tbuckley/cabot-search huggingface dataset:
Comparison of cyclin expression between endometrioid-type endometrial cancer (EEC) and endometrioid ovarian cancer (EOC)
Authors: S. Nishimura, H. Tsuda, Y. Hashiguchi, E. I. O. Garner, T. Inoue, N. Kawamura, S. C. Mok
Journal: Journal of Clinical Oncology (2004)

5013 Background: The biological behavior of EEC and EOC differs despite their histologic similarity. While EEC is usually diagnosed at an early stage and has a good prognosis, EOC is generally advanced at diagnosis and shows a poor prognosis. Cyclins are reported to regulate the cell cycle and influence the prognosis of several cancers. We compared the pattern of cyclin expression between EEC and EOC, and evaluated the relationship among cyclin expression, estrogen receptor (ER) status, and the Ki67 labeling index (Ki67-LI). Methods: There were 36 EECs and 37 EOCs. Immunohistochemistry (IHC) was used to detect cyclin A, B1, D1, E and F (CNA, CNB1, CND1, CNE, CNF), Ki67, and ER. The percentage of positive nuclear staining for cyclins was calculated. Quantitative PCR was performed for CNA, CND1 and CNE. Results: (1) When EEC and EOC were compared, CNA expression was higher in EEC. In contrast, CND1 and CNE expression were higher in EOC. The Ki67-LI was also higher in EOC than EEC. Conversely, ER positivity was higher in EEC than EOC (80.6% vs 35.1%, p=0.0007). (2) EEC: Only CNA expression was significantly correlated with the Ki67-LI (r=0.55, p=0.0004). ER status was not related to cyclin expression. Protein and mRNA levels were significantly correlated for CNA and CNE. (3) EOC: Expression of CNA and CND1 was weakly correlated with the Ki67-LI (r=0.54, p=0.001; r=0.38, p=0.04). CNA expression was higher in ER-negative tumors than ER-positive tumors (23.7 vs 9.6, p=0.027). CND1 expression was also higher in ER-negative than ER-positive tumors (12.1 vs 0, p=0.065). CND1, and CNE protein and mRNA levels were significantly correlated. Conclusions: The pattern of cyclin expression differed between EEC and EOC. No significant financial relationships to disclose.
Eosinophils in Blood and Gut
Authors: M I Brookler
Journal: New England Journal of Medicine (1967)

I am a practicing internist but I have been interested in the various problems associated with contraceptive oral medications.  For this reason I have been carefully examining a number of female patients who are taking these hormones and have found much to my surprise a very definite loud high-pitched systolic bruit over the abdomen at aorta and at times radiating into either flank.  The pulses in all these patients have been completely normal and there has been no evidence of any abdominal aneurysm.  This finding of what significance I am not completely sure was noticed in at least a dozen patients whom I have examined over the past two or three months.  In 1 patient whose initial problem was acute abdominal pain and who had the bruit a femoral arteriogram and intravenous pyelogram were completely normal.  In at least half the patients to whom I have suggested that they stop the hormones the bruits have become much fainter but have not completely disappeared.  However they stopped the medication for the period of only one menstrual cycle.(Full text)
Role of ERCC1, XRCC3, Aurora A and TGFBR1 single-nucleotide polymorphisms (SNP) and CHFR and 14–3-3σ methylation in a customized cisplatin (cis) trial based on ERCC1 mRNA levels in stage IV non-small cell lung cancer (NSCLC) patients (pts)
Authors: M. Taron, M. Cobo, D. Isla, B. Massuti, A. Montes, J. Sanchez, M. Botia, M. Domine, M. Sanchez-Ronco, R. Rosell
Journal: Journal of Clinical Oncology (2007)

7687 Background: The primary aim of this trial was response. In both the control arm and in the genotypic arm with low tumor ERCC1 mRNA levels, pts received docetaxel (doc)/cis; in the genotypic arm with high tumor ERCC1 mRNA levels, pts received doc/gemcitabine. Response was significantly higher in the genotypic arms. We examined 324 pts for genetic markers that could influence response, including ERCC1 118 C/T, ERCC1 C8092A, XRCC3 241 (Thr to Met), Aurora A 91 T&gt;A, Aurora A 169G&gt;A, a SNP within intron 7 of the TGFBR1 gene (Int7G24A), and an in-frame germline deletion (TGFBR1*6A). Methylation of 14–3-3s and CHFR were also analyzed. Methods: DNA from peripheral lymphocytes was used for genotyping (Taqman assay) and methylation-specific PCR was used for 14–3- 3s and CHFR in pretreatment serum DNA. Results: There were no differences in clinical characteristics among the different SNP types, except that pts with Aurora A 91 AA had higher tumor ERCC1 mRNA levels (P=0.005). No relationship was found between ERCC1 SNPs and tumor ERCC1 mRNA levels. A strong correlation was found between the Int7G24A and XRCC3 241 SNPs (P=0.03). The Int7G24A GA type had a higher odds ratio (OR) of response (OR 2.32) than the AA type (OR 3.15) (P=0.02). XRCC3 241 MetMet had a lower probability of response (OR 0.23) (P=0.04). No other differences in response were observed according to any of the other SNPs or methylation. In the multivariate model, the best response was observed in pts with performance status (PS) 0, low ERCC1 levels, and XRCC3 241 SNP ( Table ). Conclusions: Further research is warranted to define the role of theTGFBR1 Int7G24A gene in customized treatments. No significant financial relationships to disclose. [Table: see text]
Genomic landscape of the individual host response and outcomes in sepsis: a prospective cohort study
Authors: Emma E Davenport, Katie L Burnham, Jayachandran Radhakrishnan, Peter Humburg, Paula Hutton, Tara C Mills, Anna Rautanen, Anthony C Gordon, Christopher Garrard, Adrian V S Hill, Charles J Hinds, Julian C Knight
Journal: The Lancet Respiratory Medicine (2016)

BackgroundEffective targeted therapy for sepsis requires an understanding of the heterogeneity in the individual host response to infection. We investigated this heterogeneity by defining interindividual variation in the transcriptome of patients with sepsis and related this to outcome and genetic diversity.MethodsWe assayed peripheral blood leucocyte global gene expression for a prospective discovery cohort of 265 adult patients admitted to UK intensive care units with sepsis due to community-acquired pneumonia and evidence of organ dysfunction. We then validated our findings in a replication cohort consisting of a further 106 patients. We mapped genomic determinants of variation in gene transcription between patients as expression quantitative trait loci (eQTL).FindingsWe discovered that following admission to intensive care, transcriptomic analysis of peripheral blood leucocytes defines two distinct sepsis response signatures (SRS1 and SRS2). The presence of SRS1 (detected in 108 [41%] patients in discovery cohort) identifies individuals with an immunosuppressed phenotype that included features of endotoxin tolerance, T-cell exhaustion, and downregulation of human leucocyte antigen (HLA) class II. SRS1 was associated with higher 14 day mortality than was SRS2 (discovery cohort hazard ratio (HR) 2·4, 95% CI 1·3–4·5, p=0·005; validation cohort HR 2·8, 95% CI 1·5–5·1, p=0·0007). We found that a predictive set of seven genes enabled the classification of patients as SRS1 or SRS2. We identified cis-acting and trans-acting eQTL for key immune and metabolic response genes and sepsis response networks. Sepsis eQTL were enriched in endotoxin-induced epigenetic marks and modulated the individual host response to sepsis, including effects specific to SRS group. We identified regulatory genetic variants involving key mediators of gene networks implicated in the hypoxic response and the switch to glycolysis that occurs in sepsis, including HIF1α and mTOR, and mediators of endotoxin tolerance, T-cell activation, and viral defence.InterpretationOur integrated genomics approach advances understanding of heterogeneity in sepsis by defining subgroups of patients with different immune response states and prognoses, as well as revealing the role of underlying genetic variation. Our findings provide new insights into the pathogenesis of sepsis and create opportunities for a precision medicine approach to enable targeted therapeutic intervention to improve sepsis outcomes.FundingEuropean Commission, Medical Research Council (UK), and the Wellcome Trust.
An exploratory feasibility study examining the addition of arsenic trioxide (ATO) and ascorbic acid (AA) to bortezomib, thalidomide, and dexamethasone (VTD) in the treatment of relapsed and refractory multiple myeloma
Authors: J. N. Valent, R. M. Snyder, A. S. Azmi, R. Mohammad, T. Weyer, K. O’Riley, S. Lalo, M. Rivero-Perry, J. A. Zonder
Journal: Journal of Clinical Oncology (2008)

19541 Background: VTD is a highly active combination in pts with relapsed/refractory multiple myeloma (RRMM). ATO alone has modest activity but AA may enhance the cytotoxic effects of ATO. V, T, and ATO inhibit NF-κB, but it is unknown if combining these agents results in increased NF-κB inhibition. This study was undertaken to generate preliminary data on the combination of ATO, AA, and VTD for the treatment of RRMM. Methods: Five male pts (ages 49–77 yrs old) were enrolled in this IRB approved study between Sept 2005 and Aug 2006. The mean number of prior treatments was 3 (range 1–7; autologous transplant in 3 pts). Pts received D 40 mg po/IV and V 0.7 mg/m2 IV on days 1, 4, 8, and 11 of a 21-day cycle and T 50 mg daily po. Starting with cycle 2, ATO (given at an initial dose of 0.10 mg/kg IV) and AA (1000 mg IV) were added on days 1, 4, 8, and 11. Blood samples were drawn prior to and 1 hour after the administration of V on day 1 of cycle 1, and 1 hour after administration of therapy (V + ATO/AA) on day 1 of cycles 2 and 3 in two pts to assess the added effect of ATO/AA on NF-κB inhibition using EMSA. Results: Four of 5 pts completed ≥3 cycles of treatment. Two pts responded to treatment: 1 partial response (71% decrease in M-Protein and decreased bone pain) and another patient with nonsecretory MM had a decrease in size of plasmacytoma. The regimen was well tolerated, with only one pt discontinuing therapy due to side effects: grade 1 peripheral neuropathy with pain after 6 cycles of therapy. In one non-responder, adding ATO/AA did not increase NF-κB inhibition beyond that achieved with VTD alone; in contrast, in one responder, there was a 15-fold decrease in post-therapy NF- κB activation in cycle 3 compared to baseline. Conclusion: Adding ATO/AA to VTD to treat RRMM was well tolerated. There were no unexpected grade 3 or 4 toxicities. Although these data suggest that treatment with VTD plus ATO/AA may increase NF-κB inhibition more than VTD alone in some pts, further studies would be needed to elucidate whether the addition of ATO/AA adds to the clinical efficacy of VTD, as well as the maximally tolerated doses of each drug. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Celgene Celgene, Cephalon, Millennium
A phase I study of an oral formulation of ixabepilone (ixa) in patients with advanced cancer.
Authors: A. R. He, P. L. Kunz, M. J. Pishvaian, A. D. Colevas, J. J. Hwang, P. L. Clemens, M. Messina, R. Kaleta, F. Abrahao, B. I. Sikic
Journal: Journal of Clinical Oncology (2010)

e13090 Background: Ixa is approved for breast cancer and is currently being assessed in various other solid tumor types. An oral formulation would provide added convenience for patients (pts) while potentially minimizing toxicities. Preclinical antitumor efficacy of agents that suppress microtubule dynamics may be more dependent on time of drug concentration above a minimum effective concentration (Te) whereas neurotoxicity may be more dependent on Cmax. Splitting a single dose into two or more, smaller administrations may deliver an optimal therapeutic index by minimizing Cmax and maintaining or extending Te. Methods: A phase I, open-label, single-arm, dose-escalation study of oral ixa administered every 6 hours for 3 doses (q6hx3) on day 1, every 21 days in pts with advanced cancer. The starting dose was 30mg q6hx3. The primary endpoints were determining the maximum tolerated dose (MTD), dose limiting toxicities (DLT) and the recommended phase II dose. Efficacy and pharmacokinetic parameters were evaluated. Results: Eighteen pts were treated in three cohorts: 3 pts at 30mg, 9 pts at 40mg and 6 pts at 50mg q6hx3. Two pts presented DLTs: One at 40mg q6hx3-febrile neutropenia (Grade 4; G4) and, mucositis (Grade 3; G3); and another pt at 50mg q6hx3-neutropenic sepsis G4, pneumonitis G4, thrombocytopenia G4, diarrhea G3 and mucositis G3. Other severe non-hematologic toxicities were diarrhea G3 (1); dysphagia G3 (2); fatigue G4 (1); mucositis G3 (1); muscular weakness G4 (1); infection G3 (1). The DLTs observed occurred in the two pts with the highest exposure to ixa. There were no objective responses. Five pts achieved stable disease, one was not evaluated and 12 pts had a best overall response of disease progression. The exposure for orally administered ixa was more variable than that for the intravenously administered formulation. Conclusions: This study and the oral ixa development program have been terminated due to high inter- and intra-patient PK variability with potential to negatively impact both safety and efficacy. No objective responses were observed at the examined dose levels. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb
Pediatric Hospital Discharges to Home Health and Postacute Facility Care
Authors: Jay G. Berry, Matt Hall, Helene Dumas, Edwin Simpser, Kathleen Whitford, Karen M. Wilson, Margaret O’Neill, Vineeta Mittal, Rishi Agrawal, Michael Dribbon, Christopher J. Haines, Christine Traul, Michelle Marks, Jane O'Brien
Journal: JAMA Pediatrics (2016)

Acute care hospitals are challenged to provide efficient, high-quality care to children who have medically complex conditions and may require weeks or months for recovery. Although the use of home health care (HHC) and facility-based postacute care (PAC) after discharge is well documented for adults, to our knowledge, little is known for children.To assess the national prevalence of, characteristics of children discharged to, and variation in use across states of HHC and PAC for children.Retrospective analysis of 2,423,031 US acute care hospital discharges in 2012 for patients ages 0 to 21 years from the nationally representative Agency for Healthcare Research and Quality Kids' Inpatient Database.Discharges to HHC (eg, visiting or private-duty home nursing) and PAC (eg, rehabilitation facility) were identified from Centers for Medicare and Medicaid Services Discharge Status Codes. We compared children's characteristics (eg, race/ethnicity and number of chronic conditions) by discharge type using generalized linear regression.The median age of participants was 3 years (interquartile range, 0-13 years), and 45.6% were female. Of 2,423,031 US acute care hospital discharges in 2012 for patients ages 0 to 21 years, 122,673 discharges (5.1%) were to HHC and 26,282 (1.1%) were to PAC facilities. Neonatal care was the most common reason (44.5%, n = 54,589) for acute care hospitalization with discharge to HHC. Nonneonatal respiratory, musculoskeletal, and trauma-related problems, collectively, were the most common reasons for discharge to PAC (42.9%, n = 11,275). When compared with PAC, more discharges to HHC had no chronic condition (34.4% vs 18.0%, P < .001) and fewer discharges to HHC had 4 or more chronic conditions (22.5% vs 37.7%, P < .001). In multivariable analysis, Hispanic children were less likely to use PAC (0.8% vs 1.1%; odds ratio [OR], 0.9 [95% CI, 0.8-0.9]) or HHC (3.3% vs 5.5%; OR, 0.8 [95% CI, 0.7-0.8]) compared with other children. Children with 4 or more chronic conditions compared with no chronic conditions had a higher likelihood of HHC use (11.0% vs 4.4%; OR, 2.9 [95% CI, 2.8-3.0]) and PAC (3.9% vs 0.8%; OR, 4.5 [95% CI, 4.3-4.9]). After case-mix adjustment, there was significant (P < .001) variation across states in HHC (range, 0.4%-24.5%) and PAC (range, 0.4%-4.9%) use.Home health care and PAC use after discharge for hospitalized children is infrequent, even for children with multiple chronic conditions. It varies significantly by race/ethnicity and across states. Further investigation is needed to assess reasons for this variation and to determine for which children HHC and PAC are most effective.
Solving a disaster following coronary bypass operation
Authors: Philipp-Alexander Neumann, Mike Laukoetter, Rudolph Mennigen, Linus Kebschull, Dominik Bettenworth, Frank Lenze, Hansjoerg Ullerich, Norbert Senninger, Thorsten Vowinkel
Journal: Gut (2016)

A 72-year-old male patient underwent coronary bypass surgery and presented with atrial fibrillation upon completion of the operation. Intraoperative transesophageal echocardiography (TEE) was performed, followed by successful electric cardioversion. The initially stable patient developed a systemic inflammatory response syndrome on day 7 after the operation. The septic course progressed over the next days, necessitating reintubation and placement of a nasogastric feeding tube. Since the patient did not stabilise despite escalation of antibiotic therapy, he was referred to our department of general surgery. A CT scan of thorax and abdomen revealed the images shown in figure 1.



Figure 1 
CT scan of the upper abdomen showing free air …
Utilization of antineoplastic therapy (ANT) in advanced cancer patients admitted to an acute palliative care unit (APCU) at a comprehensive cancer center
Authors: D. Hui, E. Bruera, Z. Li, J. L. Palmer, M. de la Cruz, A. Elsayem
Journal: Journal of Clinical Oncology (2009)

9590 Background: Cancer patients admitted to a palliative care unit generally have a poor prognosis. The role of ANT (chemotherapy and targeted agents) in these patients is unclear. We examined the frequency, trends, factors and survival associated with ANT use in hospitalized patients who required an APCU stay. Methods: All patients admitted to APCU between September 1, 2003 and August 31, 2008 were included. Demographics, cancer diagnosis and ANTs utilization from day of hospitalization to discharge, and survival information were retrieved retrospectively. Results: 2604 cancer patients had the following characteristics: median age 59 (range 18–101), male 51%, hematologic malignancy 11%, median hospital stay 11 (Q1-Q3 8–17) days, median APCU stay 7 (Q1-Q3 4–10) days and median survival 22 days. During hospitalization, 393 patients (15%) received ANTs, including chemotherapy (N=297, 11%) and targeted therapy (N=155, 6%). No significant change in frequency of ANTs was detected over the 5 year period. Multivariate logistic regression analysis ( Table ) revealed that younger age, cancer primaries and longer admissions were associated with ANT use. Patients with hematologic malignancies received more chemotherapy (38% vs. 8%, p&lt;0.001) and targeted agents (18% vs. 4%, p&lt;0.001) compared to patients with solid tumors. ANT use was associated with longer overall survival in univariate analysis (median 25 days vs. 21 days, p=0.001); however, this was no longer significant in multivariate Cox regression analysis. Conclusions: The use of ANT during hospitalization that included an APCU stay was limited to a highly selected group of patients, and did not increase overtime. ANT use was associated with younger age, specific cancer primaries, longer admissions, and no significant improvement in survival. The APCU at our cancer center facilitates simultaneous care where patients access palliative care while on ANT. [Table: see text] No significant financial relationships to disclose.
O-016 Exploratory analysis of tumor growth rate in patients with advanced gastrointestinal stromal tumors (GIST) treated with regorafenib in the GRID phase 3 trial
Authors: C. Kappeler, P. Reichardt, Y.-K. Kang, J.-Y. Blay, H. Joensuu, K. Schaefer, J. Chung, A. Wagner, P.G. Casali, G. Demetri
Journal: Annals of Oncology (2015)
LAPATAX: A randomized phase II trial of FEC-docetaxel combined with lapatinib and/or trastuzumab as neoadjuvant therapy of HER2-positive breast cancer—EORTC 10054 trial.
Authors: D. A. Cameron, S. Marreaud, K. Zaman, A. Bodmer, J. Pierga, E. Brain, C. Veyret, J. M. Bartlett, J. Bogaerts, H. R. Bonnefoi
Journal: Journal of Clinical Oncology (2010)

TPS116 Background: Patients with HER2 +ve breast cancer suitable for neoadjuvant chemotherapy (NAC) have been shown in a series of clinical trials to have the best outcome when treated with anthracyclines (A), taxanes (T), and trastuzumab (Tz). Recent evidence confirms that adjuvant Tz is more effective when given concomitantly rather than sequentially with T (Perez SABCS 2009). Whilst there remains uncertainty as to the most efficacious A-T regimen and duration of Tz, there is widespread use in Europe of FEC-D [3 cycles of 5-FU 500 mg/m2, epirubicin 100 mg/m2 and cyclophosphamide 500 mg/m2 (FEC100) followed by 3 cycles of docetaxel 100 mg/m2 (D) q3w] following the results of PACS-01. The advent of TKI anti-HER2 agents such as L could offer superior outcomes if combined with NAC. However, a phase I study in heavily pre-treated advanced breast cancer reported difficulties in combining lapatinib (L) with D 100 mg/m2 (LoRusso JCO 2008). Methods: EORTC 10054 is designed as a two-part study to compare FEC-D with either Tz, L or their combination as NAC for patients with HER2 +ve large operable or locally advanced breast cancer. Before and on-treatment frozen tumor and blood samples will be taken to better define which tumours are particularly sensitive to either Tz and/or L. Stage 1: (complete) a dose- finding study has confirmed that with primary prophylactic G-CSF, D 100 mg/m2 can be safely and effectively given with L 1,250 mg daily continuously. The dose-limiting toxicity was myelosuppression, and there was no significant diarrhoea or cardiac toxicity (ESMO 2009 abstr P- 5073). Stage 2: (opening Q1 2010) will enroll 150 patients from European centres into a 3-arm randomized trial whose primary endpoint is pathological complete response. All patients will receive FEC-D before primary surgery: 3 cycles of FEC (without anti-HER2 therapy) followed by 3 cycles of D plus either Tz (conventional weekly schedule), monotherapy L, or the combination of Tz and L, using doses based on the EGF100161 dose-finding study in 1st line metastatic therapy of D+L+Tz. After surgery all patients will receive standard 3-weekly Tz, radiotherapy and endocrine therapy as per local guidelines. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline, Roche GlaxoSmithKline, Roche Roche