tbuckley/cabot-search huggingface dataset:
Platinum-based chemotherapy in metastatic prostate cancer with alterations in DNA damage repair genes.
Authors: Jose Mauricio Mota, Ethan Barnett, Jones Nauseef, Konrad Hermann Stopsack, Andreas Georg Wibmer, Daniel Costin Danila, Dana E. Rathkopf, Susan F. Slovin, Philip W. Kantoff, Howard I. Scher, Michael J. Morris, David B. Solit, Wassim Abida
Journal: Journal of Clinical Oncology (2019)

5038 Background: Platinum-based chemotherapy has shown palliative and radiographic benefit in small unselected studies of metastatic castration-resistant prostate cancer (mCRPC). Alterations in DNA damage repair genes (DDRmut), which occur in ~25% of patients with mCRPC, may sensitize to platinum-based chemotherapy, and may aid in the selection of patients for this therapy. We sought to evaluate the efficacy of platinum-based chemotherapy in DDRmut mCRPC. Methods: We performed a retrospective review of patients with prostate cancer who underwent tumor genomic profiling and received platinum-based chemotherapy. Deleterious alterations in a panel including BRCA2, BRCA1, ATM, FANCA, CDK12 or PALB2 were classified as DDRmut. Absence of deleterious alterations in those genes was classified as DDRwt. MSI-H cases were excluded from analysis. Electronic charts, PSA values, and scans were reviewed to assess for outcomes. Results: From October 2013 to July 2018, 109 patients with mCRPC received platinum-based chemotherapy. 64/109 had prior taxane progression and were PARP inhibitor (PARPi) naïve at the time of platinum-based chemotherapy. DDRmut was found in 16/64 (25%) of patients ( BRCA2, n = 6; ATM, n = 2; CDK12, n = 4; FANCA, n = 4; PALB2, n = 1). Visceral metastasis occurred in 4/16 (25%) of DDRmut patients and in 22/48 (46%) of DDRwt patients. PSA50 responses were more common among DDRmut (8/15 evaluable = 53%, 95% CI, 30-75%) than among DDRwt patients (5/42 evaluable = 12%, 95% CI, 5-25%). Time on platinum-based chemotherapy tended to be longer in the DDRmut group (median 3.1 vs 1.8 months; HR 0.73, 95% CI 0.42-1.26). Of 8 DDRmut patients ( BRCA2, n = 6; BRCA1, n = 1; ATM, n = 2) who received platinum-based chemotherapy after progression on a PARPi, 3/7 evaluable patients (43%) had RECIST response or stable disease, and 2/7 evaluable patients (29%) had a PSA50 response. Of 4 patients with ATM deleterious mutations, none had a radiographic or PSA50 response to platinum-based chemotherapy. Conclusions: Platinum-based chemotherapy showed activity in DDRmut mCRPC patients before and after PARPi treatment.
Risk factors for progression or death in ovarian cancer patients who completed first-line platinum treatment.
Authors: Shannon Neville Westin, Melinda Louie-Gao, Enkhe Badamgarav, Mohan V. Bala, Premal H. Thaker
Journal: Journal of Clinical Oncology (2019)

5548 Background: Limited real-world information is available in ovarian cancer (OC) regarding prognostic factors for disease progression or death after initial treatment. Here, we assessed potential prognostic risk factors in OC patients (pts) who completed first-line (1L) platinum-based chemotherapy (CT) using real-world data. Methods: This retrospective study identified 5535 pts diagnosed with OC from January 2011–October 2018 from the Flatiron database, a longitudinal, demographically and geographically diverse database derived from health records from &gt; 265 cancer clinics and &gt; 2 million US cancer pts. Stage III/IV OC pts who completed 1L platinum-based CT after primary debulking or interval debulking surgery were included. Pts who received a poly(ADP-ribose) polymerase inhibitor (PARPi) in 1L treatment or as maintenance therapy after 1L treatment were excluded. Cox proportional hazards model was used to assess the association between baseline factors (neoadjuvant CT, disease stage, residual disease, BRCA status, ECOG, age, platelet count, hemoglobin, and neutrophil count) and time to next treatment (TTNT; a proxy for progression-free survival) or overall survival (OS) in these pts. Results: 1064 of 5535 pts were eligible per our inclusion/exclusion criteria. Neoadjuvant treatment, stage of disease, residual disease after surgery, and BRCA mutation ( BRCAmut) status were significant prognostic factors for either TTNT or OS. Neoadjuvant chemotherapy pts had a shorter TTNT (hazard ration [HR] = 1.37; P= .001) and OS (HR = 1.64; P= .0002) than pts who underwent primary surgery after adjusting for other covariates. Stage IV pts had a shorter TTNT (HR = 1.26; P= .01) and OS (HR = 1.24; P= .09) than stage III pts. OS was also worse in pts with vs without residual disease (HR = 1.27; P= .04) and worse in BRCAwt than BRCAmut pts (HR = 1.37; P= .10). Conclusions: In this retrospective analysis of a real-world data set, BRCAwt status was associated with higher risk of death. Receipt of neoadjuvant CT, higher stage of disease at diagnosis, or presence of residual disease after surgery were also associated with a shorter TTNT or higher risk of death. These real-world data confirm previously identified prognostic factors.
Cost effectiveness of updated laboratory monitoring schedule for immunotherapy regimes.
Authors: Karine Ronan, Elly Hanis Che Othman, Susan McKenna, Cian Anderson, David Sheehan, Margaret Griffin, Ray McDermott, Jennifer Westrup
Journal: Journal of Clinical Oncology (2019)

e18363 Background: Patients being treated with immunotherapy undergo frequent laboratory testing to monitor for immune-related adverse events (IRAEs) as per National Cancer Control Programme (NCCP) guidelines in Ireland. Current NCCP guidelines advise pre-treatment testing of thyroid function, glucose and cortisol and follow-up TFTs and glucose levels with each cycle of therapy. 1,2,3,4 . Endocrinopathies occur in approximately 10% of patients on immunotherapy, 5 with most occurring in the first three months of treatment. 6 Hypophysitis is a relatively common adverse event associated with ipilimumab and with combination treatments, with incidence rates reported at 10-15%. 7,8 Methods: On review of our own cohort and recent publications on incidence rates of IRAEs, 5 we adopted updated guidelines for routine laboratory monitoring on immunotherapy. These guidelines incorporate increased monitoring intervals and enhanced surveillance for diabetes mellitus, hypophysitis and adrenal insufficiency. Results: Our proposed schedule advises pre-treatment testing of FBC, U&amp;E, LFTs, TFTs, serum glucose, HbA1c, ACTH and serum cortisol levels. Monitoring then occurs every 3-4 weeks with FBC, LFTs, U&amp;E, TFTs, serum glucose, and routinely testing ACTH and cortisol for Ipilimumab and combination treatments only, for six months duration. After six months, the interval increases to monitoring every 6-8 weeks with the same tests. We have compared the cost of monitoring for one year using our guidelines versus NCCP guidelines, 1,2,3,4 using pricing as per a single institution laboratory. We also compared the frequency of monitoring over one year with monitoring versus NCCP guidelines. Conclusions: We conclude that our proposed algorithm for monitoring for IRAEs is cost effective, despite more frequent monitoring of ACTH and cortisol, and carries a lower burden of testing for patients, when compared with monitoring as per current NCCP guidelines. [Table: see text]
Improved outcomes in testicular germ cell tumor patients treated at the referral center in Slovakia in the last decade.
Authors: Michal Chovanec, Katarina Rejlekova, Zuzana Sycova-Mila, Jana Obertova, Patrik Palacka, Nikola Hapakova, Valentina De Angelis, Katarina Kalavska, Daniela Svetlovska, Daniel Pindak, Jozef Mardiak, Michal Mego
Journal: Journal of Clinical Oncology (2019)

e16059 Background: Treatment at expert centers results in superior survival in patients with germ cell tumors (GCTs). This study evaluated outcomes in patients treated at National Cancer Institute in Slovakia before and after the year 2008 after refining the treatment strategies. Methods: Our institutional database was searched for GCT patients treated at National Cancer Institute in Slovakia between 1992 and 2016. A year of 2008 was selected for cutoff to compare changes in outcomes before and after this time-point due to refining treatment strategies such as centralization of post-chemotherapy surgery and incorporation of granulocyte-colony stimulating factor (G-CSF) for routine prophylaxis of febrile neutropenia. Kaplan-Meier product limit and log-rank test were used for statistical analysis. Results: This retrospective study included 485 patients treated for metastatic GCT. Two hundred and sixty-three patients (54%) were treated before 2008 (group 1) and 222 patients (46%) were treated after 2008, including (group 2). Progression-free survival (PFS) and overall survival (OS) was significantly improved in group 2 vs 1 (HR = 0.63, 95% CI 0.46-0.87; P= 0.0039 for PFS and HR = 0.44, 95% CI 0.30-0.65; P = 0.0003 for OS, respectively). In a subgroup analysis of International Germ Cell Cancer Collaborative Group criteria, favorable change in survival was observed in good-risk GCTs (HR = 0.40, 95% CI 0.24-0.67; P = 0.0009 for PFS, and HR = 0.20, 95% CI 0.10-0.38; P = 0.0002 for OS), but nor in intermediate or poor risk group. Conclusions: Treatment outcomes of GCTs have significantly improved in the last decade at our institution. We hypothesize that changes in treatment approach contributed to this improvement including centralization of post-chemotherapy retroperitoneal lymph-node dissections and routine use of granulocyte-colony stimulating factors that have been implemented in 2007. Referral bias for extremely poor risk patients in recent years may be an accounting factor for lack of improvement in this subgroup.
FRI0043 CHARACTERISTICS OF PATIENTS WITH RHEUMATOID ARTHRITIS ADMITTED TO AN INTENSIVE CARE UNITIN SPAIN SINCE 2005–2015. TREND-AR STUDY
Authors: Alberto García-Vadillo, Natalia Crespí-Villarías, Carmen Barbadillo, Manuel Fernandez-Prada, María Galindo-Izquierdo, Hilda Godoy, Angeles Herranz Varela, Cristina Macía-Villa, Concepción Morado Quiroga, Jose Luis Morell Hita, Elia Perez-Fernandez, Javier Quirós, Virginia Villaverde, María Espinosa, Cristina Martinez-Prada, Ramón Mazzucchelli
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Objectives:</h3> To analyse the clinical features of patients with Rheumatoid Arthritis (RA) that were admitted to an Intensive Care Unit (ICU) from January 2005 to December 2015. <h3>Methods:</h3> A retrospective observational populational study was conducted analysing the national database that includes the Minimum Basic Data Sets (MBDSs) of admissions of RA patients to an ICU during the 2005-2015 period. Demographic characteristics, length of stay, clinical course, outcome and the MBDS codes for the main reason of admission were recorded. The cases were detected by the presence of their CIE-9 codes in the primary or secondary diagnoses. Statistical analysis was performed with Stata 15.0 software. <h3>Results:</h3> During the 11 years of the study, a total of 2719 RA patients required 2806 admissions to an ICU. Average age was 69.7 ± 10.8 years and women constituted 58.5% of the cases. 30% of the patients admitted to an ICU had required ≥ 3 previous admissions and 11% required readmission within the next 30 days. Average Charlson index was 2.33 ± 1.4. Average length of stay was 9.3 ± 14 days and 64.2% died in the ICU during hospitalization. The main causes of hospitalization were cardiovascular events (45.7%), lung diseases (16%) and infections (10%). In the univariant analysis mortality was significantly increased in patients presenting infections (90%), lung disease (89%), severe hepatopathy defined by ascites and/or encephalopathy and/or gastrointestinal bleeding (88%), nephropathy/kidney disease (73%) and a higher Charlson index (2.4 vs 2.2). Multivariant analysis showed that mortality was increased among patients presenting respiratory complications and infections. <h3>Conclusion:</h3> The most frequent hospitalization causes for patients with Rheumatoid Arthritis in Spain between 2005 and 2015 were cardiovascular, pulmonary and infectious diseases. RA patients that were admitted to the ICU showed an increased mortality. This increased mortality was mainly found in patients presenting respiratory or infectious conditions. <h3> Disclosure of Interests:</h3> None declared
[18F] Fluorodeoxyglucose positron emission (FDG-PET) in breast cancer: Clinical utility in neoadjuvant and metastatic setting.
Authors: Serafin Morales Murillo, Ariadna Gasol Cudós, Joel Veas Rodriguez, Carles Canosa Morales, Jordi Melé Olivé, Antonia Salud
Journal: Journal of Clinical Oncology (2019)

e12584 Background: FDG-PET in clinical practice is based on the detection of a relapse and the initial staging but its role as a predictive factor or its correlation with biological parameters is very controversial. Methods: We analyzed the SUV of FDG-PET in a cohort with 36 patients in neoadjuvant setting and 112 with metastatic disease. Results: The median of SUV in neoadjuvant was 8,95 (range 2,8-30) with higher SUV in triple negative (11,7 range 2,8-18,8) than HER2 positive (8,75 range 4-30) and luminal patients (7,9 range 4,4-16). We don´t find a correlation between the SUV with either histological and clinical variables but there was a slightly correlation with residual tumor (p:0,068) and initial node involvement (p:0,069). In the 112 metastatic cohort the median SUV was 7,95 (range 2-28) with higher SUV in triple negative (10,1 range 3,4-19) than HER2 positive (9,7 range 4-28) and luminal patients (7,6 range 2.21). We found only a correlation between the SUV and progesterone receptor value (OR 0,875 p:0,005) but not in estrogen receptor, Ki67 index and HER2 status. In the survival analysis we don´t find a correlation between the SUV value and the disease free and overall survival included the analysis for different phenotypes. Conclusions: The SUV of the FDG-PET is very variable in all phenotypes of breast cancer being higher in the triple negative phenotype and lower in the luminal. The SUV value is very similar in neoadjuvant and metastatic setting. We only correlated the SUV value with the progesterone receptor in the metastatic cohort. We don´t find a prognostic value of the initial value of SUV in the two cohorts.
Toward dental caries: Exploring nanoparticle-based platforms and calcium phosphate compounds for dental restorative materials
Authors: Abdulrahman A. Balhaddad, Anmar A. Kansara, Denise Hidan, Michael D. Weir, Hockin H.K. Xu, Mary Anne S. Melo
Journal: Bioactive Materials (2018)

Millions of people worldwide suffer from a toothache due to tooth cavity, and often permanent tooth loss. Dental caries, also known as tooth decay, is a biofilm-dependent infectious disease that damages teeth by minerals loss and presents a high incidence of clinical restorative polymeric fillings (tooth colored fillings). Until now, restorative polymeric fillings present no bioactivity. The complexity of oral biofilms contributes to the difficulty in developing effective novel dental materials. Nanotechnology has been explored in the development of bioactive dental materials to reduce or modulate the activities of caries-related bacteria. Nano-structured platforms based on calcium phosphate and metallic particles have advanced to impart an anti-caries potential to restorative materials. The bioactivity of these platforms induces prevention of mineral loss of the hard tooth structure and antibacterial activities against carries-related pathogens. It has been suggested that this bioactivity could minimize the incidence of caries around restorations (CARS) and increase the longevity of such filling materials. The last few years witnessed growing numbers of studies on the preparation evaluations of these novel materials. Herein, the caries disease process and the role of pathogenic caries-related biofilm, the increasing incidence of CARS, and the recent efforts employed for incorporation of bioactive nanoparticles in restorative polymer materials as useful strategies for prevention and management of caries-related-bacteria are discussed. We highlight the status of the most advanced and widely explored interaction of nanoparticle-based platforms and calcium phosphate compounds with an eye toward translating the potential of these approaches to the dental clinical reality.
Crosstalk between autophagy and epithelial-mesenchymal transition and its application in cancer therapy
Authors: Hong-Tao Chen, Hao Liu, Min-Jie Mao, Yuan Tan, Xiang-Qiong Mo, Xiao-Jun Meng, Meng-Ting Cao, Chu-Yu Zhong, Yan Liu, Hong Shan, Guan-Min Jiang
Journal: Molecular Cancer (2019)

Autophagy is a highly conserved catabolic process that mediates degradation of pernicious or dysfunctional cellular components, such as invasive pathogens, senescent proteins, and organelles. It can promote or suppress tumor development, so it is a "double-edged sword" in tumors that depends on the cell and tissue types and the stages of tumor. The epithelial-mesenchymal transition (EMT) is a complex biological trans-differentiation process that allows epithelial cells to transiently obtain mesenchymal features, including motility and metastatic potential. EMT is considered as an important contributor to the invasion and metastasis of cancers. Thus, clarifying the crosstalk between autophagy and EMT will provide novel targets for cancer therapy. It was reported that EMT-related signal pathways have an impact on autophagy; conversely, autophagy activation can suppress or strengthen EMT by regulating various signaling pathways. On one hand, autophagy activation provides energy and basic nutrients for EMT during metastatic spreading, which assists cells to survive in stressful environmental and intracellular conditions. On the other hand, autophagy, acting as a cancer-suppressive function, is inclined to hinder metastasis by selectively down-regulating critical transcription factors of EMT in the early phases. Therefore, the inhibition of EMT by autophagy inhibitors or activators might be a novel strategy that provides thought and enlightenment for the treatment of cancer. In this article, we discuss in detail the role of autophagy and EMT in the development of cancers, the regulatory mechanisms between autophagy and EMT, the effects of autophagy inhibition or activation on EMT, and the potential applications in anticancer therapy.
A prospective study on the circulation and central nervous system after primary central nervous system B cell lymphoma treatment with rituximab.
Authors: Tongyu Lin, Chen Peng, Shu Liu, Cheng-cheng Guo, Zhao Wang, He Huang, Xiaojie Fang, Huang Ming Hong, Quanguang Ren, Fangfang Li, Xue Ying Li, Ying Tian
Journal: Journal of Clinical Oncology (2019)

e13518 Background: The use of rituximab(RTX)for the treatment of primary central nervous system lymphoma(PCNSL) is controversial, and whether the RTX permeability of the blood-brain barrier can be improved by craniotomy is unknown. Methods: ImmunocompetentPCNSL patients newly diagnosed via craniotomy or stereotactic biopsy were enrolled and received RTX (375 mg/m 2 , Q3w) treatment. Systemicnon-Hodgkin's B cell lymphoma (systemic-B-NHL)patients without CNS involvement served as the control group. The trough concentrations of RTX (C RTX ) and CD19 levels in cerebrospinal fluid (CSF) and plasma were analyzed by ELISA and flow cytometry methods during each treatment cycle.The efficacy and adverse effects were recorded. Results: From December 2016 to February 2018, 21 PCNSL and 32 systemic-B-NHL patientswere enrolled. The CSF C RTX in the craniotomy-PCNSL group (0.2198±0.1866μg/ml) was significantly higher than those in the stereotactic-PCNSLgroup (0.0613±0.0408 μg/ml, P = 0.031) and the systemic-B-NHLgroup (0.0799±0.0614μg/ml, P = 0.046). The BBB penetrabilityof RTX in the craniotomy-PCNSL group (1.52±1.05%) was nearly four times that in the stereotactic-PCNSL group (0.41±0.19%, P = 0.048) and nearly three timesthat in the systemic-B-NHL group (0.54±0.61%, P = 0.012). No significant differences in the C RTX or BBB penetrability of RTX were observedbetween the stereotactic-PCNSL and systemic-B-NHL groups. CD19 levels in plasma fell below 0.1% in all patients before the second cycle of chemotherapy, and the time required for CSF CD19cell clearance in craniotomy-PCNSL patients tended to be reduced compared with that required by stereotactic-PCNSL patients. The CR and ORR rates of craniotomy-PCNSL patientswere 30% higher than those of stereotactic-PCNSL patients. Conclusions: The BBB penetrability of RTXand the CSF C RTX are significantly improved in PCNSL patients diagnosed via craniotomy.Rituximab could be recommended for routine use in craniotomy PCNSL patients. Clinical trial information: ChiCTR-TRC-11001687.
Effect of additional administration of pertuzumab for the post-treatment in patients with HER2-positive locally advanced/metastatic breast cancer who were previously treated with pertuzumab.
Authors: Shinichiro Kubo
Journal: Journal of Clinical Oncology (2019)

e12500 Background: Currently, there are no data related to re-administering trastuzumab (T) + pertuzumab (P) beyond the second-line therapy to patients with human epidermal growth factor receptor 2-positive advanced/metastatic breast cancer (HER2-MBC) who had previously received P. The present study targeted patients with HER2-MBC who were previously treated with P and aimed to evaluate the efficacy and safety of additional administration (top-up intervention) of P post-disease progression (PD) after standard treatment with T plus chemotherapy vinorerbine(VNR) or eribulin (ERI). Methods: SBP-08 was a multicenter, collaborative, single-arm phase II study of HER2-MBC patients who had previously received P. After standard treatment with T and chemotherapy, P was additionally administered (top-up intervention) post-PD. Results: Eleven HER2-MBC patients, recruited between June 2016 and June 2018, who had previously received P participated in this study. Their mean age was 63.5 years, and 45% were estrogen receptor (ER)-negative, while 55% were ER-positive. The mean chemotherapy history was 3.6 regimens, with a median of four regimens. Previous treatment regimens with P had been effective in all patients. All patients had organ metastasis and treatment histories with TDM-1. Initially, during the two-year case collection period, registration of 30 patients was planned. However, the study was terminated because the interim analysis did not demonstrative effectiveness, and it was decided that there were no potential benefits to the patients. The overall response rate (ORR) of the standard treatment was 0%, stable disease (SD) was 36%, PD was 55%, and the clinical benefit rate (CBR) was 0%. The following combination anticancer agents were used: VNR (10 patients) and ERI (one patient). The intervention treatment (top-up with P) achieved the following: ORR 0%, SD 22%, PD 78%, and CBR 0%. PFS for the standard treatment was 1.6 months, whereas PFS for the intervention treatment was 1.3 months. In the standard treatment, febrile neutropenia was observed in two patients. No increases in adverse events were observed with the intervention treatment. Conclusions: No clinical benefit was demonstrated with the intervention treatment in the present study. Top-up with P after standard treatment with T and chemotherapy post-PD was deemed ineffective. Clinical trial information: UMIN000020837.