tbuckley/cabot-search huggingface dataset:
Final results of controlled IL-12 monotherapy in adults with grade III or IV gliomas.
Authors: E. Antonio Chiocca, Rimas Vincas Lukas, John Yu, Bakhtiar Yamini, Nancy Ann Oberheim Bush, Christina Amidei, Jill Yannetti Buck, Nathan A. Demars, Nira Hadar, John Miao, Taylor Estupinan, Yunxia Wang, John W. Loewy, Arnold Bruce Gelb, Laurence JN Cooper
Journal: Journal of Clinical Oncology (2020)

3040 Background: Interleukin-12 (IL-12), a master regulator of the immune system, results in anti-tumor responses in preclinical models, but safe use requires tightly controlled production. This phase 1 trial (NCT02026271) is the first to evaluate the safety and tolerability of Ad-RTS-hIL-12 (Ad) under transcriptional control with veledimex (V) in adults with grade III or IV gliomas. Methods: Multicenter, phase 1, open-label, 3 + 3 dose escalation study of Ad (a single intratumoral injection, 2 × 10 11 viral particles, Day 0) with oral V dosing (Days 0 to 14) of 10, 20, 30, and 40 mg in subjects with rGBM. Results: 38 subjects were treated (resection group: V 10 mg (n = 6); 20 mg (n = 15); 30 mg (n = 4); 40 mg (n = 6); and, stereotactic group: V 20 mg, n = 7). The adverse event profile of Ad+ V, was predictable and controllable, with the main adverse reactions (ARs) being mild to moderate. All ARs were manageable and reversible upon withholding V. We observed increased peak (mean ± SEM) serum recombinant IL-12 and downstream endogenous IFN-g: V 10mg 21.4 ± 11.7 pg/mL and 14.6 ± 7.1 pg/mL; V 20 mg 25.8 ± 7.1 pg/mL and 57.0 ± 26.5 pg/mL; V 30 mg 65.7 ± 45.5 pg/mL and 60.7 ± 50.0 pg/mL; V 40mg 108.8 ± 41.0 pg/mL and 167.5 ± 70.9 pg/mL, V 20mg (stereotactic) 25.1 ± 7.2 pg/mL and 69.8 ± 48.5 pg/mL, respectively. In the V 20 mg cohort , there was an increase in tumor-associated T cells (CD3 + CD8 + %) from pre-Ad (mean ± SEM) 0.6 ± 0.4 to biopsy (~5 mons) 6.3 ± 5.0 and production of IFN-g 97.2 ± 85.3 pg/g (n = 2). Median overall survival (mOS) in the V 20 mg cohort (resection, n = 15) was 12.7 mons (mean follow-up, 13.1 mons). Subjects with unifocal disease (n = 6) who received low-dose (≤ 20mg total) dexamethasone during active dosing (Days 0-14) had an mOS of 17.8 mons. Tumor response data will be presented. Conclusions: Results of Controlled IL-12 in rGBM are promising, with V-dependent and proportional increases in IL-12 and IFN-g resulting in immune activation, with a favorable safety profile and encouraging survival. The 20 mg V dose is the recommended phase 2 dose. Controlled IL-12 is being evaluated in a monotherapy substudy (n = 36, V 20 mg) and two combination studies with immune checkpoint inhibitors for rGBM. Clinical trial information: NCT02026271 .
Infiltration of tumor by T cells following treatment with DPX-Survivac and intermittent low dose cyclophosphamide (CPA) leads to clinical responses in advanced recurrent ovarian cancer (OvCa).
Authors: Oliver Dorigo, Lisa Diana MacDonald, Joanne Schindler, Yogesh Bramhecha, Heather Torrey, Valarmathy Kaliaperumal, Olga Hrytsenko, Brennan Dirk, Kelcey Patterson, Marianne Stanford, Stephan Fiset
Journal: Journal of Clinical Oncology (2020)

6075 Background: DPX-Survivac is a novel T-cell activating therapy designed to elicit an effective immune response against survivin expressing tumors. Its unique mechanism of action (MOA) facilitates active and sustained uptake of target peptides by APC at the injection site. APCs subsequently present the antigen in local lymph nodes generating survivin-specific T cells that traffic to distant tumor sites and elicit effective tumor cell death. DPX-Survivac is used in combination with intermittent low dose CPA which acts as an immunomodulator of T-cell responses. Methods: The study enrolled 22 patients with recurrent, advanced platinum-sensitive and -resistant ovarian cancer. Patients received 2 subcutaneous injections of DPX-Survivac 3 weeks apart and every 8 weeks thereafter, and intermittent low dose CPA for up to 1 year. Paired tumor biopsies were performed prior to treatment and on treatment. Primary endpoints were ORR, DCR and safety. Secondary endpoints include cell mediated immunity, immune cell infiltration in paired biopsy samples, DOR, TTP, OS and biomarker analyses. Results: Twenty-two patients were enrolled in the study. Three patients were discontinued prematurely due to early progression leaving 19 patients for response evaluation. The population is heavily pre-treated with a median of 3 lines of prior treatment [range 1 to 8]; 77.3% of patients are platinum-resistant. At the time of data cut-off, 3/19 patients (15.8%) achieved PR and one additional patient met PR on target lesions but had a newly detected lesion; 10/19 patients (52.6%) showed tumor regression on target lesions at &gt; 1 scan. The median time on study (N=19) is 131 days [63 to ˃295]. Six patients are still on trial. The clinical responses and benefits observed with treatment are associated with an increase in systemic survivin-specific T cells and tumor immune-infiltration. Moreover, RNAseq analysis on paired tumor tissue revealed an enrichment in cytolytic T-cell signature. The most common AEs were grade 1-2 injection site reactions; 4 treatment-related SAEs were reported. Conclusions: DPX-Survivac and intermittent low dose CPA shows promising clinical activity in heavily pre-treated patients with recurrent OvCa. The preliminary results, supported by strong translational data, link the observed clinical benefits with the unique MOA of DPX-Survivac. These clinical results suggest that DPX-Survivac/CPA is an active regimen in OvCa and warrant testing in an expanded cohort of patients. Clinical trial information: NCT02785250.
Analysis of treatment efficacy in the GEM-CESAR trial for high-risk smoldering multiple myeloma patients: Comparison between the standard and IMWG MRD criteria and QIP-MS including FLC (QIP-FLC-MS).
Authors: Noemí Puíg, Teresa Contreras, Bruno Paiva, M Teresa Cedena, Joaquin Martinez-Lopez, Albert Oriol, Norma Gutiérrez, Rafael Ríos-Tamayo, Laura Rosiñol, María José Calasanz, Joan Bargay, Javier de La Rubia, Luis Palomera, Hernández-Garcia Miguel Teodoro, Ramón Garcia-Sanz, Joan Blade, Juan José Lahuerta, Jesus San Miguel, Maria-Victoria Mateos
Journal: Journal of Clinical Oncology (2020)

8512 Background: The GEM-CESAR trial is a potentially curative strategy for high-risk smoldering multiple myeloma (HRsMM) patients (pts) in which the primary endpoint is the achievement of sustained minimal residual disease (MRD) negativity in the bone marrow (BM) by next generation flow (NGF). The value of BM MRD assessment in MM is proven, but alternative, non-invasive methods, accurately reflecting disease burden are needed. Methods: Pts received six 4-week cycles of KRd as induction (K:36mg/m2 twice weekly, R: lenalidomide 25mg po od days 1-21 and d:dexamethasone 40mg po weekly) followed by melphalan 200mg/m2, two further cycles of KRd as consolidation and up to 2 years of Rd (R:10mg/d, d:20mg/week). Efficacy was analyzed in parallel in BM samples by NGF and in serum by SPEP/IFE and QIP-MS/QIP-FLC-MS in 52 out of the 90 pts enrolled in the trial. Standard and MRD responses were carried out as per the IMWG guidelines. For QIP-MS serum immunoglobulins were purified using polyclonal antibodies (anti-IgG, -IgA, -IgM, -total κ and -total λ light chain, -free κ and -free λ light chain). Mass spectra were generated on a MALDI-TOF-MS system. Results: Overall response rate (ORR) was 98% post-induction, 98% post-ASCT, and 100% post-consolidation; 38.4%, 61.5% and 68.6% of pts reached ≥ complete response at each time-point and, among them, 23%, 44% and 55% achieved flow MRD-negativity. Using the combination of QIP-MS/QIP-FLC-MS, the percentage of pts without detectable disease at each timepoint lowered to 12%, 27% and 38% reflecting the higher sensitivity of the method. Against NGF, QIP-MS/QIP-FLC-MS provided negative predictive values of 67%, 92% and 89% (p = 0,0206; p &lt; 0,001; p = 0,003) and identified disease in 95%, 97% and 92% of pts that were positive by NGF-MRD at each respective timepoint. Three pts from this cohort have progressed so far: two were NGF+/MS+ at the three timepoints whilst 1 remained NGF- but QIP-MS/FLC-MS+ throughout. Conclusions: The GEM-CESAR treatment strategy induces a high ORR in HRsMM pts, and the % of cases achieving flow-MRD negativity post-ASCT meets the primary endpoint of the trial. The combined use of QIP-MS and FLC-MS offers higher sensitivity relative to standard methods and may provide relevant information about the right timing for performing a BM aspirate/biopsy. Clinical trial information: NCT02415413 .
A phase I trial of nab-paclitaxel/bevacizumab (AB160) nano-immunoconjugate therapy for unresectable stage IV malignant melanoma (MM): MC1371 (NCT02020707).
Authors: Matthew Stephen Block, Vera J. Suman, Wendy Kay Nevala, Heidi Diann Finnes, Jill Schimke, Carrie Strand, Anastasios Dimou, Lisa A. Kottschade, Yiyi Yan, Joel M. Reid, Craig Hocum, Svetomir Markovic, Robert R. McWilliams
Journal: Journal of Clinical Oncology (2020)

e22020 Background: The combination of nab-paclitaxel (NP) and bevacizumab (BEV) in patients with MM has shown promising clinical activity. AB160 is a 160 nm nano-immunoconjugate of NP nanoparticles non-covalently coated with BEV for targeted delivery into high VEGF expressing tissues. Preclinical data showed that AB160 improved tumor targeting/ tumor inhibition more than NP followed by BEV. Methods: A 3+3 phase I trial was conducted in patients (pts) with MM who had prior systemic treatment for metastatic disease to determine the maximum tolerated dose of AB160 administered intravenously on days 1, 8 and 15 of a 28-day cycle. Dose level 1 (DL1) was 125 mg/m 2 NP /50 mg/m 2 BEV. Dose limiting toxicities (DLT) included grade (G) 4 neutropenia or anemia, PLT &lt; 25,000, serum creatinine ≥ 2 times baseline, G2-4 neurologic toxicity or G3-4 non-hematologic toxicities. Tumor evaluations (RECIST) were conducted every 8 weeks. Treatment continued until progression or intolerability. Results: 21 pts (11 ♀) aged 36-78 years old were enrolled. One of the first 3 pts on DL1 developed a G2 colonic perforation; this was considered a DLT. One of the next 3 pts on DL1 had a DLT: G4 neutropenia. Of the 3 pts on DL-1 (100 mg/m 2 NP/40 mg/m 2 BEV), 2 had no DLTs and 1 died of sepsis after C1D1 dose. Enrollment was suspended until an amendment modifying the eligibility criteria was approved by the IRB. The trial reopened. One of the 4 pts on DL-1 and 1 of the 5 pts on DL1 had a DLT: G3 pain and G3 fatigue, respectively. Enrollment ended after 2 of the 3 pts on DL2 (150 mg/m 2 NP/ 60 mg/m 2 BEV) developed G4 neutropenia. Thus, MTD is DL1. A median of 3 cycles was administered. Treatment ended due to progression (9), intolerability (9), refusal (2) and death (1). There were no objective tumor responses. Common G3-4 toxicities were: neutropenia (33%) and thromboembolic events (19%). Conclusions: AB160 was found to have insufficient clinical benefit in patients with previously treated MM to justify further development. However, parallel phase I testing in gynecologic cancers suggests clinical benefit (abstract #300225). Clinical trial information: NCT02020707.
Clinical predictors of long-term response to capecitabine in metastatic breast cancer (MBC).
Authors: Deirdre Kelly, Sasha M. Lupichuk, Philippe L. Bedard, Karen King, David W. Cescon, Zachary William Neil Veitch
Journal: Journal of Clinical Oncology (2020)

1088 Background: Select patients (pts) with metastatic breast cancer (MBC) treated with capecitabine (cape) experience long-term disease control. We aimed to evaluate the clinical and biological predictors of long-term response. Methods: Pts receiving cape monotherapy for breast cancer from 01/2006 to 01/2016 at Princess Margaret Cancer Centre in Toronto, Canada (N = 352) or Alberta, Canada (N = 798) were identified through central pharmacy records. A median time-to-progression (MTTP) 3-fold higher (19.3 months) than those seen in published studies for patients treated with cape monotherapy at 1000mg/m2 was applied to select for pts with long-term response. MBC pts meeting these criteria were identified through chart review, with collection of clinical, pathological, and survival outcomes in addition to oncologist assessed (o) best response (eg: oCR, oPR, oSD) by radiology report review. Descriptive statistics, Kaplan-Meier and Cox-regressions were applied. Results: Overall, 41 (4%) pts met long-term response criteria. Median age of the study cohort was 62 (range 40-80), with 39% metastatic at diagnosis and 76% post-menopausal. At initiation of cape, a majority of pts were HR positive (85%), with an LDH &lt; ULN (56%), and had bone (83%) or visceral (63%) metastases. Only 1 (2%) patient was HER2+. In the metastatic setting, most patients were chemotherapy-naive (83%) and had received 0-1 lines of hormonal therapy (61%). Median treatment duration with cape was 2.2 years (range 1.7-5.7) with 37% of pts having ≥40 cycles (range 22-94). Visceral (49%), bone (34%), and lymph nodes (24%) were the most common sites of progression, with 41% requiring 1 dose reduction and 27% requiring 2 dose reductions of cape. Overall response rate was 56% (oCR = 2%, oPR = 54%) with 44% having oSD as best response. Median follow-up was 6.8 years (95%CI: 5.5-8.2). Median PFS was 2.3 years (2.0-2.6), with a median OS of 3.8 years (2.9-4.6). 5 patients (12%) remained alive at data-cutoff, and 1 (2%) remained on treatment after 94 cycles of cape. Conclusions: Clinical features associated with long-term response on cape include HR positive, HER2 negative postmenopausal patients with bone predominant metastasis who have received 0-2 lines of prior hormone therapy and 0-1 lines of chemotherapy in the metastatic setting. This is the largest reported analysis of MBC patients with prolonged responses to cape. In the absence of randomized controlled trials; real-world evidence could aid clinicians in the optimal patient selection for treatment with cape.
Improving the Quality of Care for Adolescents and Adults With Sickle Cell Disease—It’s a Long Road
Authors: Charity Oyedeji, John J. Strouse
Journal: JAMA Network Open (2020)

Julie Kanter, MD; Robert Gibson, PhD; Raymona H. Lawrence, DrPH, MPH; Matthew P. Smeltzer, PhD; Norma L. Pugh, MS; Jeffrey Glassberg, MD; Rita V. Masese, MD; Allison A. King, MD, MPH; Cecelia Calhoun, MD; Jane S. Hankins, MD, MS; Marsha Treadwell, PhD
Characteristics of carrier cells associated with clinical response in children treated with adenoviral virotherapy administered in autologous marrow-derived mesenchymal cells.
Authors: Manuel Ramirez, Lidia Franco-Luzón, África González-Murillo, Gustavo Melen, David Ruano, Álvaro Lassaletta, Luis Madero
Journal: Journal of Clinical Oncology (2020)

e15217 Background: We used oncolytic virotherapy carried by autologous marrow-derived mesenchymal cells to treat children with metastatic/refractory tumors (NCT01844661; 10.1016/j.ymthe.2020.01.019 and 10.1016/j.canlet.2015.11.036). Most patients did not show clinical response while a small group did. Methods: We have carried out a comprehensive study of the transcriptome of this new advanced therapy medicine (ATM) to find determinants that might be associated with clinical outcome. Results: The study of the ATM's transcriptome from a first cohort of patients identified signatures associated to biological processes in the infected carrier cells that distinguished responders from non-responders (viral infection and nucleic acid metabolism; immune regulatory routes; cell-cell adhesion; mitosis; cell metabolism; response to stress; and bone marrow fibrosis). Next, we used an approach based on systems biology and neural networks to identify candidates responsible for the differences found in gene expression signatures. We then validated the identified candidates using samples obtained from a second independent cohort of patients, by quantitative PCR and ELISA. Mesenchymal cells of the responding patients expressed significantly lower levels of the MAVS and NDRG1 genes compared with those of the non-responders after oncolytic adenoviral infection. Both genes are related to cellular antiviral responses and cellular metabolism. Accordingly, mesenchymal cells of responders produced significantly lower amounts of IL-6 and CCL-2 than non-responders’ cells. Conclusions: These results point to possible pretreatment biomarkers and the possibility of optimizing a universal version of the carrier cells for the oncolytic virus in this new ATM.
上呼吸道感染用抗生素吗
Authors: 周仲华
Journal: BMJ (2008)

我有一个经常来全科门诊随访的病人叫保罗,是一个25岁的留学生.他2年前在美国被诊断为原发性高血压,一直规律地服用降压药,加上他积极锻炼身体,减轻体重,血压控制一直很好.通过1年多时间的随诊,我们已经建立了很好的医患关系,他对我很信任。
Abstract 11163: Brown Adipose Tissue Dysfunction is Involved in the Pathologies of Pressure Overload-Induced Heart Failure
Authors: Yohko Yoshida, Ippei Shimizu, Tohru Minamino
Journal: Circulation (2018)

Prognosis of severe heart failure is unacceptably high, and it is our urgent task to find therapies for this critical condition. It has been reported that low body temperature predicts poor clinica...
Neoadjuvant endobronchial delivery of gene mediated cytotoxic immunotherapy (GMCI) for non-small cell lung cancer (NSCLC): Safety and immunologic activity.
Authors: Laura K. Aguilar, Jarrod D. Predina, Andrew Haas, Shaun O'Brien, Edmund K. Moon, Marina Martinez, Christopher Corbett, Lydia Frenzel Sulyok, Mitchell G. Bryski, Evgeniy Eruslanov, Charuhas Deshpande, Brian W. Guzik, Andrea G. Manzanera, Estuardo Aguilar-Cordova, Sunil Singhal, Steven M. Albelda
Journal: Journal of Clinical Oncology (2020)

9050 Background: GMCI is a tumor-specific immuno-oncology approach implemented through local delivery of aglatimagene besadenovec(AdV-tk) followed by anti-herpetic prodrug. This leads to immunogenic tumor cell death, antigen presenting cell activation, and T cell stimulation resulting in CD8 + T cell dependent protection, as demonstrated in preclinical models and clinical trials in other tumor types. This is the first study to assess endobronchial delivery of AdV-tk for NSCLC. Methods: This Phase I dose escalation trial enrolled patients with suspected NSCLC who were candidates for surgery. A single AdV-tk injection was performed by endobronchial ultrasound (n = 11) or mediastinoscopy (n = 1) during the diagnostic staging procedure 3 weeks prior to surgery. Three dose levels were evaluated: 2.5x 10 11 , 5x10 11 , and 1x10 12 vector particles (vp) in a 3+3 design. Valacyclovir was administered for 14 days, starting the day after AdV-tk injection. To assess the local and systemic effects of GMCI, immune biomarkers were evaluated in blood and tumor samples before and after GMCI. Results: From 2017-2019, 12 patients (9 men, 3 women, median age 65 [range 55-80]) received GMCI followed by surgery. Average tumor size was 5.1 cm (largest diameter) and final pathologic stage was I (n = 4), II (n = 3), and III (n = 5). Treatment-related adverse events were CTC grade 1 fever (n = 1), flu-like symptoms (n = 1) and nausea/vomiting/diarrhea (n = 1). The only &gt; grade 2 lab abnormality was transient grade 3 lymphopenia (n = 2). A measurable reduction in tumor size was observed in one patient. The average amount of tumor necrosis was 29.4%. Significant infiltration of CD8 + T cells (5.2-fold compared to baseline, p = 0.001) was found in tumor 19-22 days after AdV-tk injection. Within the CD8 + tumor infiltrating lymphocytes, there was increased expression of CD38 (2.5-fold, p = 0.002), Ki67 (4.8-fold, p = 0.02), PD1 (1.9-fold, p = 0.002), CD39 (2.9-fold, p = 0.04) and CTLA-4 (4.8-fold, p &lt; 0.001), without significant detected differences in Tim3 or TIGIT. Simultaneously, peripheral blood CD8 + cells displayed significant increases in CD38 (3.4-fold, p = 0.006), HLA-DR (4.2-fold, p = 0.002), and Ki67 (5.8-fold, p = 0.017). Conclusions: Intratumoral injection of AdV-tk into lung tumors was safe and feasible. Further, AdV-tk effectively induced peripheral blood and intra-tumoral CD8 T cell activation. Consequent upregulation of inhibitory receptors suggests a potential benefit for combination therapies. Clinical trial information: NCT03131037.
Real-world burden of myelosuppression in patients with small cell lung cancer (SCLC): Retrospective, longitudinal data analysis.
Authors: Robert S. Epstein, JoAnn Krenitsky, Roshanthi K. Weerasinghe, Amy S. Parrish, Rachel E. Sanborn, Tehseen Salimi
Journal: Journal of Clinical Oncology (2020)

e19300 Background: Myelosuppression is a common side effect of chemotherapy (CT) that can compromise patient (pt) and economic outcomes. To evaluate the overall burden of myelosuppression, a longitudinal, patterns of care analysis was conducted among pts with SCLC treated with CT in routine clinical practice. Methods: Data were obtained from Providence St. Joseph Health electronic medical records between Jan 2016 and Dec 2019. Hematologic adverse events, treatment patterns, and hospital-based healthcare resource utilization and costs were assessed during the 12 months from first diagnosis of SCLC in pts who had CT-induced grade 3/4 myelosuppression in 1 st or 1 st /2 nd /3 rd -line (1/2/3L) treatment settings. Descriptive statistics were utilized to summarize key findings. Costs of care were calculated from actual treatment costs for inpatient, outpatient, and emergency room services after first diagnosis and treatment with CT. Professional billing was not included due to variability in physician employment by the system. Results: 347 pts were eligible for analysis; mean age (SD) was 66 (9.0) years, 49% were female, and 89% were Caucasian. Prominent comorbidities included chronic obstructive pulmonary disease (52%), diabetes (23%), and peripheral vascular disease (20%). 264 pts (76%) received 1L treatment only, while an additional 83 pts (24%) had both 1L and 2/3L treatment. Of 339 evaluable pts with longitudinal laboratory data, grade 3/4 cytopenias were reported as follows: 45%, neutropenia; 41%, anemia; and 25%, thrombocytopenia. 43% and 15% of pts received red blood cell or platelet transfusions, respectively. 49% of pts received prophylaxis (6%) or treatment (43%) with G-CSF, and 4% of pts were treated with erythropoiesis-stimulating agents. Average total costs of care (post initial-diagnosis and treatment) for pts without grade 3/4 hematologic events (n = 110) were $67,802 per pt throughout the 12 months’ follow-up. On average, annual per pt costs for those with grade 3/4 hematologic events were $131,047 for neutropenia, $95,954 for anemia, and $90,053 for thrombocytopenia. Conclusions: A large and meaningful proportion of pts had grade 3/4 myelosuppression with annual incremental associated costs per pt ranging from $22,251 for pts with thrombocytopenia to $63,245 for pts with neutropenia. Despite the availability of protocols of care and various rescue treatments, CT-induced myelosuppression places a significant real-world burden on pts and the healthcare system.