tbuckley/cabot-search huggingface dataset:
ATIM-16. VALIDATION OF RESPONSE TO NEOADJUVANT ANTI-PD-1 IMMUNOTHERAPY IN RECURRENT GLIOBLASTOMA
Authors: Frances Chow, Aaron Mochizuki, Alexander Lee, Mildred Galvez, Joey Orpilla, Richard Everson, Linda Liau, Timothy Cloughesy, Robert Prins
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Recurrent glioblastoma has a poor median overall survival despite multimodal treatment. The use of pembrolizumab, an anti-PD-1 monoclonal antibody, demonstrates promise, including improved overall survival and increased immune response, when used in the neoadjuvant setting. METHODS We evaluated 13 patients with surgically accessible recurrent glioblastoma who were treated at the University of California, Los Angeles with neoadjuvant checkpoint inhibition prior to tumor resection. Combining data with our previously published multi-center study, we followed this cohort prospectively, performing tumor gene expression to validate the immune response and improved survival following neoadjuvant therapy with pembrolizumab. RESULTS When combined with findings from our prior study, patients in the neoadjuvant group (n = 27) had an overall survival of 400 days, whereas those in the adjuvant-only group (n = 19) had a median overall survival of 228 days by Kaplan-Meier estimator (P = 0.029, log-rank test). Progression-free survival in the neoadjuvant group was 108 days, whereas in the adjuvant-only group it was 72.5 days (P = 0.017, log-rank test). In elastic net penalized Cox proportional hazards regression, neoadjuvant anti-PD-1 blockade continued to be associated with improved overall survival, with a hazard ratio of 0.11 (P=0.003, log-rank test). Bulk tumor gene expression corroborates our previously described pattern of increased T-cell- and IFN-g-related gene expression, decreased cell-cycle-related signatures and their association with clinical response. Additionally, epigenetic regulation inversely correlated with clinical response. CONCLUSIONS Our findings support the neoadjuvant timing of PD-1 blockade in enhancing local immune responses and prolonging overall- and progression-free-survival. Correlative biological studies suggest a potential role for cell-cycle-related gene expression as a biomarker to predict response to therapy. Continued data collection and the addition of patients to the neoadjuvant arm of the trial, will be crucial to determine the potential role of checkpoint inhibition in the treatment of this deadly disease.
Manganese homeostasis: from rare single-gene disorders to complex phenotypes and diseases
Authors: Nathan Katz, Daniel J. Rader
Journal: Journal of Clinical Investigation (2019)

Manganese (Mn) participates in a variety of distinct physiological processes, including acting as a cofactor for several enzymes and metalloenzymes, in addition to playing a role in immune function, endocrine function, hematopoiesis, and oxidative stress regulation. Mn homeostasis is tightly regulated via intestinal absorption and hepatobiliary and intestinal excretion. In this issue of the JCI, Mercadante and colleagues explored the role of the metal transporter Slc30a10 in vivo using a mouse model system. The authors used whole-body and tissue-specific gene knockouts to show that Slc30a10 is paramount for Mn excretion in the liver and small intestines. These findings provide further insights into mechanisms for Mn homeostasis as well as potential targets for addressing Mn-associated disorders or environmental exposures.
TP53 Status As Well As Cytogenetic Complexity Significantly Impact on Prognosis in Myelodysplastic Syndromes with Complex (≥3 anomalies) Aberrant Karyotypes
Authors: Christina Ganster, Roxana Schaab, Katayoon Shirneshan, Lea Naomi Eder, Anna Mies, Ulrich Germing, Ahmet Elmaagacli, Francesc Sole, Laura Palomo, Jennifer Kaivers, Ulrike Söling, Frank Lange, Nicolaus Kröger, Bernd Hertenstein, Konstanze Döhner, Gesine Bug, Barbara Hildebrandt, Marc Talló Parra, Maike Nickelsen, Bertram Glass, Uwe Platzbecker, Ulrike Bacher, Friederike Braulke, Julie Schanz, Detlef Haase
Journal: Blood (2019)
Updated results on long-term overall survival (OS) of the French randomized phase II trial TORAVA in metastatic renal cell carcinoma (mRCC) patients.
Authors: Jacques-Olivier Bay, Sylvie Negrier, David Pérol, Gwenaelle Gravis, Christine Chevreau, Remy Delva, Ellen Blanc, Lionnel Geoffrois, Eric Legouffe, Celine Ferlay, Bernard J. Escudier
Journal: Journal of Clinical Oncology (2012)

4625 Background: Temsirolimus combined with bevacizumab (T+B) failed to improve the progression rate in treatment naive mRCC pts when treated in parallel to sunitinib (S) or B + Interferon (B+I) combination (Lancet Oncol 2011; 12:673-80). Long term updated survival and data on 2d line treatments were analyzed. Methods: 171 pts were treated with T+B (n=88), S (n=42) and B+I (41) respectively. Updated survival data (December 2011) and 2d line therapy after failure of the randomly assigned treatment were updated. OS was defined from the date of randomization until the date of death due to any cause, or the date of last contact. A two-tailed log-rank test was used to compare the OS distribution between the 3 arms with a 5% alpha level. Results: The median follow-up is 35.1 months (range 24.2 to 44.7). In an intent-to-treat analysis, 35-month OS rates were 37% (95% CI 27 to 48), 55% (95% CI 40 to 69) and 62% (95% CI 47 to 76) in arms T+B, S and B+I respectively (3-arm global comparison: p-value=0.0279). OS was not significantly lower in T+B arm than S arm (HR = 0.67, 95% CI 0.40 to 1.12), but significantly lower in T+B arm than B+I arm (HR = 0.48, 95% CI 0.27 to 0.86). Tyrosine kinase inhibitors were administered in 55 (79.7%), 19 (79.2%) and 23 (63.9%) pts in arms T+B, S and B+I respectively, without significant difference between arms (Fisher’s exact test: p=0.20). To note, 21% pts in S arm and 15% pts in B+I arm received an mTOR inhibitor in 2d line therapy. Conclusions: A large majority of pts in all treatment groups received a 2d line therapy after initial treatment failure. The OS rates confirm the absence of synergy or addictive effect of the B+T combination as well as the prolonged survival of pts treated with B+I.
Mutation Profile of PPM1D and TP53 in Patients with Myelodysplastic Syndromes and Complex Chromosome Abnormalities
Authors: Lea Naomi Eder, Christina Ganster, Katayoon Shirneshan, Ulrich Germing, Ahmet H. Elmaagacli, Anna Mies, Bernd Hertenstein, Susanne Simon-Becker, Uwe Platzbecker, Sascha Dierks, Katharina Rittscher, Roxana Schaab, Roman Martin, Ulrike Söling, Daniel Heudobler, Frank Lange, Barbara Hildebrandt, Bertram Glass, Friederike Braulke, Julie Schanz, Detlef Haase
Journal: Blood (2019)
Prediction of PFS using a dynamic assessment of ctDNA in patients with EGFR mutated NSCLC with osimertinib therapy
Authors: F. Moiseenko, M. Stepanova, A. Zhabina, A. Myslik, V. Klimenko, N. Rysev, E. Artemieva, K. Shelekhova, A. Bogdanov, N. Volkov, V. Moiseenko
Journal: Annals of Oncology (2019)
Differentiation Therapy with Novel Epigenetic Inhibitors in Acute Myeloid Leukemia
Authors: Edurne San Jose, Naroa Gimenez-Camino, Obdulia Rabal, Estibaliz Miranda, Leire Garate, Fernando Garcia, Ana Alfonso Pierola, Sara Villar, Jose J. Rifon Roca, Antonio Pineda-Lucena, Bruno Paiva, Javier Muñoz, Jesús San-Miguel, Julen Oyarzabal, Xabier Agirre, Felipe Prósper
Journal: Blood (2019)
Evaluation of the necessity of bilateral bone marrow aspirates and biopsies for the diagnosis of metastatic disease in pediatric patients with solid tumors.
Authors: Fernanda L. Abrantes, Lucas B. Vergamini, Carlos Rodriguez-Galindo, Inga Hofmann, Wendy B. London, Karina Braga Ribeiro, A. Lindsay Frazier, Pengling Sun
Journal: Journal of Clinical Oncology (2013)

10054 Background: Standard practice for staging solid tumors has been to perform bilateral bone marrow aspirates (BMA) and biopsies (BMB). However, the diagnostic yield of performing all 4 tests has not been thoroughly evaluated. This study evaluated the concordance between test types (aspirate and biopsy) and sites (right and left) to evaluate whether one type or one side would be sufficient. Methods: All patients with solid tumors who underwent a diagnostic bilateral bone marrow biopsy and aspirate performed between 2006 and 2011 at Children’s Hospital Boston were identifed in a search of hematopathology records.. Kappa coeffcients were estimated. Results: A search of the hematopathology data records revealed a total of 112 patients who had had a diagnostic bilateral BMA and BMB including patients with neuroblastoma (n=70 ), Ewing’s Sarcoma (n=11), rhabdomyosarcoma (n=25), retinoblastoma (n=5), and undifferentiated sarcoma (n=1). 73% (n=82) of the patients were negative for all tests; 27% (n=30) had at least one positive test. The results between right and left and aspirate and biopsy were highly correlated.(Kappa statistics: BMA and BMB (0.85); BMA-left and BMB-left (0.82); BMA-right and BMB-right (0.84); BMA-left and BMA-right (0.77); BMB-left and BMB-right (0.95). All 4 tests were positive in 63%, 3 tests positive in 10%, 2 tests positive in 13% and one test positive in 13%. The distribution of positive results did not differ by disease. Among 11 patients with less than 4 positive tests, 10 would have been diagnosed correctly with bilateral aspirates; only one patient (neuroblastoma) had positive results on biopsy only. In this patient, neither aspirate had spicules and was therefore likely an inadequate specimen. Conclusions: Bone marrow biopsy may not be essential for accurate diagnosis of metastatic disease in pediatric solid tumor patients. Further confirmation of these findings in a larger sample is warranted.
EXTH-42. QUANTITATIVE BIODISTRIBUTION OF ADOPTIVELY TRANSFERRED T CELLS IN BRAIN TUMOR-BEARING MICE
Authors: Lan Hoang-Minh, Fernanda Pohl-Guimarães, Angelie Rivera-Rodriguez, Seth Currlin, Kevin Otto, Carlos Rinaldi, Duane Mitchell
Journal: Neuro-Oncology (2019)

Abstract SIGNIFICANCE Adoptive T cell therapy (ACT) has emerged as the most effective treatment strategy against advanced malignant melanoma, eliciting remarkable objective clinical responses in up to 75% of patients with refractory metastatic disease, including those with lesions within the central nervous system. Importantly, immunologic surrogate endpoints that correlate with treatment outcome have been identified in these patients, with clinical responses being dependent on the migration of transferred T cells to sites of tumor growth. OBJECTIVE We investigated the biodistribution of exogenously administered T cells in a murine model of glioblastoma at whole body, organ, and cellular levels. METHODS T cells were isolated from the spleens of DsRed transgenic C57BL/6 mice and injected intravenously, after in vitro expansion and activation, in murine KR158B glioma-bearing mice. To determine transferred T cell spatial distribution, brains, lymph nodes, hearts, lungs, spleens, livers, kidneys and stomachs were isolated for active clearing, immunostaining, and 3D imaging using light sheet microscopy, or processed for fluorescent immunohistochemistry and confocal imaging. Transferred T cell quantification in various organs was performed using flow cytometry, 2D optical imaging (IVIS), and magnetic particle imaging (MPI) after ferucarbotran nanoparticle labeling. T cell distribution was also assessed in vivo using IVIS and MPI. RESULTS The spleen, liver, and lungs accounted for more than 90% of transferred T cells in the body. The proportion of DsRed T cells in tumor-bearing brains was found to be very low, hovering below 1% (and representing ~15% of total tumor-infiltrating lymphocytes). Transferred T cells mostly concentrated at the periphery of the tumor mass and in proximity to blood vessels. CONCLUSIONS The success of ACT immunotherapy for brain tumors likely requires optimization of delivery route, dosing regimen, and modification of tumor-specific lymphocyte trafficking and effector functions in order to achieve maximal penetration and persistence at sites of invasive tumor growth.
Clearance of Somatic Gene Mutations in Patients with Acute Myeloid Leukemia Prior to Allogeneic Hematopoietic Cell Transplantation (HCT) Predicts Outcome
Authors: Onyee Chan, Chetasi Talati, Hannah Asghari, Nelli Bejanyan, Hany Elmariah, Mohammad Hussaini, Farhad Khimani, Jongphil Kim, Rami S. Komrokji, Andrew T Kuykendall, Jeffrey E. Lancet, Alan F. List, Michael Nieder, Taiga Nishihori, Eric Padron, Lia Perez, Joseph Pidala, Jinming Song, Junmin Zhou, David A Sallman, Kendra L. Sweet, Asmita Mishra
Journal: Blood (2019)
Akalazya Tedavisinde Pnömotik Dilatasyonve Heller Miyotomisinin Uzun Dönem Etkinliği
Authors: Marcelo F. Vela, Joel E. Richter, Farah Khandwala, Eugene H. Blackstone, Don Wachsberger, Mark E. Baker Ve Thomas W. Rice
Journal: Clinical Gastroenterology and Hepatology (2006)
Panobinostat As a Maintenance Therapy after Autologous Hematopoietic Cell Transplantation for Patients with Multiple Myeloma
Authors: Taiga Nishihori, Rachid Baz, Leonel Ochoa, Omar Alexis Castaneda Puglianini, Kenneth H. Shain, Jason B. Brayer, Frederick L. Locke, Jongphil Kim, Jinming Song, Michael Dumala, Melissa Alsina
Journal: Blood (2019)
TREATMENT OF BRONCHIAL ASTHMA
Authors: H. B. Wilmer
Journal: JAMA (1927)

<h3>To the Editor:</h3> —Through an error in the preparation of my paper, "Studies in the Treatment of Bronchial Asthma" (The Journal, September 17, p. 956), reference to Dr. Nathan S. Schiff's article, "Management of Allergic Phenomena" (<i>Ann. Clin. Med</i>.<b>5</b>:374 [Oct.] 1926), was omitted. It is with regret that this mistake has been made, as the writer is deeply indebted to Dr. Schiff for the use of some of the material in his paper. <h3>Mouth Hygiene.</h3> —During recent years, schools have been established for the training of teachers of mouth hygiene... generally designated as dental hygienists, and twenty states have passed laws providing for the issuance of licenses to those who have been so trained. The program of the dental hygienist should be incorporated into the program of health education. This program consists in the making of: 1. Classroom talks and stories intended to gain the interest of children
Unheralded Pulmonary Embolism
Authors: H. Cohen, J. J. Daly
Journal: BMJ (1957)

The haemodynamic response to myocardial ischaemia in patients with variant angina during ambulatory activity is unknown. Ambulatory pulmonary artery pressure monitoring with a transducer tipped catheter and simultaneous frequency modulated electrocardiograms was used to assess changes in left ventricular function in five male patients (mean age 51.8 years) during variant angina; four patients had coronary artery stenosis and one had normal coronary arteries. Two hundred and seventy hours of ambulatory recordings were analysed. Twenty episodes (12 painful, 8 silent) of ST segment change greater than 1 mm occurred. Episodes tended to occur more frequently in the early morning hours. Six episodes of painful ST elevation were associated with a rise in pulmonary artery diastolic pressure. In the remaining episodes ST segment elevation was of shorter duration and there was no rise in pulmonary artery diastolic pressure. Pain was usually a late feature. Silent ST segment elevation occurred at rest and pulmonary artery diastolic pressure increased in all but one episode. Silent exertional ST segment depression was associated with a greater increase in pulmonary artery diastolic pressure than that seen during ST segment elevation. ST segment depression preceded or followed ST segment elevation in two episodes. The onset of ST segment elevation nearly always preceded the onset of a rise in pulmonary artery diastolic pressure. Ergometrine maleate provocation produced a rise in pulmonary artery diastolic pressure in three patients. In one there was no response to 1000 micrograms but spontaneous episodes of ST segment elevation were recorded during ambulatory monitoring. Treadmill exercise resulted in both ST segment elevation and depression with a similar haemodynamic response during both types of electrocardiographic change. When there is important coronary artery disease in two or more vessels ST segment changes may occur in different territories during treadmill exercise and during spontaneous episodes. Ambulatory pulmonary artery diastolic pressure monitoring is a useful technique for the investigation of variant angina.
NIMG-60. IDH MUTANT GLIOMAS WITH 1p/19q CO-DELETION ARE LESS ACIDIC THAN NON-CO-DELETED GLIOMAS AS MEASURED WITH PH-WEIGHTED AMINE CEST-MRI AND AMINO ACID PET
Authors: Jingwen Yao, David Nathanson, William H Yong, Noriko Salamon, Albert Lai, P Leia Nghiemphu, Robert Prins, Whitney Pope, Johannes Czernin, Richard Everson, Linda Liau, Timothy Cloughesy, Benjamin Ellingson
Journal: Neuro-Oncology (2019)

Abstract 1p/19q co-deleted gliomas are known to have slower growth rates and are more sensitive to chemotherapy and radiotherapy. This may be partially explained by the lower tumor acidosis compared to non-co-deleted gliomas, as extracellular acidosis is one of the driving forces toward tumor invasion and resistance to treatments. Amine CEST-EPI is a fast chemical exchange saturation transfer (CEST) imaging technique sensitive to decreased extracellular pH, transverse relaxation rate, and amino acid concentration. In the current study, we demonstrated that 1p/19q co-deleted gliomas are less acidic than non-co-deleted gliomas, using a combination of pH-sensitive amineCEST-EPI, T2 relaxometry, and 18F-FDOPA (18[F] fluorodopa) amino acid PET. 70 histologically-confirmed glioma patients (World Health Organization WHO grade II, N=35; grade III, N=35) received amine CEST-EPI scans. Among them, 16 patients received 18F-FDOPA PET scan and 45 patients received T2 relaxometry quantification. Mann-Whitney u-test is performed to evaluate the differences. Median MTRasym at 3ppm (magnetization transfer ratio asymmetry at amine proton resonance frequency) within T2 hyperintense lesions was significantly lower in 1p/19q co-deleted gliomas compared to non-co-deleted ones (co-deleted 1.19±0.31%; non-co-deleted 1.66±0.45%; p&lt; 0.0001). The significantly lower MTRasym persists when comparing within grade II (p=0.003), grade III (p=0.031), IDH1 mutated gliomas (p=0.002), and gliomas exhibiting classical oligodendroglial histology (p=0.0007). The ROC analysis shows that the prediction of 1p/19q status using MTRasym has area under the curve (AUC) of 0.80 (sensitivity 75.6%. specificity 72.7%). Median FDOPA and T2 in T2-hyperintense lesions were not different between 1p/19q co-deleted and non-co-deleted tumors (FDOPA p=0.84; T2 p=0.63). Results suggest 1p/19q co-deleted gliomas have notably lower acidity compared with non-co-deleted gliomas, as indicated by lower MTRasym and no differences in amino acid concentration or transverse relaxation rate. Further, data indicate the 1p/19q co-deleted gliomas may have distinct metabolic characteristics and tumor microenvironment that can be measured using pH-sensitive amineCEST-MRI at 3T.
Eliminating Cervical Cancer
Authors: M. Lewis
Journal: BMJ (1964)

Eliminating Cervical Cancer SIR,-In your leading article (5 December, p. 1409) you stress the need for a comprehen- sive programme to screen symptomless women for carcinoma of the cervix uteri.Part of such a programme is the investigation of possible alternatives to cytology.Two years ago Bonham and Gibbs' re- ported excellent results using the biochemical estimation of 6-phosphogluconate-dehydrogenase activity in vaginal fluid as a screening test.Comparing this enzyme assay with cytology in an extensive trial, we too have been impressed by the consistently raised 6- phosphogluconate dehydrogenase activity in the presence of early invasive carcinoma of both cervix and corpus uteri.However, there are several serious limitations to the use of this technique as a screening test at present.The first of these is that only half of the patients with carcinoma in situ have raised 6-phosphogluconate-dehydrogenase activity.The second is that the incidence of falsepositive reactors, women with raised enzyme activity but no clinical or cytological evidence of malignancy, is high particularly in the post-menopausal group.Thirdly, no way has yet been found to preserve the activity of the enzyme long enough for the convenient cen- tralization of samples for analysis.If these limitations can be overcome, and we think there is a reasonable chance that they can be, such a biochemical assay would be very welcome, as it lends itself readily to automation.We envisage its place being that of a first screening test.Samples would be taken concurrently for both enzyme analysis and for cytology, but only in those cases with a positive enzyme test would the smears need to be examined cytologically.-Weare, etc.,
β2- Adrenergic Signaling Regulates Graft Versus Host Disease after Allogenic Transplantation While Preserving Graft Versus Leukemia Effect
Authors: Hemn Mohammadpour, Joseph L. Sarow, George L. Chen, Cameron R. MacDonald, Umesh Sharma, Megan M. Herr, Theresa E. Hahn, Elizabeth A. Repasky, Philip L. McCarthy
Journal: Blood (2019)
Overall and Progression Free Survival from the Mcrn-003/Myx.1 Trial: A Single Arm Phase II Study of High-Dose Weekly Carfilzomib Plus Cyclophosphamide and Dexamethasone in the Treatment of Relapsed Multiple Myeloma
Authors: Christopher P Venner, Richard Leblanc, Irwindeep Sandhu, Darrell J White, Andrew Belch, Donna E Reece, Christine I Chen, Sean Dolan, Marc Lalancette, Martha L Louzada, Andrea Kew, Arleigh McCurdy, Tony Reiman, Max Sherry, Gail T. McDonald, Bethany Elaine Monteith, Engin Gul, Bingshu E. Chen, Annette E. Hay
Journal: Blood (2019)
PATH-04. INFLUENCE OF INDIVIDUAL CpG METHYLATION STATUS OF THE MGMT PROMOTOR ON OUTCOME IN ADULT PATIENTS WITH GLIOBLASTOMA MULTIFORME RECEIVING ALKYLATING AGENT TREATMENT
Authors: Sebastian Siller, Michael Lauseker, Armin Giese, Joerg-Christian Tonn, Karim-Maximilian Niyazi, Niklas Thon, Bogdana Suchorska, Friedrich-Wilhelm Kreth
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Methylation of O-6-methylguanine-DNA-methyltransferase (MGMT) promotor causes gene silencing and has been associated with a favourable prognosis in patients with glioblastoma multiforme (GBM) receiving alkylating chemotherapy. However, analysis of MGMT promotor methylation is usually reported as a cut-off depending on the results of the correspondent CpG-site testing. This approach disregards a possible heterogeneity concerning the methylation status within the individual CpG-sites and its possible association with prognosis in GBM patients. The current study aimed at elucidating the association between methylation of CpG-sites 74–98 within the MGMT promotor region and outcome in GBM patients receiving alkylating agents. METHODS Individual methylation status of 230 patients with histologically proven GBM following concomitant radio-chemotherapy with TMZ after stereotactic biopsy or open tumor resection was assessed by the Sanger-sequencing approach. Methylation of CpG-sites 74–98 within the MGMT promotor region was defined according to a ratio of cytosine/thymine peak &gt; 50%. The total number of methylated CpG-sites was correlated with outcome using proportional hazards models. In a subset of 34 patients, a correlation between individual CpG-site methylation and MGMT mRNA-expression was performed. RESULTS Median progression-free (PFS) and overall survival (OS) were 7.8 and 14.6months, respectively. The cumulative total number of methylated loci within the CpG-sites 74–98 was strongly associated with both PFS and OS and retained its prognostic influence on outcome in multivariate models (p&lt; 0.001). Furthermore, a linear coherence between the total number of methylated CpG-sites 74–98 and survival parameters could be observed. Moreover, low number of methylated CpG-sites was observed in tumor specimen with a high mRNA-expression and vice versa (Spearman-correlation-coefficient: -0.62). CONCLUSION Our data suggest a strong linear coherence between outcome and the total number of methylated CpG-sites 74–98, thus an up-front analysis of the individual GpC-site methylation status prior to initiation of alkylating chemotherapy might help improving treatment response in GBM patients.