tbuckley/cabot-search huggingface dataset:
Sequential inhibition of DNA methyltransferase (DNMT) and CDK 4/6 in a panel of colon cancer cells.
Authors: Angela Damato, Carlo Astarita, Ang Sun, Antonio Pesce, Carmine Pinto, Antonio Giordano
Journal: Journal of Clinical Oncology (2018)

e15704 Background: Colorectal cancer (CRC) results from the accumulation of both genetic and epigenetic modifications. DNA methylation is one of the most frequent epigenetic mechanisms. D-cyclin-dependent kinase (CDK) 4/6 are essential for driving the cell cycle progression from G1 to S phase. We have addressed the hypothesis that DNMT inhibitor, 5-AZA-2'-deoxycytidine (DAC) could sensitize CRC cells to the effect of CDK4/6 inhibitor, palbociclib. Methods: A panel of CRC cell with different genetic and epigenetic profiles (Table 1) were sequentially treated with DAC (50 nM) from Day 1 to Day 3, and palbociclib (1 µM) from Day 6 to Day 8. Cells viability were evaluated from Day 1 to Day 9 using CellTiterGlo (Promega). Results: Comparing with the cells without any treatments, DAC alone significantly (p < 0.05) inhibited the growth of all the cell lines, except for LoVo. On Day 6, HT-116 cells were 87.6% (p < 0.001); LoVo cells were 57.4% (p < 0.001); DLD-1 cells were 43.9% (p < 0.001); HT-29 cells were 42.1% (p < 0.05); fewer than the control (CTR). LoVo, the only CIMP negative cell line, did not achieve statistically significant (p = 0.058) result evaluating DAC alone with CTR on Day 8. Only in DLD-1, comparing CTR and palbociclib alone the inhibition reached statistical significance (p < 0.05). Interestingly, in DLD-1 cells treatment with DAC and palbociclib maximally had 44.8% (p < 0.001) and 25.8% (p < 0.01) fewer cells, respectively, than treating the cells with palbociclib or DAC alone. The synergistic effect of DAC and palbociclib failed to achieve statistical significance in the other 3 cell lines, although combination treatments always resulted in fewer cells than DAC alone. Conclusions: CRC cell lines respond differently to DAC, palbociclib, and their association. Whether the differences in this outcome might be dictated by the discrepancy in the genetic and epigenetic profile needs further studies. Moreover, exploring CDKs expression and role in CRC might highlight several alterations which explain the resistance to palbociclib and perhaps display different targets for other CDK inhibitors to use in association with DAC. CIMP 1 CIMP 2 KRAS BRAF TP53 HCT-116 + + G13D wt wt HT-29 + + wt V600E R273H DLD-1 + + G13D wt S241F LoVo - - G13D; A14V wt wt
Can dynamic changes in prognostic markers predict survival in patients receiving VEGF-targeted therapy in clear cell renal cell carcinoma?
Authors: Scott Thomas Colville Shepherd, Peter Hall, Janet Elizabeth Brown, James M. G. Larkin, Robert J. Jones, Christy Ralph, Robert E. Hawkins, Simon Chowdhury, Ekaterini Boleti, Amit Bahl, Kate Fife, Andrew Webb, Simon J. Crabb, Thomas R. Geldart, Joanna Dunlop, Duncan McLaren, Charlotte Ackerman, Luis Beltran, Paul D. Nathan, Thomas Powles
Journal: Journal of Clinical Oncology (2017)

e16061 Background: Markers of the systemic inflammatory response have prognostic value in ccRCC prior to starting treatment. Dynamic changes during therapy and their role in predicting prognosis are not well characterised. Methods: A retrospective analysis was conducted of a randomised, double-blind phase II study evaluating cediranib vs cediranib and saracatinib in patients with relapsed metastatic ccRCC (COSAK). Haemoglobin (Hb), neutrophil count (N0) platelet count (Plt), lactate dehydrogenase (LDH) and C-reactive protein (CRP) were recorded at randomisation, 8-weeks and progression (PD). Change in mean values at each time point were compared. Baseline prognostic values for overall survival (OS) were assessed using Cox regression. Absolute changes in parameters were calculated at 8 weeks and PD, patients were grouped around the upper or lower quartile. Prognostic value of dynamic changes was assessed at 8 weeks and PD using the Kaplan-Meier method. Results: 138 patients were assessed; median OS was 12.0 months (IQR 8.1-15.6 months). Outcomes in the combination arm were similar to single agent arm (HR 1.28 (1.00–1.63)). On multivariate analysis at baseline, MSKCC score (0/1-2/≥3) (HR 2.52 (1.60 -3.96)), CRP ( &lt; 10/≥10mg/L) (HR 1.72 (1.04 – 2.86)) and N0 ( &lt; 7.5/≥7.5x109) (HR 2.38 (1.43 – 3.96)) were independent predictors of OS. Mean CRP was significantly different at baseline, 8 weeks and PD (64.9, 42.3 and 85.7 mg/L respectively, p &lt; 0.001). Mean N0 count at baseline was 5.3 x109/L and was significantly higher 6.3x 109/L at PD (p &lt; 0.001). Mean Hb at baseline, 8 weeks and PD was 11.5, 13.0 and 12.9g/L respectively (P &lt; 0.001). A rise in CRP or N0 at 8 weeks was predictive of poor outcome ((HR 1.62 (1.10-2.56) and (HR 1.77 (1.19-2.61) respectively). A fall in Hb was predictive of poor outcome at 8 weeks (HR 1.75 (1.18-2.60)) and PD (HR 1.80 (1.20-2.76)). Conclusions: Dynamic changes occur in prognostic markers in patients receiving VEGF-targeted therapy in ccRCC and may predict OS.
Optima: A phase II dose and volume de-escalation trial for high- and low-risk HPV+ oropharynx cancers.
Authors: James Melotek, Tanguy Y. Seiwert, Elizabeth A. Blair, Theodore G. Karrison, Nishant Agrawal, Louis Portugal, Zhen Gooi, Kerstin Stenson, Ryan J. Brisson, Saba Arshad, Allison Dekker, Sara Kochanny, Vassiliki Saloura, Michael T. Spiotto, Victoria Meucci Villaflor, Daniel J. Haraf, Everett E. Vokes
Journal: Journal of Clinical Oncology (2017)

6066 Background: In this prospective phase II de-escalation study, we used induction chemotherapy to identify favorable HPV+ oropharyngeal cancer (OPC) pts, including those with high-risk tumors, and applied significantly lower radiation or chemoradiation doses than previously reported. Methods: Pts with HPV+ OPC were classified as low-risk (≤T3, ≤N2B, ≤10 PYH) or high-risk (T4 or ≥N2C or &gt; 10 PYH). Pts received 3 cycles of carboplatin (AUC 6, D1) and nab-paclitaxel (100 mg/m2, D1/8/15). 1) Low-risk pts with ≥50% response received low-dose radiotherapy alone to 50Gy (RT50). 2) Low-risk pts with 30-50% response OR high-risk pts with ≥50% response received low-dose chemoradiotherapy to 45Gy (CRT45). 3) All other ( = poor response) pts received regular-dose CRT (CRT75). All pts also received de-escalated RT volumes limited to the first echelon of uninvolved nodes. CRT consisted of paclitaxel, 5-FU, hydroxyurea, and 1.5Gy twice daily RT every other week. Primary site biopsy and neck dissection were performed only after de-escalated treatment (RT50, CRT45) for pathologic confirmation. The primary endpoint was 2-year PFS. Secondary endpoints included pathologic complete response (pCR) rate and toxicity. Results: 62 pts were enrolled. 28 pts (45.2%) were low-risk and 34 pts (54.8%) were high-risk. 71.4% of low-risk pts received RT50 and 21.4% received CRT45. 70.6% of high-risk pts received CRT45. The pCR rate was 94.4% after RT50 and 92.3% after CRT45. Median follow-up is 1 year. The 2-year PFS and OS were both 100% for low-risk pts, and 91.6% and 97.0% for high-risk pts. Significant decrease in the rates of grade ≥3 mucositis (15.8% RT50, 46.4% CRT45, 60.0% CRT75, p = .033) and grade ≥3 dermatitis (0% RT50, 21.4% CRT45, 30.0% CRT75, p = .056) were observed. PEG-tube dependency was improved at 3 months (0% RT50, 14.8% CRT45, 70.0% CRT75, p &lt; .001) and 6 months (0% RT50, 3.7% CRT45, 20.0% CRT75, p = .066) post-treatment. Conclusions: Favorable response to induction chemotherapy appears to be a powerful biomarker for dose and volume de-escalation with 50Gy RT or 45Gy CRT. Outstanding survival and high pCR rates suggest that completion neck dissection may not be necessary. Toxicity and functional outcomes are significantly improved. Clinical trial information: NCT02258659.
Death certificates should record antimicrobial resistance as cause of deaths, says CMO
Authors: Adrian O’Dowd
Journal: BMJ (2018)

Doctors should record if a patient dies because of antimicrobial resistance to an infection, according to England’s chief medical officer.

Sally Davies, giving evidence to the parliamentary health and social care committee on 4 September, said that she wanted to see a new approach that acknowledged the growing problem of resistance to antibiotics.

For their inquiry into antimicrobial resistance (AMR), MPs on the committee asked witnesses how the problem was being tackled and what more could be done.

Davies said: “One of the problems is that families often don’t know that their relative’s death was because of infection, and they’re rarely told that the infection …
Lysyl-tRNA synthetase–expressing colon spheroids induce M2 macrophage polarization to promote metastasis
Authors: Seo Hee Nam, Doyeun Kim, Doohyung Lee, Hye-Mi Lee, Dae-Geun Song, Jae Woo Jung, Ji Eon Kim, Hye-Jin Kim, Nam Hoon Kwon, Eun-Kyeong Jo, Sunghoon Kim, Jung Weon Lee
Journal: Journal of Clinical Investigation (2018)

Lysyl-tRNA synthetase (KRS) functions canonically in cytosolic translational processes. However, KRS is highly expressed in colon cancer, and localizes to distinct cellular compartments upon phosphorylations (i.e., the plasma membranes after T52 phosphorylation and the nucleus after S207 phosphorylation), leading to probably alternative noncanonical functions. It is unknown how other subcellular KRSs crosstalk with environmental cues during cancer progression. Here, we demonstrate that the KRS-dependent metastatic behavior of colon cancer spheroids within 3D gels requires communication between cellular molecules and extracellular soluble factors and neighboring cells. Membranous KRS and nuclear KRS were found to participate in invasive cell dissemination of colon cancer spheroids in 3D gels. Cancer spheroids secreted GAS6 via a KRS-dependent mechanism and caused the M2 polarization of macrophages, which activated the neighboring cells via secretion of FGF2/GROα/M-CSF to promote cancer dissemination under environmental remodeling via fibroblast-mediated laminin production. Analyses of tissues from clinical colon cancer patients and Krs–/+ animal models for cancer metastasis supported the roles of KRS, GAS6, and M2 macrophages in KRS-dependent positive feedback between tumors and environmental factors. Altogether, KRS in colon cancer cells remodels the microenvironment to promote metastasis, which can thus be therapeutically targeted at these bidirectional KRS-dependent communications of cancer spheroids with environmental cues.
Selective benefit of adjuvant chemoradiation in resectable pancreatic cancer.
Authors: Jesse P Wright, Cameron Schlegel, Rebecca A Snyder, Liping Du, Yu Shyr, Dana Backlund Cardin, Nipun B. Merchant, Alexander A. Parikh
Journal: Journal of Clinical Oncology (2017)

4122 Background: Although level 1 data supports the use of adjuvant chemotherapy (ACT) in resected pancreatic adenocarcinoma (PDAC), the role of adjuvant chemoradiation (ACRT) remains controversial. The objective of this study is to investigate the impact of adding ACRT to ACT on overall survival (OS), based on lymph node (LN) and margin status. Methods: Resected AJCC Stage I and II PDAC patients from 2004-2013 identified within the National Cancer Database were classified into groups based on treatment: surgery alone (SX), ACT alone, ACT+ACRT, and ACRT only. Kaplan-Meier analyses were performed to determine median OS. Multivariable (MV) Cox regression models with interactions of treatment with LN and margin status were constructed to examine the independent effects of ACT and ACT+ACRT in these subgroups. Results: Of 31,348 patients, 30% were treated with SX, 30% with ACT, 38% with ACT+ACRT, and 2% with ACRT alone. Median OS (mos.) for ACT (22.5, 95% CI 21.9-23.1) and ACT+ACRT (23.7, 23.3-24.2) were significantly longer than SX (14, 13.4-14.5) or ACRT (11.2, 9.8-12.9). MV analysis confirmed a significant OS benefit of both ACT and ACT+ACRT controlling for patient and tumor related factors. ACRT+ACT was associated with improved OS compared to ACT in patients with positive margins and/or LN. Those with negative margins and LN did not benefit from the additional use of ACRT (Table). Conclusions: This large hospital-based study demonstrates that ACT and ACRT are associated with improved OS when compared to SX. The addition of ACRT to ACT, however, was only beneficial in high-risk patients with positive margins and/or LN. ACT+ACRT in patients with both margin and LN negative disease may not be warranted. Future clinical trials should stratify patients based on LN and margin status in order to determine which patients are most likely to benefit from the use of ACRT. [Table: see text]
Incidence of brain metastases in metastatic renal cell carcinoma in the era of targeted therapies.
Authors: I. Alex Bowman, Tri Le, Alana Christie, James Brugarolas
Journal: Journal of Clinical Oncology (2016)

e16103 Background: The cumulative incidence of brain metastasis (BM) in metastatic renal cell carcinoma (mRCC) has historically been quoted as 10%. This figure is based on data collected before the introduction of targeted therapies that improve the survival of patients with mRCC. We hypothesize that, as has been reported with other solid tumor malignancies, as patients with mRCC survive longer the incidence of BM may increase. A more complete understanding of the incidence rate of BM may inform imaging surveillance for mRCC. Methods: Patients with mRCC evaluated at the University of Texas Southwestern Medical Center between January 2006 and October 2015 were identified within the electronic medical record by diagnostic code and their clinical records reviewed to confirm a diagnosis of mRCC. The clinical diagnosis of BM was determined by the treating physicians based on characteristic radiographic findings. Results: We identified 322 patients with mRCC treated at our institution. BM had been diagnosed in 19.25% (62/322) patients at the time of this analysis. Based on a subset analysis of 151 patients identified prior to May 2013, for whom overall survival data was available, the incidence rate of BM after the diagnosis of mRCC was 7.9% per person-year (25 cases over 318 person-years of follow-up). Only 4.6% (7/151) of this subset was lost to follow-up as of October 2015. Conclusions: The incidence rate of BM from our single-institution experience is 7.9% per year after the diagnosis of mRCC, with an overall frequency approaching 20%. This is higher than has been historically cited and may be due to an improved overall survival in the era of targeted therapy. This higher incidence rate may justify considering new strategies for active surveillance of BM in mRCC patients.
Prognostic factors for overall survival (OS) in metastatic melanoma (MM) patients (pts) treated with immune checkpoint inhibitors: A single institution study of 696 pts.
Authors: Meredith Ann McKean, Lauren Elaine Haydu, Junsheng Ma, Roland L. Bassett, Wen-Jen Hwu, Sapna Pradyuman Patel, Adi Diab, Isabella Claudia Glitza, Hussein Abdul-Hassan Tawbi, Michael K Wong, Jennifer Leigh McQuade, Patrick Hwu, Michael A. Davies, Rodabe Navroze Amaria
Journal: Journal of Clinical Oncology (2017)

9574 Background: Limited OS data, including prognostic and predictive factors of response, is available in mm pts treated with immune checkpoint inhibitors. Methods: A single-institution retrospective review was conducted on 696 mm pts treated with single-agent anti CTLA-4 or anti PD-1 on and off clinical trial between 2011-2015. Median OS was calculated from mm diagnosis. Results:Median age at mm diagnosis was 60 years old (range 15-86) and 65.2% were male. Subtypes were 63.2% non-acral cutaneous, 17.2% unknown primary, 7.8% mucosal, 6.5% acral, and 5.3% uveal. AJCC v7 staging at diagnosis was 7.9% M1a, 16.5% M1b, 33.0% M1c, and 42.5% not staged due to unknown LDH. LDH was elevated in 18.0% (400 pts). Mutation rates were 30.0% BRAF V600E/K (636 pts tested) and 24.5% NRAS (429 pts tested). First-line therapy for BRAF V600E/K mm pts included anti CTLA-4 (24.1%), BRAF/MEK targeted therapy (21.5%) and anti PD-1 (8.9%). First-line therapy for BRAF WT mm pts included anti CTLA-4 (28.1%) and anti PD-1 (12.8%). Median OS from mm for the cohort was 36.5 months (95% CI 33.3-44.9). Elevated LDH and staging correlated with OS (p &lt; 0.001, p &lt; 0.001, respectively) on univariate analysis. Age, gender, subtype and mutation status were not significantly associated with OS. Compared to BRAF WT, pts with BRAF V600E/K mutation were younger (median = 53 vs 62 yrs, p &lt; 0.001), more likely to have non-acral cutaneous mm (83.2% vs 58.0%, p &lt; 0.001) and have a diagnosis of brain metastasis during the disease course (57.0% vs 28.8%, p &lt; 0.001). While adjusting for stage, there was no significant difference in OS based on first or second line therapy in pts with BRAF V600E/K mm or first line therapy in BRAF WT MM; however, BRAF WT pts treated second line with anti-PD1 were observed to have improved OS compared with pts receiving anti-CTLA 4 (HR 0.43 95% CI:0.23-0.84 p = 0.012). Conclusions: This study demonstrates that LDH and stage are prognostic of OS in all mm pts treated with single agent immune therapy. Second line therapy in BRAF WT pts treated with single agent immune therapy is also prognostic of OS thus prompting further investigation to determine advantageous therapy sequencing in MM.
Olaparib-induced severe folate deficiency in women with relapsed ovarian cancer: First report and case series.
Authors: Jamile M. Shammo, Lydia Usha, Kristin J. Richardson, Elizabeth Elliott, Summer Dewdney, Parameswaran Venugopal, Melody A. Cobleigh, Timothy Kuzel
Journal: Journal of Clinical Oncology (2018)

e17540 Background: We discovered severe folate deficiency in a patient taking the Poly (ADP-Ribose) Polymerase (PARP)-inhibitor olaparib (Lynparza) for relapsed ovarian cancer (OC). Discovery of nearly undetectable serum folate without a plausible explanation led us to identify other olaparib-treated patients with severe folate deficiency contributing to anemia, which often necessitated blood transfusion, dose reduction, and at times, drug discontinuation. To our knowledge, this is the first description of an association between olaparib therapy and folate deficiency. Methods: We performed a chart review of patients with relapsed OC undergoing treatment with olaparib to determine the incidence of folate deficiency in this population. Patients found to be folate deficient were started on oral folic acid supplementation with close follow up. We assessed the response of folic acid supplementation on anemia. We also assessed the impact of anemia on olaparib dosing. Results: We identified a total of 7 patients on active olaparib therapy for treatment of relapsed OC. 6 out of 7 patients were noted to have moderate to severe folate deficiency while taking olaparib, 5 of whom developed undetectable or near-undetectable folate levels ≤1.6 ng/mL. 3 out of 6 patients required dose-reduction or drug discontinuation due to the development of transfusion-dependent anemia, with a mean time of 39 days from the initiation of olaparib to hemoglobin nadir. In those found to have folate deficiency, folic acid supplementation was started at 1 mg daily, with subsequent improvement of serum folate level, anemia and tolerability of olaparib. Conclusions: In our small case series, we discovered that folate deficiency occurred in a majority of patients within weeks of initiating olaparib treatment. Based on these findings, we think that identifying and treating folate deficiency in this population is warranted, and may improve dose delivery and safety of olaparib therapy. Further studies should provide insight into potential interaction between PARP-inhibition, the folate pathway, and BRCA mutations in ovarian and other cancers. We are conducting translational research to elucidate the mechanism of this association.
Pulmonary endarterectomy and the cost of patient refusal
Authors: Nick H. Kim, Eckhard Mayer
Journal: European Respiratory Journal (2018)

<b>The recommended treatment for operable chronic thromboembolic pulmonary hypertension is pulmonary endarterectomy, and patients who refused surgery in the current study had worse long-term survival than those who underwent surgery</b> http://ow.ly/WJ0P30lBxY9
A multicenter retrospective analysis of the effect of DPP4 inhibitors on progression-free survival in advanced airway and colorectal cancers.
Authors: Azka Ali, Alejandra Fuentes, William Paul Skelton, Yu Wang, Susan P. McGorray, Long H. Dang, Nam H. Dang
Journal: Journal of Clinical Oncology (2018)

e24004 Background: Cluster of differentiation 26 (CD26), also known as dipeptidyl peptidase IV (DPP4), is a multifunctional cell surface protein expressed in most cell types. As a complicated molecule with pleotropic effects, CD26/DPP4 can act as either a tumor suppressor or activator, depending on the cancer type and tumor microenvironment. Nonetheless, an enlarging body of pre-clinical evidence supports an association between CD26/DPP4 and tumor invasion and metastasis. CD26/DPP4 has thus been proposed as a target in the treatment of certain malignancies. In this study, we retrospectively analyzed diabetic patients (pts) with colorectal and airway malignancies to examine the effect of DPP4-inhibitors on progression free survival (PFS). Methods: We performed a multi-center retrospective review of pts with advanced (stage 3 or 4) colorectal or airway (lung, head and neck) cancer and reviewed the PFS of their respective malignancy on DPP4 inhibitors. All pts were diabetic on anti-hyperglycemic therapy and all received standard chemotherapy. Control group included pts on metformin and a sulfonylurea, and study group included pts on metformin and a DPP4 inhibitor. Fisher exact test was performed for univariate analysis and a multivariate regression logistic model was performed to calculate statistical significance. Results: Ninety-six patients were eligible to be included in the study. 18.4% of pts treated with DPP4 inhibitors had progression of their malignancy, compared to 48.1% of pts in the control group with an Odds Ratio 0.203 (95% CI: 0.063-0.646) and p-value 0.007. There was a statistically significant improvement in PFS in the study group (medium follow up of 18.5 months) when compared to control group (median follow up of 26 months) with a Hazard Ratio 0.423 (95% CI: 0.21-0.84) and p-value 0.014. Overall survival was improved but not significantly (p = 0.11). Conclusions: Exposure to DPP4 inhibitors in pts with diabetes and advanced colorectal or airway cancers led to statistically significant improvement in PFS. Further investigation with prospective randomized design is needed to validate the relationship between DPP4 inhibition and progression of malignancy.
“Ride the Green Light”: Indocyanine Green–marked Off-clamp Robotic Partial Nephrectomy for Totally Endophytic Renal Masses
Authors: Giuseppe Simone, Gabriele Tuderti, Umberto Anceschi, Mariaconsiglia Ferriero, Manuela Costantini, Francesco Minisola, Giulio Vallati, Giuseppe Pizzi, Salvatore Guaglianone, Leonardo Misuraca, Michele Gallucci
Journal: European Urology (2018)
TCT-460 Prognostic value of irregular protrusion and subsequent neoatherosclerosis after second-generation drug-eluting stent implantation - Optical Coherence Tomography Study-
Authors: Kounosuke Inoue, Shinjo Sonoda, Yoshinori Sanuki, Koushi Setoyama, Toshiya Miura, Akiyoshi Shimizu, Reo Anai, Yoshitaka Muraoka, Yuki Tsuda, Masaru Araki, Yutaka Otsuji
Journal: Journal of the American College of Cardiology (2018)