tbuckley/cabot-search huggingface dataset:
Paclitaxel once weekly (wP) combined with fixed dose of oral metronomic cyclophosphamide (OMC): A dose-escalating phase I trial.
Authors: Diane Pannier, Antoine Adenis, Emmanuelle Tresch-Bruneel, Emilie Bogart, Farid El Hajbi, Eric Dansin, Nuria Kotecki, Luc Ceugnart, Thomas Ryckewaert, Stephanie Clisant Delaine, Geraldine Lauridant Philippin, Anne Lesoin, Sandrine Ducornet, Marie Vanseymortier, Emilie Decoupigny, Marie-Cecile Le Deley, Nicolas Penel
Journal: Journal of Clinical Oncology (2017)

e14015 Background: OMC, as continuous administration of low doses of chemotherapy acts as direct cytotoxic as well as antiangiogenetic agent. wP also induces antiangiogenic effects in mouse models. The aims of this trial were to determine the recommended Phase 2 dose (RP2D) of wP given in combination with OMC, and estimate activity and safety of the combination. Methods: Methods This is a single-center, phase 1 trial. Patients (pts) &gt; 18 years with refractory metastatic cancers were eligible if no standard curative measures existed. Paclitaxel was administered IV weekly (D1, D8, D15; D1 = D28) in combination with a fixed dose of OMC (50mg x2/day). A 3+3 design was used for Dose-Escalation of wP (40 mg/m² to 75 mg/m²), followed by an expansion cohort at RP2D. The primary endpoint was the dose-limiting toxicity (DLT), defined as grade &gt; 3 non-hematological or grade 4 hematological toxicity (NCI-CTCAE v4.0) occurring in the first 28 days, or any toxicity leading to a dose reduction. Results: 28 pts (18 in dose-escalation phase and 10 in expansion cohort) were included between May 2011 and December 2013. The sex ratio was 2:1, the median age was 54.5 (range, 26-67); the most common primary tumors were colorectal cancers (n = 9), sarcomas (n = 4), Head &amp; Neck (n = 3). 16/18 pts enrolled in the dose-escalation phase were evaluable for DLT. DLT occurred in 0/3, 1/6 (neuropathy), 0/3 and 2/4 pts (hematological toxicity) at dose 40, 60, 70 and 75 mg/m² of wP, respectively. The RP2D of wP was 70 mg/m2; 1/10 pts in the expansion phase had an hematological DLT. At RP2D (n = 14), the maximal grade of adverse events (AE), regardless of causality, was Gr2 in 3 pts, Gr3 in 7 pts, Gr4 in 3 pts and Gr5 in 1 pt; the maximal grade of treatment-related AE was Gr1 in 1 pt, Gr2 in 8 pts, Gr3 in 3 pts and Gr4 in 1 pt (no AE in 1 pt). At RP2D, the median PFS was 2.8 mo and Growth Modulation index was ≥1.33 in 4/14 pts (29%). There was 1 objective response (1/14; 7%): 1 pt with lung adenocarcinoma achieved a partial response. Conclusions: The combination of OMC and wP resulted in an acceptable safety profile. Further evaluation of this combination with wP at 70mg/m² could be warranted in a phase 2 trial. Clinical trial information: NCT01374620.
SPLUNC1 degradation by the cystic fibrosis mucosal environment drives airway surface liquid dehydration
Authors: Megan J. Webster, Boris Reidel, Chong D. Tan, Arunava Ghosh, Neil E. Alexis, Scott H. Donaldson, Mehmet Kesimer, Carla M.P. Ribeiro, Robert Tarran
Journal: European Respiratory Journal (2018)

The multi-organ disease cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane regulator gene (CFTR) that lead to diminished transepithelial anion transport. CF lungs are characterised by airway surface liquid (ASL) dehydration, chronic infection/inflammation and neutrophilia. Dysfunctional CFTR may upregulate the epithelial Na+ channel (ENaC), further exacerbating dehydration. We previously demonstrated that short palate lung and nasal epithelial clone 1 (SPLUNC1) negatively regulates ENaC in normal airway epithelia.Here, we used pulmonary tissue samples, sputum and human bronchial epithelial cells (HBECs) to determine whether SPLUNC1 could regulate ENaC in a CF-like environment.We found reduced endogenous SPLUNC1 in CF secretions, and rapid degradation of recombinant SPLUNC1 (rSPLUNC1) by CF secretions. Normal sputum, containing SPLUNC1 and SPLUNC1-derived peptides, inhibited ENaC in both normal and CF HBECs. Conversely, CF sputum activated ENaC, and rSPLUNC1 could not reverse this phenomenon. Additionally, we observed upregulation of ENaC protein levels in human CF bronchi. Unlike SPLUNC1, the novel SPLUNC1-derived peptide SPX-101 resisted protease degradation, bound apically to HBECs, inhibited ENaC and prevented ASL dehydration following extended pre-incubation with CF sputum.Our data indicate that CF mucosal secretions drive ASL hyperabsorption and that protease-resistant peptides, e.g. SPX-101, can reverse this effect to rehydrate CF ASL.
Subcortical brain volumes and neurocognitive function in survivors of childhood acute lymphoblastic leukemia (ALL) treated with chemotherapy-only.
Authors: Nicholas Steve Phillips, John O Glass, Matthew Scoggins, Yin Ting Cheung, Wei Liu, Robert J. Ogg, Daniel A. Mulrooney, Ching-Hon Pui, Leslie L. Robison, Wilburn E. Reddick, Melissa M. Hudson, Kevin R. Krull
Journal: Journal of Clinical Oncology (2017)

10517 Background: Brain deep grey nuclei and glucocorticoid receptor rich hippocampal subregions may be sensitive to neurotoxic effects of chemotherapy-only protocols for childhood ALL and associated with neurocognitive problems in long-term survivors. Methods: Brain MRIs and neurocognitive tests were obtained on 176 survivors (49% male, mean [range] age at diagnosis 6.8 [1-18] years, 14.5 [8-27] years at evaluation). MRI’s were also obtained on 82 healthy community controls (57% male, 13.8 [8-26] years at evaluation). General linear models were used to compare subcortical brain volumes between survivors and controls. Among survivors, gender stratified multivariable linear models were used to test associations between subcortical volumes, and serum concentration of dexamethasone (DEX) and high-dose methotrexate (HDMTX), adjusting for age at diagnosis, and intracranial volume (ICV). Volumes were also compared to neurocognitive tests. Results: Survivors had smaller volumes in bilateral thalami (p’s &lt; 0.05) and hippocampal subregions (p’s &lt; 0.001) compared to controls. After controlling for ICV, HDMTX exposure and younger age at diagnosis were associated with smaller bilateral thalami in male survivors (p’s &lt; 0.05). DEX was associated with a smaller right thalamus in males (p = 0.04). Smaller hippocampi in both males and females were associated with younger age at diagnosis (p’s &lt; 0.01). Smaller left thalamus was associated with worse verbal fluency scores in all survivors (p’s &lt; 0.05). Smaller bilateral thalami and hippocampal subregions in girls were associated with worse processing speed, inhibition and cognitive flexibility; poor memory span correlated with smaller left CA1 and right thalamus volumes (all p’s &lt; 0.05). Smaller bilateral thalami and right hippocampal subregions, in girls, correlated with slower processing speed (p’s &lt; 0.05). In males, smaller left fimbria volume was correlated with poor attention (p = 0.03). Conclusions: ALL survivors have significantly smaller thalamic and hippocampal volumes compared to healthy community controls. In survivors, smaller volumes correlate with worse cognitive performance.
The association between blood lipid and breast cancer risk: Evidence based on a dose-response meta-analysis comprising 900,669 participants.
Authors: Kang Liu, Dingli Song, Shuai Lin, Meng Wang, Tian Tian, Peng Xu, Yuyao Zhu, Linghui Zhou, Ying Wu, Zhijun Dai
Journal: Journal of Clinical Oncology (2018)

e24331 Background: The association between blood lipid and breast cancer risk has been paid much attention in the past few years, but the findings were still controversial. In addition, no study has examined the exact shape of the dose-response relationship between blood lipid and breast cancer risk before. Methods: Linear and nonlinear trend analyses were conducted to explore the shape of the dose-response relationship between blood lipid and breast cancer risk. The summary relative risk (SRR) and 95% confidence intervals (CIs) were used to evaluate the cancer risk. Results: The overall results showed a weak positive association between a 1 mmol/L total cholesterol (TC) increment and breast cancer risk, indicating that per 1 mmol/L increment on total cholesterol was corresponded to a 2 % increase of breast cancer risk (SRR: 1.02, 95%CI: 1.01-1.03, P = 0.00). However, we found that higher HDL-cholesterol (HDL-C) or higher triglycerides (TG) could have no influence on breast cancer risk (SRR: 0.96, 95%CI: 0.91-1.02, P = 0.16; SRR: 0.98, 95%CI: 0.95-1.01, P = 0.17 respectively). Furthermore, the dose-response result demonstrated that there was a linear association between TC, HDL-C or TG and breast cancer risk (Pnon-linearity = 0.659, 0.518 and 0.918 respectively). Conclusions: A total of 13 prospective cohort studies comprising 900,669 participants were included in our meta-analysis. Our study indicated that higher TC was associated with higher breast cancer risk in women. However, higher HDL-C and TG have little effect on breast cancer risk. Further studies are necessary to testify these findings and elucidate the pathogenic mechanisms.
Pembrolizumab-induced immune related adverse events and survival outcomes in advanced melanoma.
Authors: Aleksi Emil Suo, Yin Chan, Winson Y. Cheung, Jose Gerard Monzon, Michael Smylie, John WT Walker, Donald Morris, Tina Cheng
Journal: Journal of Clinical Oncology (2018)

e21577 Background: Anti-PD-1 checkpoint immunotherapies have distinct toxicity profiles that include immune-related adverse events (irAE). Objective response rates (ORR) appear to be higher in patients who develop irAE, but whether survival is impacted is not clear. Methods: Patients with unresectable stage III or stage IV melanoma treated with pembrolizumab in the province of Alberta from June 2014 to May 2017 were identified through the provincial pharmacy database. Chart review identified and categorized all irAE that occurred while on pembrolizumab. Primary objective was to compare overall survival (OS) with patients who developed any irAE versus those who did not. Secondary outcomes included ORR and progression free survival (PFS). Results: Among 144 patients, any grade and grade ≥ 3 irAE occurred in 38% and 14% of patients, respectively; one patient died of pneumonitis. Patients who developed any irAE were more likely to have better performance status (P = .011), normal lactate dehydrogenase (LDH) levels (P = .037), and receive more cycles (median 11 v 4, P < .001). ORR was 35% and higher in patients who developed any irAE, 67% v 16% (P < .001). Development of any irAE was also associated with longer median PFS, 24.6 v 2.5 months (P < .001), and OS, 39.6 v 4.6 months (hazard ratio [HR], 0.19, P < .001). A landmark analysis excluding patients who died within 12 weeks still demonstrated a median OS of 39.6 v 10.2 months (HR, 0.23, P < .001) for any irAE and no irAE, respectively. In multivariate analysis, elevated LDH (HR, 2.15, P = .003), each additional cycle received (HR, 0.89, P < .001) and the development of any irAE (HR, 0.24, P < .001) were significantly associated with longer OS. Conclusions: Pembrolizumab-associated irAE in advanced melanoma patients is associated with better patient outcomes, including survival. Table 1. Subgroup median OS Characteristic mOS Months (95% CI) HR (95% CI) P LDH Normal 21.6 (10.6 - 32.5) 2.90 (1.86 - 4.52) < .001 Elevated 4.4 (1.2 - 7.7) M stage 0/1a Not reached 1 .007 1b 16.1 (6.2 - 25.9) 2.54 (1.10 - 5.83) 1c 12.2 (2.6 - 21.9) 3.26 (1.46 - 7.29) 1d 6.4 (3.0 - 9.8) 3.81 (1.76 - 8.22) Any irAE No 4.6 (2.5 - 6.7) .19 (.11 - .34) < .001 Yes 39.6 (20.3 - 58.9) Grade ≥ 3 irAE No 8.5 (3.3 - 13.7) .27 (.11 - .68) .005 Yes Not reached
Impact of <i>SLCO1B3</i> single nucleotide polymorphisms (SNPs) on outcomes in patients with castration resistant prostate cancer (CRPC) treated with docetaxel.
Authors: Abhishek Tripathi, Wanling Xie, Christopher Sweeney, Atish Dipankar Choudhury, Mark Pomerantz, Xiao X. Wei, Mary-Ellen Taplin, Toni K. Choueiri, Gwo-Shu Mary Lee, Philip W. Kantoff, Lauren Christine Harshman
Journal: Journal of Clinical Oncology (2018)

e17027 Background: The organic anion transport polypeptide SLCO1B3 is expressed on both hepatocytes and CRPC tumor cells and mediates docetaxel transport. Preclinically, loss of expression of SLCO1B3 on tumor cells has been shown to confer taxane resistance. We hypothesized that SNPs in SLCO1B3 can also affect docetaxel transport and thus, its efficacy. Through this retrospective institutional analysis, we evaluated the impact of SLCO1B3 genotype on outcomes in CRPC patients treated with docetaxel. Methods: The study included CRPC patients treated with docetaxel who underwent genotyping for a previously identified SNP in SLCO1B3 (rs4149117; Yang et al JCO 2011). Associations of SNP with PSA response (≥50% decline from baseline), time to treatment failure (TTTF: time from docetaxel initiation to start of next therapy or death from any cause) and overall survival (OS) were evaluated in multivariable logistic and Cox regression models, adjusted for known prognostic factors. Results: SLCO1B3 genotyping and follow up data were available for 289 CRPC patients. The most common rs4149117 genotype was GG (67%; n = 194) followed by GT (29%; n = 84) and TT (4%; n = 11). The rs4149117 GT/TT > GG genotype was associated with improved TTTF (median 8.9 vs. 6.7 mos; hazard ratio: 0.69; 95%CI: 0.53-0.90; P = 0.007). There was no significant difference among the genotypes in terms of PSA response rate or OS (Table). Conclusions: Our findings suggest that the SLCO1B3 genotype could impact clinical outcomes in CRPC patients treated with docetaxel. Additional studies are needed to evaluate both SLCO1B3 genotype and its expression on tumor cells as pharmacogenomic predictors of outcomes in CRPC. Genotype PSA response (n = 268) TTTF (n = 288) OS (n = 289) N (%) OR*, 95%CI Median, 95%CI HR*, 95%CI Median, 95%CI HR*, 95%CI GG 89 (50) Ref 6.7 (5.9-8.2) Ref 18.4 (16.3-19.8) Ref GT/TT 46 (51) 1.00 (0.59-1.69) 8.9 (7.4-10.9) 0.69 (0.53-0.90) 19.4 (16.0-23.7) 0.78 (0.59-1.04) P value 0.991 0.007 0.095 *Adjusted for biopsy Gleason, type of primary therapy, prior abiraterone/enzalutamide use, metastatic status (none, bone/LN only or visceral), age and PSA at docetaxel initiation
TCT-516 The Outcome of Transcatheter Aortic Valve Replacement Compared to Surgical Aortic Valve Replacement in Patients with Heart Failure With Reduced Ejection Fraction
Authors: Yasser Al-khadra, Fahed Darmoch, Homam Moussa Pacha, Mohamad Soud, Anwar Zaitoun, Amir Kaki, M Chadi Alraies
Journal: Journal of the American College of Cardiology (2018)
P04.47 Nrf2 mediates hypoxic tolerance in human glioblastoma cells
Authors: N I Lorenz, A Luger, P S Zeiner, A L Engel, P N Harter, J P Steinbach, M W Ronellenfitsch
Journal: Neuro-Oncology (2018)

Oxidative stress is one of the major challenges of glioblastoma (GB) cells in the tumor microenvironment. Induction can be triggered by both local metabolic conditions including nutrient and oxygen deprivation as well as therapeutic interventions including radio- and chemotherapy. Cancer cell survival and clonal successfulness requires adaptation and ultimately therapeutic resistance. Since multiple conditions result in induction of oxidative stress, we hypothesized that glioma cells can develop cross-tolerance to differing stress stimuli. In this concept exposure to one oxidative stressor will induce adaptive programs that will prepare GB cells to better cope with subsequent other oxidative stressors. For example a hypoxic tumor microenvironment-mediated oxidative stress might induce programs allowing better coping with subsequent oxidative stress caused e.g. by chemotherapy. One key player of the oxidative stress response is the transcription factor Nrf2, which is upregulated in many human cancers. Oxidative stress causes Nrf2 release from its cytosolic sequestor KEAP1 and nuclear activation of transcriptional programs for adaptation including transcription of heme oxygenase 1, thioredoxin 1 and NAD(P)H-quinone-oxidoreductase. In order to investigate the role of Nrf2 activation especially under hypoxic conditions in malignant glioma cells we used two selective small-molecule inhibitors of the Nrf2-Keap1-interaction, ML334 and RA839. The human GB cell lines LNT-229, LN-308, T98G and the immortalized astrocyte cell line SVG were used as a representative panel. The effects of the pharmacological inhibitors of the Nrf2-Keap1 interaction, ML334 and RA839, were analyzed by measuring Nrf2 target gene expression. Furthermore the role of Nrf2 for survival under conditions of the tumor microenvironment was analyzed in a paradigm of hypoxia-induced cell death by LDH release measurement and PI staining. Glucose consumption was analyzed by an enzyme-based assay. Both ML334 and RA839 caused Nrf2 activation in all tested cell lines followed by Nrf2 target gene expression. Hypoxic conditions (0.1% O2) similarly induced Nrf2. Pharmacological Nrf2 activation resulted in protection from hypoxia-induced cell death even though glucose consumption of the cells increased after pharmacological Nrf2 activation. Nrf2-dependent adaptive programs are functional in human GB as well as immortalized astrocytic cells. Activation of Nrf2 increases hypoxia tolerance under conditions of the tumor microenvironment. Nrf2 may be a therapeutic target in GB treatment. Experiments on effects of chemotherapy sensitivity are ongoing.
Abstract #313: Effect of intermittent fasting on prostate cancer tumor growth in a mouse model
Authors: Jean Thomas, Susan Poulton, Tameika Phillips, Mark Dewhirst, Stephen Freedland
Journal: Cancer Research (2009)

Introduction: Caloric restriction is a well established approach to slow tumor growth in animal models. However, this approach is limited in humans due to poor compliance with weight loss regiments. Therefore, we previously investigated intermittent fasting (i.e. intermittent severe caloric restriction) as a means to slow prostate cancer growth in a xenograft model. In our pilot study, we found trends for mice that were fasted 2 days/week and fed ad libitum the other 5 days to have delayed tumor growth while maintaining normal body weight. Herein we sought to validate these findings using a larger sample size and better powered study. Methods: One Hundred male SCID mice (~8 weeks old) were subcutaneously implanted with 1x105 LAPC-4 cells. All mice were initially fed ad libitum Western diet (40% calories from fat; 45% from simple carbohydrates). When tumor volumes reached 200 mm3, mice were randomized to ad libitum feeding or intermittent fasting 2 days/week with ad libitum feeding on the non-fasting days. To date, 32 mice have been randomized to ad libitum feeding and 31 to intermittent fasting. Mice body weights and tumor volumes were measured twice per week. At the conclusion of each fasting day and prior to refeeding, urinary ketone levels for both ad libitum fed and fasted mice were measured. Comparisons of body weight and tumor volumes between groups were performed using the rank sum test. Results: By day 14 after randomization (longest point of follow-up to date), there was no difference in body weights (p=0.81) or tumor volumes (p=0.24) between ad libitum fed and intermittently fasted mice. Intermittently fasted mice were initially ketotic on day 0 after randomization with moderate (~40ng/ml) levels of post-fasting ketonuria. However, by Day 14 after randomization, post-fasting urine ketone levels had decreased to trace levels (~5ng/ml). Ad libitum fed mice had trace to no detectable urinary ketone levels at any time point (  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 313.
P05.58 Active beam scanning proton therapy for large skull base benign meningiomas: early outcomes
Authors: D Scartoni, D Amelio, S Lorentini, L Widesott, F Fellin, D Donner, I Giacomelli, M Schwarz, F Chierichetti, M Farsad, M Amichetti
Journal: Neuro-Oncology (2018)

To report preliminary results of active beam scanning proton therapy (PT) for large skull base benign meningiomas. Thirty-three patients (pts) with large skull base meningiomas were treated with PT between January 2015 and February 2018. Median age was 53 years (range, 28–82) while KPS ranged between 60 and 100 (median 90); 26 were female (79%), and 7 were male (21%). Twelve pts (36%) had histologically proven World Health Organization (WHO) Grade I tumors. In remaining pts diagnosis was based on the typical imaging appearance of benign meningioma. All patients received PT for residual, progressive or non-operable lesions. Newly diagnosed tumors received total dose of 50 GyRBE (RBE: relative biologic effectiveness) while progressing meningiomas 54 GyRBE. All the treatments were delivered at 2 GyRBE per fraction. Treatment planning was based on morphological magnetic resonance imaging (MRI) with contrast enhancement medium administration. All pts received also 68-Ga-DOTATOC-PET. Any area of contrast enhancement on MRI was used to identify the gross tumor volume. We used the pathological distribution of 68Ga-DOTATOC in brain tissue to identify the so-called Biological Tumor Volume. Gross tumor volume ranged from 21 to 107 cc. Toxicity was assessed according to Common Terminology Criteria for Adverse Events version 4.0. Median follow-up time was 9 months (range, 3–37). All pts completed the treatment without breaks. Acute side effects include grade 1 (21%) and grade 2 (9%) skin erythema, grade 1 (9%) and grade 2 (9%) alopecia, grade 1 (48%) fatigue, grade 1 (6%) and grade 2 (15%) conjunctivitis, grade 1 (15%) pain, grade 1 (15%) blurred vision, grade 1 (15%) headache, and grade 2 (15%) skin hyperpigmentation. One pt experienced grade 3 pain. There were no further grade 3 or higher acute toxicities. Late side effects include grade 1 (9%) and grade 2 (9%) alopecia, grade 1 (21%) fatigue, grade 1 (9%) and grade 2 (6%) headache, grade 1 (6%) dizziness, grade 1 (6%) blurred vision, grade 1 (6%) and grade 2 (6%) pain, grade 1 (6%) dry eye, and grade 1 (15%) skin hyperpigmentation. One pts experienced grade 3 pain. There were no further grade 3 or higher late toxicities. One pts (3%) with cavernous sinus meningioma experienced complete obstruction of intracavernous carotid artery with mild transient symptoms that resolved in few days and brain tissue ischemia detected at MRI (grade 2). Before irradiation this pts already had a meningioma-related near-complete obstruction of the intracavernous carotid artery and received a vascular surgery evaluation. Currently, absolute tumor control is 100%. Moreover, relief of symptoms recorded before irradiation occurred in 24% of pts. PT is feasible and safe treatment for pts with large skull base benign meningiomas. Longer follow-up is necessary to assess definitive efficacy.
Chris Burns-Cox: driving force behind altruistic kidney donation
Authors: Matt Limb
Journal: BMJ (2018)

Chris Burns-Cox was a campaigning physician who wanted to alleviate suffering wherever he found it and championed many humane causes throughout his life. He became a driving force in the promotion of altruistic kidney donation after donating a kidney to a stranger in 2010, when aged 72. He was convinced it was “the most useful thing” he could do to “convert somebody’s life from major misery and early death to normal again.”

He wrote, “I had been a doctor for 50 years and was aware how enormously fortunate I had been in my own good health. And I just came to the conclusion that I didn’t need two kidneys.”

Patients typically live 10 to 15 years longer with a kidney transplant than if they are kept on dialysis. For Burns-Cox it was a tragedy that hundreds of those on the transplant waiting list died each year, and he wanted more people to know they could give a kidney safely.

Burns-Cox helped to set up the charity Give a Kidney, which he chaired for four years from 2012 to 2016). He thought that once the public realised that “donation is no big deal for the donor—but a really enormous one for the recipient,” many would join the altruistic donors’ club.

They did. Altruistic kidney donations rose from 15 in 2009-10 to 118 within five years.

Initially, however, not everyone in the medical establishment was convinced that altruistic or non-directed kidney donation was a good thing. For a …