decreased growth of intracranial orthotopic ATRT brain tumors as evaluated by T2 MRI imaging and prolonged survival compared to control animals. Further idasanutlin potentiated radiation induced DNA damage and increased sensitivity to radiaton of ATRT cells. These findings highlight the TP53-MDM2 axis as a rational therapeutic target in ATRT.
Impact of the sessile serrated polyp pathway on predicted colorectal cancer outcomes in the CRC-AIM model.
Authors: John B. Kisiel, Steven H. Itzkowitz, A. Burak Ozbay, Leila Saoud, Marcus Parton, David A. Lieberman, Paul J. Limburg
Journal: Journal of Clinical Oncology (2021)

10545 Background: Approximately 20–30% of colorectal cancers (CRC) arise from the serrated polyp pathway. The multitarget stool DNA (mt-sDNA) test has greater sensitivity to detect sessile serrated polyps (SSPs) than a leading fecal immunochemical test (FIT). However, most modeling analyses do not account for the contribution of the SSP pathway to risk of CRC. We used the CRC-AIM model to assess the impact of the SSP pathway on predicted CRC outcomes with mt-sDNA or FIT screening. Methods: A simulated cohort of average-risk US patients underwent triennial mt-sDNA or annual FIT screening from ages 50–75. The percentage of CRCs arising from the SSP pathway were modeled at 0% (base case), 20%, and 30%, with stool screening adherence based on theoretical (100%) or previously reported (mt-sDNA 71%; FIT 43%) rates. Published SSP sensitivities for mt-sDNA and FIT were used. All other model inputs were identical to CISNET models. Sensitivity analyses used screening adherence rates of 40–70%. Key outcomes were life-years gained (LYG), CRC incidence and CRC mortality per 1000 patients. Results: Including SSPs in the model demonstrated a greater loss of LYG with FIT than mt-sDNA (Table). At 100% adherence, compared with base case, modeling 20% or 30% SSP pathway CRCs resulted in a decrease of 9–15 LYG with FIT and 2–4 LYG with mt-sDNA, a decrease in CRC incidence reduction of 3.9–6.1% with FIT and 0.7–1.1% with mt-sDNA, and a decrease in CRC mortality reduction of 2.6–4.0% with FIT and 0.4–0.8% with mt-sDNA. Using previously reported adherence, compared with base case, modeling 20% or 30% SSP pathway CRCs resulted in a decrease of 13–20 LYG with FIT and 2–5 LYG with mt-sDNA, a decrease in CRC incidence reduction of 4.4–6.9% with FIT and 0.6–1.1% with mt-sDNA, and a decrease in CRC mortality reduction of 3.5–5.4% with FIT and 0.4–0.9% with mt-sDNA. Assuming reported adherence and 30% SSP pathway CRCs, mt-sDNA had 48 more LYG, 14.6% greater CRC incidence reduction, and 12.4% greater CRC mortality reduction than FIT. Assuming 30% SSP pathway CRCs, outcomes favored mt-sDNA vs FIT even after modeling equivalent adherence rates ranging from 40–70%. Conclusions: After incorporating the SSP pathway into the model, outcomes with mt-sDNA neared those of FIT at 100% screening adherence rates and surpassed FIT at more realistic reported screening adherence rates.[Table: see text]
Leukemia in hospitalized patients with inflammatory bowel disease: An analysis of the National Inpatient Sample (NIS) database.
Authors: Colin Wikholm, Shiva Shankar Vangimalla, Ehab Abaza, Akram Ahmad, Ioannis Pothoulakis, Urvish Patel, Asma Ali Dilawari, Won Kyoo Cho
Journal: Journal of Clinical Oncology (2021)

10576 Background: Inflammatory bowel disease (IBD) and use of immunosuppressive therapy in IBD is linked with increased risk of leukemia. We studied the NIS database from 2003-2017 to analyze trends in any type of leukemia in IBD hospitalizations over time and examined the role of age, sex, and race. Methods: We analyzed NIS data of all adult hospitalizations for ulcerative colitis (UC) or Crohn’s disease (CD) with any type of leukemia as a primary or secondary diagnosis using validated ICD 9/10 codes. Age, sex, and racial demographics were collected. Trend analysis of leukemia was performed with Cochran-Armitage and Jonckheere-Terpstra tests. Results: Overall Trends: From 2003-2017, a total of 11,385 of 2,235,413 (0.51%) CD hospitalizations and 8,105 of 1,324,746 (0.61%) UC hospitalizations contained diagnosis of leukemia. An increase in leukemia was seen in both CD and UC group from 0.24% to 0.79% (pTrend &lt; 0.0001) and 0.28% to 0.81% (pTrend &lt; 0.0001) respectively. Sex: In both UC and CD patients, leukemia diagnoses were predominantly male in 2003 but approximated a near 1:1 ratio by 2017 (Table). In CD, the proportion of female (FEM) leukemia diagnoses grew from 31.33% to 45.05% from 2003 to 2017 (pTrend = 0.1898). In UC, the proportion of female leukemia diagnoses grew from 27.49% to 45.79% from 2003 to 2017 (pTrend = 0.0030). Age: Leukemia was more common with increasing age, with no significant changes in proportion of cases between age groups over time (pTrend &gt;.05). Ethnicity: White patients composed 87.80% and 84.24% of leukemia diagnoses in CD and UC, respectively. In CD, an increasing proportion of leukemia diagnoses occurred in black (BK) patients, and a decreasing proportion occurred in white patients (pTrends &lt;.0001; Table 1) during the study time. No trends in race were observed in the UC group (pTrend = 0.4229). Conclusions: Our study showed an increased prevalence of leukemia in CD and UC hospitalizations from 2003-2017 which may be related to increasing use of immunosuppressants such as anti-TNF medications. In both CD and UC, leukemia was male-predominant, but increasingly female by 2017. Rate of leukemia diagnosis increased with age. In the CD group but not the UC group, leukemia was increasingly prevalent in black patients.[Table: see text]
Arsenic Trioxide and Interferon-Alpha Eradicate Adult T Cell Leukemia Initiating Cells through PML/p53 Senescence and Activation of Innate Immunity
Authors: Hiba El Hajj, Rita Hleihel, Zaatari Ghazi, Julie Bruneau, Hideki Hasegawa, William Hall, Olivier Hermine, Ali Bazarbachi
Journal: Blood (2017)
HGG-03. THE GLYCOSPHINGOLIPIDS METABOLISM IS A NOVEL TARGET IN H3K27M-MUTANT DIFFUSE MIDLINE GLIOMA
Authors: Claudia Paret, Roger Sandhoff, Khalifa El Malki, Katrin B M Frauenknecht, Arthur Wingerter, Nadine Lehmann, Nadine Vewinger, Jörg Faber
Journal: Neuro-Oncology (2021)

Abstract H3K27M-mutant diffuse midline glioma (H3K27M-mutant DMG) is a rare malignant brain tumour entity in children and adults with a median overall survival of around 12 months. Genomic and proteomic analysis may help to identify new target structures, however not all relevant targets are covered by these analyses. Glycosphingolipids and particularly gangliosides play a major role in brain development and have been involved in the pathology of brain tumours. The conversion of ceramide to glucosylceramide via glucosylceramide synthase (GCS) is one of the first steps in the synthesis of glycosphingolipids. Therefore, targeting GCS will inhibit their synthesis. Here we analysed the glycosphingolipids composition and tested GCS inhibitors in an in vitro model of H3K27M-mutant DMG. Methods: H3K27M-mutant DMG primary cells were established from needle biopsies of two paediatric patients and characterised by immunohistochemistry. Glycosphingolipids were analysed by thin layer chromatography, liquid chromatography-coupled tandem mass spectrometry and flow cytometry. The effect of the GCS inhibitor eliglustat on the cell proliferation was examined. Results. The primary cells maintained the features of the tumour of origin, including the H3K27M mutation. Neutral glycosphingolipids with 1 to 4 monosaccharides and the ganglioside GD2 were expressed at high concentration. Eliglustat completely abrogated the proliferation of the H3K27M-mutant DMG primary cells. Conclusions. The glycosphingolipids oncometabolism represents a novel target in H3K27M-mutant DMG. The GCS inhibitors eliglusat and miglustat are already used to treat paediatric patients with the lysosomal storage disorders Niemann Pick’s and Gaucher′s disease and miglustat can cross the blood-brain barrier. Thus, our finding may accelerate the access of H3K27M-mutant DMG patients to novel innovative clinical studies based on the inhibition of the glycosphingolipids metabolism.
More Comprehensive Care for Miscarriage Needed Worldwide
Authors: Bridget M. Kuehn
Journal: JAMA (2021)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
LGG-12. SAFETY AND EFFICACY OF DUAL THERAPY WITH DABRAFENIB AND TRAMETINIB IN AN INFANT WITH BRAF V600E MUTANT INOPERABLE LOW GRADE GLIOMA
Authors: Sage Green, Andrew Walter, Joseph Piatt, Gurcharanjeet Kaur
Journal: Neuro-Oncology (2021)

Abstract Objective To describe safety and efficacy of dual targeted therapy with dabrafenib (BRAFi) and trametinib (MEKi) in an infant with inoperable low grade glioma with BRAF V600E mutation. Introduction Safety and efficacy of dual targeted therapy with BRAFi and MEKi for pediatric low grade glioma (pLGG) is currently being evaluated, however, infants are usually not included in these clinical trials. Case We report a case of a 2-month-old male infant who presented with involuntary movements and gaze deviation concerning for seizures. MRI brain revealed a tumor involving the medulla, T2/FLAIR dimensions: 2.5 x 2.2 x 2.7 cm and drop metastases to the cauda equina. An EEG ruled out seizure activity. Tumor biopsy was performed revealing Ganglioglioma, WHO grade I. IHC and somatic next generation sequencing revealed BRAF V600E point mutation. Germline testing was negative. Due to tumor progression on traditional chemotherapy, compassionate use of dual targeted therapy with dabrafenib (5.25mg/kg/day divided twice daily) and trametinib (0.032mg/kg daily) was initiated at 4.5 months of age. The patient has tolerated dual therapy for nearly 1 year without significant toxicity with exception of grade I skin rash. In terms of functional outcomes, previously noticed vocal cord paresis has resolved and our patient with global developmental delay continues to make developmental gains, albeit slowly. On recent neuroimaging, pLGG has continued to grow T2/FLAIR dimensions: 3.5 x 3.5 x 3.7 cm, however, combination therapy has halted the rate of growth of this tumor. Conclusion To our knowledge, our patient is the youngest to receive combination of BRAFi and MEKi. Tumor targeted therapy could be an important treatment option for infants with inoperable pLGG where aggressive surgery and radiation therapy are associated with significant morbidity. Multi-institutional clinical trials that include infants are needed to further comment on safety and efficacy of these agents.
Spatial and cell type transcriptional landscape of human cerebellar development
Authors: Kimberly A. Aldinger, Zachary Thomson, Ian G. Phelps, Parthiv Haldipur, Mei Deng, Andrew E. Timms, Matthew Hirano, Gabriel Santpere, Charles Roco, Alexander B. Rosenberg, Belen Lorente-Galdos, Forrest O. Gulden, Diana O’Day, Lynne M. Overman, Steven N. Lisgo, Paula Alexandre, Nenad Sestan, Dan Doherty, William B. Dobyns, Georg Seelig, Ian A. Glass, Kathleen J. Millen
Journal: Nature Neuroscience (2021)
Carcinogenicity risk of low-dose MeIQx
Authors: Keiichirou Morimura, Hideki Wanibuchi, Anna Kinoshita, Manabu Hoshi, Shoji Fukushima
Journal: Cancer Research (2004)

1337  More than 80% of human cancers may be related to carcinogenic environmental chemicals. For managing the hazards of environmental carcinogens, an assessment based on some scientific data should be necessary. Carcinogenicity of chemical agents is generally detected by long-term carcinogenicity testing in rodents using doses considerably in excess of human exposure levels and the extrapolation from the doses used in this carcinogenicity test is now accepted for the assessment of actual human cancer risk. On the other hand, there are limited data available for estimating the carcinogenic potential of low-dose genotoxic carcinogens. In the present study, for clarification of human risk assessment of genotoxic carcinogens, we examined the low-dose carcinogenicity of 2-amino-3,8-dimethylimidazo[4,5-f]quinoline (MeIQx) which is one of food-derived heterocyclic amine mutagens. A total of 885 male 21-day-old F344 rats were received MeIQx at doses of 0, 0.001 (equivalent to human daily intake), 0.01, 0.1, 1, 10, 100 ppm in powered diet for 16 weeks. Numbers of glutathione S-transferase placental form (GST-P)-positive foci, which are established as preneoplastic markers in the rat liver, were counted in unit area of the rat livers. The numbers of GST-P positive foci of groups receiving 0.001 ppm to 1 ppm of the carcinogen did not differ from the control value, in contrast to the increase observed with 10 ppm and the clear, significant elevation with 100 ppm. We also examined the formation of MeIQx-DNA adducts and 8-Hydroxy-2’-deoxyguanosine (8-OHdG) levels in the liver. There was linear relationship between the various doses of MeIQx and the levels of MeIQx-DNA adducts. Concerning the 8-OHdG levels, no significant differences among groups receiving MeIQx from 0.001 ppm to 0.1 ppm and the control group were apparent, although values were linearly elevated from 1 ppm and above, with statistical significance. cDNA microarray using 3D array system was applied for liver tissues of 16 weeks treatment groups. No over-expression was detected in metabolizing enzymes for 0 to 1 ppm but slight increase was seen in high dose treatment. Some genes related with signaling pathways were down-regulated. Moreover, the in vivo mutagenicity assay using Big Blue rats treated for 16 weeks with same low doses of MeIQx was examined. The mutation frequency from 0.001 ppm to 1 ppm were same level at control group and the values for 10 ppm and 100 ppm showed significant increase compared with the control group. The present results indicate that the dose-response curve of genotoxic carcinogen, MeIQx, at low-dose is different from that of high-dose. Threshold may exist for the hepatocarcinogenic potential of MeIQx. These results are important regarding how we should view the impact of genotoxic carcinogens, in the human environment in relation to cancer risk assessment and management.
The effects of different mitogens on the proliferation of estrogen-dependent breast cancer cells after inactivation of the estrogen receptor
Authors: Gudmundur Thordarson, Laura Hernandez, Lucinda Jurden, Sandra Macias
Journal: Cancer Research (2007)

308  Approximately 75% of breast cancers in women at diagnosis are estrogen receptor (ER)-positive and up to 70% of these tumors regress upon hormone therapy, that is they depend on estrogen for growth. How estrogen exerts its growth stimulation on breast cancer cells is still being debated, but evidence support the hypothesis that at least to some extent estrogen enhances cell proliferation via stimulating synthesis of local growth factors that in turn stimulate growth of the cancers. In this study, mitogens that are known to stimulate growth of breast epithelia were tested for their ability to stimulate proliferation of the ER positive MCF-7 breast cancer cells after the cells had been treated with the pure antiestrogen ICI 182,780 (ICI). For growth studies, the MCF-7 cells were plated in phenol red free DME/F12 medium containing 50 μg/ml gentamicin, and 10% fetal bovine serum onto 24-well culture plates (50,000 cells/well) and incubated 24 h. at 37 C in 100% humidity with 5% CO2/95% air. Medium was then changed to serum-free medium and the cells cultured 24 h. followed by 4-day treatments with different mitogens and inhibitors. For isolation of total protein for western blot analyses, the cells were cultured in 100 mm diameter culture dishes for 2 days in the same medium. Treatment with ICI (10-6 M) alone caused significant reduction in the expression of the ERα to a level barely detectable using western blotting concomitant with a significant cell death compared to untreated controls. Simultaneous treatment of the MCF-7 cells with ICI and different breast epithelia mitogens prevented cell death caused by ICI, and in some cases the mitogens continued to stimulate cell proliferation. The most effective growth stimulators of the MCF-7 cells in the presence of ICI were insulin-like growth factor-I and hepatocytes growth factor that were particularly effective when administered together. It is concluded that estrogen-dependent breast cancer cells will continue to proliferate under conditions of very low ERα expression when stimulated with certain mitogens other than estrogen.