tbuckley/cabot-search huggingface dataset:
A phase I, pharmacokinetic (PK) and pharmacodynamic (PD) study of MDX-214, a novel immune-mediated mechanism agent targeting the epithelial growth factor receptor (EGFR), in patients with advanced solid tumors
Authors: C. A. Mita, K. Papadopoulos, M. M. Mita, A. Ricart, J. Sarantopoulos, K. Berg, B. Uritz, E. Levy, I. Lowy, A. W. Tolcher
Journal: Journal of Clinical Oncology (2006)

2523 Background: MDX-214 is a recombinant fusion protein between human EGF and the Fab′ fragment of a fully human anti-CD89 (IgA FcR) MAb. MDX-214 is designed to block EGFR and activate neutrophils via CD89 stimulation, and promotes EGFR+ cell killing in vitro by both mechanisms. Methods: The objectives of this study were to evaluate the safety and tolerability, to determine the maximum tolerated dose (MTD), to characterize the PK, to assess PD markers and to explore the antitumor activity of MDX-214 administered intravenously weekly for 4 weeksin EGFR+ malignancies. PD studies included monitoring immune cell trafficking to tumors by paired In 111 WBC scans at the final dose level, MDX-214 saturation of CD89+ neutrophils in blood, as well as EGFR signaling in skin. Pts were permitted only 1 course of therapy. Results: To date, 18 pts (median age 61, range 48–83, 10 M/8 F) have been treated over 4 dose levels at 0.4, 1, 4 and 10 mg/m 2 , respectively. Tumor types included renal (4), colorectal (2), pancreatic (2), head/neck (2), tracheal, parotid, esophageal, breast, anal, thyroid, hepatocellular, and skin carcinomas. DLT was encountered at 10 mg/m 2 with one grade 3 reversible infusion reaction of rigors, erythema and transient hypoxemia. In the 6 pts treated at this dose level, 2 additional pts experienced grade 2 infusion reactions despite premedication, and one grade 2 hypotension. The MTD was therefore 4 mg/m 2 . Other grade 1–2 toxicities included nausea/vomiting (9), diarrhea (2), fatigue (4), headache (4). There were 7 pts with stable disease at 6 weeks. The serum half-life was &lt; 30 min but neutrophil-bound MDX-214 was detectable for 24 h. In 111 WBC scans are under analysis. Conclusion: Weekly administration of MDX-214, a novel immune mediated therapeutic strategy targeting EGFR is feasible with an MTD of 4 mg/m 2 . This dose results in neutrophil labeling with MDX-214 for over 24 hours, and may permit activated neutrophil localization at tumor sites. Accrual at the MTD is ongoing. [Table: see text]
A novel peptide with a potential to enhance sorafenib’s therapeutic effects in hepatocellular carcinoma.
Authors: Joline Sijing Lim, Todor Dimitrov, Kol Jia Yong, Chong Gao, Daniel G Tenen, Li Chai
Journal: Journal of Clinical Oncology (2012)

e13505 Background: Hepatocellular carcinoma (HCC) is the third leading cause of cancer related deaths worldwide, with chemotherapy or targeted therapy such as sorafenib achieving limited success. Recently stem cell factor SALL4 has emerged as a novel oncogene associated with leukemogenesis and is also implicated in many solid tumors. We have observed that SALL4 is not expressed in adult human liver tissues, but expressed in 30-40% of liver cancer, and this is associated with poorer prognosis and overall survival. We further tested whether inhibition of SALL4 function could be used for HCC treatment. Methods: A novel peptide blocking SALL4 function was designed and used to treat HCC lines with or without SALL4 expression. This is followed by evaluation for binding affinity, tumor growth inhibitory activity and mechanism of action. Treated cells were then transplanted in vivo into NOD/SCID mice and monitored for tumor growth. Comparison and/or combination of peptide with sorafenib were also carried out. Further modification of the peptide was done to allow for in vivo administration. Results: The peptide can effectively block SALL4 function. When used to treat HCC cell lines, it showed inhibitory effects in SNU398 cells (SALL4 expression), but not SNU387 cells (non-SALL4 expression). Post-xenotransplant, mice which received cells treated with peptide had slower rate of tumor growth (p=0.028) and lower tumor burden at dissection 26 days post transplant (p=0.048). Searching for its mechanism of action, we discovered that the peptide could affect the PTEN/AKT pathway, which was validated by western blot. When the peptide was combined with sorafenib, decreased cell viability was observed (p=0.03), suggestive of at least an additive effect between the peptide and sorafenib. Modification of peptide with TAT-protein showed similar inhibition of growth in vitro and was tested for further in-vivo usage through intraperitoneal injection. Conclusions: Our proof-of-principle studies have showed that a peptide blocking the function of stem cell factor SALL4 can be used as a novel approach for treating HCC. Combined with sorafenib, it may be able to enhance cell death and potentially lead to better outcomes in HCC patients.
Nintedanib and Sildenafil in Patients with Idiopathic Pulmonary Fibrosis and Right Heart Dysfunction. A Prespecified Subgroup Analysis of a Double-Blind Randomized Clinical Trial (INSTAGE)
Authors: Jürgen Behr, Martin Kolb, Jin Woo Song, Fabrizio Luppi, Birgit Schinzel, Susanne Stowasser, Manuel Quaresma, Fernando J. Martinez
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

Rationale: In the INSTAGE trial in patients with idiopathic pulmonary fibrosis (IPF) and severely impaired gas exchange, nintedanib plus sildenafil was associated with numerical benefits on St. George's Respiratory Questionnaire (SGRQ) total score, brain natriuretic peptide (BNP), and FVC decline versus nintedanib alone. Exploratory analyses of the STEP-IPF (Sildenafil Trial of Exercise Performance in IPF) trial suggested that sildenafil may have a greater effect on SGRQ score in patients with IPF who have right heart dysfunction (RHD).Objectives: Assess whether RHD influenced the effects of nintedanib plus sildenafil versus nintedanib alone in the INSTAGE trial.Methods: Subgroup analyses of patients with (n = 117) versus those without (n = 156) echocardiographic signs of RHD at baseline.Measurements and Main Results: There was no heterogeneity between subgroups by presence of RHD in the effect of nintedanib plus sildenafil versus nintedanib alone on change in SGRQ total score at Week 12 (P = 0.74) or Week 24 (P = 0.90), or change in FVC at Week 12 (P = 0.58) or Week 24 (P = 0.55). In both subgroups, nintedanib plus sildenafil had a numerically greater effect on reducing FVC decline versus nintedanib alone. Between-group differences in change in BNP at Week 24 were -119.9 ng/L (95% confidence interval = -171.3 to -68.5) and -3.6 ng/L (95% confidence interval = -47.2 to 40.0) in patients with and without signs of RHD at baseline, respectively (P < 0.01).Conclusions: In the INSTAGE trial, there were no significant differences in the effects of nintedanib plus sildenafil versus nintedanib alone on changes in SGRQ and FVC between patients with or without echocardiographic signs of RHD at baseline. The benefit of combination therapy on stabilizing BNP was more pronounced in patients with RHD at baseline.Clinical trial registered with www.clinicaltrials.gov (NCT02802345).
Renal tubular cell spliced X-box binding protein 1 (Xbp1s) has a unique role in sepsis-induced acute kidney injury and inflammation
Authors: Silvia Ferrè, Yingfeng Deng, Sarah C. Huen, Christopher Y. Lu, Philipp E. Scherer, Peter Igarashi, Orson W. Moe
Journal: Kidney International (2019)
Abstract MP19: Can Clinical Measurements of Blood Pressure Replace Research-based Measurements?
Authors: Olive Tang, Stephen Juraschek, Lawrence Appel, Lisa Cooper, Jeanne Charleston, Kathryn Carson, Hsin-Chieh Yeh, Edgar R Miller
Journal: Circulation (2018)

Introduction: There is growing interest in embedding research protocols into clinical practice, including use of electronic health records (EHR) for measures of blood pressure (BP). However, the accuracy and reliability of EHR-derived BP compared to research-based BP are unknown. Hypothesis: We hypothesized EHR-derived measurements would overestimate systolic BP (SBP) and have higher variance compared to research measurements. Methods: We analyzed EHR-derived BP and research BP measurements in participants from a randomized trial, Five+ Nuts and Beans. EHR-derived measurements were made following the implementation of a standardized BP protocol, including the use of automated devices, clinical training, and systems support, to enhance the quality of clinic BP measurements. EHR-derived SBP measurements and change in SBP, calculated from closest clinic visits prior to the start and after the end of the trial period, were compared with measures obtained in the research setting. Results: Participants were 87% female (107 of 123); mean age was 58.6±9.7 yrs. Of the 123 participants, 118 had at least one primary care visit within 6 months of the research period. EHR-derived SBP were higher and more variable than research measurements, though these differences were attenuated for visits occurring within 7 days of research measurements (Table 1). EHR-based change in SBP was also more variable (SD=19.6) than research-based change (SD=14.0); using these SD’s, we estimate that a 2-arm trial conducted with clinic measurements would need to enroll 95% more participants (324 vs 166) to detect a 5 mmHg difference in SBP at a power of 0.9. Conclusions: Despite implementation of a standardized BP protocol, clinic measurements of SBP were higher and more variable than research protocol-based measurements. These results suggest that, in clinical trials, use of BP measurements obtained in clinical care, even if standardized, will reduce power and require greater sample size compared to measurements obtained in research settings.
Prognostic relevance of the novel TNM-classification system for neuroendocrine tumors of foregut origin
Authors: U. Pape, H. Jann, U. Berndt, B. Wiedenmann
Journal: Journal of Clinical Oncology (2007)

15147 Background: Until recently no TNM-classification existed for neuroendocrine tumors (NET) of the gastroenteropancreatic system. In 2006 Rindi et al. proposed a new TNM-classification system for foregut-NET of gastric, duodenal and pancreatic origin. The present study validates prognostic significance of the new TNM-classification in a cohort from a German referral center. Methods: The case files of 193 patients with histologically proven foregut NET were analyzed retrospectively. Patients were classified according to Capella (1995) and the WHO (2000) and to the new TNM-classification. Uni- and multivariate analysis was performed using log-rank and Cox regression methods. Results: Primary tumors localization was gastric (n=48), duodenal (23) and pancreatic (122); 35 patients (18%) died during the observation period. Overall 5- and 10-year survival rates (YSR) were 76% and 65% resp., while 5- and 10-YSR according to NET-related deaths (74% of all deaths, 26/35) were 83% and 74% resp.. The classifications by Capella and the WHO significantly discriminated between low and high grade malignant NET (p&lt;0,001 and 0,002 resp.), but did not allow further prognostic differentiation. In contrast, the newly proposed TNM-classification system was able to significantly differentiate stage IV NET from all other stages (I vs. IV p=0,001; II vs. IV p=0,001; III vs. IV p=0,008) as well as stage III from stage I NET (p=0,038). Furthermore, the new classification system which includes a grading system according to the mitotic index (Ki67-index; G1 &lt;3%, G2 3–20%, G3 &gt;20%) was also able to significantly distinguish all three groups from each other (G1 vs. G3 p&lt;0,001; G2 vs. G3 p&lt;0,001). On multivariate analysis stage I and II as well as stage III-NET had a decreased hazard ratio (HR) when compared to stage IV-NET (I/II: HR 0,094, p=0,003; III: HR 0,38, p=0,096). In the same model G1 and G2-NET were associated with an decreased HR as compared to G3-NET (G1: HR 0,05, p=0,01; G2: HR 0,20, p=0,002). Conclusions: Here we demonstrate prognostic relevance of the newly proposed TNM-classification system for foregut-NET with statistical significance which therefore provides a new and powerful tool for future classification of NET. No significant financial relationships to disclose.
The large granular lymphocytic leukemia registry: A detailed analysis of 79 patients with LGL leukemia and rheumatoid arthritis.
Authors: Kirsten Marie Boughan, Thomas P. Loughran
Journal: Journal of Clinical Oncology (2012)

6590 Background: The purpose of this study is to analyze patients enrolled in the LGL leukemia registry to distinguish the similarities between LGL leukemia and rheumatoid arthritis in order to access overlapping immune mechanisms that may be responsible for neutrophil mediated destruction. Methods: A retrospective chart review was performed on 79 patients enrolled in the LGL registry at Penn State Cancer Institute. All patients enrolled in the study had a diagnosis of both rheumatoid arthritis and potentially LGL leukemia. Data was collected for age, sex, RF factor positivity, family history, autoimmune disease, T-cell receptor gene rearrangement, and bone marrow invasion. Results: Of 79 patients the mean age of onset for LGL leukemia was 60 years old with no discrepancy noted between sexes, 37 M, 42 F. 49 patients were positive for rheumatoid factor. 27 patients had rheumatoid arthritis in a first degree relative with no discrimination between maternal or paternal inheritance. 22 patients were positive for any other autoimmune process. 60 patients were positive for T-cell receptor gene rearrangement. Of the remaining 19 patients that were negative for T-cell receptor rearrangement, 12 had evidence of bone marrow invasion (CD3/CD8+ infiltrate in &gt;20% bone marrow) and two showed bone marrow invasion of NK cell LGL (CD3/CD8-, CD57+) (Table). Conclusions: Patients with T cell LGL leukemia and rheumatoid arthritis appear to be clinically similar with regard to age, duration of disease, and other autoimmune disorders as patients with rheumatoid arthritis alone. Our patient population showed those with TLGL and RA also tends to have a positive family history of RA in up to 20% as opposed to 5-10% in RA patients. Given that RA and TLGL have a significantly higher expression of the HLA-DR4 haplotype than healthy patients, it is conceivable that with shared genetic alterations, and gene environment interactions that may promote posttranslational modification, there may be a loss of tolerance resulting in T cell activation, and eventual transformation into a T cell clone. [Table: see text]
Supporting smokers’ quit attempts reduces national smoking prevalence
Authors: Tim Coleman
Journal: Thorax (2019)

Smoking remains a massive health problem. Although smoking prevalence is declining in high-income countries, rates are still increasing in many low-income and middle-income jurisdictions.1 Internationally, the eradication of smoking would transform global health but achieving this will likely require resolute, combined individual-level and population-level approaches.2 For individuals, effective interventions like behavioural support3 and pharmacotherapy4 5 can equip people with the skills to try stopping and successfully stop. However, these interventions are of limited use if they are seldom used or not readily accessible and this is where concomitant population-level tobacco control strategies can help. For example, antismoking publicity campaigns can encourage people to try stopping and making evidence-based support, like pharmacotherapy, cost-free can encourage more quitters to use it. By reaching many people, population-level strategies can have substantial impacts.2 

Smoking is probably the most comprehensively researched unhealthy behaviour. There is an abundance of robust, high-quality randomised controlled trials (RCTs) testing the efficacy of individual-level smoking cessation interventions summarised in over 80 Cochrane Tobacco Addiction Group systematic reviews.6 Evidence for what works at a population level is much thinner. It is challenging to secure the very strongest research evidence for population-level approaches; to evaluate national tobacco control policies with RCTs would require countries to accept random allocation to different policies and this is evidently unfeasible. However, in this edition of Thorax , Beard et al report an imaginative, non-RCT evaluation of population-level tobacco control strategies using national survey data collected between 1973 and 2016. This suggests that the very comprehensive tobacco control policies introduced into the UK around the millennium, including the provision of national stop smoking services, had very positive, population-level impacts on rates of starting and stopping smoking and also on smoking prevalence.

The UK has a long history of conducting large-scale, …
Complete remission after induction therapy of donor cell derived secondary AML in a CML transplant patient
Authors: A. A. Fauser, L. Kraut, G. Trebeljahr, B. Thiele, N. Gulzad, E. Roemer
Journal: Journal of Clinical Oncology (2006)

16523 Background: Malignant diseases arising from donor derived cells are an exceptionally rare condition with approximately 20 cases only reported in the literature. We report on diagnosis and salvage chemotherapy of a CML transplant patient relapsing with donor cell derived secondary MDS resp. AML. Methods: Chimerism analysis were performed by quantitative short tandem repeat (STR) DNA detection in bone marrow as well as in peripheral blood, detection limit 0.5%. Standard procedures were used for all other methods. Results: In a female patient transplanted with a HLA-DRB1 mismatched female unrelated donor in July 1998 for Ph + CML, secondary MDS was diagnosed in March 2005 transforming into secondary AML in June 2005. The results from chimerism analysis after diagnosis of sMDS resp. sAML in this transplant patient, i.e. no detection of the STR pattern of the recipient, clearly confirmed a donor cell derived sMDS resp. sAML almost 7 years after allogeneic BMT. Cytogenetics showed a normal female karyotype, and no molecular aberrations were detected by FISH resp. PCR. After diagnosis of sAML the patient received 2 induction courses consisting of FLAG-Ida and MTC regimen, respectively. Bone marrow analysis after the first and second course revealed no evidence of blasts whereas the MDS continued to be detectable. Cytogenetics during and after reinduction therapy were normal. Repeated chimerism analysis showed complete donor chimerism (&gt; 99.5%). Thus, a complete remission of donor cell derived sAML using conventional induction chemotherapy was achieved. This remission is now lasting 6 months without intensification. Medical evaluation of the donor did not reveal any disturbed or malignant hematological disorder. Conclusions: This is an interesting case of rare donor cell derived leukemia and its successful treatment. The question arises with regard to altered stromal factors in the bone marrow of the patient as potential cause of the disease. No significant financial relationships to disclose.
Multicenter randomized controlled phase III study of nivolumab alone or in combination with ipilimumab as immunotherapy vs standard follow-up in surgical resectable HNSCC after adjuvant therapy.
Authors: Chia-Jung Busch, Adrian Muenscher, Christian Stephan Betz, Volkan Dogan, Philippe Schafhausen, Carsten Bokemeyer, Mascha Binder
Journal: Journal of Clinical Oncology (2019)

TPS6095 Background: Surgically treated locally advanced head and neck squamous cell carcinoma (LA HNSCC) often requires postoperative chemoradiation with high risk of acute and late toxicity. Disease-free survival (DFS) after 2 years is approximately 70%. Combining Nivolumab (N), a PD-1inhibitor, and Ipilimumab, a CTLA4 inhibitor, as maintenance therapy may improve DFS due to anti-tumor effects of immunotherapy by enhancing cross-presentation of tumor antigens. The IMSTAR HN study compares neoadjuvant N and N±I 6 months after adjuvant therapy vs the standard therapy as first-line treatment for LA HNSCC. Methods: Eligible pts are ≥18 years old with treatment-naive LA HNSCC (oral cavity, oropharynx p16-, hypopharynx, and larynx), ECOG PS ≤1, and no distant metastasis. 276 pts will be randomized (2:1) into 2 arms and approximately 10 centers in Germany will be involved. Standard of care (arm II) consists of surgical resection followed by risk-adapted adjuvant (chemo)radiation. The experimental arm I receives neoadjuvant N 3mg/kg. After treatment according to standard arm a second randomization will be performed: In arm Ia N 3mg/kg will be given every 2 weeks until progression or up to 6 months. In arm Ib I 1mg/kg will be applied additionally every 6 weeks also until progression or up to 6 months. Primary endpoints is DFS in arms I and II. Secondary endpoints: Local regional control (LRC), distant metastasis free survival (DMFS), overall survival (OS), quality of life (QoL), survival depending on PD-L1 status, comparison of arm Ia vs arm II and Ib vs. II. AEs, graded per CTCAE v4.03, are evaluated for at least 12 months after randomization. The translational program includes investigations concerning immunmodulation, mutational load in general, but also specific mutations in targets involved in immune function and antigen presentation. Recruitment started in August 2018. Clinical trial information: NCT03700905.
The use of insulin and the effect on survival of non-small cell lung cancer patients
Authors: S. Y. Farhan, M. Jankowski, A. Hanbali, D. Wang
Journal: Journal of Clinical Oncology (2009)

e22073 Background: Diabetes mellitus (DM) is one of the common morbidities in United States. Insulin therapy has been frequently used in its treatment. Some studies have postulated that activation of Insulin and Insulin-like growth factor (IGF) pathway may contribute to cancer proliferation, growth and resistance to anticancer therapies. The impact of insulin on diabetic patients with non-small cell lung cancer (NSCLC) has not been reported. Methods: 1,233 patients with NSCLC diagnosed between January 1999 and December 2004 were identified from the Tumor Registry at Henry Ford Health System. Based on inclusion criteria, data from 1,206 patients were extracted from the electronic medical records. Statistical analyses were performed between insulin and non insulin users. Results: Out of 1,206 patients, 193 patients had NSCLC and DM. Data was available from 192 patients. Sixty (31.3%) were on insulin at the time of NSCLC diagnosis and defined as insulin users, while 132 were not on insulin and defined as non- users (68.7%). Demographics, co-morbidities, disease stage at diagnosis, therapeutic interventions, and laboratory values were analyzed for overall and cancer-specific survival. More insulin users (81%) than non-users (64%) presented with advanced disease (stage ≥ 3) at diagnosis (P=0.02). Although no significant difference of Hemoglobin A1c was observed, the median survival from all causes of death was 6.5 months for insulin-users versus 9.9 months for non-users (P=0.08). When survival time was calculated from cancer-specific death, the median survival between insulin and non-insulin users was 7.2 months versus 38.7 months, respectively (P=0.002), with a hazard ratio (HR) for insulin use equals 1.91. Results from our univariable and multivariable analyses will be presented at the ASCO annual meeting in detail. Conclusions: This data indicates that the use of insulin may adversely affect the biology and clinical course of NSCLC with a tendency of advanced disease stage at diagnosis and a shorter cancer-specific survival time. Prospective study of DM with NSCLC or other cancer diagnosis will improve our understanding of this potential adverse effect on cancer biology and provide scientific rational to target IGF-pathway especially in diabetic patients. No significant financial relationships to disclose.
Prevalence, Risk, and Genetic Association of Reticular Pseudodrusen in Age-related Macular Degeneration
Authors: Amitha Domalpally, Elvira Agrón, Jeong W. Pak, Tiarnan D. Keenan, Fredrick L. Ferris, Traci E. Clemons, Emily Y. Chew
Journal: Ophthalmology (2019)