tbuckley/cabot-search huggingface dataset:
Predicting the risk of neutropenic complications and reduced dose intensity in patients with early-stage breast cancer (ESBC): Results from a prospective nationwide registry
Authors: G. H. Lyman, J. Crawford, D. C. Dale, D. A. Wolff, E. Culakova
Journal: Journal of Clinical Oncology (2004)

776 Background: Chemotherapy-induced neutropenia is frequently associated with neutropenic complications (NC) resulting in reduced relative dose intensity (RDI) potentially compromising patient outcomes. Retrospective analyses have identified several risk factors but are limited by variable reporting and missing data. Methods: A prospective registry of chemotherapy patients at 137 centers has been established. Both unconditional (pretreatment) models and models conditional on first cycle events for risk of NC and reduced RDI have been developed. Results: Overall, 2222 patients have been registered prior to chemotherapy including 617 patients with ESBC of which 525 have completed at least one cycle of chemotherapy. Adverse outcomes include ANC<1000 (58%); neutropenic complications (ANC<500 or infection) (42%) and RDI<85% (11.3%). Regimens include: AC or AC-T (53%); CMF (12%); and CAF (9%). In unconditional models, significant predictors of NC include: anthracycline regimens (OR=7.9) and prior chemotherapy (OR=3.52) (Model P<.001; R2=0.15; c-statistic 0.62). In models conditional on first cycle events, significant predictors of NC include: 1st cycle nadir (OR= 8.98); 1st cycle infection (OR=3.15); prior chemotherapy (OR=10.02); and BSA>2 M2(OR=0.51) (Model P<.001; R2=0.61; C-statistic 0.86). In models for reduced RDI, stage and practice center were also significant independent predictors. Separate validation of these models will be presented. Conclusions: Recent large practice surveys demonstrate that breast cancer patients often receive reduced chemotherapy dose intensity, primarily due to NC. A reliable tool to identify patients at risk for NC should permit more rational use of targeted supportive care and delivery of optimal chemotherapy dose intensity. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen Amgen Amgen Inc
GLP-1 acts on habenular avoidance circuits to control nicotine intake
Authors: Luis M Tuesta, Zuxin Chen, Alexander Duncan, Christie D Fowler, Masago Ishikawa, Brian R Lee, Xin-An Liu, Qun Lu, Michael Cameron, Matthew R Hayes, Theodore M Kamenecka, Matthew Pletcher, Paul J Kenny
Journal: Nature Neuroscience (2017)
Enhanced sensitivity to insulin-like growth factors in SLUG-induced epithelial-mesenchymal transition
Authors: Ramadoss Sivakumar, Hironori Koga, Takafumi Yoshida, Michiko Maeyama, Karuppaiyah Selvendiran, Takato Ueno, Michio Sata
Journal: Clinical Cancer Research (2007)

B49   Epithelial-mesenchymal transition (EMT) is an important phenomenon in embryogenesis and cancer progression. Snail group of proteins, including SLUG, is known to initiate this process by repressing the expression of E-cadherin and other membranous proteins (Cell 2004). In our preliminary study, we found a drastic activation of the Akt signaling in the SLUG-induced EMT. Therefore, the AIM of this study was to unravel the underlying molecular mechanism of the SLUG-mediated activation of Akt signaling. Methods: Madin-Darby canine kidney (MDCK) cells were transfected with  SLUG  cDNA or empty vector, and stable transformants (SLUG-MDCK cells) were selected using the antibiotic G418. After analyzing the phenotypic changes and protein profiling to confirm the EMT, the cells were used in this study. Results: The SLUG-induced activation of Akt pathway was re-confirmed in this study. In this regard, we focused on the insulin-like growth factor type-I receptor (IGF-IR)-insulin receptor substrate (IRS)-Akt axis, and found that a significant tyrosine-phosphorylation of IGF-IR, coupled with a clear phosphorylation of Akt, in the SLUG-MDCK cells, suggesting a higher sensitivity to IGF stimulation in EMT. Indeed, the phosphorylation of both IGF-IR and Akt was inhibited by IGF binding protein-3. Of interest, the activation of IGF-IR in SLUG-MDCK cells was, at least in part, due to an increased production of IGFs from these transformed cells, suggesting an autocrine loop involving IGF-IR activation. It was previously suggested that IGF-IR was constitutively phosphorylated in cells over expressing Src (Mol Cell Biol 1997). Thus, we examined the correlative activation of IGF-IR and Src in SLUG-MDCK cells. We identified an increased phosphorylation of Src in SLUG-MDCK cells; however, this phosphorylation was not always coupled with the constitutive activation of IGF-IR, since the specific Src inhibitor PP2 failed to decrease IGF-IR phosphorylation. Although PP2 did not inhibit the IGF-IR activation, it clearly abolished the phosphorylation of Akt, leading to apoptosis in SLUG-MDCK cells, but not in MDCK cells. Conclusion: The enhanced IGF signaling in an autocine manner was first identified in the SLUG-induced mesenchymally-transformed cells. This hypersensitivity to IGF/insulin signaling these transformed cells may imply a significant cancer progression in diabetic patients with high serum insulin levels. In addition, the results from this study may provide a deep insight into a future strategy targeting IGF as well as Src signaling in overt cancers through EMT program.
Impact of Treatment with Iron Chelators in Lower-Risk MDS Patients Participating in the European Leukemianet MDS (EUMDS) Registry
Authors: Saskia Langemeijer, Louise De Swart, Ge Yu, Alex Smith, Simon Crouch, Tom Johnston, Pierre Fenaux, Argiris Symeonidis, Jaroslav Cermak, Eva Hellstrom-Lindberg, Guillermo Sanz, Reinhard Stauder, Luca Malcovati, Ulrich Germing, Mette Skov Holm, Moshe Mittelman, Krzysztof Madry, Aurelia Tatic, Antonio Almeida, Aleksandar Savic, Sophie Park, Odile Beyne-Rauzy, Raphaël Itzykson, Corine van Marrewijk, David Bowen, Theo de Witte
Journal: Blood (2016)
Chemoradiation in anal carcinoma using a combination of Mitomycin C (MMC) and cisplatin (CDDP): a feasibility study
Authors: G. Crehange, M. Bosset, F. Lorchel, J. Buffet-Miny, M. Puyraveau, M. Mercier, J.-F. Bosset
Journal: Journal of Clinical Oncology (2004)

4079 Background: In anal cancer, the EORTC 22953 phase II study established the feasibility of the following treatment scheme: first sequence: 36 Gy over 4 weeks (large volume), 5-FU infusion 200 mg/m2/d1-d26, MMC 10 mg/m2/d1. Gap duration 16 days. Then 23.4 Gy over 17 days (small volume), 5-FU 200 mg/m2/d1-d17, MMC 10 mg/m2/d1. Because it appeared highly effective with few acute and late toxic effects, this scheme is considered as standard by EORTC (Bosset Eur J Cancer 2003). Chemoradiation with 5-FU and CDDP showed also promising results. Methods: Radiotherapy scheme: as above. MMC 10 mg/m2/d1 of each sequence. CDDP 25 mg/m2 every week of radiotherapy. Treatment delivered as an out-patient basis. Results: Between 7/01 and 11/03, 17 patients (pts) have been recruited: 4 males, 13 females; median age 56y (40–75y); WHO status 0: 11 pts, 1 : 6pts . T2–4 N0: 14 pts, T1–2 N1: 3 pts. Compliance with first sequence : radiation dose and timing : 100 % ; MMC dose and timing: 100 %; CDDP doses and timing: 100%. Median gap duration: 16.5days (14–30 d). Compliance with second sequence: radiation dose and timing: 100% ; MMC dose and timing: 77%; CDDP doses and timing: 82%. Four pts did not receive chemotherapy at the second sequence for the following reasons: MMC: 1 pt by omission; CDDP and MMC: 3 pts due to toxicities. ≥ Grade 2 acute toxicity: vomits: 2 pts; granulopenia: 3 pts; anemia: 2 pts; nephrotoxicity: 1 pt; diarrhoea: 4 pts; perineal skin: 10 pts . Eight weeks after treatment, 15 pts were in CR among 16 evaluable pts. Conclusions: Combining Radiation, MMC and CDDP for the treatment of anal cancer is feasible. The on-going EORTC phase II-III chemoradiation trial is comparing 5-FU-MMC vs CDDP-MMC as the chemotherapy component, the radiation being identical in both arms. No significant financial relationships to disclose.
The antihelminthic drug niclosamide effectively inhibits the malignant phenotypes of uveal melanoma <i>in vitro</i> and <i>in vivo</i>
Authors: Jingfeng Zhou, Bei Jin, Yanli Jin, Yizhi Liu, Jingxuan Pan
Journal: Theranostics (2017)

Uveal melanoma (UM) is a lethal intraocular malignancy with an average survival of only 2~8 months in patients with hepatic metastasis. Currently, there is no effective therapy for metastatic UM. Here, we reported that niclosamide, an effective repellence of tapeworm that has been approved for use in patients for approximately 50 years, exhibited strong antitumor activity in UM cells in vitro and in vivo. We showed that niclosamide potently inhibited UM cell proliferation, induced apoptosis and reduced migration and invasion. p-Niclosamide, a water-soluble niclosamide, exerted potent in vivo antitumor activity in a UM xenograft mouse model. Mechanistically, niclosamide abrogated the activation of the NF-κB pathway induced by tumor necrosis factor α (TNFα) in UM cells, while niclosamide elevated the levels of intracellullar and mitochondrial reactive oxygen species (ROS) in UM cells. Quenching ROS by N-acetylcysteine (NAC) weakened the ability of niclosamide-mediated apoptosis. Matrix metalloproteinase 9 (MMP-9) knockdown by shRNA potentiated, while ectopic expression of MMP-9 rescued, the niclosamide-attenuated invasion, implying that MMP-9 is pivotal for invasion blockage by niclosamide in UM cells. Furthermore, our results showed that niclosamide eliminated cancer stem-like cells (CSCs) as reflected by a decrease in the Aldefluor+ percentage and serial re-plating melanosphere formation, and these phenotypes were associated with the suppressed Wnt/β-catenin pathway by niclosamide in UM. Niclosamide caused a dose- and time-dependent reduction of β-catenin and the key components [e.g., DVLs, phospho-GSK3β (S9), c-Myc and Cyclin D1] in the canonical Wnt/β-catenin pathway. Additionally, niclosamide treatment in UM cells reduced ATP and cAMP contents, and decreased PKA-dependent phosphorylation of β-catenin at S552 and S675 which determine the stability of β-catenin protein, suggesting that niclosamide may work as a mitochondrial un-coupler. Taken together, our results shed light on the mechanism of antitumor action of niclosamide and warrant clinical trial for treatment of UM patients.
Access to care in cancer: Barriers and challenges.
Authors: Maria Belen Gonzalo, Linda House, Kristen Santiago, Joanne S Buzaglo, Alexandra K Zaleta, Niraj K. Gupta
Journal: Journal of Clinical Oncology (2017)

33 Background: In the current climate of health care reimbursement, coverage reform, and escalating health care costs, navigating cancer care becomes increasingly complex for patients and caregivers. Given the truly fluid marketplace and many payment and care models being established sans engagement with or even information from the patient, it is imperative to assess the ongoing reality of patient access to comprehensive, quality cancer care: care that includes biomedical as well as psychosocial care. Methods: We launched an online research survey project to further explore the cancer patient experience as it relates to accessing health care and living within a new and evolving system of health care. The analysis is based upon a cross-sectional survey of adults (18 years old and older) affected by cancer. The survey was conducted online between June and August of 2016. 1,218 cancer survivors completed survey questions regarding access to insurance, services, and providers as well as direct and indirect costs of care. Results: 78% of patients with cancer either have not or do not recall discussing costs with their health care team prior to treatment. 53.5% of survey respondents reported not knowing the meaning of the term “Clinical Practice Guidelines,” and 73% of participants had never heard the term “Clinical Pathway.” 25% of patients experienced delays in accessing cancer care, 18% of patients reported that costs inhibited them from filling prescription drugs to treat their cancer, 22% of patients chose not to get some of the healthcare services they needed due to high out-of-pocket costs, and 53% reported not receiving social or emotional support. Conclusions: These findings demonstrate that despite progress being made in expanding access to health care, many patients still experience significant barriers and challenges to accessing care. We also find there is a gap in patient knowledge about practice guidelines and payment policies. To create a system where all patients have access to high-quality and comprehensive cancer care, educational efforts are needed to enhance patient understanding of information about practice guidelines and payment policies, including information regarding health risk and benefits, costs, patient health, and quality-of-life outcomes.
In Reply:
Authors: Ritsuko Komaki, Ryohei Sasaki, Pamela K. Allen
Journal: Journal of Clinical Oncology (2005)

We thank Dr Atkins for his comments.Dr Atkins suggested that the prognostic significance of the standardized uptake value (SUV) in non-small-cell lung cancer, 1 might be overestimated with reference to a report by Dr Altman et al. 2 We agree with Dr Atkins that any investigator needs to pay full attention to avoiding falsepositive results.However, we disagree with his suggestion for the following reasons.First, Dr Atkins recognized SUV as a very simple continuous variable such as the S phase fraction (SPF) in breast cancer and said our data should be corrected by the formula proposed by Dr Altman et al.However, the SUV should be carefully considered and determined by many factors, such as the dose of [ 18 F]fluorodeoxyglucose (FDG), the time needed to acquire images and data, determination of the region of interest, methods of reconstruction, fasting, and the blood sugar level of the patient.Therefore, the SUV is a continuous variable; however, we could not confirm that the SUV should be treated like the SPF.For this same reason, a comparison of SUVs between institutions is quite difficult.Second, Dr Altman et al 2 recommended in their conclusion that to avoid false-positive results, it is better to use three or four subgroups rather than two, and if an investigator needs to analyze two subgroups, the investigator should use the correcting formula of Dr Altman et al.Using their recommendation, we reanalyzed the prognostic importance of the SUV of the primary tumor with three subgroups (SUV Յ 4, n ϭ 32; 4 Ͻ SUV Յ 10, n ϭ 70; 10 Ͻ SUV, n ϭ 60).The prognostic importance of the SUV was conserved for both overall survival (P ϭ .027by log-rank test, P ϭ .029by Wilcoxon test) and disease-free survival (P ϭ .0042by log-rank test, P ϭ .0021by Wilcoxon test).Therefore, we believe that the SUV of the primary tumor was not overestimated and is still a significant prognostic factor and a useful decision-making tool.Third, as shown in our previous report, 1 the SUV was determined to be an independent and significant prognostic factor by multiple regression analysis using the Cox proportional hazards model in both overall and disease-free survival.Moreover, a report combining four Radiation Therapy Oncology Group studies showed that multiple factors, in-
The role of cisplatin (CDDP) or carboplatin (CARBO) plus pemetrexed (PEM) in nonsquamous (NON-SQM) non-small cell lung cancer (NSCLC): Results of an Italian retrospective multicentric study.
Authors: Hector J. Soto Parra, Adolfo G. Favaretto, Alessandra Bearz, Diego Luigi Cortinovis, Domenico Galetta, Saverio Cinieri, Vincenzo Adamo, Carmelo Giannitto-Giorgio, Paolo Tralongo, Nicolo Borsellino, Massimiliano Spada, Francesco Ferraú, Alfredo Butera, Vito Barbieri, Livio Blasi, Marco M Aiello, Nunzio Restuccia, Tindara Franchina, Massimiliano Alu, Paolo Bruzzi
Journal: Journal of Clinical Oncology (2014)

e19072 Background: The combination of Platinoids (PLs) and Pemetrexed (PEM) currently represents the treatment of choice for NON-SQM NSCLC pts with locally advanced or metastatic disease. Withdrawing PLs after four cycles while continuing PEM until progression (PD) has yielded promising results in responsive or stable disease (SD) pts in terms of both median PFS 6.9 mos and OS 16.9 mos. Methods: We reviewed the clinical records of stage IIIB-IV NON-SQM NSCLC pts with responsive or SD after PLs (CARBO AUC 5-6 or CDDP 75 mg/sqm) plus PEM 500 mg/sqm in which physicians decided to deliver PEM alone q21days until disease PD. Aims: To evaluate PFS according to the type of PL employed, number of PL cycles delivered and response. Results: The records of 165 pts recruited by 15 Italian centers were evaluated and 154 fulfilled the criteria for this analysis. Pts characteristics were as follows: M/F = 87/67; median age 60 (range 30-78); PS on the ECOG scale 0/1/2 = 86/64/4; histotype: adeno/other=149/5; stage: IIIB/IV=10/144; smokers/non-smokers/unknown=95/51/8; EGFR mutant/wild-type/unknown=11/101/42; PL cycles delivered 4/5/6/>6=30/18/100/6. Complete Responses (CR)+Partial Responses (PR) were 68%, with 32% of subjects presenting SD. Eighty-seven (56%) and 67 (44%) pts received CDDP-PEM and CARBO-PEM, respectively. At 01/14, 124 (81%) pts had discontinued treatment (PD 84 pts, toxicity 19, physician or pt decision 18 , other 3) and 30 (19%) are still receiving PEM. The median number of cycles with front-line PLs-PEM and the overall median number of chemotherapy delivered until PD was 6 and 11, respectively. PFS for the entire population was 45.9 weeks (wks). PFS was similar according to PL combinations: CDDP-PEM 46 wks, CARBO-PEM 44.7 wks(p=0.3). Numbers of front-line PLs cycles (4 vs >4) did not influence PFS 44.5 vs 45.9 wks (p=0.17). Conclusions: These results confirm the efficacy of PLs plus PEM for stage IIIB/IV NON-SQM NSCLC pts suggesting that continuing PEM alone in subjects with responsive and SD is both feasible and effective. While CDDP and CARBO seem equally beneficial for these pts, PLs should be avoided after the fourth cycle.
Significant and sustained reduction in chemotherapy errors though improvement science.
Authors: Brian D. Weiss, Melissa Scott, Kathleen Demmel, John Peter Perentesis, Uma R Kotagal, Kathleen Walsh
Journal: Journal of Clinical Oncology (2017)

37 Background: The majority of children with cancer are now cured with highly complex chemotherapy regimens incorporating multiple drugs and demanding monitoring schedules. The risk for error is high and can occur at any stage in the process, from order generation through pharmacy formulation to bedside drug administration. Our objective is to describe a program to eliminate errors in chemotherapy use among children. Methods: To increase reporting of chemotherapy errors, we supplemented the hospital-reporting system with a new chemotherapy near-miss reporting system. Following the model for improvement, we then implemented several interventions, including a daily chemotherapy huddle, improvements to the preparation and delivery of intravenous therapy, headphones for clinicians ordering chemotherapy, and standards for chemotherapy administration throughout the hospital. Results: Twenty-two months into the project, we saw a centerline shift in our U Chart of chemotherapy errors that reached the patient from a baseline rate of 3.82/1,000 doses to 1.9/1,000 doses. This shift has been sustained for over 4 years. In Poisson regression analyses, we found an initial increase in error rates, followed by a significant decline in errors after 16 months of improvement work (p &lt; 0.001). Conclusions: Following the model for improvement, our improvement efforts were associated with significant reductions in chemotherapy errors which reached the patient. Key drivers for our success included error vigilance through a huddle, standardization, and minimized interruptions during ordering.
Impact of atrasentan on prostate-specific outcomes with hormone refractory prostate cancer patients
Authors: S. Yount, D. Cella, P. Mulani, D. Sleep, A. Allen, J. Isaacson, S. Hulting, T. Ashsraf
Journal: Journal of Clinical Oncology (2004)

4582 Background: For men with advanced cancer facing reduced life expectancy and no possibility of cure, symptom relief and maintenance of function are primary objectives of treatment. The Functional Assessment of Cancer Therapy-Prostate (FACT-P) quality of life (QOL) instrument incorporates a disease-specific, 12-item prostate cancer (PCa) subscale (PCS) that includes assessment of PCa-related symptoms such as pain and fatigue. The recently developed FACT Advanced Prostate Symptom Index (FAPSI), an 8-item index derived from the FACT-P, assesses weight loss, urinary problems, pain and fatigue. Scores range from 0–48 for PCS and 0–32 for FAPSI with higher scores indicating better QOL and fewer symptoms. The impact of atrasentan on PCS and FAPSI was evaluated in a phase 3, randomized, placebo-controlled study in men with metastatic hormone refractory PCa (HRPC) (N=809). Methods: All randomized patients with a baseline and final QOL assessment were analyzed. Mean change from baseline to final PCS and FAPSI scores was analyzed using analysis of covariance to compare treatments. The same analyses were performed on a subset of patients (N = 474) with HRPC metastastic only to bone. Results: Patients treated with placebo recorded a greater deterioration in both the PCS and FAPSI than those receiving atrasentan (p=0.032 and p=0.081). For both indices, the treatment difference was greater and statistically significant in men with bone metastases. The difference between groups was less than the minimally important difference (MID) of 3 points. However, as a group, the placebo-treated patients deteriorated beyond the MID, whereas the atrasentan-treated patients did not. Conclusion: These data indicate that atrasentan modestly improves PCa-specific outcomes relative to placebo. The QOL benefit observed with atrasentan therapy was most apparent in HRPC patients with metastases only to bone. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Abbott Laboratories Abbott Laboratories Abbott Laboratories
Molecular convergence in ex vivo models of Diamond-Blackfan anemia
Authors: Kelly A. O'Brien, Jason E. Farrar, Adrianna Vlachos, Stacie M. Anderson, Crystiana A. Tsujiura, Jens Lichtenberg, Lionel Blanc, Eva Atsidaftos, Abdel Elkahloun, Xiuli An, Steven R. Ellis, Jeffrey M. Lipton, David M. Bodine
Journal: Blood (2017)