tbuckley/cabot-search huggingface dataset:
Interleukin-2, interferon alpha and 5-fluorouracil immunochemotherapy with and without 13-cis-retinoic acid in patients with metastatic renal cell carcinoma: Results of a prospective randomized trial
Authors: S. Bierer, M. E. Bode, O. A. Brinkmann, L. Hertle
Journal: Journal of Clinical Oncology (2006)

14571 Background: Combined immunochemotherapy with interleukin 2, interferon alpha and 5-fluorouracil in patients with metastatic renal cell carcinoma has shown objective response rates up to 30% and more. The therapeutic effect of adding 13-cis-retinoic acid still remains controversial. Methods: Between 05/2001 and 11/2003 we randomly assigned patients with metastatic renal cell carcinoma either to receive a combined immunochemotherapy of interleukin 2 (s.c.), interferon alpha (s.c.) and 5-fluorouracil (i.v.) = group A or the same regimen plus 3 × 20 mg 13-cis-retinoic acid daily (p.o.) = group B. 83 patients were eligible (41 in group A and 43 in group B). All patients had ECOG 0 or 1 and no prior systemic therapy. Objective response (OR = Complete response, CR + Partial response, PR + Stable disease, SD), time to progression (TTP) and median survival were determined. Results: Patient characteristics were well balanced between both groups. There was no significant difference in objective response between both groups (A/B: CR 2%/2%, PR 22%/5%, SD 46%/69%, p = 0.8). The responders in both groups showed no significant difference in TTP (A/B: 11.5/9.5 months, p = 0.4). Median survival was 23 months for all patients with no significant difference between the two groups (A/B: 26/22 months, p = 0.42). Slightly more therapeutic side effects (e.g. mucositis) were seen in group B. Conclusions: The addition of 13-cis-retinoic acid to a combined immunochemotherapy of interleukin 2, interferon alpha and 5-fluorouracil in patients with metastatic renal cell carcinoma does not seem to have a therapeutic benefit. No significant financial relationships to disclose.
Immunotherapy of Relapsed and Refractory Solid Tumors With Ex Vivo Expanded Multi-Tumor Associated Antigen Specific Cytotoxic T Lymphocytes: A Phase I Study
Authors: Amy B. Hont, C. Russell Cruz, Robert Ulrey, Barbara O’Brien, Maja Stanojevic, Anushree Datar, Shuroug Albihani, Devin Saunders, Ryo Hanajiri, Karuna Panchapakesan, Sam Darko, Payal Banerjee, Maria Fernanda Fortiz, Fahmida Hoq, Haili Lang, Yunfei Wang, Patrick J. Hanley, Jeffrey S. Dome, Catherine M. Bollard, Holly J. Meany
Journal: Journal of Clinical Oncology (2019)

PURPOSE Tumor-associated antigen cytotoxic T cells (TAA-Ts) represent a new, potentially effective and nontoxic therapeutic approach for patients with relapsed or refractory solid tumors. In this first-in-human trial, we investigated the safety of administering TAA-Ts that target Wilms tumor gene 1, preferentially expressed antigen of melanoma, and survivin to patients with relapsed/refractory solid tumors. MATERIALS AND METHODS TAA-T products were generated from autologous peripheral blood and infused over three dose levels: 1, 2, and 4 × 10 7 cells/m 2 . Patients were eligible for up to eight infusions administered 4 to 7 weeks apart. We assessed dose limiting toxicity during the first 45 days after infusion. Disease response was determined within the context of a phase I trial. RESULTS There were no dose-limiting toxicities. Of 15 evaluable patients, 11 (73%) with stable disease or better at day 45 postinfusion were defined as responders. Six responders remain without progression at a median of 13.9 months (range, 4.1 to 19.9 months) after initial TAA-Ts. Patients who were treated at the highest dose level showed the best clinical outcomes, with a 6-month progression-free survival of 73% after TAA-T infusion compared with a 38% 6-month progression-free survival with prior therapy. Antigen spreading and a reduction in circulating tumor-associated antigens using digital droplet polymerase chain reaction was observed in patients after TAA-T infusion. CONCLUSION TAA-Ts safely induced disease stabilization, prolonged time to progression, and were associated with antigen spreading and a reduction in circulating tumor-associated antigen DNA levels in patients with relapsed/refractory solid tumors without lymphodepleting chemotherapy before infusion. TAA-Ts are a promising new treatment approach for patients with solid tumors.
Image Gallery: Atypical rash in an HIV‐infected woman
Authors: M. Mailhe, H. Tissot‐Dupont, J.‐C. Lagier
Journal: British Journal of Dermatology (2019)

Funding sources: none. Conflicts of interest: none to declare. Dear Editor, A 43‐year‐old woman with HIV‐infection (CD4 count 224 cells/mm3) presented with a 10‐day afebrile rash on her chest, back and arms (Fig. 1). Bacterial culture of a skin swab was negative. Real‐time polymerase chain reaction (PCR) of Treponema pallidum on a skin swab from a lesion was positive, as were T. pallidum enzyme immunoassay and Venereal Disease Research Laboratory test. The patient recovered completely after a treatment with doxycycline (she was allergic to betalactamins). This case demonstrates the importance of screening syphilis for any rash, especially in patients with HIV.1 Furthermore, it highlights that swab PCR is a powerful diagnostic tool for syphilis2 and for skin infections with eschar.3 ...
Long-term Benefits of Sustained Virologic Response for Patient-Reported Outcomes in Patients With Chronic Hepatitis C Virus Infection
Authors: Zobair M. Younossi, Maria Stepanova, Andrei Racila, Arian Afendy, Eric J. Lawitz, Christian Schwabe, Peter J. Ruane, Jay Lalezari, K. Rajender Reddy, Ira M. Jacobson, Andrew J. Muir, Anuj Gaggar, Robert P. Myers, Issah Younossi, Fatema Nader
Journal: Clinical Gastroenterology and Hepatology (2019)
Evaluation of the first-in-class antimitochondrial metabolism agent CPI-613 in hematologic malignancies.
Authors: Timothy S. Pardee, Laura M DeFord-Watts, Erica Peronto, Denise A. Levitan, David Duane Hurd, Steven Kridel, Robin Harrelson, Megan Manuel, Susan Lyerly, Bayard L. Powell
Journal: Journal of Clinical Oncology (2012)

6524^ Background: Altered metabolism is a hallmark of cancer, including hematologic malignancies. Most tumor cells use glycolysis even under aerobic conditions (the Warburg effect). This altered metabolism is a possible therapeutic target. The novel lipoate derivative CPI-613 is a first-in-class agent that targets a key mitochondrial enzyme, pyruvate dehydrogenase complex (PDH). Methods: CPI-613 was tested against leukemia cell lines in vitro and in vivo. It is also the subject of a phase I clinical trial for patients with hematologic malignancies. Results: CPI-613 was active against HL60, Jurkat, and K562 cells, with an average IC50 value of 14 μM (range 12.2 – 16.4). CPI-613 was synergistic with doxorubicin, with Combinatorial Index (CI) values of 0.478 to 0.765. CPI-613 sensitivity increased with knockdown of p53 or MN1 expression, despite their increased resistance to standard therapy. CPI-613 was synergistic with nilotinib against BCR-ABL-expressing cells and with sorafenib against Flt3 ITD-expressing cells. CI values for nilotinib + CPI was 0.059 (+/-0.002) and for sorafenib + CPI was 0.581 (+/-0.052). In vivo, CPI-613 synergized with doxorubicin; median survival improved from 12 days with doxorubicin to 16 days with CPI-613 plus doxorubicin (p=0.0001). In the phase I clinical trial, 7 of 13 evaluable patients had a response of stable disease or better, for an overall response rate of 54% (see table). CPI-613 was well tolerated, with no evidence of marrow suppression and no dose limiting toxicity identified. Conclusions: The novel agent CPI-613 has activity against a variety of hematological malignancies, including acute leukemias. The therapeutic index appears high, with only minor toxicities observed. [Table: see text]
Safety and efficacy of the combination of high-dose calcitriol, docetaxel and aoledronic acid in hormone-refractory prostate cancer (HRPC): Interim report of a phase II trial
Authors: A. Shamseddine, J. Makarem, Z. Abdel Khalik, M. Bulbul, A. Taher, R. Khawli, K. Hemadeh, N. El-Saghir
Journal: Journal of Clinical Oncology (2006)

14600 Background: The purpose of this study is to assess the efficacy and safety of Calcitriol, Docetaxel and Zoledronic acid in patients with metastatic HRPC. The primary endpoint of the study is the toxicity profile. Secondary endpoints include prostate specific antigen PSA response and time to disease progression. Methods: 16 patients with HRPC were enrolled. All patients had confirmed diagnosis of prostate cancer and no previous cytotoxic therapy. All patients signed an informed consent. Patients received oral Calcitriol 0.5μg/kg on day 1 on weekly basis six out of eight-week cycles, Docetaxel 36mg/m 2 on day 2 on weekly basis six out of eight-week cycles, and Zoledronic acid 4mg intravenously on weeks 1 and 5 of every 8-week cycle. Results: A total of 52 cycles were administered and toxicity was acceptable. No treatment-related mortality was encountered. No grade IV anemia, neutropenia, thrombocytopenia or diarrhea was reported. No grade IV gastrointestinal toxicities or thromboembolic events were reported. Grade IV infection was seen in 2 (3.8%) cycles (herpetic esophagitis and listeria meningitis). Grade III neutropenia was seen in 2 cycles (3.8%). Grade III diarrhea was seen in 1 cycle (1.9%) and grade II diarrhea in 4 cycles (7.7%). Grade II to III nausea and vomiting was reported in 8 cycles (15.4%). Grade II to III sensory neuropathy was noted after 17 cycles (32.7%). Grade III fatigue was reported in 5 cycles (9.6%). 14 patients were eligible for response analysis. Overall PSA response rate of our patients was 57.2%. Median time to disease progression was 6.5 months (range 2–15). One year survival was 57.1% (8 out of 14 patients). Conclusions: This interim analysis showed that the addition of Calcitriol to Docetaxel showed an acceptable safety profile as compared to Docetaxel regimens alone with less incidence of neutropenia and diarrhea. Previous studies using Docetaxel alone has reported higher incidence of neutropenia reaching 43–56% and grade III to IV diarrhea (10–34%). Our study suggests that Calcitriol might have a protective effect against the Docetaxel toxicities. No significant financial relationships to disclose.
Abstract 2756: A high-resolution G-quadruplex structure involved in <i>cmyc</i> oncogene regulation
Authors: Jonathan Dickerhoff, Luying Chen, Guanhui Wu, Buket Onel, Clement Lin, Danzhou Yang
Journal: Cancer Research (2019)

Abstract Gene expression needs strict regulation in human cells to prevent tumorigenesis. Among other control mechanisms, guanine-rich sequences which are clustered in promoter regions of oncogenes can form four stranded nucleic acid structures, called G-quadruplexes (G4), and regulate their transcription. The cmyc protein is the most important cellular regulator for proliferation and is often overexpressed in cancer cells. The DNA G-quadruplex formed in the cmyc promoter is a transcriptional silencer element and stabilization of this G4 by small molecules suppresses cmyc transcription, making it a promising target for cancer therapy. High-resolution structures of the highly diverse G4s provide the opportunity to understand their molecular interactions with transcription factors and to design small molecules that specifically bind a particular G4 conformer. Characteristically, multiple G4s can be formed in gene promoter regions because their G-rich sequence generally contains more than the minimum of four G-stretches. While all reported cmyc G4s share the same core with parallel oriented strands, their overall shape is individualized by distinct combinations of varying flanking and loop motifs. In this study, we present a new high-resolution NMR structure of a G4 found to form in the cmyc promoter region. The determined cmyc G4 has a 1:6:1 loop-size arrangement and its conformation is largely defined by its long central loop of 6 nt. We show that this G4 structure is the preferred target of nucleolin protein in comparison to other G4s formed in the cmyc promoter, demonstrating how the polymorphism of a G-rich sequence can modulate the interaction with transcription factors and other regulators. Our NMR structure shows that, despite the length of the 6-nt loop motif and the associated increased flexibility, the folding converges well due to a base pairing between the central loop and the 5’-flanking. Thus, the long loop is pulled towards the 5’-end while analogous loop-flanking interactions are prevented at the opposite 3’-site. In conclusion, the presented new addition to the ensemble of possible cmyc promoter G4 conformations extends the folding landscape for this promoter region, in particular due to the long central loop. This may shed light on how proteins such as nucleolin can target specific G4 and shift the equilibrium of folding to fine-tune gene expression. Finally, this new structure is another promising target for cancer drug development. Citation Format: Jonathan Dickerhoff, Luying Chen, Guanhui Wu, Buket Onel, Clement Lin, Danzhou Yang. A high-resolution G-quadruplex structure involved in cmyc oncogene regulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2756.
Analysis of Human Performance Deficiencies Associated With Surgical Adverse Events
Authors: James W. Suliburk, Quentin M. Buck, Chris J. Pirko, Nader N. Massarweh, Neal R. Barshes, Hardeep Singh, Todd K. Rosengart
Journal: JAMA Network Open (2019)

<h3>Importance</h3> Potentially preventable adverse events remain a formidable cause of patient harm and health care expenditure despite advances in systems-based risk-reduction strategies. <h3>Objective</h3> To analyze and describe the incidence of human performance deficiencies (HPDs) during the provision of surgical care to identify opportunities to enhance patient safety. <h3>Design, Setting, and Participants</h3> This quality improvement study used a new taxonomy to inform the development and implementation of an HPD classifier tool to categorize HPDs into errors associated with cognitive, technical, and team dynamic functions. The HPD classifier tool was then used to concurrently analyze surgical adverse events in 3 adult hospital affiliates—a level I municipal trauma center, a quaternary care university hospital, and a US Veterans Administration hospital—from January 2, 2018, to June 30, 2018. Surgical trainees presented data describing all adverse events associated with surgical services at weekly hospital-based morbidity and mortality conferences. Adverse events and HPDs were classified in discussion with attending faculty and residents. Data were analyzed from July 9, 2018, to December 23, 2018. <h3>Main Outcomes and Measures</h3> The incidence and primary and secondary causes of HPDs were classified using an HPD classifier tool. <h3>Results</h3> A total of 188 adverse events were recorded, including 182 adverse events (96.8%) among 5365 patients who underwent surgical operations and 6 adverse events (3.2%) among patients undergoing nonoperative treatment. Among these 188 adverse events, 106 (56.4%) were associated with HPDs. Among these 106 HPD adverse events, a total of 192 HPDs (mean [SD], 1.8 [0.9] HPDs per HPD event) were identified. Human performance deficiencies were categorized as execution (98 HPDs [51.0%]), planning or problem solving (55 HPDs [28.6%]), communication (24 HPDs [12.5%]), teamwork (9 HPDs [4.7%]), and rules violation (6 HPDs [3.1%]). Human performance deficiencies most commonly presented as cognitive errors in execution of care or in case planning or problem solving (99 of 192 HPDs [51.6%]). In contrast, technical execution errors without other associated HPDs were observed in 20 of 192 HPDs (10.4%). <h3>Conclusions and Relevance</h3> Human performance deficiencies were identified in more than half of adverse events, most commonly associated with cognitive error in the execution of care. These data provide a framework and impetus for new quality improvement initiatives incorporating cognitive training to mitigate human error in surgery.
Interesting possibilities to improve the safety of ipilimumab.
Authors: Tibor Bakacs, Ralph W Moss, Jitendra Mehrishi, Miklos Szabo
Journal: Journal of Clinical Oncology (2012)

e13102 Background: The problem of the ipilimumab therapy is that a common molecular target (CTLA-4 receptor) is expressed on the targeted and non-targeted T cells, respectively. We suggest that the frequency of immune-related adverse events can be reduced by treating conditions in which the number of the targeted cells is larger than the non-targeted ones and/or by improving the accuracy of the targeting. Methods: The first approach was tested in a phase I clinical trial in patients with relapsed malignancy following allogeneic hematopoietic stem cell transplantation. An ipilimumab blockade was used against CTLA-4 positive allogeneic T cells (responding patients had greater than 80% donor T-cell chimerism). The graft-versus-malignancy (GVM) effects were augmented without a significant impact on graft-versus-host disease (GVHD). A feasible approach could also be pretargeting that has been worked out for radioimmunodetection and radioimmunotherapy. To this end we suggest a testable thought experiment for the treatment of chronic lymphocytic leukemia (CLL). First a streptavidin (StAv) modified anti-CD19 mAb is administered, which is followed by the subsequent delivery of biotin labeled anti-CTLA-4 mAb. The latter endows T cells with the ability to travel to tumor sites without prematurely succumbing to apoptosis, while streptavidin’s ultra-high affinity for biotin (10 -15 M) ensures a tight bond to the biotin labeled anti-CTLA-4. Results: Using the law of mass action we calculated that above 1 mg/L ipilimumab concentration (i.e. about 5 mg/patient ~70kg) more than 80% of anti-CD19-StAv sensitized B cells will have been bound to anti-CTLA-4-biotin sensitized T cells. Conclusions: This way, the forces of the immune system liberated by the anti-CTLA-4 antibody blockade could be focused with laser sharp accuracy on CLL cells without collateral damage to normal host cells. One should note that 0.3 mg/kg ipilimumab alone already caused mild autoimmunity.
Age-Related Characteristics and Outcomes of Patients With Heart Failure With Preserved Ejection Fraction
Authors: Jasper Tromp, Li Shen, Pardeep S. Jhund, Inder S. Anand, Peter E. Carson, Akshay S. Desai, Christopher B. Granger, Michel Komajda, Robert S. McKelvie, Marc A. Pfeffer, Scott D. Solomon, Lars Køber, Karl Swedberg, Michael R. Zile, Bertram Pitt, Carolyn S.P. Lam, John J.V. McMurray
Journal: Journal of the American College of Cardiology (2019)
US government resumes executions using pentobarbital injection
Authors: Janice Hopkins Tanne
Journal: BMJ (2019)

The US federal government announced last week that it would resume executing prisoners in December, after a moratorium of 16 years. It will use only an injection of pentobarbital.1

The first five prisoners to be executed have been found guilty of federal crimes and have exhausted all their appeals. The five men murdered and in some cases tortured and raped their victims. The executions will take place in the US penitentiary in Terre Haute, Indiana. Three executions are set for December and two for January. Other executions will take place later.

Attorney general William P Barr said he was directing the Federal Bureau of Prisons to adopt the execution protocol using only pentobarbital, a method used by Georgia, Missouri, and Texas. Previously a three drug regimen was …
BATTLE-2 program: A biomarker-integrated targeted therapy study in previously treated patients with advanced non-small cell lung cancer (NSCLC).
Authors: Vassiliki Papadimitrakopoulou, Ignacio Ivan Wistuba, J. Jack Lee, Anne S. Tsao, Neda Kalhor, Frank V. Fossella, John Heymach, Christine M Alden, Scott N. Gettinger, Kevin R. Coombes, Pierre Saintigny, Ximing Tang, Emily Duffield, Julie Boyer, Suzanne E Davis, Garth Powis, David J. Mauro, Eric H. Rubin, Waun Ki Hong, Roy S. Herbst
Journal: Journal of Clinical Oncology (2013)

TPS8118 Background: New strategies incorporating a personalized medicine approach for NSCLC treatment are increasingly explored and were pioneered in the prospective, biomarker-driven clinical program titled Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE-1) (Kim et al Cancer Discov 2011;1:44). Effective therapeutic strategies for mutant KRAS and other biomarkers of resistance in refractory NSCLC remain an unmet medical need. The BATTLE-2 clinical study is using EGFR, PI3K/AKT and MEK inhibitors and is designed to identify biomarkers for optimal patient selection for these therapies, with a long-term goal to significantly improve the survival of NCSLC patients (pts) (ClinicalTrials.gov NCT01248247). Methods: This is a four-arm, open-label, multi-center, biopsy-driven, adaptive randomization, phase II clinical trial in refractory NSCLC pts (failed at least 1 prior line of therapy). After a study-entry tumor biopsy, pts are adaptively randomized, based on KRAS status, to 4 trial arms: erlotinib, erlotinib plus the AKT inhibitor MK-2206, MK-2206 plus the MEK inhibitor selumetinib, and sorafenib. The primary objective is 8-week disease control rate (DCR). Baseline tumor testing includes KRAS and EGFR mutations and EML4/ALK translocation, the latter two being exclusion criteria. The trial is conducted in 2 stages. In Stage 1, 200 evaluable pts are adaptively randomized (AR) based on observed 8-week DCR and KRAS status while predictive biomarkers are being developed. In Stage 2, the AR model is refined to include the most predictive biomarkers tested in Stage 1, with subsequent Stage 2 AR based on the new algorithm, to a total of 400 evaluable pts. Selection of Stage 2 single and/or composite markers (“signatures”) follows a rigorous, internally and externally reviewed statistical analysis. All Stage 1 and 2 randomization biomarker assays are CLIA-certified. 219 pts have been enrolled and 124 pts randomized. 100 pts are evaluable for the 8-week DCR endpoint. Accrual updates, demographics, and further details will be presented at the meeting. Supported by NCI R01CA155196-01A1. Clinical trial information: NCT01248247.