tbuckley/cabot-search huggingface dataset:
Prognostic Factors for Late Mortality Among Day 100 Survivors after Allogeneic Hematopoietic Cell Transplantation (HCT)
Authors: Sagar S. Patel, Lisa Rybicki, Donna Abounader, Brian J. Bolwell, Robert Dean, Hien K. Liu, Aaron T. Gerds, Rabi Hanna, Brian T. Hill, Deepa Jagadeesh, Matt Kalaycio, Brad Pohlman, Ronald Sobecks, Navneet S. Majhail, Betty K. Hamilton
Journal: Blood (2016)
Proton pump inhibitor use does not raise dementia and Alzheimer’s risk, study suggests
Authors: Ingrid Torjesen
Journal: BMJ (2017)

A US study1 has not confirmed earlier reports that proton pump inhibitor (PPI) use is linked to an increased risk of dementia and Alzheimer’s disease.2 In contrast, the latest study, published in the Journal of the American Geriatrics Society ,1 found that continuous or intermittent PPI use was associated with a lower risk of cognitive decline.

Using the National Alzheimer’s Coordinating Center database covering 2005-15 the researchers identified patients aged over 50 who had normal cognition or mild cognitive impairment (with cognitive test scores lower than normal …
Single centre study of wireless capsule endoscopy in patients with suspected small bowel diseases
Authors: NM Kelly, JSA Collins, RGP Watson, HR Ferguson, E Warwick
Journal: Endoscopy (2005)

Aims: Wireless capsule endoscopy is a new, painless method of imaging the entire small bowel. We retrospectively reviewed n=59 wireless capsule endoscopy (WCE) studies in 54 patients over an eighteen month period.
Prognostic factors in 868 advanced gastric cancer patients exposed to second-line therapy.
Authors: Valentina Fanotto, Caterina Fontanella, Mario Uccello, Giulia Pasquini, Silvia Bozzarelli, Francesco Leone, Riccardo Giampieri, Gerardo Rosati, Marco Imperatori, Samantha Di Donato, Gianluca Tomasello, Nicola Silvestris, Filippo Pietrantonio, Luisa Bellu, Antonio Avallone, Valeria Pusceddu, Saverio Cinieri, Lorenzo Antonuzzo, Antonio Pellegrino, Giuseppe Aprile
Journal: Journal of Clinical Oncology (2016)

e15553 Background: Although second-line therapy is often considered for advanced gastric cancer (AGC) patients (pts), the optimal candidates are not well defined. Methods: To describe possible prognostic factors, we retrospectively collected baseline parameters, tumor features, and treatment data of 868 AGC pts exposed to multiple treatment lines at 17 Italian Centers. Cross-tables and chi-square test were used to describe categorical features. To predict the impact of clinical variables on progression-free survival (PFS) and overall survival (OS) we performed Kaplan Meier and Cox Regression analyses. Results: 67.6% were male; the most frequent site of primary tumor was gastric body (30.5%). Intestinal histotype accounted for 41.5% of cases, 50.8% of pts had G3-4 tumors and 12.4% had a HER2-positive disease. At second-line therapy start, the median age was 64.8 years (25th-75th percentiles 55.2-71.9). Overall, 40.3% received single-agent chemotherapy, 47.4% a doublet, and 7.3% a triplet. Fluoropyrimidines were the most frequently used agents (50.1%), followed by irinotecan, taxanes, and platinum salts. Median second-line PFS was 2.8 months (25th-75th percentiles 1.8-5.2), median second-line OS was 5.6 months (25th-75thpercentiles 2.9-10.0). Multivariate analysis of potential prognostic factor is shown. Conclusions: AGC patients with favorable ECOG PS, lower LDH levels, and a lower N/L ratio at second-line start seem to have a better outcome, regardless of age and intensity of treatment. A longer PFS in first-line had also positive prognostic value. Our real-life study might help clinicians to identify AGC pts who may benefit most from a second-line therapy. 2nd-line PFS 2nd-line OS p HR 95% CI p HR 95% CI Age <40 vs ≥40 yrs 0.119 1.52 0.90 – 2.56 0.065 1.63 0.97 – 2.74 Doublet/Triplet vs single-agent 0.865 1.02 0.83 – 1.25 0.672 1.05 0.85 – 1.29 PFS in first line ≥6.8 vs <6.8 mo 0.02 0.79 0.65 – 0.96 0.002 0.72 0.59 – 0.89 LDH ≤480 vs >480 UI/L 0.01 0.64 0.46 – 0.90 0.037 0.70 0.50 – 0.98 ECOG PS 0 vs 2-3 <0.0001 0.33 0.25 – 0.44 <0.0001 0.28 0.20 – 0.37 ECOG PS 1 vs 2-3 <0.0001 0.57 0.44 – 0.75 <0.0001 0.53 0.40 – 0.69 Neutrophils/ Lymphocytes ratio <2.7 vs ≥2.7 0.007 0.75 0.61 – 0.93 <0.0001 0.66 0.53 – 0.81
C/EBPβ-elafin pathway is involved in generation of cyclin E low molecular weight isoforms in breast cancer
Authors: Tomoya Yokota, Yanna Liu, Kelly Hunt, Khandan Keyomarsi
Journal: Cancer Research (2007)

421  Cyclin E is a positive regulator of the G1 to S phase transition of the cell cycle. Previously, we have reported that cyclin E is overexpressed and present in low molecular weight (LMW) isoforms in breast tumor tissues compared to normal tissues. The frequent appearance of the LMW forms of cyclin E is a very strong predictor of poor outcome in breast cancer patients. Furthermore, only tumor cells and not normal cells have the machinery to proteolytically cleave the full length cyclin E into these LMW forms through the action of the elastase. Elafin is an endogenous inhibitor of elastase, and plays a key role in inhibiting the synthesis of LMW cyclin E in normal cells. The elafin gene is transcriptionally downregulated through its promoter in most tumor cell lines but is consistently expressed in normal cells. Our previous promoter analyses raise a possibility that the CCAAT/enhancer-binding protein (C/EBP) beta could regulate the elafin gene. In this study, we demonstrate that C/EBPβ-elafin pathway is involved in generation of the LMW forms of cyclin E in breast tumors.  We have two lines of evidence showing that there is cross-talk between C/EBPβ and elafin in human mammary epithelial cells. First, depletion of C/EBPβ by siRNA resulted in suppression of the elafin expression. Second, downregulation of elafin led to upregulation of C/EBPβ levels, suggesting that C/EBPβ could be induced to compensate for elafin loss. To investigate whether C/EBPβ regulates the transcription of elafin, cotransfection studies were carried out to test the effect of C/EBPβ on the elafin promoter in human breast cancer cells which do not express elafin. Wild-type elafin promoter activity was significantly stimulated with increasing amounts of C/EBPβ, whereas C/EBPβ mutant elafin promoter did not respond to a C/EBPβ overexpression plasmid. Furthermore, Northern blotting and RT-PCR revealed that overexpression of C/EBPβ enhanced the elafin mRNA levels. Taken together, these results suggest that C/EBPβ transactivates the elafin gene through the C/EBPβ binding sites of its promoter in human breast cancer cells. Lastly, the stable overexpression of C/EBPβ in human breast cancer cells results in the stable overexpression of elafin and inhibition of the LMW cyclin E generation. Our findings provide the evidence that C/EBPβ is an important transcription factor regulating the elafin gene, and that the C/EBPβ-elafin pathway plays a crucial role in inhibition of the cleavage of cyclin E LMW forms in breast tumor cells. These results suggest that methods to overexpress elafin can provide breast cancer patients with biological modulators of cyclin E.
Vibrational Profiling of Brain Tumors and Cells
Authors: Sultan L Nelson, Dustin T Proctor, Ahmad Ghasemloonia, Sanju Lama, Kourosh Zareinia, Younghee Ahn, Mustafa R Al-Saiedy, Francis HY Green, Matthias W Amrein, Garnette R Sutherland
Journal: Theranostics (2017)

This study reports vibration profiles of neuronal cells and tissues as well as brain tumor and neocortical specimens.A contact-free method and analysis protocol was designed to convert an atomic force microscope into an ultra-sensitive microphone with capacity to record and listen to live biological samples.A frequency of 3.4 Hz was observed for both cultured rat hippocampal neurons and tissues and vibration could be modulated pharmacologically.Malignant astrocytoma tissue samples obtained from operating room, transported in artificial cerebrospinal fluid, and tested within an hour, vibrated with a much different frequency profile and amplitude, compared to meningioma or lateral temporal cortex providing a quantifiable measurement to accurately distinguish the three tissues in real-time.Vibration signals were converted to audible sound waves by frequency modulation, thus demonstrating, acoustic patterns unique to meningioma, malignant astrocytoma and neocortex.
Depolarized GABAergic Signaling in Subicular Microcircuits Mediates Generalized Seizure in Temporal Lobe Epilepsy
Authors: Yi Wang, Cenglin Xu, Zhenghao Xu, Caihong Ji, Jiao Liang, Ying Wang, Bin Chen, Xiaohua Wu, Feng Gao, Shuang Wang, Yi Guo, Xiaoming Li, Jianhong Luo, Shumin Duan, Zhong Chen
Journal: Neuron (2017)
Breast Cancer
Authors: Jay R. Harris, Marc E. Lippman, Umberto Veronesi, Walter Willett
Journal: New England Journal of Medicine (1992)

StagingStaging refers to the grouping of patients according to the extent of their disease. Breast cancer is staged initially on a clinical basis, according to the results of the physical examination and laboratory and radiologic evaluations, and provides an important documentation of a patient's characteristics at presentation. This information can be useful in choosing treatments, estimating prognosis, and comparing the results of different treatment programs. An internationally recognized staging system — the TNM system — has been adopted by both the Union Internationale Contre le Cancer and the American Joint Commission on Cancer Staging and End-Results Reporting.100 This system . . .
Cut-off analysis and prognostic relevance of Ki67 for resected early stage pure invasive lobular breast carcinoma (ILC).
Authors: Luisa Carbognin, Isabella Sperduti, Maria Vittoria Dieci, Gaia Griguolo, Valentina Guarneri, Matteo Brunelli, Lisa Marcolini, Enrico Orvieto, Rolando Nortilli, Sara Pilotto, Elisa Filippi, Elena Fiorio, Erminia Manfrin, Francesca Pellini, Franco Bonetti, Giovanni Paolo Pollini, Pier Franco Conte, Giampaolo Tortora, Emilio Bria
Journal: Journal of Clinical Oncology (2016)

544 Background: In clinical practice, the prognostic potential (and best cut-off) of Ki67 for pure ILC is usually borrowed from the ductal histotype, though a formal validation has not yet been fully established. Thus, the aim of this analysis was to investigate the best prognostic cut-off value of Ki67 and its long-term impact assay in a multi-center series of patients affected by early stage pure ILC. Methods: Clinical-pathological data of consecutive patients affected by pure ILC undergone surgery between January 1990 and December 2013, diagnosed at 2 Italian institutions, were retrospectively correlated with overall survival and disease-free survival (OS/DFS) using a Cox model. The maximally selected Log-Rank statistics analysis was applied to the Ki67 continuous variable to estimate the appropriate cut-off. Kaplan-Meier curves were compared with Log-Rank analysis. Internal cross-validation was accomplished. Results: Data from 457 pts were gathered (median age 61 years [yrs], range 35-96 yrs). At median follow-up of 75 months, 5-/10-years DFS and OS were 82.5%/71.4% and 91.8%/81.7%, respectively. The maximally selected Log-Rank statistics analysis identified 4% as optimal cut-offs for OS. Ki67 (HR 2.28, 95% CI 1.0-5.19, p=0.05), ECOG Performance Status (PS) (HR 3.27, 95% CI 1.49-7.18, p=0.003), lymph-node status (HR 2.96, 95% CI 1.53-5.74, p=0.001), and tumor-size according to TNM (HR 2.6, 95% CI 1.31-5.13, p=0.006) were independent predictors for OS at the multivariate analysis. Log-rank analysis is shown in the table. Ki67 highly replicated at the internal cross-validation analysis. PS (HR 3.73, 95% CI 1.50-9.30, p=0.005) and lymph-node status (HR 3.75, 95% CI 1.70-8.26, p=0.001) were independent predictors for DFS. Conclusions: Despite the retrospective and exploratory nature of the study, a very low cut-off of Ki67 (4%) was able to significantly discriminate the prognosis of patients with ILC. 5-yrs OS (%) 10-yrs OS (%) Log-Rank Ki67≤4% 96.9 89.9 p=0.008 Ki67>4% 90.1 77.2 T 1-2 93.8 84.6 p<0.0001 T 3-4 77.7 62.0 Nodes negative 96.4 89.6 p<0.0001 Nodes positive 85.0 69.5 PS 0 91.5 81.7 p<0.0001 PS 1-2 56.4 33.9
HPV testing with abnormal cervical cytology speeds up diagnosis of cervical disease
Authors: Susan Mayor
Journal: BMJ (2017)

Testing for human papillomavirus (HPV) in women with abnormal cervical cytology leads to faster diagnosis of cervical disease and fewer missed cases, a large observational study has found.1

Cervical cytology has considerably reduced the incidence and mortality of cervical cancer by detecting and treating precursor lesions before progression to more advanced disease. However, it has not been clear how best to manage women with atypical squamous cells of undetermined significance (ASC-US) without imposing repeat biopsies or testing on the women who …
A U.S. Food and Drug Administration (FDA) pooled analysis of outcomes for bone only metastatic breast cancer (MBC).
Authors: Suparna B. Wedam, Julia A. Beaver, Laleh Amiri-Kordestani, Erik Bloomquist, Shenghui Tang, Rajeshwari Sridhara, Amna Ibrahim, Geoffrey Kim, Paul Gustav Kluetz, Amy E. McKee, Richard Pazdur
Journal: Journal of Clinical Oncology (2016)

570 Background: Although bone involvement is common in MBC, little is known about the subset of patients with bone only (BO) disease and difficulties surround the radiographic assessment of bone metastases. Methods: Data was analyzed from eleven prospective studies (n = 7950) of nine experimental agents submitted for treatment of MBC in initial or supplemental New Drug or Biologics License Applications since 2005. Analyses were performed in three subsets: BO, bone with other metastases (BWO), and no bone metastases (NBO). Early discordance rate (EDR; investigator calls progression event earlier than blinded independent central review {BICR}) and late discordance rate (LDR; investigator calls progression event later than BICR) were estimated on 4012 patients subject to a BICR. Results: Bone metastases were identified in 35-57% of patients across studies. BO disease was present in 4-26% of patients, dependent on subtype. EDR for patients with lesions outside the bone (n = 3691) was 40%, and LDR was 45%. For the BO subset (n = 321), EDR was 65%, and LDR was 24%. Exploratory progression free survival (PFS) results are shown in the following table. Conclusions: This exploratory analysis suggeststhe BO subset of patients may have a distinct natural history and a differential response to Her2 targeted agents. In addition, there appears to be bias on the part of the investigator when assessing this subset of patients. Further efforts to better standardize bone radiographic evaluation for clinical trials and clinical practice is warranted. BO BWO NBO All Agents: N = 921 N = 3583 N = 3446 Median PFS (months) Control Arm 8.3 5.6 6.6 Treatment Arm 11.4 8.0 8.5 Hazard Ratio 95% CI 0.737 (0.621, 0.874) 0.756 (0.700, 0.817) 0.788 (0.727, 0.854) Her2 Targeted Agents: N = 119 N = 779 N = 1111 Median PFS (months) Control Arm 14.5 8.2 8.3 Treatment Arm 12.2 10.9 12.5 Hazard Ratio 95% CI 0.899 (0.556, 1.445) 0.716 (0.600, 0.853) 0.64 (0.549, 0.745)
Debio 1347, an oral FGFR inhibitor: Results from a first-in-human, phase I dose-escalation study in patients with FGFR genomically activated advanced solid tumors.
Authors: Martin Henner Voss, Cinta Hierro, Rebecca Suk Heist, James M. Cleary, Funda Meric-Bernstam, Leena Gandhi, Nobuya Ishii, Yulia Kirpicheva, Valerie Nicolas-Metral, Anna Pokorska-Bocci, Daniela Purcea, Anne Vaslin, Corinne Moulon, Claudio Zanna, Keith Flaherty, Josep Tabernero, Jose Baselga
Journal: Journal of Clinical Oncology (2017)

2500 Background: Oncogenic alterations in fibroblast growth factor receptors (FGFR) are seen across multiple solid tumor malignancies. Debio 1347 is an orally available, highly selective panFGFR inhibitor with potent antitumor effect in preclinical models bearing FGFR1-3 genetic alterations. Methods: Patients harboring defined FGFR 1, 2 or 3 alterations received escalating doses of Debio 1347 starting from 10 mg once daily. Dose escalation followed a 3+3+3 algorithm based on a modified Fibonacci sequence. The MTD was defined as the level where ≥ 3/9 patients suffer a DLT. Pharmacokinetics (PK) and pharmacodynamic were serially evaluated in blood, skin and/or tumor tissue. Results: Fifty-six patients were enrolled, including patients with mutations (n = 17), amplifications (n = 28) and fusions (n = 11). The dose was escalated up to 150 mg over 8 cohorts. DLTs were experienced by 4/56 patients, including G2 intolerable dry mouth + eyes at 60 mg, G3 hypercalcemia + hyperamylasemia at 80 mg, and G3 bilirubin increase at 110 mg. At data cut-off, the most common treatment-emergent adverse events (TEAE) were hyperphosphatemia (73%), fatigue (41%), diarrhea (39%), nausea (37%), and inappetence (32%). Fifteen patients (27%) experienced a grade ≥ 3 related TEAE. Twenty-five patients (47%) required dose modification, primarily due to hyperphosphatemia and cutaneous toxicity. An MTD has not been reached. PK appeared overall linear, with a half-life of 14 hours; hyperphosphatemia was dose-dependent. Among the 54 response-evaluable patients, 4 confirmed and 1 unconfirmed partial responses were observed in patients with cholangiocarcinoma (FGFR2 mutant), uterine (FGFR2 and FGFR1 amplified), colon (FGFR2 fusion), and urothelial cancer (FGFR3 fusion); an additional 10 patients had target regression &lt; 30%. Conclusions: Debio 1347 had a tolerable and manageable safety profile. Encouraging antitumor activity was seen in several tumor types, mainly in patients with FGFR2 or 3 gene alterations, including fusion events, treated at 80 mg and 110 mg daily. Efficacy will be further explored in disease-specific and molecularly defined expansion cohorts. Clinical trial information: NCT1948297.
Determining the clinical value of germline genetic testing coupled with tumor mutation profiling.
Authors: Edward Esplin, Shan Yang, Scott T. Michalski, Karen Ouyang, Jennifer Fulbright, Barbara Hamlington, Karl Erhard, Hio Chung Kang, Carli Tejada, Michelle Jacobs, Stephen E Lincoln, Robert L. Nussbaum, Amie Blanco
Journal: Journal of Clinical Oncology (2017)

1577 Background: Somatic mutation analysis by next-generation sequencing (NGS) is an expanding clinical assessment offered to cancer patients. Studies report that 4–12% of patients have a positive tumor mutation profiling (TMP) result in a known cancer predisposition gene also identified in their germline, which has potential implications for the patient’s acute treatment, ongoing surveillance, and the screening of family members. We report a series of patients with TMP coupled with germline genetic testing and include yield of pathogenic germline mutations, discordance between germline and TMP findings, and potential clinical impact. Methods: Our study used de-identified data from 182 consecutive patients who underwent TMP followed by germline testing with an NGS-based hereditary cancer gene panel. Results: 50/182 cases (27%) had one or more likely pathogenic or pathogenic (LP/P) germline variants, which is higher than previous reports. Among these 50, 28 (56%) met guidelines for germline testing by personal or family history criteria, 10 (20%) met recently established NCCN criteria for germline testing of patients with BRCA1/2 tumor variants, and 12 (24%) had TMP results that suggested a germline mutation but did not meet any guidelines for germline testing. We identified 52 LP/P germline variants in BRCA2 (17), BRCA1 (7), PALB2 (6), MUTYH (5), CHEK2 (2), and 15 other genes, all with established guidelines that would impact the clinical management of patients and their family members. In 9/50 cases, germline testing revealed variants that were absent in TMP results and provided new information with clinical implications for patients and their families, including variants in BRCA1 and CHEK2. Conclusions: In TMP patients, 50 of 182 had a medically actionable germline mutation with established management guidelines. Among these 50, 12 (24%) met neither current personal or family criteria nor the latest NCCN guidelines for germline testing in patients with TMP. Also striking were nine patients whose germline LP/P mutations were absent in TMP results. These data suggest that indications for germline testing of cancer patients must be expanded to avoid missing important germline findings in patients undergoing TMP.
Targeting factor D of the alternative complement pathway reduces geographic atrophy progression secondary to age-related macular degeneration
Authors: Brian L. Yaspan, David F. Williams, Frank G. Holz, Carl D. Regillo, Zhengrong Li, Amy Dressen, Menno van Lookeren Campagne, Kha N. Le, Robert R. Graham, Tatiana Beres, Tushar R. Bhangale, Lee A. Honigberg, Ashley Smith, Erin C. Henry, Carole Ho, Erich C. Strauss
Journal: Science Translational Medicine (2017)

The phase 2 MAHALO clinical trial shows that lampalizumab reduces geographic atrophy secondary to age-related macular degeneration and implicates complement dysregulation in disease pathogenesis.
Beneficial influence of bifidobacterium infantis feeding on secretagogue response in rats recovering from colitis
Authors: N O'Brien, D Sommerfield, B Kiely, JK Collins, F Shanahan, L O'Mahony, EMM Quigley
Journal: Endoscopy (2005)

Aim: To examine the effects of the probiotic Bifidobacterium infantis on colonic electrolyte transport in rats recovering from colitis.
Wong was right
Authors: A. McCombe
Journal: BMJ (1995)

the reduction was to only 83 hours a week.Furthermore, although we included some of the more benign comments of the trainees in our article, many of them, though entertaining, were unprintable.We agree that the Junior Doctors Committee (which allegedly disbelieved our data) is out of touch with the wishes of many junior staff, particularly surgical trainees.Perish the thought that we should shorten our hours to the levels in Europe.For example, in Denmark (where they have a 37 hour week), on a urological unit a little bigger than ours there are eight senior registrars.The trainee who covers a weekend has to have the whole of the next week off.Surely even the Junior Doctors Committee cannot believe that this is compatible with an adequate training programme.One of the great advantages of consultant practice in Britain is personal autonomy (though this also is under threat).This requires a higher level of exposure and experience than is needed by our counterparts in Europe, who are more protected.