tbuckley/cabot-search huggingface dataset:
XPD 312 single nucleotide polymorphism (SNP) in stage IIIA-B non-small cell lung cancer (NSCLC) patients (p) &lt;59 years (y) treated with chemotherapy followed by surgery
Authors: M. Santarpia, P. Garrido, J. Gonzalez-Larriba, P. Azagra, F. Cardenal, J. Ramirez, I. de Aguirre, M. Sanchez-Ronco, M. Taron, R. Rosell
Journal: Journal of Clinical Oncology (2007)

7652 Background: SNPs in DNA repair genes may affect response to cytotoxic therapy. We investigated SNPs in XPD codons 751 and 312 and in RRM1 −37 in 109 stage IIIA (N2) and IIIB NSCLC p treated with neoadjuvant chemotherapy and correlated results with event- free (EFS) and median (MS) survival. Methods: p eligible for surgery received cisplatin day (d) 1, gemcitabine d 1,8, docetaxel d 1,8,15, every 3 weeks for 3 cycles, followed by thoracotomy. DNA was extracted from baseline peripheral lymphocytes and genotyping was performed by Taqman. Results: Median age, 60 y (range 31–77); 92 males (84%); 45 squamous cell (41%). 4 p (3.9%) attained complete response; 55 (53.9%) partial response. 75 p underwent surgery (62 complete, 13 incomplete resection); remaining 34 p were unresectable. Median follow-up was 15.7 months (m) (range, 0.5–74). MS for p still alive is 49.8 m (range, 6.7–74). MS: 48 m with complete resection, 13 m with incomplete resection, 17 m for unresected p. In the univariate analysis of survival, age &lt;59 y (P=0.03), resection (P&lt;0.001) and XPD312 AspAsp (P=0.05) emerged as predictive markers of longer survival. For all 109 p, those with XPD312 AspAsp had longer EFS and MS than p with Asn variants ( Table ). In addition, for 51 p &lt;59 y, EFS was longer for 24 p with XPD312 AspAsp (36.4 m) than for 27 p with Asn variants (9.8 m) (P=0.009); MS in this group of younger p was 45.4 m for AspAsp vs 15.8 m for Asn (P=0.04). No other significant correlation between SNPs and survival was observed ( Table ). Conclusions: Interaction between SNPs, age and risk of lung cancer has previously been described. XPD312 AspAsp in p &lt;59 y predicts longer survival in stage IIIA (N2) and IIIB NSCLC treated with neoadjuvant chemotherapy. No significant financial relationships to disclose. [Table: see text]
Progressive Hydrocephalus Due to Ventriculoperitoneal Shunt Infection
Authors: Boon Mathew, Nilendu C. Purandare, Archi Agrawal, Sneha Shah, Ameya Puranik, Venkatesh Rangarajan
Journal: Clinical Nuclear Medicine (2019)

Ventriculoperitoneal shunt malfunction is common in patients after shunt surgery. Imaging is done to reveal the underlying cause and confirm the diagnosis. Shunt infection is one of the common causes of shunt malfunction. FDG PET CT is an accepted infection imaging tool and can be used to diagnose shunt infection accurately in a patient with high clinical suspicion.
Cure candidates: Characteristics of &gt;10yr progression-free survivors (PFS-10) and continuous CR (CCR-10) after total therapy 1 and 2 (TT1, TT2) for multiple myeloma (MM).
Authors: Sarah Waheed, Frits Van Rhee, Adam Rosenthal, Saad Zafar Usmani, Mian Adnan Waheed, Antje Hoering, Bart Barlogie
Journal: Journal of Clinical Oncology (2013)

8603 Background: Our TT studies demonstrate that long term progression free survival is achievable in MM pointing to the possible curability of MM. We report here on the base line characteristics of 33/231 TT1 patients and 109/475 TT2 patients qualifying for PFS-10, including 45/245 randomized to the control arm and 64/230 randomized to thalidomide. Methods: Baseline and response levels were compared between &lt;10yr and &gt;=10yr survivors and logistic regression applied to identify the critical features linked to PFS-10 status. Results: Compared to the remainder, PFS&gt;=10yr and CCR&gt;=10yr were characterized by lower frequencies of cytogenetic abnormalities (CA), B2M&gt;=3.5mg/L and age &gt;=65yr. More females and more patients with platelets &gt;150.000/uL qualified for the &gt;=10yr category. Finally, timely administration of 2 transplants was also over-represented in these patients. Conclusions: Long-term survival PFS-10 and CCR-10 were adversely affected by by CA and elevated B2M levels. Females more frequently attained PFS-10. Assessment of MRD by 8-color flow cytometry in these patients is in progress and will be presented at the meeting. Clinical trial information: NCT00580372, NCT 00083551. [Table: see text] [Table: see text]
Autologous peripheral blood stem cell transplantation in first remission in adult patients with Burkitt and lymphoblastic lymphoma: A single center phase-II study
Authors: S. Ataergin, F. Arpaci, M. Pektas, M. Beyzadeoglu, A. Ozet, S. Komurcu, B. Ozturk, O. Kuzhan, M. Ozturk
Journal: Journal of Clinical Oncology (2006)

16517 Background: Optimal therapeutic modality and duration of adult Burkitt and lymphoblastic lymphoma (LL) are still unknown. Despite long-lasting and intensive chemotherapy administration, post-therapy relapses are common. Methods: In this single center phase-II prospective study, high-dose therapy (HDC) and autologous peripheral blood stem cell transplantation (APSCT) was done during the first remission following induction and consolidation therapy for 18 patients with Burkitt (n: 5) and LL (n: 13) without bone marrow and central nervous system involvement at presentation. Cyclophosphamide, vincristine, prednisolone, adriamycin with or without L-asparaginase induction regimen was followed by dexamethasone, cytarabine, and cisplatin consolidation therapy with total body irradiation and cyclophoshamide conditioning. Results: Mean patient age was 24.6 (range: 21–55) years and male to female ratio was 5 to1. 44% (8/18) of the patients were in the intermediate and high-risk groups of International Prognostic Index. Median treatment duration until APSCT was 104 days (range: 87–128). 83% and 17% of the patients were in complete and partial remission before transplantation. One patient with Burkitt lymphoma out of 5 (20%) and 6 patients with LL out of 13 (46%) have died of progression. Overall survival (OS) at 113-month follow-up for all patients was 59.03% with 59.26% of disease-free survival (DFS). However, LL cases revealed OS and DFS rates of 50.35% and 50.77%, respectively. Only one early death (5.5%) was noted due to liver toxicity following HDC and APSCT. Conclusions: In conclusion, this single center phase-II study reveals an acceptable toxicity, short treatment period and high survival rate in adult Burkitt and LL cases, suggesting APSCT to be a good treatment option in the first remission. No significant financial relationships to disclose.
Babylon plans US and Asia expansion as new funders boost company value to $2bn
Authors: Elisabeth Mahase
Journal: BMJ (2019)

Babylon is now worth more than $2bn (£1.6bn; €1.8bn), after some new funders, including the Saudi Arabian government and a major US health insurer, invested $550m in the private health company.1

Babylon, known for running the NHS digital service GP at Hand, said that the new money would be used to “fund extensive product innovation to …
Clinical outcomes and alternative chemotherapy (CT) options in patients (pts) with de novo carboplatin (carbo)-resistant stage III or IV ovarian cancer (CA) based on the drug-induced apoptosis (MiCK) assay.
Authors: Matthew O. Burrell, Michael Stany, James Rutledge, Emery Manuel Salom, Manuel Penalver, Allan Hallquist, Cary A. Presant
Journal: Journal of Clinical Oncology (2013)

e16525 Background: In order to understand platinum-resistant ovarian CA better, we evaluated the outcomes of pts with in vitro carbo resistance and CT alternatives based on the MiCK assay. Methods: 77 pts with primary stage III or IV ovarian CA previously untreated with CT had a MiCK assay prior to therapy. The MiCK assay was performed as described (J Trans Med 2012; 10:162). Physicians did not receive the results of the assay prior to CT. The time to recurrence in pts treated with standard carbo+paclitaxel CT who had in vitro de novo carbo resistance (carbo KU&lt;1 in the MiCK assay) was compared to time to recurrence in pts treated with carbo+paclitaxel with no in vitro resistance (carbo KU&gt;1) using the log-rank test. The pattern of assay sensitivity to other drugs was analyzed. Results: In pts with de novo carbo resistance in the MiCK assay who were treated with carbo+paclitaxel, the median time to recurrence was only 5.0 months compared to 16 months in pts with carbo sensitivity (p = 0.01). In patients with de novo carbo resistance, 63% of pts were still sensitive (KU&gt;1) to cisplatin in the MiCK assay. For those pts resistant to carbo in the MiCK assay, alternative active CTs were cisplatin 63%, docetaxel 50%, cisplatin+gemcitabine 60%, topotecan 25%, liposomal doxorubicin 20%, etoposide 50%, gemcitabine 17% and cyclophosphamide 50%. The MiCK assay was able to rank individual drugs and combinations with highest drug induced apoptosis for individual patients. Conclusions: Pts with de novo in vitro carbo resistance have more rapid relapse, and can be prospectively rapidly identified before initial CT (time required for MiCK assay 48 hours). Alternative drugs or combinations with in vitro activity (still using drugs within national evidence based treatment guidelines) can be identified with the MiCK assay. This suggests that for pts with relapsing disease with clinically apparent carbo resistance, the MiCK assay can identify individualized CT for such pts. This study gives the framework for a prospective randomized phase III trial of assay-directed CT versus standard CT in platinum-resistant ovarian CA. Clinical trial information: NCT 00443196.
Exhibition of a stem-cell like phenotype with the expression of CD271 in drug-resistant melanoma cells.
Authors: Elizabeth Ann Teresa Lieser, Alexey A Leontovich, Shernan G. Holtan, Wendy Kay Nevala, Svetomir Markovic
Journal: Journal of Clinical Oncology (2012)

8599 Background: Chemotherapy resistance is a common, difficult problem for melanoma patients needing long term care and those suffering from recurrence. Neural growth factor receptor (NGFR), also known as CD271, is commonly expressed on mesenchymal stem cells and is important for development, survival and differentiation of cells. This has previously shown to be expressed on melanoma stem cells. We hypothesized that treatment with carboplatin enriches the population of tumor cells for cancer stem cells (CSC) as a mechanism of chemotherapy resistance. Methods: Core tumor samples from 118 patients with metastatic melanoma were obtained from formalin-fixed paraffin embedded specimens. Slides were stained using an anti-CD271 antibody for IHC. A375 melanoma cells were treated with increasing concentrations of carboplatin for approximately 1 year. WT, 6 mg/mL and 10 mg/mL resistant cells were tagged with CD271-PE antibody and run on a flow cytometer. These cells were then tested for gene expression by microarray using an Affymetrix human 133 plus 2.0 chip, and analyzed on Partek software. Pathway analysis of these carboplatin resistant cells was preformed using Ingenuity. Results: Virtually all melanoma tumor samples stained positively for CD271 by IHC, with a median of 50% cells within tumor samples expressing the cytoplasmic marker. Flow cytometry demonstrated an increase in the percentage of cells expressing CD271 as resistance to carboplatin increased. Wild type A375 cells contained 30% positive CD271, A375 6mg/mL resistant contained 42% positive and A375 10mg/mL resistant showed 66% positive. Microarray also exhibited a direct correlation between CD271 gene expression with increasing carboplatin resistance. Functional ontology enrichment revealed development and regulation of the EMT pathway as an important process impacted by our resistant cell line. Conclusions: The data suggests that as melanoma cells become resistant to certain chemotherapy drugs they essentially loose their differentiated phenotype and become more stem cell-like. Monitoring melanoma expression of CD271 could help individualize therapy and anticipate chemotherapeutic resistance in this high-risk group of patients.
How to predict sunitinib exposure and toxicity: A pharmacokinetic-pharmacodynamic study.
Authors: Anatole Cessot, Celine Narjoz, Audrey Thomas-Schoemann, Pascaline Boudou-Rouquette, Jean-Louis Golmard, Jean-Philippe Durand, George Emile, Michel Tod, Michel Vidal, Marie-Anne Loriot, Benoit Blanchet, Francois Goldwasser
Journal: Journal of Clinical Oncology (2013)

e15592 Background: Su (su), a tyrosine kinase VEGFR inhibitor, is subject to large inter-individual variability in drug exposure (AUC) and toxicity. We investigated the variability factors influencing AUC as well as the relationship between acute severe toxicity, AUC and genetic polymorphisms in adult cancer patients under su. Methods: The plasma concentrations of su and SU12662 (active metabolite) were assessed on day 7 and 21 of the first cycle. For variability investigation, su, SU 12662 and composite AUC (su+SU12662) were estimated from a population approach, then normalized to 50mg daily dose of su. Genetic polymorphisms for CYP3A4, CYP3A5, CYP1A2, NR1I2, NR1I3, P-gP and BCRP1 were analyzed. Clinical acute toxicity was graded using the NCI 4.0 scale on days 7 and 21. Baseline clinical and biologic characteristics including the lean body mass (LBM), absolute AUC and pharmacogenetic variants were tested univariately for association with toxicities. LBM was simply estimated from gender, height and weight. Candidate variables with p&lt;0.1 were analyzed in a multivariate analysis. Results: Ninety-two pts were evaluable whose 66 for genetic analysis. Sixty-three percent of pts were male, 71% were PS 0-1, 60% had renal carcinoma. A large interindividual variability in normalized composite AUC was observed (CV=40%); LBM and ABCG2polymorphism (421C&gt;A) were identified as major variability factors (p&lt;0.0001 and p=0.014, respectively). Grade³2 hypertension, thrombocytopenia and hand-foot skin reaction were observed in 50, 11 and 10% respectively. Age (OR=1.47 [1.01-2.15], p=0.048) and su AUC (OR=1.16 [1.05-1.28], p=0.005) were independently associated with grade³3 toxicity within the first month, and SU12662 AUC with grade 3 thrombocytopenia (OR=1.27 [1.03-1.57], p=0.028). A formula was built from LBM to define the initial su dose to reach a target composite AUC of 1500ng/mL.h. Conclusions: Monitoring sunitinib and SU12662 exposure may be helpful to prevent severe toxicities. The estimation of LBM, based on gender and anthropometric characteristics, is useful to determine the initial daily dosing of sunitinib.
Cross-sectional study of reversible airway obstruction in LAM: better evidence is needed for bronchodilator and inhaled steroid use
Authors: Jan Johnson, Simon R Johnson
Journal: Thorax (2019)

Lymphangioleiomyomatosis can be associated with reversible airflow obstruction and although no guidelines around reversibility testing or inhaled therapy exist, many patients receive bronchodilators and inhaled corticosteroids. To better identify those who may benefit, we examined bronchodilator reversibility and inhaled therapy in a national cohort of 213 subjects. 20% of those tested had airway reversibility by standard criteria. 55% of patients used 13 different combinations of bronchodilators and inhaled corticosteroids. Increasing inhaler classes were associated with reversibility and more rapid FEV1 decline. Reversibility testing should be performed in all patients and inhaled therapy should be formally studied.
Therapeutically relevant engraftment of a CRISPR-Cas9–edited HSC-enriched population with HbF reactivation in nonhuman primates
Authors: Olivier Humbert, Stefan Radtke, Clare Samuelson, Ray R. Carrillo, Anai M. Perez, Sowmya S. Reddy, Christopher Lux, Sowmya Pattabhi, Lauren E. Schefter, Olivier Negre, Ciaran M. Lee, Gang Bao, Jennifer E. Adair, Christopher W. Peterson, David J. Rawlings, Andrew M. Scharenberg, Hans-Peter Kiem
Journal: Science Translational Medicine (2019)

CRISPR-Cas9–edited hematopoietic stem cells produce long-term engraftment and fetal hemoglobin reactivation in nonhuman primates.
Lysozyme elicits pain during nerve injury by neuronal Toll-like receptor 4 activation and has therapeutic potential in neuropathic pain
Authors: Saurabh Yadav, Avadhesha Surolia
Journal: Science Translational Medicine (2019)

Neuronal Toll-like receptor 4 activation by lysozyme enhances pain perception during nerve injury and emerges as neuron intrinsic axis to treat it.
Discovery of a CD10-negative B-progenitor in human fetal life identifies unique ontogeny-related developmental programs
Authors: Sorcha O’Byrne, Natalina Elliott, Siobhan Rice, Gemma Buck, Nicholas Fordham, Catherine Garnett, Laura Godfrey, Nicholas T. Crump, Gary Wright, Sarah Inglott, Peng Hua, Bethan Psaila, Benjamin Povinelli, David J. H. F. Knapp, Antonio Agraz-Doblas, Clara Bueno, Ignacio Varela, Phillip Bennett, Hashem Koohy, Suzanne M. Watt, Anastasios Karadimitris, Adam J. Mead, Phillip Ancliff, Paresh Vyas, Pablo Menendez, Thomas A. Milne, Irene Roberts, Anindita Roy
Journal: Blood (2019)
Antithrombotic prophylaxis (AP) and catether-related infections in cancer patients (pts) carrying central venous devices (CVD): An observational study
Authors: D. Fagnani, R. Franchi, C. Porta, M. Giordano, A. Scanni, A. Bertolini, M. Duro, A. Ardizzoia, V. Filipazzi, C. Cimminiello
Journal: Journal of Clinical Oncology (2006)

18550 Background: Recent data underline the possibility to reduce catheter-related infections in cancer pts having placed a central line by using low-dose heparin. Here we report the results of an observational prospective study aimed at recording management and outcome, including infective complications, of pts affected by solid tumors undergoing a CVD placement. Methods: The study was named “Registro CVD-POLO NORD” and involved 18 centers of oncology in Lombardia (Italy). Starting from January 2003 and with an accrual period of 30 months, 1418 pts entered the study and their data were recorded. Both bloodstream infections and local infections of the subcutaneous pocket were considered as catheter-related infections. Results: On September 2005, 1253 pts had a follow-up of at least 4 months, the median follow-up period being 6 months. Of them, 424 subjects (34%) received a continuous AP consisting mainly of very low-dose warfarin. CVD-related infections occurred in 46 pts (3.6%, 95 CI 2.6%–4.7%). In the table the frequency of infective complications is reported according to type of cancer, stage of disease, treatment with chemotherapy (CT) and administration of AP. The use of central venous catheter (CVC) and peripherally inserted central catheter (PICC) as well as CT were significantly more associated with infections. On the contrary, low-dose warfarin appeared to be protective. No difference was found as regard to the primary tumor site. There were no major bleeding complications among subjects receiving AP. Conclusions: Confirmatory of previous reports, our data underscore the increased risk of infections related to the use of certain devices and CT administration. The role of fibrin deposition in favouring bacterial colonization of CVD seems to be confirmed by the protective effect of low-dose warfarin which represents a feasible way to obtain a long-term reduction of catheter-related infections. [Table: see text] No significant financial relationships to disclose.
Opsin 3 is a key regulator of ultraviolet A‐induced photoageing in human dermal fibroblast cells
Authors: Y. Lan, Y. Wang, H. Lu
Journal: British Journal of Dermatology (2019)

BackgroundChronic exposure to ultraviolet (UV) radiation (mainly UVA) induces a sustained increase of matrix metalloproteinases (MMPs), especially MMP1, MMP2, MMP3 and MMP9 in human skin fibroblasts. MMPs can lead to the degradation of fibrous connective tissue, which is the main cause of skin photoageing. The molecular mechanisms through which fibroblasts sense UVA and trigger the cell signalling pathways involved in the upregulation of MMPs have not been well elucidated.
Phase I trial of temsirolimus and lenalidomide in pts with rel/ref lymphomas.
Authors: Sonali M. Smith, Kenneth Stuart Cohen, Justin Paul Kline, Jose D Zavala, Kathy Conner, Sachdev P Thomas, Patricia Lesho, Laurence A. Doyle, Walter Michael Stadler, Theodore Karrison, Amy Sarah Kimball
Journal: Journal of Clinical Oncology (2012)

8075 Background: The PI3K/Akt/mTOR axis is deregulated in lymphomas and is an emerging therapeutic target. We previously reported activity of temsirolimus (TEM) in DLBCL and FL (JCO 2010 28(31); however, the response duration was short. Lenalidomide (LEN) is an immunomodulatory agent with multiple anti-tumoral and microenvironmental effects, with activity across lymphoma subtypes. We are thus conducting a phase I/II study of TEM plus escalating doses of LEN. The phase I portion is completed. Methods: Patients (pts) had rel/ref lymphoma after &gt;1 cytotoxic regimen. Other criteria: ANC &gt; 1000/mL, platelets &gt; 75,000/mL, nl renal and hepatic function, no VTE within 3 months, non-pregnant. A standard “3 + 3” design was used with dose levels (DL) listed (Table). TEM was given IV weekly and LEN was dosed orally on D1-D21, q28 days. Dose-limiting toxicity (DLT) was defined as cycle 1 grade 3 or 4 non-hematologic toxicity not responsive to standard supportive care, grade 4 thrombocytopenia &gt; 7 days (or associated with bleeding or requiring more than 1 platelet transfusion), ANC &lt; 500/mL &gt; 7 days despite growth factors, or any thromboembolic event. Results: 18 pts (13M, 5F), med age 64 y (range, 42-80 y) were enrolled. 3 pts are ineval for DLT evaluation: one withdrew consent before starting treatment, 1 withdrew consent after a single dose, and 1 died of rapid disease progression after 1 dose. There was 1 DLT at DL1 and 2 DLTs at DL3 (Table). Adverse effects that did not meet DLT criteria: hypokalemia, hypertriglyceridemia, vomiting, urinary tract infection, skin infection, nausea, hypoxia, hyponatremia, diarrhea, and hyperglycemia (each occurring in one pt). There are 5 partial responses, 4 stable disease, 3 progressive disease, 2 not adequately assessed, and 4 still on active treatment. Conclusions: The combination of weekly intravenous TEM plus oral LEN is well-tolerated in a heavily pretreated group of pts with rel/ref lymphomas. The recommended phase II doses are TEM 25mg weekly plus LEN 20mg (D1-D21, q28d). [Table: see text]
Targeting pyrimidine synthesis accentuates molecular therapy response in glioblastoma stem cells
Authors: Xiuxing Wang, Kailin Yang, Qiulian Wu, Leo J. Y. Kim, Andrew R. Morton, Ryan C. Gimple, Briana C. Prager, Yu Shi, Wenchao Zhou, Shruti Bhargava, Zhe Zhu, Li Jiang, Weiwei Tao, Zhixin Qiu, Linjie Zhao, Guoxing Zhang, Xiqing Li, Sameer Agnihotri, Paul S. Mischel, Stephen C. Mack, Shideng Bao, Jeremy N. Rich
Journal: Science Translational Medicine (2019)

Concurrent targeting of pyrimidine synthesis and oncogenic driver pathways improves therapeutic efficacy in glioblastoma.