tbuckley/cabot-search huggingface dataset:
Randomized phase III study of panitumumab (pmab) vs. cetuximab (cmab) in chemorefractory wild-type (WT) <i>KRAS</i> exon 2 metastatic colorectal cancer (mCRC): Outcomes by hypomagnesemia (hypomag) in ASPECCT.
Authors: Timothy Jay Price, Marc Peeters, Tae Won Kim, Jin Li, Stefano Cascinu, Paul Ruff, Attili Venkatasatya Suresh, Anne Thomas, Sergei Tjulandin, Kathy Zhang, Roger Sidhu, Swaminathan Murugappan
Journal: Journal of Clinical Oncology (2015)

705 Background: ASPECCT met its primary endpoint of non-inferiority of overall survival (OS) of pmab vs. cmab. We evaluate outcomes by hypomag, an on-treatment, anti-EGFR related adverse event that develops due to the inhibition of EGFR function. Conflicting reports have suggested hypomag is associated with survival. Methods: Patients with previously treated WT KRAS exon 2 mCRC were randomized 1:1 to receive pmab or cmab. The primary endpoint was non-inferiority of OS. Progression-free survival (PFS) and objective response rate (ORR) were secondary endpoints. Patients were categorized ± any grade hypomag during the study and data analyzed by treatment arm. Analysis of Mg supplementation during hypomag was not conducted. Results: 999 patients were randomized and treated: 499 pmab, 500 cmab. Any grade hypomag was 28.8% and grade ≥3 was 7.3% in the pmab arm vs. 18.9% and 2.6% in the cmab arm, respectively. Median time to first hypomag onset was 82 days in the pmab arm and 57 days in the cmab arm. In the pmab arm, 1.0% of patients discontinued treatment and 5% of patients had dose modifications due to hypomag vs. &lt;0.5% and 3% in the cmab arm, respectively. Results are shown (Table). Conclusions: In ASPECCT, rates of hypomag were higher in the pmab vs. the cmab arm. Patients who developed any grade hypomag with pmab or cmab had higher ORR, PFS, and OS compared with those patients who did not. Clinical trial information: NCT00788957. [Table: see text]
Phase I study of pharmacologically based dosing of carboplatin with filgrastim support in women with epithelial ovarian cancer.
Authors: M J Lind, S Ghazal-Aswad, L Gumbrell, K Fishwick, D Craigs, M J Millward, N P Bailey, F Dore-Green, F Chapman, D Simmons, M Proctor, A Oakey, L Robson, I Middleton, E McCann, D Sinha, A H Calvert
Journal: Journal of Clinical Oncology (1996)

PURPOSE The aim of this study was to increase the dose intensity of carboplatin in women with International Federation of Gynecology and Obstetrics (FIGO) Stage Ic-IV epithelial ovarian cancer with the use of granulocyte colony-stimulating factor (G-CSF; filgrastim; Amgen, Thousand Oaks, CA). PATIENTS AND METHODS A phase I study of escalating target area under the curves (AUCs) of carboplatin with G-CSF (filgrastim) ws undertaken. The target AUCs were 5 mg/mL.min every 21 days for four cycles, 5 mg/mL.min every 14 days for four cycles, 7 mg/mL.min every 14 days for four cycles, 9 mg/mL.min every 14 days for four cycles, and 11 mg/mL.min every 14 days for four cycles. G-CSF was given at a dose of 5 microg/kg/d starting 24 hours after carboplatin administration and lasting until 24 hours before the next cycle and until day 14 after the last cycle. RESULTS We were able to escalate to an AUC level of 9 mg/mL.min every 14 days for four cycles. At this dose, severe thrombocytopenia, that necessitated dosage delays, and failure to give subsequent cycles of carboplatin were observed. We then reduced the AUC level to 8 mg/mL.min every 14 days for four cycles. However, severe thrombocytopenia was also observed at this level. CONCLUSION An AUC of 7 mg/mL.min every 14 days for four cycles is the maximum tolerated AUC level that can be achieved with G-CSF. Further escalations may be possible using either combinations of cytokines or peripheral stem-cell collections.
Quantitative detection of rare interphase chromosome breaks and translocations by high-throughput imaging
Authors: Bharat Burman, Tom Misteli, Gianluca Pegoraro
Journal: Genome biology (2015)

Abstract We report a method for the sensitive detection of rare chromosome breaks and translocations in interphase cells. HiBA-FISH (High-throughput break-apart FISH) combines high-throughput imaging with the measurement of the spatial separation of FISH probes flanking target genome regions of interest. As proof-of-principle, we apply hiBA-FISH to detect with high sensitivity and specificity rare chromosome breaks and translocations in the anaplastic large cell lymphoma breakpoint regions of NPM1 and ALK . This method complements existing approaches to detect translocations by overcoming the need for precise knowledge of translocation breakpoints and it extends traditional FISH by its quantitative nature.
IMA901 Multipeptide Vaccine Randomized International Phase III Trial (IMPRINT): A randomized, controlled study investigating IMA901 multipeptide cancer vaccine in patients receiving sunitinib as first-line therapy for advanced/metastatic RCC.
Authors: B. I. Rini, T. Eisen, A. Stenzl, W. Brugger, T. Weinschenk, A. Mahr, J. Fritsche, N. Hilf, R. Mendrzyk, J. Lindner, A. Schmid, A. Kirner, S. Walter, H. Singh, C. Reinhardt
Journal: Journal of Clinical Oncology (2011)

TPS183 Background: IMA901 is a therapeutic vaccine composed of multiple naturally presented tumor-associated peptides (TUMAPs). Previous data have indicated that vaccination with IMA901 results in a relevant clinical benefit, ie. advanced RCC patients with detectable T cell responses against TUMAPs had a better disease control and overall survival as compared to patients without such responses. Furthermore, pre-treatment with a single dose of cyclophosphamide (CY; 300mg/m2) was able to reduce regulatory T cells (Treg) and improve survival compared to patients vaccinated without prior CY, resulting in considerably longer median survival than expected (>24 months in second-line cytokine pre-treated mRCC patients). Treatment with IMA901 was overall well tolerated with most AE being local side effects. Suntinib is a standard treatment for mRCC and was approved based on the improvement of PFS. It has been speculated that sunitinib may also favorably alter immune regulation via reduction of Treg and myeloid-derived suppressor cells (MDSC). Various pre-clinical and clinical data have suggested that the combination of sunitinib and therapeutic vaccines is feasible, safe, and potentially synergistic. Methods: This is a randomized phase III study to investigate whether IMA901, when administered in addition to sunitinib, can prolong overall survival (OS; primary endpoint). Secondary endpoints include a subgroup analysis of OS in patients positive for a pre-defined biomarker signature, PFS, best overall objective response, immunomonitoring, and safety. Approximately 330 patients will be randomized to receive sunitinib or sunitinib plus IMA901 (total of 10 i.d. vaccinations together with 75 µg GM-CSF starting in the first "off-phase" and preceeded by a single low-dose CY). Main inclusion criteria comprise advanced/metastatic clear cell RCC without prior systemic therapy for advanced disease, HLA-A*02 expression, favorable or intermediate risk according to Heng. Screening has started in December 2010 and first data are expected by the second half of 2013.
Results of interleukin-2-based treatment in advanced melanoma: a case record-based analysis of 631 patients.
Authors: U Keilholz, C Conradt, S S Legha, D Khayat, C Scheibenbogen, N Thatcher, S H Goey, M Gore, T Dorval, B Hancock, C J Punt, R Dummer, M F Avril, E B Bröcker, A Benhammouda, A M Eggermont, M Pritsch
Journal: Journal of Clinical Oncology (1998)

PURPOSE In patients with stage IV melanoma, durable responses have been reported with treatment regimens that involve high-dose interleukin-2 (IL-2). We analyze long-term results of 631 melanoma patients from 12 institutions who had received IL-2 alone, in combination with interferon alfa 2a or 2b (IFNalpha), or with cytotoxic drugs. METHODS Case records that contained pretreatment parameters, response data, and updated survival information were collected. After univariate analysis, the multivariate evaluation of the impact of pretreatment parameters on response and survival was performed by logistic regression and Cox's regression, respectively. RESULTS Patients were divided into four groups according to treatment: IL-2 alone (n=117), IL-2 and chemotherapy (n=49), IL-2 and IFNalpha (n=153), and IL-2, chemotherapy, and IFNalpha (n=312). The median survival of all patients was 10.5 months and the 2- and 5-year survival rates were 19.9% and 10.4%, respectively. Independent prognostic factors for response and survival were entirely different, treatment group being the only significant factor for response, and serum lactate dehydrogenase (LDH), metastatic site, and performance predicting survival. The addition of IFNalpha to IL-2 was associated with prolonged survival, but the effect of additional chemotherapy was less obvious. CONCLUSION Serum LDH, metastatic site, and performance status are useful stratification factors for randomized trials in metastatic melanoma. The improved long-term survival rates observed in melanoma patients treated with IL-2/IFNalpha-containing regimens are notable in contrast to the reported 5-year survival rates of 2% to 6% achieved with chemotherapy, but because selection bias cannot be ruled out, the impact of IL-2, as well as all other components of the treatment regimens, on survival needs to be confirmed in prospective randomized trials.
ARRY-502, a potent, selective, oral CRTh2 antagonist reduces Th2 mediators in patients with mild to moderate Th2-driven asthma
Authors: Sally Wenzel, David Chantry, Christine Eberhardt, Robert Hopkins, Michael Saunders, Lisa Anderson, Roger Aitchinson, Stacie Bell, Kenji Izuhara, Junya Ono, Laurence Burgess
Journal: European Respiratory Journal (2014)

Asthma and other allergic diseases are associated with mast cell activation and prostaglandin D 2  (PGD 2 ) generation. PGD 2  exerts pro-inflammatory activity via chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTh2). The safety and efficacy of CRTh2 antagonist ARRY-502 was studied in mild atopic asthmatic adults in a double-blind, placebo-controlled 4 week phase 2a study. Enrolled patients were free of inhaled corticosteroids with an FEV1% predicted of 60-85%. Potential participants were screened and randomized to receive 200 mg BID ARRY-502 (n = 93) or matching placebo (n = 91). In patients with elevated Th2 associated biomarkers at baseline there were significant improvements in spirometric outcomes, measures of asthma control and quality of life. In addition, there was a significant reduction in markers of Th2 driven inflammation in these patients. For example, patients that exhibited FENO levels at or above the median value of 48 ppb at baseline experienced a reduction in FENO of 27.0 ppb (pl0.0001) at week 4 in the ARRY-502 group versus placebo group. This indicates significant anti-inflammatory activity of ARRY-502 via CRTh2 antagonism. Other markers of Th2 inflammation were also reduced including serum periostin, serum squamous cell carcinoma antigens 1 & 2, serum TARC (CCL17), and blood CRTh2 +  eosinophils. These results imply that ARRY-502 controls multiple Th2 inflammatory pathways and could be beneficial in patients that suffer from other Th2-driven allergic diseases like atopic dermatitis and allergic rhinitis.
Evaluation of dendritic cell population in chronic obstructive pulmonary disease
Authors: César Gutiérrez, Carmen Calero, Elena Arellano, Ana Blanco, Daniela Tobar, Ana Montes, Nicolas Moreno, Jose Luis Lopez-Campos
Journal: European Respiratory Journal (2012)

Chronic obstructive pulmonary disease (COPD) is characterized by an increase in CD8+ T cells within the central and peripheral airways suggesting an antigen-specific adaptive immune response. It usually requires the assistance of antigen-presenting cells (APCs), like dendritic cells (DCs), that recognize, process, and present the processed antigen to naive lymphocytes. In human airway tissue three different pulmonary DC subsets have been described: type 1 myeloid DCs (BDCA1), type 2 myeloid DCs (BDCA3), and plasmacytoid DCs (BDCA2).

The objective of this study was to assess dendritic cells in the airway tissue in patients with COPD.

In this case-control study, a total of 31 lung biopsies were obtained from a group of patients undergoing major lung resection because of suspected neoplasm. There were 16 COPD patients and 15 controls. Flow cytometry method was used to quantify the number and subsets of DCs in lung parenchymal.

There was no significant difference in baseline characteristics between the two groups. We observed a lower proportion of BDCA1 as well as BDCA2 cells in COPD patients than in control patients (10% and 18% respectively). The number of BDCA3 cells was 37% lower in the control group.

We found a higher concentration of mature DCs identified by CD40/CD80/CD83/CD86 expression in the COPD group. The results of this study support the role of dendritic cells in the systemic inflammation in COPD. Pulmonary DCs migration in COPD seems to be accompanied by DCs maturation.
Common Pathway for Tumor Cell Uptake of Gallium-67 and Iron-59 via a Transferrin Receptor
Authors: S M Larson, J S Rasey, D R Allen, N J Nelson, Z Grunbaum, G D Harp, D L Williams
Journal: JNCI Journal of the National Cancer Institute (1980)

We studied the tumor uptake of [67Ga]citrate, [59Fe]citrate, and 125I-labeled transferrin (TF) by the in vitro growth form of EMT-6, a sarcoma-like mammary tumor of BALB/c mice. In analyzing the binding experiments, we developed a new mathematical model based on a formulation originally used to express the interaction of hormones with specific tissue receptors. The uptake of both carrier-free 67Ga and 59Fe by tumor cells was mediated by kinetically identical TF receptors. We also studied teric acid extracts of the stroma of EMT-6 tumors grown both in vivo and in vitro. Chromatography of these extracts on Sephacryl S-200 SF demonstrated that the cellular stroma contained specific TF-binding macromolecules. On the basis of these findings, we proposed the "transferrin receptor hypothesis" for the mechanism of 67Ga uptake by tumors. According to this view, a tumor-associated TF receptor is the functional unit responsible for the affinity of gallium for certain neoplasms. This receptor was also active in the uptake of iron by tumors.
Adjuvant intraperitoneal cisplatin chemotherapy does not improve long-term survival after surgery for advanced gastric cancer.
Authors: T Sautner, F Hofbauer, D Depisch, R Schiessel, R Jakesz
Journal: Journal of Clinical Oncology (1994)

PURPOSE The long-term survival probability of patients who undergo surgery for stage 3 and 4 gastric cancer is poor, predominantly due to metastatic spread of the tumor. Depending on the type of tumor histology, the pathway of metastases is mainly peritoneal or hepatic dissemination. Interruption of this mechanism may be possible by intraperitoneal chemotherapy (IPT). PATIENTS AND METHODS In a prospective randomized trial of 67 patients undergoing surgery for stage 3 and 4 gastric cancer, 33 patients underwent adjuvant postoperative IPT with cisplatin, while 34 control subjects remained untreated. RESULTS Patients in the treatment group received a median of four IPT perfusions. Apart from frequent nausea, no adverse reactions or complications were noted. The median disease-free survival durations were 12.7 months and 9.7 months in treated patients and controls, respectively (P = .8). After a median follow-up duration of 72 months, 54 patients (80%) had died of primary disease or related complications. The median survival duration for IPT patients was 17.3 months as compared with 16.0 months for controls (P = .6). Autopsies were performed on 12 (18%) of 54 patients who died, and showed tumor spread to the peritoneal cavity and/or to the liver, irrespective of the application of IPT. CONCLUSION IPT with cisplatin monotherapy does not improve survival probability after surgery for stage 3 and 4 gastric cancer. The reasons for ineffectiveness of IPT may be the choice of an unsuitable chemotherapeutic agent, an inefficient modus of application, or a lack of sufficient drug penetration into the serosa or peritoneal metastasis.
The Degree of Branching of the Glycans of α<sub>1</sub>-Acid Glycoprotein in Asthma
Authors: MICHEL M. VAN DEN HEUVEL, DENNIS C. W. POLAND, CASPER S. DE GRAAFF, ELISABETH C. M. HOEFSMIT, PIETER E. POSTMUS, ROB H. J. BEELEN, WILLEM VAN DIJK
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

Alpha(1)-acid glycoprotein (AGP) is a plasma protein belonging to the group of acute-phase proteins. It contains five N-linked glycans which, depending on pathophysiologic state, differ in their degree of branching (i.e., in the relative proportions of di-, tri-, and tetraantennary glycans). Changes in the degree of branching of these glycans have been shown to affect various immunomodulatory properties of AGP. We wanted to investigate whether changes occur in the branching of AGP glycans in plasma and in bronchoalveolar lavage fluid (BALF) in asthma. For this purpose, we selected three groups of patients for study: patients with atopic asthma (AA), atopic nonasthmatic patients, and a group of patients with various interstitial lung diseases (ILDs). The plasma AGP concentration was normal in both atopic study groups, but was increased in ILD patients. In contrast, the branching of glycans of AGP was altered in subjects with AA, whereas it was normal in the other study groups. The presence of asthma symptoms correlated with the increased glycan branching of AGP in both plasma and BALF. Additionally, the degree of branching of AGP in BALF was related to FEV(1), to the provocative dose of histamine causing a 20% decrease in FEV (PD(20)), and to the number of eosinophils. In conclusion, asthma is accompanied by changes in the branching of AGP glycans that indicate an inflammatory reaction that differs markedly from a normal acute-phase response, in which decreased branching of AGP occurs.
Acute Stress Disorder and Posttraumatic Stress Disorder in Victims of Violent Crime
Authors: Chris R. Brewin, Bernice Andrews, Suzanna Rose, Marilyn Kirk
Journal: American Journal of Psychiatry (1999)

In a group of crime victims recruited from the community, the authors investigated the ability of both a diagnosis of acute stress disorder and its component symptoms to predict posttraumatic stress disorder (PTSD) at 6 months.A mixed-sex group of 157 victims of violent assaults were interviewed within 1 month of the crime. At 6-month follow-up 88% were reinterviewed by telephone and completed further assessments generating estimates of the prevalence of PTSD.The rate of acute stress disorder was 19%, and the rate of subsequent PTSD was 20%. Symptom clusters based on the DSM-IV criteria for acute stress disorder were moderately strongly interrelated. All symptom clusters predicted subsequent PTSD, but not as well as an overall diagnosis of acute stress disorder, which correctly classified 83% of the group. Similar predictive power could be achieved by classifying the group according to the presence or absence of at least three reexperiencing or arousal symptoms. Logistic regression indicated that both a diagnosis of acute stress disorder and high levels of reexperiencing or arousal symptoms made independent contributions to predicting PTSD.This exploratory study provides evidence for the internal coherence of the new acute stress disorder diagnosis and for the symptom thresholds proposed in DSM-IV. As predicted, acute stress disorder was a strong predictor of later PTSD, but similar predictive power may be possible by using simpler criteria.
Definition of Prostaglandin E2–EP2 Signals in the Colon Tumor Microenvironment That Amplify Inflammation and Tumor Growth
Authors: Xiaojun Ma, Tomohiro Aoki, Tatsuaki Tsuruyama, Shuh Narumiya
Journal: Cancer Research (2015)

Abstract Inflammation in the colon contributes significantly to colorectal cancer development. While aspirin reduces the colorectal cancer risk, its action mechanism, especially in inflammation in tumor microenvironment, still remains obscure. Here, we examined this issue by subjecting mice deficient in each prostaglandin (PG) receptor to colitis-associated cancer model. Deficiency of PGE receptor subtype EP2 selectively reduced, and deficiency of EP1 and EP3 enhanced, the tumor formation. EP2 is expressed in infiltrating neutrophils and tumor-associated fibroblasts in stroma, where it regulates expression of inflammation- and growth-related genes in a self-amplification manner. Notably, expression of cytokines such as TNFα and IL6, a chemokine, CXCL1, a PG-producing enzyme, COX-2, and Wnt5A was significantly elevated in tumor lesions of wild-type mice but this elevation was significantly suppressed in EP2-deficient mice. Intriguingly, EP2 stimulation in cultured neutrophils amplified expression of TNFα, IL6, CXCL1, COX-2, and other proinflammatory genes synergistically with TNFα, and EP2 stimulation in cultured fibroblasts induced expression of EP2 itself, COX-2, IL6, and Wnt genes. EP2 expression in infiltrating neutrophils and tumor-associated fibroblasts was also found in clinical specimen of ulcerative colitis-associated colorectal cancer. Bone marrow transfer experiments suggest that EP2 in both cell populations is critical for tumorigenesis. Finally, administration of a selective EP2 antagonist potently suppressed tumorigenesis in this model. Our study has thus revealed that EP2 in neutrophils and tumor-associated fibroblasts promotes colon tumorigenesis by amplifying inflammation and shaping tumor microenvironment, and suggests that EP2 antagonists are promising candidates of aspirin-alternative for chemoprevention of colorectal cancer. Cancer Res; 75(14); 2822–32. ©2015 AACR.
Behavioural and emotional disturbances associated with sleep disturbances in children with Down's syndrome
Authors: Ewan McConnell, Elizabeth Hill, Athanasia Pataka, Renata Riha
Journal: European Respiratory Journal (2013)

Background:  Children with Down’s syndrome (DS) are predisposed to obstructive sleep apnoea syndrome (OSAS). In children with DS, behavioural and emotional disturbances secondary to OSAS may be overlooked and assumed to be the result of DS-related intellectual impairment.   Aims:  1) To determine the prevalence of behavioural and emotional disturbances associated with sleep disturbances in a population of children with Down’s Syndrome in Scotland in 2012. 2) To assess changes in sleep disturbance prevalence over a 7 year period (2005 – 2012).   Method:  A questionnaire based on the pilot study completed in 2005, consisting of a modified sleep questionnaire, the Epworth Sleepiness Scale (ESS) with additional paediatric question and the Developmental Behaviour Checklist (DBC-P24), was sent to the carers of 261 children aged 4 - 15 years with DS.   Results:  Presence of choking attacks (p = 0.001,) the paediatric ESS (p = 0.001) and the standard ESS (p =    Conclusion:  This is the first study to document a high prevalence of sleep disordered breathing (SDB) (>50%) in the Scottish DS population. Sleepiness and SDB were independently associated with worse behaviour scores.