tbuckley/cabot-search huggingface dataset:
Updated efficacy and safety of KEYNOTE-224: A phase II study of pembrolizumab (pembro) in patients with advanced hepatocellular carcinoma (HCC).
Authors: Masatoshi Kudo, Richard S. Finn, Julien Edeline, Stéphane Cattan, Sadahisa Ogasawara, Daniel H. Palmer, Chris Verslype, Vittorina Zagonel, Laetitia Fartoux, Arndt Vogel, Debashis Sarker, Gontran Verset, Stephen Lam Chan, Jennifer J. Knox, Bruno Daniele, Ellen B Gurary, Abby B. Siegel, Lokesh Jain, Ann-Lii Cheng, Andrew X. Zhu
Journal: Journal of Clinical Oncology (2020)

518 Background: Pembro received accelerated approval in pts with advanced HCC in the second-line setting based on results of the KEYNOTE-224 trial. Results of a 2 y follow-up analysis of the efficacy and safety in this trial are presented here. Methods: Eligible pts had histologically confirmed HCC, radiographic progression on/intolerance to sorafenib and disease not amenable to curative treatment, Child Pugh A, ECOG PS 0-1 and BCLC stage C or B. Pts received pembro 200 mg IV Q3W for 2 y or until disease progression, unacceptable toxicity, consent withdrawal or investigator decision. Response was assessed every 9 wk. Primary endpoint was ORR (RECIST v1.1, central review). Secondary endpoints were DOR, DCR, PFS, OS and safety. Results: Efficacy and safety were assessed in 104 pts. The median time from randomization to data cutoff (Jun 05, 2019) was 31.2 mo (27.5-35.5 mo). Pt characteristics were: median age 68 y (43-87), 21.2% HBV+, 25% HCV+, 94.2% Child Pugh A, 79.8% had PD on sorafenib, 17.3% had MVI and 64.4% had extrahepatic disease. ORR was 18.3% (95% CI 11.4-27.1) and was similar across subgroups. Median DOR was 21.0 mo (3.1-28+ mo); 77% had responses lasting ≥12 mo (Kaplan Meier). Best overall responses were 4 (3.8%) CRs, 15 (14.4%) PRs, 45 (43.3%) SDs and 34 (32.7%) PDs; DCR was 61.5%. The median PFS (95% CI) was 4.9 mo (3.5-6.7) and OS was 13.2 mo (9.7-15.3). PFS 24 mo rate was 11.3% and OS 24 mo rate was 30.8%. ORR was shown to be a predictor of longer OS by landmark analysis. Treatment-related AEs occurred in 76 (73.1%) pts; the most common AEs were fatigue, increased aspartate aminotransferase, pruritus and diarrhea observed in ≥10% pts. Grade ≥3 treatment related AEs occurred in 27 (26.0%) pts. Immune-mediated hepatitis occurred in 3 (2.9%) pts; no cases of HBV/HCV flare were identified. Conclusions: At 2 y follow-up, pembro continued to provide durable anti-tumor activity and prolonged survival (30.8% OS, 24 mo rate), further supporting its use in previously treated pts with advanced HCC. With longer follow-up, increases in ORR (18.3% vs 17.0%), DOR ≥12 mo (77.0% vs 61.4%) and CR rates (3.8% vs 1%) were seen. The safety profile was similar to the primary analysis. Clinical trial information: NCT02702414.
Measuring Clinical Importance in a Trial of Interventions for Mixed Urinary Incontinence
Authors: Toshi A. Furukawa
Journal: JAMA (2020)

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Use and impact of perioperative chemotherapy in patients with resectable colorectal cancer metastases.
Authors: Amy Body, Margaret Lee, Hui-Li Wong, Alun Pope, Azim Jalali, Jeremy David Shapiro, Suzanne Kosmider, Jeanne Tie, Frances Sarah Barnett, Gary Edward Richardson, Desmond Yip, Stephanie Hui-Su Lim, Joseph James McKendrick, Peter Gibbs, Rachel Wong
Journal: Journal of Clinical Oncology (2020)

159 Background: There is conflicting evidence regarding benefit of perioperative chemotherapy (p-chemo) for metastatic colorectal cancer (mCRC) patients (pts) undergoing resection of metastases (mets). Aims: To describe use of and outcomes from p-chemo in mCRC pts who underwent resection of isolated liver or lung mets. Methods: Pts were identified from the TRACC (Treatment of Recurrent and Advanced Colorectal Cancer) database, a multi-centre registry of mCRC pts. P-chemo was defined as chemotherapy within 12 weeks of surgery. Multivariate (MV) analysis using a Cox proportional hazards model was undertaken. Results: 371 pts were identified. Median age was 64 (27 – 90), 169 (45%) had de novo stage IV disease, 96% were ECOG 0-1. 284 (77%) had liver-only and 87 (23%) lung-only mets. 242 (65%) pts received p-chemo (58 pre-op alone, 134 post-op alone, 50 both). 62 (19%) pts also received a biologic agent (47/62 pre-op). Median age was 68 and 61 years in no p-chemo and p-chemo groups, respectively (p&lt;0.0001). 53% of no p-chemo pts and 23% of p-chemo pts had had prior adjuvant chemotherapy (p&lt;0.001). On MV analysis, p-chemo was a significant predictor of survival (HR 0.52, 95% CI 0.32-0.88, p=0.014). The other significant predictor of improved survival was ECOG PS of 0 (HR 0.58, p=0.019). Predictors of worse survival were rectal primary (HR 1.98 p=0.009), male gender (HR 1.69 p=0.03) and de-novo metastatic disease (HR 2.63, p=0.006). Prior adjuvant chemo, age, liver vs lung mets, use of perioperative biologics, BRAF and RAS status had no significant impact. In an exploratory analysis, the group considered “resectable” upfront (n=281) was analysed separately, perioperative chemotherapy was not a significant predictor of survival in this subgroup (HR 0.69, p=0.26). Conclusions: In routine care there is a variable approach to the use of p-chemo in pts with potentially resectable liver or lung mets. P-chemo is associated with improved survival in this analysis, although this was not confirmed in the separate analysis of the “resectable” subgroup. Due to the retrospective nature of the study confounding by unmeasurable factors is possible. This study supports ongoing consideration of P-chemo in pts with resectable mets.
Alpha-synuclein-induced mitochondrial dysfunction is mediated via a sirtuin 3-dependent pathway
Authors: Jae-Hyeon Park, Jeremy D. Burgess, Ayman H. Faroqi, Natasha N. DeMeo, Fabienne C. Fiesel, Wolfdieter Springer, Marion Delenclos, Pamela J. McLean
Journal: Molecular Neurodegeneration (2020)

Misfolding and aggregation of the presynaptic protein alpha-synuclein (αsyn) is a hallmark of Parkinson's disease (PD) and related synucleinopathies. Although predominantly localized in the cytosol, a body of evidence has shown that αsyn localizes to mitochondria and contributes to the disruption of key mitochondrial processes. Mitochondrial dysfunction is central to the progression of PD and mutations in mitochondrial-associated proteins are found in familial cases of PD. The sirtuins are highly conserved nicotinamide adenine dinucleotide (NAD
Understanding and Addressing the Role of Coping in Palliative Care for Patients With Advanced Cancer
Authors: Joseph A. Greer, Allison J. Applebaum, Juliet C. Jacobsen, Jennifer S. Temel, Vicki A. Jackson
Journal: Journal of Clinical Oncology (2020)

Advanced cancer, with its considerable physical symptoms and psychosocial burdens, represents an existential threat and major stressor to patients and their caregivers. In response to such stress, patients and their caregivers use a variety of strategies to manage the disease and related symptoms, such as problem-focused, emotion-focused, meaning-focused, and spiritual/religious coping. The use of such coping strategies is associated with multiple outcomes, including quality of life, symptoms of depression and anxiety, illness understanding, and end-of-life care. Accumulating data demonstrate that early palliative care, integrated with oncology care, not only improves these key outcomes but also enhances coping in patients with advanced cancer. In addition, trials of home-based palliative care interventions have shown promise for improving the ways that patients and family caregivers cope together and manage problems as a dyad. In this article, we describe the nature and correlates of coping in this population, highlight the role of palliative care to promote effective coping strategies in patients and caregivers, and review evidence supporting the beneficial effects of palliative care on patient coping as well as the mechanisms by which improved coping is associated with better outcomes. We conclude with a discussion of the limitations of the state of science, future directions, and best practices on the basis of available evidence.
Trends in Clinical Characteristics and Prescribing Preferences for SGLT2 Inhibitors and GLP-1 Receptor Agonists, 2013–2018
Authors: Chintan V. Dave, Sebastian Schneeweiss, Deborah J. Wexler, Gregory Brill, Elisabetta Patorno
Journal: Diabetes Care (2020)

There is a paucity of data evaluating recent changes in clinical and prescriber characteristics of patients initiating sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1RA).U.S.-based administrative claims data (July 2013 to June 2018) were used to identify initiators of SGLT2i and GLP-1RA.Over 5 years, empagliflozin initiation (as a proportion of SGLT2i) increased by 57.1% (P < 0.001 for trend), while canagliflozin initiation declined by 75.1% (P < 0.001). Empagliflozin was the only agent within SGLT2i with an increase in the proportion of patients with myocardial infarction, stroke, or heart failure (collectively called CVD-HF) (P < 0.001). Liraglutide initiation (as a proportion of total GLP-1RA) declined by 32.1% (P < 0.001), and dulaglutide initiation increased by 34.1% (P < 0.001); the proportion of patients with CVD-HF increased the most in liraglutide initiators (5.1% increase; P < 0.001). Most prescribers were internists or endocrinologists; cardiologist prescribing remained low (<1%).For SGLT2i, shifts in preference for empagliflozin followed changes in drug labels and guidelines, while for GLP-1RA, other factors such as price or ease of administration may have led to a preference for dulaglutide over liraglutide.
<i>UBR5</i> Is Coamplified with <i>MYC</i> in Breast Tumors and Encodes an Ubiquitin Ligase That Limits MYC-Dependent Apoptosis
Authors: Xi Qiao, Ying Liu, Maria Llamazares Prada, Aravind K. Mohan, Abhishekh Gupta, Alok Jaiswal, Mukund Sharma, Joni Merisaari, Heidi M. Haikala, Kati Talvinen, Laxman Yetukuri, Joanna W. Pylvänäinen, Juha Klefström, Pauliina Kronqvist, Annika Meinander, Tero Aittokallio, Ville Hietakangas, Martin Eilers, Jukka Westermarck
Journal: Cancer Research (2020)

Abstract For maximal oncogenic activity, cellular MYC protein levels need to be tightly controlled so that they do not induce apoptosis. Here, we show how ubiquitin ligase UBR5 functions as a molecular rheostat to prevent excess accumulation of MYC protein. UBR5 ubiquitinates MYC and its effects on MYC protein stability are independent of FBXW7. Silencing of endogenous UBR5 induced MYC protein expression and regulated MYC target genes. Consistent with the tumor suppressor function of UBR5 (HYD) in Drosophila, HYD suppressed dMYC-dependent overgrowth of wing imaginal discs. In contrast, in cancer cells, UBR5 suppressed MYC-dependent priming to therapy-induced apoptosis. Of direct cancer relevance, MYC and UBR5 genes were coamplified in MYC-driven human cancers. Functionally, UBR5 suppressed MYC-mediated apoptosis in p53-mutant breast cancer cells with UBR5/MYC coamplification. Furthermore, single-cell immunofluorescence analysis demonstrated reciprocal expression of UBR5 and MYC in human basal-type breast cancer tissues. In summary, UBR5 is a novel MYC ubiquitin ligase and an endogenous rheostat for MYC activity. In MYC-amplified, and p53-mutant breast cancer cells, UBR5 has an important role in suppressing MYC-mediated apoptosis priming and in protection from drug-induced apoptosis. Significance: These findings identify UBR5 as a novel MYC regulator, the inactivation of which could be very important for understanding of MYC dysregulation on cancer cells.
End-to-side <i>versus</i> side-to-side anastomosis after laparoscopic right hemicolectomy for colon cancer: Short-term outcomes of a randomized controlled trial.
Authors: Min Hyun Kim, Jung Rae Cho, Heung-Kwon Oh, Duck-Woo Kim, Sung-Bum Kang
Journal: Journal of Clinical Oncology (2020)

27 Background: A standard anastomotic configuration after right hemicolectomy is not well established, although short-term benefits of end-to-side anastomosis have been reported. This study was designed to assess the superiority of end-to-side anastomosis compared to side-to-side anastomosis after laparoscopic right hemicolectomy for colon cancer under an enhanced recovery program. Methods: Between September 2016 and August 2019, 130 patients (18–80 years) scheduled for laparoscopic right hemicolectomy were randomly assigned (1:1) to undergo end-to-side ( n = 65) or side-to-side ( n = 65) anastomosis. All patients underwent an enhanced recovery program with early diet and mobilization. The primary outcome was the cumulative recovery rate 7 days after surgery, defined as the percentage of patients who met all of the following recovery criteria: tolerated diet for 24h, analgesic-free, safe ambulation, and afebrile status without major complications. Results: The cumulative recovery rate did not differ between end-to-side (92.3%, 60/65) and side-to-side anastomosis (92.3%, 60/65) ( P = 1.000). Both approaches had similar cumulative recovery rates at 4, 5, and 6 days (end-to-side vs. side-to-side: 41.5% vs. 35.4%, P = 0.589; 73.8% vs. 63.1%, P = 0.257; 86.2% vs. 81.5%, P = 0.634; respectively) The median recovery time [interquartile range (IQR)] in the end-to-side and side-to-side groups was 105 [90-124] hours and 113 [84-139] hours, respectively ( P = 0.474), showing no significant difference. Length of stay [IQR] was similar in the end-to-side and side-to-side groups (5 [5–7] vs. 6 [5–7] days; P = 0.376). The 30-day complication rate (16.9% vs. 12.3%, P = 0.620), enhanced recovery program failure rate (10.8% vs. 7.7%, P = 0.763), and 30-day readmission rate (4.6% vs. 3.1%; P = 1.000) were not significantly different between the groups. Conclusions: This is the first randomized controlled trial showing that end-to-side anastomosis is not superior to side-to-side anastomosis in terms of short-term outcomes after laparoscopic right hemicolectomy. Clinical trial information: NCT02897531.
Two Worlds Collide: Unraveling the Role of the Immune System in BRAF–MEK Inhibitor Responses
Authors: Keiran S.M. Smalley
Journal: Cancer Discovery (2020)

Abstract Summary: Although BRAF–MEK inhibition can enhance the immune recognition of melanoma cells, the mechanisms that underlie this remain poorly defined. In this issue of Cancer Discovery, Erkes and colleagues present new data showing that BRAF–MEK inhibition activates pyroptosis in melanoma cells through gasdermin E cleavage, leading to T-cell infiltration and improved therapy responses in vivo. See related article by Erkes et al., p. 254.
Comparison of Treatment Strategies for Patients With Clinical Stage T1–3/N2 Lung Cancer
Authors: Ya-Fu Cheng, Wei-Heng Hung, Heng-Chung Chen, Ching-Yuan Cheng, Ching-Hsiung Lin, Sheng-Hao Lin, Bing-Yen Wang
Journal: Journal of the National Comprehensive Cancer Network (2020)

Background: The therapeutic strategies for clinical stage T1–3N2 (cT1–3N2) lung cancer are controversial. For operable tumors, treatment can vary by center, region, and continent. This study aimed to identify the optimal therapeutic method and type of surgical strategy for cT1–3N2 lung cancer. Methods: This retrospective evaluation analyzed the records of 17,954 patients with cT1–3N2 lung cancer treated in 2010 through 2015 from the SEER database. The effects of different therapeutic methods and types of surgical strategies on overall survival (OS) were assessed. Univariate and multivariate analyses were performed using a Cox proportional hazards model. Results: The 5-year OS rates were 27.7% for patients with T1N2 disease, 21.8% for those with T2N2 disease, and 19.9% for T3N2 disease. Neoadjuvant therapy plus operation (OP) plus adjuvant therapy, and OP plus adjuvant therapy, provided better 5-year OS rates than OP alone or concurrent chemoradiotherapy (34.1%, 37.7%, 29.3%, and 16.1%, respectively). In the T1N2, T2N2, and T3N2 groups, lobectomy provided better 5-year OS than pneumonectomy, sublobectomy, and no surgery. Both univariate and multivariate analyses showed that young age, female sex, well-differentiated histologic grade, adenocarcinoma cell type, neoadjuvant and adjuvant therapy, lobectomy, and T1 stage were statistically associated with better 5-year OS rates. Conclusions: In cT1–3N2 lung cancer, multimodal treatments tended to provide better 5-year OS than OP alone or concurrent chemoradiotherapy. In addition, lobectomy was associated with better survival than other operative methods.
The cost of chemotherapy administration: A systematic review and meta-analysis.
Authors: Gursharan Kaur Sohi, Jordan Levy, Victoria Delibasic, Laura Davis, Alyson Mahar, Elmira Amirazodi, Craig Earle, Julie Hallet, Ahmed Hammad, Nicole Mittmann, Natalie Coburn
Journal: Journal of Clinical Oncology (2020)

810 Background: Cancer treatment is a significant driver of healthcare costs worldwide, however, the economic impact of treating patients with anti-neoplastic agents is poorly elucidated. Hence, we conducted a systematic review and meta-analysis to estimate the direct costs associated with administering intravenous chemotherapy in an outpatient setting. Methods: We systematically searched four databases from 2010 to present and extracted hourly administration costs and the respective components of each estimate. Separate analyses were conducted of Canadian and United States (US) studies, respectively, to address a priori hypotheses regarding heterogeneity amongst administration cost estimates. The Drummond checklist was used to assess risk-of-bias. Data were summarized using medians with interquartile ranges and five outliers were identified; costs were presented in 2019 USD. Results: A total of 44 studies were analyzed, including sub-analyses of 19 US and seven Canadian studies. 26/44 studies were of moderate or high quality. When components of administration cost were evaluated, physician costs were reported most frequently (24 studies), followed by lab tests (13) and overhead costs (9). The median cost estimate when outliers were excluded was $142/hour (IQR = $103-166). Sensitivity analyses determined the median administration cost in the US was $149/hour (IQR = $118-158), and was $128/hour (IQR = $102-137) in Canada. Conclusions: There is currently a paucity of literature addressing the costs of chemotherapy administration, and existing studies utilize a patchwork of reporting methodologies which renders direct comparison challenging. Our results demonstrate that the cost of administering chemotherapy is approximately $125-150/hour, globally. This value is dependent upon the region of analysis, inclusiveness of cost subcomponents as well as the methodology used to estimate unit prices, as described here.
Neoadjuvant chemotherapy followed by liver resection for patients with metastatic colorectal cancer.
Authors: Rui Jin, Zhaohui Jin, Sean P. Cleary, David M. Nagorney, Rory L. Smoot, Robert R. McWilliams, Amit Mahipal
Journal: Journal of Clinical Oncology (2020)

147 Background: Colorectal cancer is one of the leading causes of cancer related deaths with liver being most common site of CRC metastasis. More than 50% of the CRC patients will develop metastatic liver lesion that eventually leads to death in about 70% of them. In this retrospective review we reviewed the outcome of pts who received neoadjuvant chemotherapy followed by resection of liver lesion for metastatic colorectal cancer. Methods: 304 pts who had preoperative chemotherapy were identified from 1045 metastatic colorectal cancer patients who had liver metastasectomy at Mayo Clinic between 1997 and 2018. A retrospective review was conducted by using data from electronic medical records. Statistical analyses utilized Kaplan-Meier method, Log-rank test, and Cox proportional hazards models. Results: There were 113 (37%) female and 191 (63%) male pts. Median age at primary disease diagnosis was 56.5 yrs. Two hundred forty-nine pts presented with stage IV metastatic colorectal cancer. Primary tumor locations were: 53 right-sided, 117 left-sided and 133 rectum. 152 (50%) pts had extrahepatic metastases. Two pts were found to be MSI-H, 113 MSS, 189 unknown. BRAF mutation was found in 6 patients. RAS mutation was present in 84 patients, with 124 unknown. Pts received chemotherapy for median of 2.82 months. Single agent fluoropyrimidine was administered in 38 (12%) pts and rest receiving chemotherapy doublet or triplet with fluropyrimidine plus oxaliplatin being most common regimen. The median overall survival from primary diagnosis for the entire group was 74.5 months. Median overall survival from liver metastasectomy was 60.0 months. In univariate analysis, metachronous disease, age &lt; 60 yrs, and an absence of extrahepatic lesions led to statistically significant improvement of overall survival from primary diagnosis. Metachronous and extrahepatic lesions remained statistically significant in multivariate analysis. Conclusions: Neoadjuvant chemotherapy followed by liver metastasectomy is beneficial for highly-selected metastatic colorectal cancer pts. Compared to a historical control of 30-36 months, our patient population had a median overall survival of about 5 years from resection.