tbuckley/cabot-search huggingface dataset:
The intersection of age and tumor biology with postoperative outcomes in patients after cytoreductive surgery and HIPEC.
Authors: Michael K. Turgeon, Adriana C. Gamboa, Rachel M. Lee, Mohammad Yahya Zaidi, Charles Kimbrough, Travis Edward Grotz, Keith F. Fournier, Sean Patrick Dineen, Jula Veerapong, Callisia Clarke, Harveshp Mogal, Sameer H. Patel, Laura A. Lambert, Sean Ronnekleiv-Kelly, Mustafa Raoof, Fabian McCartney Johnston, Charles A. Staley, Jordan Cloyd, Shishir K. Maithel, Joshua H. Winer
Journal: Journal of Clinical Oncology (2020)

184 Background: Patient age is often a significant factor in preoperative selection for major abdominal surgery. Its association with postoperative outcomes in patients undergoing cytoreductive surgery(CRS) and hyperthermic intraperitoneal chemotherapy(HIPEC) remains ill-defined. Methods: The US HIPEC Collaborative database(2000-2017) was reviewed for patients who underwent a CCR0/1 CRS/HIPEC. Age was categorized into &lt; 65 or &gt;65yrs. Primary outcomes were postoperative major complications, readmission, 30-day mortality, and non-home discharge(NHD). Analysis was stratified by disease histology: non-invasive(appendiceal LAMN/HAMN), and invasive(appendiceal/colorectal adenocarcinoma). Results: Of 1090pts identified, 22% were &gt;65yrs(n = 240), 59% were female(n = 646), 25% had non-invasive(n = 276) and 51% had invasive(n = 555) histology. Median PCI was 13(IQR7-20). Patients &gt;65yrs had a higher rate of major complications(37vs26%, p = 0.02), readmission(28vs22%,p = 0.05), 30-day mortality(3vs1%,p = 0.02), and NHD(12vs5%,p &lt; 0.01) compared to those &lt; 65yrs. On multivariable analysis accounting for extent of disease as measured by PCI, for non-invasive histology, age &gt;65yrs was an independent predictor for NHD(OR:2.54,95%CI:1.08-5.99,p = 0.03), but not major complications. For invasive histology, even when accounting for PCI, age &gt;65yrs was an independent predictor for both NHD(OR:2.54,95%CI:1.08-5.98,p = 0.03) and major complications(OR:2.04,95%CI:1.16-3.59,p = 0.05). Age was not associated with hospital readmission or 30-day mortality for any histology. Conclusions: Regardless of histology, patients &gt;65yrs are nearly at three-fold increased risk for non-home discharge after CRS/HIPEC. For invasive histology, age &gt;65yrs is also associated with increased major complication rates, but the procedure seems to be better tolerated when performed for indolent biology. These data inform preoperative counseling and risk stratification. Early planning for discharge disposition in this high-risk population can potentially translate to cost savings.
AABH (aspartyl [asparaginyl] β-hydroxylase) as a serum biomarker for breast cancer.
Authors: Kiarash Moshiri
Journal: Journal of Clinical Oncology (2020)

2 Background: Breast cancer accounts for 27% of female cancers. One in every eight women will develop breast cancer in their lifetime. More than 220,000 new cases of breast cancer will be diagnosed in the United States in 2020. Five-year survival rates for breast cancer are 98% for localized disease, 83% for regionally spread and 26% for distantly spread cancer. However, 25% of all metastases occur more than 5 years after the initial diagnosis and thus survival rates decrease as time goes out to 10 years due to disease recurrence. Current detection methods rely on imaging modalities, including mammography and MRI. No serum bio-markers have been approved for either breast cancer screening or monitoring for disease recurrence, yet. In asymptomatic women in remission from breast cancer the guidelines of the major oncologic organizations only suggest annual mammography for detection of new primary tumors. Methods: We have investigated the utility of aspartyl (asparaginyl) β-hydroxylase (AABH) as a serum bio-marker for cancer. AABH has been detected by immunohistochemical staining (IHC) in a broad range of cancers including breast cancer. It has been detected by IHC in &gt; 99% of tumor specimens tested (n &gt; 2000) but is absent in adjacent non-affected tissue, and in tissue samples from non-affected individuals. This led to the development of a sandwich ELISA that reliably measures AABH in serum. Results: In the current study we have utilized the assay to quantify AABH levels in the sera of patients diagnosed with Breast Cancer compared to women free of disease. Increased levels of AABH were found in the serum of 99% of patients with breast cancer (n = 189). In women not known to have cancer, AABH was essentially undetectable in serum (n = 65, specificity = 96%). Serum from several women currently in remission subsequent to treatment for breast cancer were also analyzed and found to be negative for AABH. Conclusions: Thus, measurement of serum AABH levels has great promise as a diagnostic tool for breast cancer with potential application in monitoring for disease recurrence. Elevated serum AABH in conjunction with mammography and MRI may greatly facilitate earlier diagnosis of both primary and recurrent Breast Cancer.
Gray areas and evidence gaps in the management of rectal cancer as revealed by the comparison of recommendations from national and international clinical guidelines.
Authors: Giacomo Bregni, Tugba Akin Telli, Silvia Camera, Chiara Baratelli, Leila Shaza, Amélie Deleporte, Luigi Moretti, Gabriel Liberale, Alain Hendlisz, Francesco Sclafani
Journal: Journal of Clinical Oncology (2020)

74 Background: While the management of nonmetastatic and oligometastatic rectal cancer has rapidly evolved over the last few decades, many grey areas and highly debated topics remain that foster significant variation in clinical practice. We aimed to identify controversial points and evidence gaps in this disease setting by systematically comparing recommendations from national and international clinical guidelines. Methods: Twenty-six clinical questions reflecting practical challenges in the routine management of nonmetastatic and oligometastatic rectal cancer patients were selected. Recommendations from the ESMO, NCCN, JSCCR, Australian and Ontario guidelines were extrapolated and compared using a 4-tier classification system (i.e., identical/very similar, similar, slightly different, different). Overall agreement between guidelines (i.e., substantial/complete disagreement, partial disagreement, partial agreement, substantial/complete agreement) was assessed for each clinical question and compared against the highest level of available evidence according to the Oxford CEBM Levels of Evidence guidelines by using the χ 2 statistic test. Results: Guidelines were in substantial/complete agreement, partial agreement, partial disagreement, and substantial/complete disagreement for 8 (30.8%), 2 (7.7%), 7 (26.9%), and 9 (34.6%) clinical questions, respectively. High level of evidence supported clinical recommendations in 2/10 cases (20%) where guidelines were in agreement and in 10/16 cases (62.5%) where guidelines were in disagreement (χ2 = 4.4726, p = 0.034). Agreement was frequently reached for questions regarding diagnosis, staging, and radiology/pathology pro-forma reporting, while disagreement characterised most of the treatment-related topics. Conclusions: Substantial variation exists across national and international clinical guidelines in the recommendations for the management of nonmetastatic and oligometastatic rectal cancer. This variation is only partly explained by the lack of supporting, high-level evidence.
Bowel anastomosis before or after HIPEC: A prospective comparative study in patients undergoing CRS+HIPEC for peritoneal surface malignancy at a tertiary care cancer center in India.
Authors: S.P. Somashekhar, Rohit Kumar C., Ashwin K. Rajgopal, Shabber Zaveri, Ramya Yethadka, Amit Rauthan
Journal: Journal of Clinical Oncology (2020)

254 Background: To do bowel anastomosis before or after HIPEC has been debated since the time heat is being used for intraperitoneal chemotherapy after cytoreductive surgery. We report our experience of impact of heat on anastomosis and leak rates. Methods: All patients diagnosed with peritoneal surface malignancy eligible for CRS+ HIPEC as per institution protocol had bowel restoration being performed with stapler &amp; second layer taken. Our institution has two teams, of which one performs anastomosis before and one after HIPEC. All the data was entered prospectively in the HIPEC registry and is being analyzed to see the effect of heat on anastomosis. Results: 220 patients underwent CRS+ HIPEC of which organ of origin was colorectal 39%, stomach 20%, mesothelioma 11%, ovary 20% and others 10%. Upfront cases were 12%, interval 58% &amp; recurrent 30%. Prior surgical score was 0 (62%), 1 (11%), 2 (23%), 3 (4%). 100 patients were in group that had anastomosis before HIPEC and 120 patients in other. Mean PCI 13.4±4.5, blood loss 1250±553.9 ml, duration of surgery 9.5±2.4 hrs, duration of hospital stay 9±3.5 days. Overall 57.05% had bowel resections, of which large bowel was 47.8%, small bowel 17.7%, stomach 6.13%. 19.6% required multivisceral resection &amp; stoma rate was 11.1% for whole group. Both the group had almost same number of total (55.4 %vs 58.6%), small (15.3%vs16.5%) &amp; large bowel resections (44.3%vs 49.5%). We had 4 (1.84%) leak overall, of which 2 were in either groups. Overall G3-4 morbidity was 28.4%, surgical G3-4 was 12.5%, perforation 3.6%, obstruction 1.84%, re exploration was 9.2%. 30-day mortality was 4.9%. Conclusions: We conclude that anastomotic integrity, leak rates &amp; complications related to small or large bowel restoration is same either before or after HIPEC as we observed no difference in our study. However, since this is not a randomized study a well-designed multi-institutional randomized study needs to be planned for stronger evidence of the same.
Upregulation of hepatic angiotensin-converting enzyme 2 (ACE2) and angiotensin-(1-7) levels in experimental biliary fibrosis
Authors: Chandana B Herath, Fiona J Warner, John S Lubel, Rachael G Dean, Zhiyuan Jia, Rebecca A Lew, A Ian Smith, Louise M Burrell, Peter W Angus
Journal: Hepatology (2007)

Background/Aims  Angiotensin-converting enzyme 2 (ACE2), its product, angiotensin-(1–7) and its receptor, Mas, may moderate the adverse effects of angiotensin II in liver disease. We examined the expression of these novel components of the renin angiotensin system (RAS) and the production and vasoactive effects of angiotensin-(1–7) in the bile duct ligated (BDL) rat.  Methods  BDL or sham-operated rats were sacrificed at 1, 2, 3 and 4 weeks. Tissue and blood were collected for gene expression, enzyme activity and peptide measurements. In situ perfused livers were used to assess angiotensin peptide production and their effects on portal resistance.  Results  Hepatic ACE2 gene and activity ( P  P  P  P  P   Conclusions  RAS activation in chronic liver injury is associated with upregulation of ACE2, Mas and hepatic conversion of angiotensin II to angiotensin-(1–7) leading to increased circulating angiotensin-(1–7). These results support the presence of an ACE2-angiotensin-(1–7)-Mas axis in liver injury which may counteract the effects of angiotensin II.
A phase II study of savolitinib (volitinib, AZD6094, HMPL-504) in subjects with <i>MET</i> amplified metastatic colorectal cancer (mCRC) detected by cell-free (cf)DNA.
Authors: Jingquan Jia, Donna Niedzwiecki, Christy Arrowood, Nancy Garett-Mead, Rebecca Nagy, Richard B. Lanman, John Wright, Andrew B. Nixon, John H. Strickler
Journal: Journal of Clinical Oncology (2020)

TPS270 Background: MET amplification (amp) is a well-described driver of acquired EGFR antibody (Ab) resistance and is found in 10-20% of pts with KRAS and NRAS wild-type mCRC treated with anti-EGFR Abs. Blood-based genomic profiling of cfDNA is a non-invasive and efficient means of identifying acquired MET amp in mCRC. Although the activity of anti-MET tyrosine kinase inhibitors (TKIs) in EGFR Ab refractory mCRC has been shown in preclinical and clinical studies, the clinical efficacy of anti-MET TKIs in pts with MET amplified mCRC is not well established. Savolitinib is a potent and highly selective oral small molecule anti-MET TKI that is currently under clinical development for MET-driven papillary renal cell carcinoma, NSCLC and gastric cancer. Methods: This single-arm phase II study will evaluate the clinical efficacy and tolerability of savolitinib in pts with MET amplified mCRC. Eligible pts include those with RAS wild-type mCRC who have been previously treated with 5-FU, oxaliplatin, irinotecan, an anti-VEGF Ab and an anti-EGFR Ab. Pts must have MET amp detected by Guardant360 (G360) cfDNA screening assay. Up to 150 patients will be screened to identify at least 15 pts for study accrual. Prior treatment with an anti-MET TKI or monoclonal Ab against c-MET or HGF is excluded. The primary objective is to estimate the objective response rate (ORR) for savolitinib. In this heavily pre-treated cohort an observed ORR of 20% is considered clinically meaningful and worthy of further study. Secondary objectives are to evaluate the efficacy (progression-free survival, duration of response), safety and tolerability. Correlation between tissue and blood-based biomarkers and clinical outcomes will be explored. Blood will be collected at baseline and each restaging to determine if savolitinib eliminates MET amp in cfDNA. Subjects will receive savolitinib at a dose of 600mg by mouth daily on 28-day cycles. Response will be assessed every 2 cycles (8 weeks) per RECIST version 1.1. This study was initiated on 1/30/2019. Recruitment is ongoing in the NCI Experimental Therapeutics Clinical Trials Network (ETCTN). Clinical trial information: NCT03592641.
TGF-β1, pSMAD and TGFβ-related markers in Patients with advanced metastatic cancer
Authors: Jose Baselga, Mace L. Rothenberg, Josep Tabernero, Joan Seone, Thomas M. Daly, Ann Cleverly, Brandi Berry, Susanne Kloeker, Lisa Ann Wallace, Jonathan Yingling, Michael Lahn, Carlos Arteaga, Michael Carducci
Journal: Cancer Research (2006)

3638  ABSTRACT Purpose: The purpose of this study was to determine the presence and the individual biological variability of phosphorylated SMAD (pSMAD) expression in peripheral blood mononuclear cells (PBMC) and Transforming Growth Factor-β1 (TGF-β1) plasma levels in patients with advanced or metastatic cancer involving the bone. Additionally, secondary markers of the TGF-β1 related-signaling pathway such as parathyroid-hormone-related peptide (PTHrP), urokinase plasminogen activator (uPA), plasminogen activator inhibitor 1 (PAI-1), vascular endothelial growth factor (VEGF) and other biomarkers were evaluated in the same patient population. Experimental Design: This trial was a non-drug interventional study to obtain blood via venapuncture a maximum of four times over a 2 to 4 week period. Parallel samples of PBMC were collected and either 1) stimulated with TGF-β1 at the local institution or 2) shipped overnight to the Sponsor and stimulated the next day. pSMAD levels in the absence and presence of TGF-β1 as well as the plasma levels of the biomarkers were measured. Results: A total of 49 patients enrolled in the study with the most common tumor types being breast and prostate cancer. The bioassay for pSMAD PBMC consistently produced pSMAD levels in all patients and the individual biological variability of this assay was 47%. The geometric mean of TGF-β1 in plasma was 1.97 ng/ml in patients that had normal levels of platelet factor 4 (PF4). The highest TGF-β1 levels were seen almost exclusively in PF4-positive samples indicating a hypercoagulation state. Lastly several differences between levels of analytes in the study population and the normal population were detected in the Rules Based Medicine (RBM) antigen panel. Some of the analytes with statistically significant difference include α2 macroglobulin (p=0.0002), CA125 (p=0.000), PAI-1 (p=0.0129), MMP-3 (p=0.000), and MMP-9 (p=0.0002). Conclusions: A novel ex vivo bioassay for the detection of pSMAD in PBMC provided reliable results in patients with advanced, metastatic cancer involving the bone. This assay consistently produced pSMAD levels in all cancer patients. TGF-β1 levels appear to be elevated for this cancer population.
Goals of care designations in advanced pancreatic cancer patients undergoing palliative chemotherapy.
Authors: Matthew Anaka, Minji Lee, Elisa Lim, Sunita Ghosh, Winson Y. Cheung, Jennifer L. Spratlin
Journal: Journal of Clinical Oncology (2020)

683 Background: Discussion of goals of care (GoC) is a key part of quality care for patients with palliative cancer. Numerous studies have shown that documentation of GoC in this population remains low. In 2014, Alberta Health Services launched a health-system wide initiative to provide patients with physical copies of their GoC designation intended to be available at all health-system interactions. Here we describe rates of GoC documentation in the period surrounding this initiative. Methods: This is a retrospective cohort analysis of 240 patients with locally advanced or metastatic pancreatic cancer treated with palliative chemotherapy from 2012-2015 in Alberta, Canada. Data were obtained from outpatient electronic medical record documentation and the provincial cancer registry. Results: 63.8% (153/240) of patients had a documented GoC discussion, with 60.4% (145/240) receiving a specific GoC designation. 59.6% (143/240) of patients were referred to palliative care, with 32.5% (78/240) seen by palliative care physician. Of 334 individual GoC discussions documented, 38.6% (129/334) were by medical oncologists, 2.3% (10/334) were by radiation oncologists, 27.2% (91/334) were by palliative care, and 19.2% (64/334) were by other inpatient physicians during hospital admissions. At least 9.6% (32/334) referenced discussions that occurred prior to initial consultation with an oncology physician. Conclusions: The majority of pancreatic cancer patients undergoing palliative chemotherapy had a documented GoC designation during the study period. Providing patients with physical copies of their GoC designation may therefore represent a simple but effective means of increasing GoC documentation in the outpatient oncology setting.
Blood-based detection of early-stage colorectal cancer using multiomics and machine learning.
Authors: Girish Putcha, Tzu-Yu Liu, Eric Ariazi, Marvin Bertin, Adam Drake, Michael Dzamba, Greg Hogan, Steven Kothen-Hill, Jeffrey Liao, Kang Li, Shivani Mahajan, Krishnan Palaniappan, Poonam Sansanwal, John St John, Peter Ulz, Nathan Wan, Hayley Warsinske, David Weinberg, Rui Yang, Jimmy Lin
Journal: Journal of Clinical Oncology (2020)

66 Background: Despite population screening efforts, screening rates for colorectal cancer (CRC) remain suboptimal. A non-invasive, blood-based screening test with high sensitivity and specificity in early-stage disease should improve adherence and ultimately reduce mortality; however, tests based only on tumor-derived biomarkers have limited sensitivity. Here we used a multiomic, machine learning platform to discover, refine, and combine tumor- and immune-derived signals to develop a blood test for the detection of early-stage CRC. Methods: Samples from 591 participants enrolled in a prospective study including average-risk screening and case-control cohorts (NCT03688906) were included in this analysis (CRC: n = 43; colonoscopy-confirmed CRC-negative controls: n = 548). Participants with CRC were 60% male with a mean age of 63, and controls were 55% male with a mean age of 60. Stage distribution was 54% early (I/II) and 34% late (III/IV) with 11% unknown. Plasma was analyzed by whole-genome sequencing, bisulfite sequencing, and protein quantification methods. Computational methods were used to assess and infer the performance of individual and combined assays. Results: For colorectal adenocarcinoma, which represents ~95% of all CRCs, our multiomic test achieved a mean sensitivity of 92% in early stage (n = 17) and 84% in late stage (n = 11) at a specificity of 90%. Across all CRC pathological subtypes, our test achieved a mean sensitivity of 80% in early stage (n = 19) and 83% in late stage (n = 12) at a specificity of 90%; the test detected the single squamous cell carcinoma but missed both neuroendocrine tumors. Individual assays achieved a mean sensitivity of 50% in early stage and 66% in late stage at a specificity of 90%. Conclusions: In a prospective cohort, we demonstrated high sensitivity and specificity for early-stage adenocarcinoma by combining tumor- and immune-derived signals from cfDNA, epigenetic, and protein biomarkers. While most CRCs are adenocarcinomas, detection of all pathological subtypes is required to maximize sensitivity in a screening population. Further analysis of molecular and pathological subtypes, as well as the entire ~3000 patient cohort, is underway. Clinical trial information: NCT03688906.
A 13-gene colorectal cancer liquid biopsy with greater than 90 percent accuracy in diagnosis and assessment of disease status.
Authors: Irvin Mark Modlin, Mark S. Kidd, Ignat A. Drozdov, Alexander Kitz, Anna Malczewska, Katarzyna Kusnierz, Harry Aslanian
Journal: Journal of Clinical Oncology (2020)

18 Background: There are a paucity of blood-based biomarkers with clinical utility for colorectal cancer (CRC) We report the use of a 13-gene colon cancer circulating-free mRNA to diagnose CRC and identify disease burden and status Clinical utility of the assay was assessed in surgical and chemotherapy patients. Methods: Gene identification and validation: Publicly available colon cancer transcriptomes (TTs) (E-MTAB-57); gene expression in 3 CRC cell-lines (LOVO, LS-180 and COLO320DM) and validated in CRC tumors ( n=33). Tumor TT analysis: co-expression network generation and differential expression analysis compared with normal blood-based TT to identify candidate markers. Blood gene expression: CRC set (cancers: n=312, controls n=117) and a CRC artificial intelligence model constructed. Normalized gene expression algorithmically scored (0-100). Matched tumor/ blood samples were available in 33 patients. RECIST criteria Clinical score assessment: Score utility was assessed in surgical and treated cohorts: Surgical: n=37, follow&gt;7 days. Treated chemotherapy: n=75; stable disease (SD): n=20, progressive disease (PD): n=55) The relationship to CEA and CA-19-9 were assessed. Statistics: Non-parametric (Mann-Whitney), Pearson-correlation, Fisher’s and AUROC analyses (Mean±SEM). Results: Transcriptomic analysis identified a13 genes blood signature for CRC. Expression levels were significantly elevated ( p&lt;0.001, 20-100-fold) in cell lines and CRC tumors. The matched tissue/blood correlation r: 0.795 ( p=0.002). In CRC, levels were 54.4±1.5 ( p&lt;0.0001) compared to controls (9.5±1.7); AUROC: 0.91±0.02, accuracy 90.5% (sensitivity 93.1%, specificity 81.2%). Surgical cohort: CRC assay accuracy 100% vs CEA (35%) or CA-19-9 (17%) (both p&lt;0.0001). Resection (R0 – 92%) significantly decreased levels (47±2) at follow-up ( p=0.0055). Treated cohort: Levels were elevated in PD (63±4.1) vs SD (30±3.2, p&lt;0.0001). Conclusions: The diagnostic accuracy of CRC blood-signature was 91%; significantly greater than CEA or CA-19 Surgical resection decreased levels. CRC score was elevated in progressive vs stable disease. A colorectal cancer liquid biopsy has probable clinical utility in management.