tbuckley/cabot-search huggingface dataset:
Trends in chronic opioid therapy among cancer survivors.
Authors: Talya Salz, Jessica A. Lavery, Allison Nicole Lipitz Snyderman, Denise Boudreau, Natalie Moryl, Erin F. Gillespie, Deborah Korenstein
Journal: Journal of Clinical Oncology (2018)

6584 Background: Cancer survivors may be at increased risk of opioid use disorders, due to opioid exposure during therapy, prevalent pain after therapy, and heightened risk of addiction among those with tobacco- and alcohol-related cancers. We hypothesized that chronic opioid therapy (COT) receipt among survivors would exceed receipt among people without cancer. Methods: Adults ≥65 years in SEER-Medicare data diagnosed with lung (N = 16,192), colorectal (15,429), or breast (23,474) cancer between 2008 and 2013 were followed through 2014 or death. Survivors were matched 1:1 at diagnosis (index date) on age, sex, and race with cancer-free controls. We defined COT receipt as the presence of claims for ≥90 consecutive days of opioid prescriptions. We described proportion of survivors and controls receiving COT each calendar year. For each year after index date, we used logistic regression to compare COT receipt between survivors and controls. Results: Among controls, there was a secular trend of increased COT receipt from 3% in 2008 to 6% in 2013. Similarly, for survivors in the first follow-up year, COT receipt increased from 5% in 2008 to 10% in 2013. For each follow-up year, COT receipt among lung and colorectal survivors (but not breast cancer survivors) exceeded that of controls. However, the odds ratios comparing COT receipt between survivors and controls diminished over time since the index date (Table). Conclusions: A secular trend of increased COT receipt over calendar years was seen in survivors and controls, but the increase was blunted among survivors. Proportion of COT receipt among survivors approached that of controls as survivors lived longer after diagnosis. Although the opioid epidemic appears to include survivors, the common use of opioids during therapy does not appear to lead to later increased rates of opioid use beyond that of the general population. Differences between cancer populations merit further investigation. Odds ratios for COT receipt (reference = controls) Follow-up years after index date 1 2 3 4 5 6 Lung 3.03* 2.84* 2.01* 1.78* 1.88* 2.80* Colorectal 1.39* 1.35* 1.23* 1.22* 1.13 1.13 Breast 1.03 1.05 1.06 0.99 0.89 0.85 * p < .05
Communication from Learned to Innate Olfactory Processing Centers Is Required for Memory Retrieval in Drosophila
Authors: Michael-John Dolan, Ghislain Belliart-Guérin, Alexander Shakeel Bates, Shahar Frechter, Aurélie Lampin-Saint-Amaux, Yoshinori Aso, Ruairí J.V. Roberts, Philipp Schlegel, Allan Wong, Adnan Hammad, Davi Bock, Gerald M. Rubin, Thomas Preat, Pierre-Yves Plaçais, Gregory S.X.E. Jefferis
Journal: Neuron (2018)

The behavioral response to a sensory stimulus may depend on both learned and innate neuronal representations. How these circuits interact to produce appropriate behavior is unknown. In Drosophila, the lateral horn (LH) and mushroom body (MB) are thought to mediate innate and learned olfactory behavior, respectively, although LH function has not been tested directly. Here we identify two LH cell types (PD2a1 and PD2b1) that receive input from an MB output neuron required for recall of aversive olfactory memories. These neurons are required for aversive memory retrieval and modulated by training. Connectomics data demonstrate that PD2a1 and PD2b1 neurons also receive direct input from food odor-encoding neurons. Consistent with this, PD2a1 and PD2b1 are also necessary for unlearned attraction to some odors, indicating that these neurons have a dual behavioral role. This provides a circuit mechanism by which learned and innate olfactory information can interact in identified neurons to produce appropriate behavior. VIDEO ABSTRACT.
Efficacy and Tolerability of First-Line Cetuximab Plus Leucovorin, Fluorouracil, and Oxaliplatin (FOLFOX-4) Versus FOLFOX-4 in Patients With <i>RAS</i> Wild-Type Metastatic Colorectal Cancer: The Open-Label, Randomized, Phase III TAILOR Trial
Authors: Shukui Qin, Jin Li, Liwei Wang, Jianming Xu, Ying Cheng, Yuxian Bai, Wei Li, Nong Xu, Li-zhu Lin, Qiong Wu, Yunfeng Li, Jianwei Yang, Hongming Pan, Xuenong Ouyang, Wensheng Qiu, Kaichun Wu, Jianping Xiong, Guanghai Dai, Houjie Liang, Chunhong Hu, Jun Zhang, Min Tao, Qiang Yao, Junyuan Wang, Jiongjie Chen, S. Peter Eggleton, Tianshu Liu
Journal: Journal of Clinical Oncology (2018)

Cetuximab in combination with chemotherapy is a standard-of-care first-line treatment regimen for patients with
Incidence of ALK, cKIT, cMET, EGFR, PD1/PD-L1, and JAK3 alterations in 170 malignant pleural mesotheliomas (MPM) and 102 peritoneal mesotheliomas.
Authors: David Arguello, Wafik S. El-Deiry, Lanlan Zhou, Sanjay S. Reddy, Walter Joseph Scott, Abass E. Abass, Larry R. Kaiser, Mark A Hallman, Rishi Sawhney, Woondong Jeong, Edward S. Kim, Stephen V. Liu, Patrick C. Ma, Zoran Gatalica, Sandeep K. Reddy, Hossein Borghaei, Joseph R. Testa
Journal: Journal of Clinical Oncology (2016)

e20076 Background: MPM is a deadly cancer associated with asbestos exposure. Therapy involves surgery, photodynamic-, chemo-, targeted-, and immuno-therapy but recurrence remains high. BAP1 mutations are associated with familial mesothelioma (Testa Nat Genet. 2011). We developed a mouse model for peritoneal mesothelioma (Zhou Oncol Rep. 2012) and suggested sorafenib as a potential therapeutic in mesothelioma (Katz Cancer Biol Ther. 2009). The goal of this analysis was further molecular characterization of the disease. Methods: 170 MPM and 102 peritoneal mesotheliomas were analyzed by Caris Life Sciences using IHC, ISH, and sequencing (Sanger or NGS). The first cohort (N = 170) included 86 epithelioid, 11 biphasic, and 7 sarcomatoid MPM. Others could not be classified based on the pathology report. Results: IHC revealed PD-1 and PD-L1 expression in 64.8% (35/54) and 26.8% (15/56) of MPMs, respectively. EGFR had high protein overexpression (95.5%, 42/44). EGFR gene amplification was 14.7% (5/34), with no ALK, HER2, MET or ROS1 ISH abnormalities detected. Deleterious abnormalities found were ATM, BRCA2, KRAS, PTEN, STK11, and TP53. Mutational aberrations in PTEN occurred in biphasic and sarcomatoid histology but not epithelioid (18.2% [2/11] and 0% [0/44], respectively; p = 0.0370). PTEN loss, TOP2A and TUBB3 were different in pleural and peritoneal mesothelioma (34.4% v 19.2%, [p = 0.0103], 54.1% v 27.7% [p = 0.0001] and 70.9% v 40.6% [p = 0.0002], respectively). ALK, cKIT, cMET, EGFR, PD-1, and PD-L1 expression occurred at comparable rates at both disease sites. Pleural and peritoneal mesothelioma showed low but detectable mutations in JAK3 (1.1% and 4.1%) and EGFR (1.1% and 2.0%) while KRAS was detected in pleural (1.1%) but not peritoneal mesothelioma. Conclusions: Gene mutations were not very common in mesothelioma compared to other solid tumors while IHC analysis provides some direction towards immunotherapy and targeted therapy. This analysis confirms reported PD-L1 expression rates in MPM. Our data provide a rationale to investigate personalized therapeutics e.g. through basket design with targeted therapies based on mutation/protein expression.
Effects of a DPP4 Inhibitor on Progression of NASH-related HCC and the p62/ Keap1/Nrf2-Pentose Phosphate Pathway in a Mouse Model
Authors: Takumi Kawaguchi, Dan Nakano, Hironori Koga, Takuji Torimura
Journal: Liver Cancer (2018)

&lt;b&gt;&lt;i&gt;Background and Aims:&lt;/i&gt;&lt;/b&gt; Diabetes mellitus is a risk factor for hepatocellular carcinoma (HCC) in patients with nonalcoholic steatohepatitis (NASH). Dipeptidyl peptidase-4 inhibitor (DPP4i), an antidiabetic agent, is reported to affect cell proliferation. We aimed to investigate the effects of DPP4i on the progression of NASH-related HCC and its metabolic pathway in a mouse model. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; A mouse model of NASH-related HCC was used in this study. Eight-week-old mice were administered either DPP4i (sitagliptin 30 mg/kg/day; DPP4i group; &lt;i&gt;n&lt;/i&gt; = 8) or distilled water (control group; &lt;i&gt;n&lt;/i&gt; = 8) for 10 weeks. Then, HCC progression was evaluated by computed tomography. Changes in metabolites of HCC tissue were analyzed by metabolomic analysis. The localization and expression of p62, Keap1, Nrf2, and MCM7 were evaluated by immunostaining and immunoblotting, respectively. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; The number and volume of HCC were significantly lower in the DPP4i group than in the control group (1.8 ± 1.2 vs. 4.5 ± 1.7/liver, &lt;i&gt;p&lt;/i&gt; &amp;#x3c; 0.01; 11.2 ± 20.8 vs. 37.5 ± 72.5 mm&lt;sup&gt;3&lt;/sup&gt;/tumor, &lt;i&gt;p&lt;/i&gt; &amp;#x3c; 0.05). Metabolome analysis revealed that DPP4i significantly increased 6-phosphogluconic acid and ribose 5-phosphate levels and decreased the AMP-to-adenine and GMP-to-guanine ratios (AMP-to-adenine ratio 0.7 ± 0.2 vs. 2.0 ± 1.2, &lt;i&gt;p&lt;/i&gt; &amp;#x3c; 0.01; GMP-to-guanine ratio 0.6 ± 0.3 vs. 1.5 ± 0.7, &lt;i&gt;p&lt;/i&gt; &amp;#x3c; 0.01). Immunostaining showed that p62 was localized in the cytoplasm of HCC in the DPP4i group, while p62 was localized in the nucleus of HCC in the control group. Keap1, Nrf2, and MCM7 expression decreased significantly in the DPP4i group compared to that in the control group. &lt;b&gt;&lt;i&gt;Conclusions:&lt;/i&gt;&lt;/b&gt; We demonstrated that DDP4i prevented the progression of NASH-related HCC in a mouse model. Furthermore, metabolome analysis revealed that DDP4i downregulated the pentose phosphate pathway with suppression of the p62/Keap1/Nrf2 pathway. Thus, DDP4i may prevent tumor progression through inhibition of metabolic reprogramming in NASH-related HCC.
Diagnosis of HPV driven head and neck cancer: Comparing p16 based algorithms with the RNAscope HPV-test.
Authors: Haitham Mirghani, Odile Casiraghi, Furrat Amen, Xiao-Jun Ma, Joanne Guerlain, V'ronique Dalstein, Isabelle Borget, Jean Lacau Saint Guily, Cecile Badoual, Philippe Vielh
Journal: Journal of Clinical Oncology (2016)

6040 Background: Accurate identification of HPV-driven oropharyngeal cancer (OPC) is a major issue and none of the current diagnostic approaches is ideal. An in situ hybridization (ISH) assay that detects high-risk HPV E6/E7 mRNA, called the RNAscope HPV-test, has been recently developed. Studies have suggested that this assay may become a standard to define HPV-status. Methods: To further assess this test, we compared its performance against the strategies that are used in routine clinical practice: p16 immunohistochemistry (IHC) as a single test and algorithms combining p16-IHC with HPV-DNA identification by PCR (algorithm-1) or ISH (algorithm-2). Results: Results: 105 OPC specimens were analyzed. The prevalence of HPV-positive samples varied considerably: 67% for p16-IHC, 54% for algorithm-1, 61% for algorithm-2 and 59% for the RNAscope HPV-test. Discrepancies between the RNAscope HPV-test and p16-IHC, algorithm-1 and 2 were noted in respectively 13.3%, 13.1%, and 8.6%. The 4 diagnostic strategies were able to identify 2 groups with different prognosis according to HPV-status, as expected. However, the greater survival differential was observed with the RNAscope HPV-test [HR: 0.19, 95% confidence interval (CI), 0.07–0.51, p = 0.001] closely followed by algorithm-1 (HR:0.23, 95% CI, 0.08–0.66, p = 0.006) and algorithm-2 (HR:0.26, 95% CI, 0.1–0.65, p = 0.004). In contrast, a weaker association was found when p16-IHC was used as a single test (HR: 0.33, 95% CI, 0.13–0.81, p = 0.02). Conclusions: Our findings suggest that the RNAscope HPV-test and p16-based algorithms perform better that p16 alone to identify OPC that are truly driven by HPV-infection. The RNAscope HPV-test has the advantage of being a single test
Grade and maximum tumor dimension (MTD) as determinants of lymphadenectomy in patients with endometrioid endometrial cancer (EEC).
Authors: Ali Ahmad Bazzi, Ameer Hamza, Riley O'Hara, Kimberly Kado, Lamia Fathallah, Robert Morris
Journal: Journal of Clinical Oncology (2018)

e17560 Background: EEC is the most common gynecologic malignancy worldwide. The role of lymphadenectomy is controversial, especially in intraoperative indications for the procedure. Criteria previously described have centered on 3 main factors: depth of myometrial invasion > 50%, MTD > 2cm and high grade histology. There are no universally established guidelines, and many institutions incorporate these criteria in varying degrees in the decision to proceed with lymphadenectomy. This investigation assesses the use of intraoperatively measured MTD with and without pre-operative histologic grade. Methods: This retrospective cohort study compares 222 EEC patients with intraoperatively measured MTD ≤2cm to those with MTD > 2cm; and compares those with MTD≤2cm with endometrial biopsy (EB) grade1-2 to patients with MTD > 2cm with EB grade 3. Lymph node metastasis (LNM), recurrence, and survival are compared in these groups. Results: In tumors > 2cm, lymph node metastasis occurred in 19.7% cases while in tumors ≤2cm, lymph nodes metastasis was found in 6.3% cases (p = 0.04). Recurrence and mean survival based on last follow up visit in these two groups were not statistically different (p = 0.78 and 0.36 respectively). When combined with preoperative EB FIGO grade, higher proportion of patients with EB FIGO Grade 3 and MTD > 2cm had LNM compared to those with EB FIGO Grade 1-2 and MTD ≤2cm (42.9% vs, 10.5%, p = 0.06) Lymph node metastasis was found in 14.5% of cases in which lymphadenectomy was performed based on current practices, whereas if the criteria of EB FIGO 3 and MTD > 2cm were used the incidence of LNM in would have been 42.9% cases. However, using this criterion, 2 patients would not have had their nodal metastases detected. Compared to the current practice, the sensitivity and specificity of the proposed criteria would be 60% and 81%, respectively. The PPV and NPV would be 42.9% and 89.5%, respectively. Conclusions: Our results indicate that MTD combined with EB FIGO grade can detect LNM in higher proportion of cases when compared to current practice. MTD combined with EB FIGO grade may eliminate the need of frozen section sampling in a substantial number of cases.
Association between baseline absolute neutrophil count (ANC), derived neutrophil-to-lymphocyte ratio (dNLR), and platelet-to-lymphocyte ratio (PLR) and response to nivolumab (Nivo) in non-small cell lung cancer (NSCLC): A preliminary analysis.
Authors: Alessandro Russo, Antonino Scimone, Maria Picciotto, Giuseppe Toscano, Fabio Raiti, Serena Sava, Alessandra Battaglia, Vincenzo Adamo
Journal: Journal of Clinical Oncology (2017)

e14617 Background: Nivo is a novel therapeutic option in 2 nd line NSCLC. However, predictive biomarkers are lacking. The presence of systemic inflammation correlated with poor outcome in many cancer types, including NSCLC. We aimed to evaluate whether there is a correlation between some indicators of inflammation and response in patients (pts) treated with Nivo or Docetaxel (D). Methods: 23 consecutive pts with NSCLC receiving Nivo were analyzed. Baseline white cell count (WBC) and ANC were collected and correlated with tumor response. 27 NSCLC pts treated with D were used as controls. An ANC ≥ 7500 cell/µl was defined neutrophilia. dNLR was calculated as: ANC/(WBC-ANC). Platelet count (PLT) ≥ 450 × 10 3 /μL was defined as thrombocytosis. PLR ratio was defined as PLT/lymphocyte count. dNLR ≥3 and PLR ≥160 were defined high. Results: Baseline characteristics: median age 66 years (range 45-82); sex M 74%; histology squamous 42%, adenocarcinoma 48%, and 10% mixed histology/NOS. Smoking status: 90% smokers/former smokers. Among non-squamous pts, 13,7% were EGFR mutated and 10,3% were KRAS-mutated, with an equal distribution in both treatment groups. Lines of therapies: range 2-8 in Nivo group and 2-3 in D group. Overall response rate (ORR): 13.6% with Nivo vs. 7.7% with D; 9% of pts with Nivo experienced unconventional responses. Baseline neutrophilia (17.4% with Nivo and 27% with D) and thrombocytosis (4.3% and 3.8%, respectively) were not associated with response (ORR 0%). High dNLR (13% and 38% with Nivo and D) correlated with no response (0% ORR), whereas high PLR correlated with no responses to D and reduced ORR to Nivo (10%). Conclusions: The results of this preliminary study suggest that baseline neutrophilia, thrombocytosis and high dNLR are associated with no response to both D and Nivo, whereas high PLR is associated with no response to D and reduced activity with Nivo. Given their relative easy estimation, baseline evaluation of these indicators of inflammation should be included before 2 nd line therapy start, especially for highly expensive treatments, such as immunotherapy.
Cardiac safety analysis of trabectedin (T) vs. dacarbazine (D) in patients (Pts) with advanced leiomyosarcoma (LMS) or liposarcoma (LPS) after prior anthracycline chemotherapy.
Authors: Scott Schuetze, Shreyaskumar Patel, Margaret von Mehren, Christopher W. Ryan, Mohammed M. Milhem, Brian Andrew Van Tine, Sharon Anne McCarthy, George C. Wang, Loreta Marquez, Trilok V. Parekh, Roland Elmar Knoblauch, George D. Demetri
Journal: Journal of Clinical Oncology (2016)

11060 Background: Anthracyclines have activity against soft-tissue sarcomas (STS), however the risk of cumulative cardiotoxicity can limit their clinical benefit. Recently, the activity of T and D in the treatment of pts with LMS or LPS, after failure of previous tx including anthracyclines, was compared in a phase 3 study (ET743-SAR-3007, Demetri et al, 2015, JCO; 62.4734). Here we report cardiac–related adverse events (AEs) observed in the study. Methods: In this study, 577 pts were randomized 2:1 to receive treatment with T or D every 3 weeks. Data regarding previous anthracycline exposure, medical history and concomitant medications, as well as baseline and end-of-treatment (EOT) left ventricular ejection fraction (LVEF) assessments, and adverse events were collected. Multivariate analysis for risk of LVEF decline on treatment evaluated cumulative anthracycline dose (CAD), LVEF at study entry, a history of cardiac disorder (HCD) and patient age. Results: Median CAD was 241 mg/m2 [D] vs. 270 mg/m2[T], with median times from last anthracycline dose to randomization of 5.9 months [D] vs. 6.9 months [T]. At baseline, 20.3% [D] vs. 24.6% [T] pts were ≥ 65 yrs, 24.4% [D] vs. 28.8% [T] pts reported HCD , 35.5% [D] vs. 45.5% [T] utilized cardiac medication, and 14.0% [D] vs. 12.7% [T] had LVEF ≤ LLN. “Cardiac Disorders” of any grade on study were reported by 14.5% [D] vs. 15.1% [T] pts, most frequently arrhythmias (7.0% [D] vs. 9.5% [T]). “Myocardial disorders” (0% [D] vs. 1.6% [T]) and heart failure (0.6% [D] vs. 2.9% [T]) were also reported. One drug-related death due to “cardiac disorder” was reported in T arm. Baseline and EOT LVEF assessments were obtained in 58.1% [D] and 66.4% [T] of pts; LVEF declines ( ≥ 15%, or ≥ 5% and < LLN) were observed in 11.0% [D] vs. 13.5% [T]. These pts received a median of 2 vs. 8.5 cycles of D vs. T, respectively. A multivariate analysis identified CAD ≥ 300 mg/m2, abnormal LVEF at baseline, a HCD, and age ≥ 65 yrs as independent predictors of LVEF decline. Conclusions: Pts with STS are at risk of cardiac events after prior treatment with anthracyclines; cardiac monitoring should be considered based on age, CAD, HCD, and LVEF. Clinical trial information: NCT01343277.
The timing of docetaxel initiation in metastatic castrate sensitive prostate cancer and the rate of chemotherapy induced toxicity.
Authors: Igal Kushnir, Kim Koczka, Michael Ong, Christina M. Canil, Elham Sabri, M. Neil Reaume
Journal: Journal of Clinical Oncology (2018)

e17005 Background: Docetaxel is currently used to treat both metastatic castrate resistant prostate cancer (mCRPC) and recently metastatic castrate sensitive prostate cancer (mCSPC). The CHAARTED protocol for mCSPC initiated chemotherapy within four months of the start of androgen deprivation therapy (ADT). There is evidence suggesting that docetaxel pharmacokinetics is affected by ADT which is attributed to change in liver metabolism induced by castration. This may explain the difference in docetaxel toxicity between patients (pts) with mCSPC and mCRPC. In this retrospective analysis we will assess whether initiating docetaxel treatment in close proximity to start of ADT therapy for mCSPC is associated with more treatment related toxicity. Methods: We identified all pts with mCSPC treated at The Ottawa Hospital Cancer Center with docetaxel chemotherapy between June 2014 - September 2017. For each patient we calculated the time to chemotherapy (TTC) interval between the start of ADT and the 1st cycle of docetaxel. We checked for an association between TTC and febrile neutropenia (FN) toxicity induced treatment delay or discontinuation, and toxicity induced dose reduction. Results: Eighty three pts were identified. The median TTC was 67 days (range 3-189). Twenty three pts (27.7%) experienced FN. Docetaxel toxicity resulted in 8 patients (9.6%) had their treatment delayed, 30 patients (36.1%) had their dose reduced and 18 (21.6%) had their treatment discontinued before completing the scheduled 6 cycles. No correlation was found between the TTC and FN (P = 0.99), docetaxel dose reduction (P = 0.95), treatment delay (P = 0.06) and treatment discontinuation (P = 0.88). Conclusions: No correlation was found between the timing of docetaxel treatment start and the rate of treatment related toxicity. Therefore, there is no indication for upfront chemotherapy delay from start of ADT unless the patient’s overall condition is not well enough and it is anticipated that ADT treatment may improve their condition. However, the rate of FN (27.7%) is much higher than expected, regardless of TTC and prophylactic granulocyte colony-stimulating factor may be considered in a real world population.
Leading hospital suspends complex heart surgery to maintain patient safety
Authors: Declan C Murphy
Journal: BMJ (2018)

A leading London teaching hospital has suspended the most complex types of heart surgery to maintain patient safety.

Jacqueline Totterdell, chief executive of St George’s University Hospitals NHS Foundation Trust, said that the decision had been taken “to protect the long term future of our cardiac surgery service.”

A trust spokesperson said that the move was a result of “response to feedback from clinicians working in the service” and was “to allow the service to focus …