tbuckley/cabot-search huggingface dataset:
A Bile Duct‐on‐a‐Chip With Organ‐Level Functions
Authors: Yu Du, Gauri Khandekar, Jessica Llewellyn, William Polacheck, Christopher S. Chen, Rebecca G. Wells
Journal: Hepatology (2019)

Chronic cholestatic liver diseases, such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), are frequently associated with damage to the barrier function of the biliary epithelium. Here, we report on a bile duct-on-a-chip that phenocopies not only the tubular architecture of the bile duct in three dimensions, but also its barrier functions.We showed that mouse cholangiocytes in the channel of the device became polarized and formed mature tight junctions, that the permeability of the cholangiocyte monolayer was comparable to ex vivo measurements, and that cholangiocytes in the device were mechanosensitive (as demonstrated by changes in calcium flux under applied luminal flow). Permeability decreased significantly when cells formed a compact monolayer with cell densities comparable to those observed in vivo. This device enabled independent access to the apical and basolateral surfaces of the cholangiocyte channel, allowing proof-of-concept toxicity studies with the biliary toxin, biliatresone, and the bile acid, glycochenodeoxycholic acid. The cholangiocyte basolateral side was more vulnerable than the apical side to treatment with either agent, suggesting a protective adaptation of the apical surface that is normally exposed to bile. Further studies revealed a protective role of the cholangiocyte apical glycocalyx, wherein disruption of the glycocalyx with neuraminidase increased the permeability of the cholangiocyte monolayer after treatment with glycochenodeoxycholic acid.This bile duct-on-a-chip captured essential features of a simplified bile duct in structure and organ-level functions and represents an in vitro platform to study the pathophysiology of the bile duct using cholangiocytes from a variety of sources.
Anastrozole compared to tamoxifen as primary endocrine therapy for early operable primary breast cancer in the elderly
Authors: M. Ying, A. Agrawal, L. Winterbottom, D. A. Morgan, I. O. Ellis, K. Cheung
Journal: Journal of Clinical Oncology (2007)

11025 Background: The optimal management of operable primary breast cancer in elderly is controversial. A high proportion of elderly patients refuse or are unfit for surgery. However the majority have oestrogen receptor positive (ER+) cancer and respond extremely well to endocrine therapy. The use of tamoxifen as primary therapy is well established but its efficacy has not been compared with the newer aromatase inhibitors in this setting. We present the clinical data of the use of anastrozole when compared with tamoxifen in elderly patients as primary therapy for operable breast cancer. Methods: During a period of 2 years, elderly patients with ER+ operable breast cancer (&lt;5cm), who either refused or were unfit for surgery, were given primary endocrine therapy. Tamoxifen was given by default but anastrozole was used when there were contraindications (eg thromboembolic and gynaecological risks). All had disease assessable to UICC criteria and were followed up in a dedicated clinic. Only patients who had treatment for =6 months (except for those who progressed prior) were included for analysis. Results: A total of 93 patients fulfilled the criteria for analysis thus far and the results are summarised as follows: 58 were given anastrozole and 35 with tamoxifen. At a median follow-up of 14.8 months (6 to 57), 8 patients have progressed. The results are summarised as follows: CR = complete response PR= partial response SD = stable disease Treatment was well tolerated in both groups and no patients withdrew due to side effects. Conclusions: The use of primary endocrine therapy in ER+ operable breast cancer in the elderly is highly effective. In this observational non randomised study there was no difference in efficacy detected between tamoxifen and anastrozole at this time, as seen in adjuvant trials. This may be due to the fact that majority of ER+ cancer in the elderly are highly ER rich as shown by high semi-quantitative scoring of immunhistological assays, making the superiority of the aromatase inhibitors less apparent. [Table: see text] No significant financial relationships to disclose.
EANO guideline on the diagnosis and treatment of vestibular schwannoma
Authors: Roland Goldbrunner, Michael Weller, Jean Regis, Morten Lund-Johansen, Pantelis Stavrinou, David Reuss, D Gareth Evans, Florence Lefranc, Kita Sallabanda, Andrea Falini, Patrick Axon, Olivier Sterkers, Laura Fariselli, Wolfgang Wick, Joerg-Christian Tonn
Journal: Neuro-Oncology (2019)

The level of evidence to provide treatment recommendations for vestibular schwannoma is low compared with other intracranial neoplasms. Therefore, the vestibular schwannoma task force of the European Association of Neuro-Oncology assessed the data available in the literature and composed a set of recommendations for health care professionals. The radiological diagnosis of vestibular schwannoma is made by magnetic resonance imaging. Histological verification of the diagnosis is not always required. Current treatment options include observation, surgical resection, fractionated radiotherapy, and radiosurgery. The choice of treatment depends on clinical presentation, tumor size, and expertise of the treating center. In small tumors, observation has to be weighed against radiosurgery, in large tumors surgical decompression is mandatory, potentially followed by fractionated radiotherapy or radiosurgery. Except for bevacizumab in neurofibromatosis type 2, there is no role for pharmacotherapy.
Comparison of circulating tumor cells (CTC) and disseminated tumor cells (DTC) in patients with colorectal carcinoma for a predictive marker for tumor recurrence.
Authors: Hideyasu Sakihama, Nozomi Kobayashi, Nozomi Minagawa, Tatsushi Shimokuni, Shigenori Homma, Norihiko Takahashi, Toshiya Kamiyama, Akinobu Taketomi
Journal: Journal of Clinical Oncology (2013)

e14548 Background: Although the presence of CTC or DTC is proposed as a pridictive or a prognostic marker in the management of colorectal carcinoma patients, it is still well unknown what is different of both types of cells. The aim of this study is to compare CTC and DTC as a predictive marker for tumor recurrence by magnetic activated cell sorting system. Methods: Peripheral blood (PB) samples (n=139) and bone marrow (BM) samples (n=41) were preoperatively collected from colorectal carcinoma patients between February 2009 and March 2012. PB samples were obtainable from all patients who provided their BM samples (n=41). Enrichment of CTC was performed by direct immunomagnetic labeling of EpCAM + cells in PB. Enrichment of DTC was done by negative selection of CD45 + cells. Subsequently, double immunofluorescences staining for cytokeratin and CD45 was performed to detect CTC or DTC. PB samples from 20 healthy volunteers and BM samples from 3 patients with benign disease were used as controls. Median follow-up time is 28.5 months (range 10-44). Written informed consent was obtained from all enrolled patients. Results: Preoperative positive rates of CTC and DTC were 20.9% (29/139) and 29.3% (12/41), respectively. No CTC or DTC was found in the control groups. In DTC + patients, only 4 patients were positive for CTC (33.3%), whereas 31% of DTC - patients had CTC. We found 13 patients who experienced postoperative recurrence among 139 patients, 7 patients of whom were CTC positive (53.8%). There is a significant higher incidence of recurrence in CTC + patients (risk ratio=4.4, p&lt;0.01). As for DTC, we found 5 patients with recurrence in 41 patients, 4 patients of whom were DTC positive (80%). DTC + patients have a significant risk of recurrence (risk ratio=9.7, p=0.01). The relationship of CTC / DTC status and the recurrence rates is as follows: 50 % in CTC + /DTC + patients (2/4); 11.1% in CTC + /DTC - patients (1/9); 25% in CTC - /DTC + patients (2/8); 0% in CTC - /DTC - patients (0/20). Conclusions: DTC status is more predictive for postoperative recurrence than CTC status. The combination of CTC and DTC analysis might predict recurrence risk more accurately than either of the two analyses.
Initial Results of a Phase Ib Study of Ibrutinib in Combination with Obinutuzumab in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia
Authors: Matthew S. Davids, Haesook T Kim, Alexandra Savell, Carlos Santiago-Medero, Karen Francoeur, Jeremy S. Abramson, Eric D. Jacobsen, Ann S LaCasce, David C. Fisher, Jennifer R. Brown
Journal: Blood (2017)
Increasing brain-computer interface media depictions: pressing ethical concerns
Authors: F Gilbert, C Pham, Jnm Viaña, W. Gillam
Journal: Brain-Computer Interfaces (2019)

This article explores how brain-computer interfaces (BCI) are depicted in the English-speaking media, especially by news outlets. We use the FACTICA database to analyze depictions of BCIs from the first time the term appeared in the media (1993) up until 31 December 2017. We found a sample of over 4064 articles on BCIs. Results indicate that 76.91% of articles portrayed BCI positively, including 25.27% that were overly positive, while 26.64 % of the total articles contain claims about BCI-enabled enhancement. In contrast, 1.6% of articles had a negative tone and only 2.7% of articles flag issues explicitly related to ethical concerns surrounding BCI technology. We propose: 1) A proactive effort by the scientific community to push-out to the media stories focused on the limits and actual capabilities of BCIs, separating science from science fiction; 2) More influence should be brought to bear on the technological risks and process of informed consent.
Impact of overweight, obesity, and post-treatment weight changes on occupational reintegration of breast cancer (BC) survivors.
Authors: Antonio Di Meglio, Gwenn Menvielle, Agnes Dumas, Arnauld S. Gbenou, Thomas Bovagnet, Elise Martin, Arlindo R. Ferreira, Laurence Vanlemmens, Olivier Arsene, Mahmoud Ibrahim, Johanna Wassermann, Anne-Laure Martin, Jerome Lemonnier, Lucia Del Mastro, Lee Jones, Ann H. Partridge, Jennifer A. Ligibel, Fabrice Andre, Stefan Michiels, Ines Maria Vaz Duarte Luis
Journal: Journal of Clinical Oncology (2019)

11562 Background: Overweight and obesity are strongly linked to poorer BC-specific outcomes, quality of life and financial burden in cancer care. Weight loss interventions have the potential to improve such outcomes. Fewer data exist on whether excess weight and post-diagnosis weight changes impact the ability of BC survivors to return to work (RTW). Methods: CANTO (NCT01993498) is a multicenter prospective longitudinal study of 12000 patients (pts) with stage I-III BC that characterizes long-term toxicities of BC treatment. Of 5801 pts enrolled from 2012-2014 (last data lock), we identified 1874 pts who were professionally active at BC diagnosis, ≥5 years (yrs) younger than minimum legal retirement age (62 yrs) and with updated work status 2 yrs after diagnosis. Logistic regression models evaluated the impact of body mass index (BMI) at diagnosis and of weight changes over 2 yrs after diagnosis on odds of non-RTW, adjusting for age, education, income, BC treatment and recreational physical activity (PA). Results: 37% pts were overweight or obese at diagnosis (BMI ≥25 kg/m 2 ): 34% of them gained ≥5% and 16% lost ≥5% weight after diagnosis. Rates of non-RTW at 2 yrs were significantly higher in overweight or obese vs under or normal weight pts (27% vs 18%, p≤.001; adjusted odds ratio 1.37, 95% Confidence Interval [CI] 1.04-1.80, p = .017). Overweight and obese pts who did not RTW experienced higher increments in weight (mean [95% CI]: +3.6% [+2.3, +4.9] vs +1.5% [+0.8, +2.2]) and reported more modest changes in PA (mean [95% CI]: +1.0 [-1.4, +3.5] vs +2.1 [+0.8, +3.3] MET-h/week) vs those who did RTW. Weight changes independently impacted odds of non-RTW in overweight and obese pts (p for interaction weight change*BMI ≤.001): a 5% weight gain was associated with 17% increase in adjusted odds of non-RTW (95% CI 2-35%, p = .024), whereas a loss ≥5% with 60% reduced odds of non-RTW vs weight gain (95% CI 18-82%, p = .013). Conclusions: Excess weight and weight changes are significantly associated with occupational reintegration after BC in overweight and obese pts. Randomized studies testing dedicated weight control interventions should also measure outcomes of social rehabilitation in this large subset of survivors. Clinical trial information: NCT01993498.
Kallikrein-related peptidases 6 and 10 are elevated in cerebrospinal fluid of patients with Alzheimer’s disease and associated with CSF-TAU and FDG-PET
Authors: Oliver Goldhardt, Inanna Warnhoff, Igor Yakushev, Ilijana Begcevic, Hans Förstl, Viktor Magdolen, Antoninus Soosaipillai, Eleftherios Diamandis, Panagiotis Alexopoulos, Timo Grimmer
Journal: Translational Neurodegeneration (2019)

Alterations in the expression of human kallikrein-related peptidases (KLKs) have been described in patients with Alzheimer's disease (AD). We elucidated the suitability of KLK6, KLK8 and KLK10 to distinguish AD from NC and explored associations with established AD biomarkers.KLK levels in cerebrospinal fluid (CSF), as determined by ELISA, were compared between 32 AD patients stratified to A/T/(N) system with evidence for amyloid pathology and of 23 normal controls with normal AD biomarkers. Associations between KLK levels and clinical severity, CSF and positron emission tomography (PET) based AD biomarkers were tested for.Levels of KLK6 and KLK10 were significantly increased in AD. KLK6 differed significantly between AD A+/T+/N+ and AD A+/T-/N+ or NC with an AUC of 0.922. CSF pTau and tTau levels were significantly associated with KLK6 in AD.KLK6 deserves further investigations as a potential biomarker of Tau pathology in AD.
Effectiveness of erlotinib in lung adenocarcinomas with classic and alternative EGFR mutations detected by Roche 454 GS-FLX next-generation sequencing (NGS).
Authors: Gyula Ostoros, Veronika Sarosi, Laszlo Mandoky, Ferenc Pinter, Richard Schwab, Istvan Petak, Laszlo Urban
Journal: Journal of Clinical Oncology (2013)

e19090^ Background: Next generation sequencing (NGS) detects all possible mutations with a higher sensitivity than Sanger sequencing. EGFR mutations are important predictors of sensitivity and resistance to EGFR tyrosine kinase inhibitors including erlotinib. The clinical significance of alternative (“rare”) EGFR mutation types, and mutation present in a small fraction of tumor cells detected by NGS is less known. Methods: For the present retrospective analysis, 100 lung adenocarcinoma tumor samples were collected from patients who participated in a previous observational cohort study of erlotinib (MOTIVATE). In this study only patients with advanced (IIIb/IV) K-RAS wild type tumors refractory to one or two previous chemotherapy were enrolled. Four exons (18, 19, 20, 21) of EGFR gene were PCR amplified and sequenced by Roche 454 GS FLX sequencer. Differences in overall survival (OS), and progression free survival (PFS) were statistically analyzed (Log Rank). Results: 47 mutations of the EGFR tyrosine kinase domain were detected in the 35 out of 100 tumors. 14 mutations were present in less than 10% of alleles. 16 tumors contained known („classic”) sensitizing mutations: nine deletions in exon 19, five L858R, one L861Q mutation in exon 21, one G719A mutation in exon 18 and one known resistance mutation D770_N771insY in exon 20. 18 tumors contained only alternative mutations with unknown functional relevance. The median PFS of patients with tumors harbouring EGFR wild type gene, classic EGFR mutations and alternative mutations were 2.9 months, 13.2 months (p&lt;0.001) and 3.0 months (P=0.43) respectively. The median OS of patients with tumors containing wild type EGFR tumors, and alternative mutations was 7.2 and 5.5 months respectively (P=0.68). The median OS of patients harbouring classic EGFR mutations was not reached. The mean OS of these patients was 29.0 months. Conclusions: NGS is a sensitive and reliable diagnostic method to detect EGFR mutations with known functional significance. Alternative mutations need further one by one functional interpretation and analytical validation before being used as positive predictors in clinical decisions.
Molecular characterization and management of secondary resistance to serial TRK inhibitors.
Authors: Michael Nathenson, Matthew Louis Hemming, Karan Malik, Jia-Ren Lin, Sandro Santagata, Ziming Du, Adrian Marino-Enriquez, Timothy J Hagan, Otari Chipashvili, Katherine Anne Thornton, Chandrajit P. Raut, Barrett H. Childs, Monica M. Bertagnolli, Ewa Sicinska, Nora Ku, George D. Demetri
Journal: Journal of Clinical Oncology (2019)

e22547 Background: TRK inhibitor drugs such as the highly selective larotrectinib (Laro), have proven highly effective in malignancies harboring fusions of NTRK1, 2, or 3. Resistance in patients (pts) with progressive disease (PD) after response to initial TRK inhibitor therapy has been attributed to secondary mutations in the solvent front or gatekeeper domains of the NTRK fusion gene. LOXO-195 (L195) is a 2 nd generation TRK inhibitor that overcomes these mutations. Mechanisms of resistance to L195 have not yet been well characterized. Methods: We analyzed molecular mechanisms of resistance in one adult pt with undifferentiated pleomorphic sarcoma (UPS) who had serial responses and PD on Laro and L195. Targeted DNA sequencing, RNA sequencing and multicolor cyclic immunofluorescence (CyCIF) were performed on pre- and post-PD specimens on both drugs. Results: The patient was enrolled on the phase 2 clinical trial of Laro (NCT02576431) with TPM3-NTRK1 fusion UPS. Multifocal PD and resistance to Laro developed after major objective response RECIST -74.9%, of 10 months (mo); the resistant tumor harbored both the initial TPM3-NTRK1 fusion but also evolved a new solvent front mutation in NTRK1 [c.1783G &gt; A (p.G595R)]. A single pt protocol (NCT03206931) was designed to treat with L195. After an initial response to L195, PD limited to 2 sites developed; both sites were resected at 5 and 10 mo. The pt continues on L195 with systemic disease control 20 mo after initiation (in total 30 mo since Laro initiation). Analysis of tumor samples pre- and post-PD on L195 identified the emergence of a KRAS G12V mutation, with associated activation of the KRAS signaling pathway and a significant infiltration by inflammatory cells. A cell line and pt-derived xenografts (PDX), all harboring the initial TPM3-NTRK1 fusion, were generated from this pt. Conclusions: Resection of oligoclonal PD and continuation of L195 post-PD can be an effective treatment strategy. Oncogenic activation of the KRAS pathway is a possible mechanism of resistance to L195. Our studies indicate that the tumor microenvironment of TRK-fusion sarcomas resistant to TRK inhibitors may increase inflammatory cell infiltrates, which may provide clues for future combination therapy.
Mass cytometry dissects T cell heterogeneity in the immune tumor microenvironment of common dysproteinemias at diagnosis and after first line therapies
Authors: Taxiarchis V. Kourelis, Jose C. Villasboas, Erik Jessen, Surendra Dasari, Angela Dispenzieri, Dragan Jevremovic, Shaji Kumar
Journal: Blood Cancer Journal (2019)

Abstract Dysproteinemias progress through a series of clonal evolution events in the tumor cell along with the development of a progressively more “permissive” immune tumor microenvironment (iTME). Novel multiparametric cytometry approaches, such as cytometry by time-of-flight (CyTOF) combined with novel gating algorithms can rapidly characterize previously unknown phenotypes in the iTME of tumors and better capture its heterogeneity. Here, we used a 33-marker CyTOF panel to characterize the iTME of dysproteinemia patients (MGUS, multiple myeloma—MM, smoldering MM, and AL amyloidosis) at diagnosis and after standard of care first line therapies (triplet induction chemotherapy and autologous stem cell transplant—ASCT). We identify novel subsets, some of which are unique to the iTME and absent from matched peripheral blood samples, with potential roles in tumor immunosurveillance as well as tumor immune escape. We find that AL amyloidosis has a distinct iTME compared to other dysproteinemias with higher myeloid and “innate-like” T cell subset infiltration. We show that T cell immune senescence might be implicated in disease pathogenesis in patients with trisomies. Finally, we demonstrate that the early post-ASCT period is associated with an increase of senescent and exhausted subsets, which might have implications for the rational selection of post-ASCT therapies.
Evaluation of the overall survival rates in locally advanced cervix cancer patients treated with radiotherapy alone and chemoradiation: A Brazilian experience.
Authors: Conceicao Souza Campos, Joao Victor Salvajoli, Paulo Eduardo Novaes, Marcelo Gurgel da Silva
Journal: Journal of Clinical Oncology (2012)

e15509 Background: Locally advanced cervical cancer is a major worldwide health problem. The treatment might include radiotherapy and few trials evaluate the timing of pelvic external irradiation (RT) and high dose rate brachytherapy (HDR) in local control and survival rates of these patients as well as the addition of chemotherapy. The objective were to evaluate the overall survival rates in locally advanced cervix cancer patients and determine the clinical and treatment prognostic factors for local control and overall survival rates. Methods: A retrospective cohort study was carried out with 261 patients stage IIIB, 164 patients received 54 Gy RT to the pelvis and 30 Gy HDR without chemotherapy and 97 patients received 54 Gy RT to the pelvis and 30 Gy HDR with weekly cisplatin 40mg/m 2 IV (CDDP) from August 1998 to June 2004 in Hospital Haroldo Juacaba, a Brazilian northeastern hospital. The mean follow-up time was 50 months (2-185 months) and the Kaplan-Meier method was used to calculate survival curves. The Cox regression was used to evaluate multivariate analysis and p values =&lt;0.05 was considered significant. Results: Local control and 5-year survival rates were 39.6% and 38.4% for exclusively radiation and 50.5% and 47.4% for chemoradiation (p = 0.19 and p = 0.36, respectively). The mean treatment time was 61 days. Both local control and overall survival rates were affected by age, parametrial involvement and the timing of brachytherapy (p&lt;0.05). The overall treatment time did not influence survival or local control rates (p&gt;0.05). But less than six cycles of chemotherapy improved local control rates better than six or more cycles (55.1% versus 44.9% p = 0.02). Conclusions: The study is a nonsuperiority one where the addition of weekly chemotherapy with six cycles of CDDP 40mg/m 2 during the irradiation did not improve overall survival rates. Further prospective studies would be useful to evaluate the benefit of adding weekly chemotherapy to the standard radiotherapy treatment as well as the financial impact of the adoption of this international guideline in patients with advanced lesions from developing countries.