Statistical methods for assays with limits of detection: Serum bile acid as a differentiator between patients with normal colons, adenomas, and colorectal cancer

In analytic chemistry a detection limit (DL) is the lowest measurable amount of an analyte that can be distinguished from a blank; many biomedical measurement technologies exhibit this property. From a statistical perspective, these data present inferential challenges because instead of precise measures, one only has information that the value is somewhere between 0 and the DL (below detection limit, BDL). Substitution of BDL values, with 0 or the DL can lead to biased parameter estimates and a loss of statistical power. Statistical methods that make adjustments when dealing with these types of data, often called left-censored data, are available in many commercial statistical packages. Despite this availability, the use of these methods is still not widespread in biomedical literature. We have reviewed the statistical approaches of dealing with BDL values, and used simulations to examine the performance of the commonly used substitution methods and the most widely available statistical methods. We have illustrated these methods using a study undertaken at the Vanderbilt-Ingram Cancer Center, to examine the serum bile acid levels in patients with colorectal cancer and adenoma. We have found that the modern methods for BDL values identify disease-related differences that are often missed, with statistically naive approaches

Ras-p53 genomic cooperativity as a model to investigate mechanisms of innate immune regulation in gastrointestinal cancers

Despite increasingly thorough mechanistic understanding of the dominant genetic drivers of gastrointestinal (GI) tumorigenesis (e.g., Ras/Raf, TP53, etc.), only a small proportion of these molecular alterations are therapeutically actionable. In an attempt to address this therapeutic impasse, our group has proposed an innovative extreme outlier model to identify novel cooperative molecular vulnerabilities in high-risk GI cancers which dictate prognosis, correlate with distinct patterns of metastasis, and define therapeutic sensitivity or resistance. Our model also proposes comprehensive investigation of their downstream transcriptomic, immunomic, metabolic, or upstream epigenomic cellular consequences to reveal novel therapeutic targets in previously “undruggable” tumors with high-risk genomic features. Leveraging this methodology, our and others’ data reveal that the genomic cooperativity between Ras and p53 alterations is not only prognostically relevant in GI malignancy, but may also represent the incipient molecular events that initiate and sustain innate immunoregulatory signaling networks within the GI tumor microenvironment, driving T-cell exclusion and therapeutic resistance in these cancers. As such, deciphering the unique transcriptional programs encoded by Ras-p53 cooperativity that promote innate immune trafficking and chronic inflammatory tumor-stromal-immune crosstalk may uncover immunologic vulnerabilities that could be exploited to develop novel therapeutic strategies for these difficult-to-treat malignancies

53BP1 expression is a modifier of the prognostic value of lymph node ratio and CA 19–9 in pancreatic adenocarcinoma

BACKGROUND: 53BP1 binds to the tumor suppressor p53 and has a key role in DNA damage response and repair. Low 53BP1 expression has been associated with decreased survival in breast cancer and has been shown to interact with several prognostic factors in non-small cell lung cancer. The role of 53BP1 in pancreatic ductal adenocarcinoma (PDAC) has yet to be determined. We aimed to investigate whether 53BP1 levels interact with established prognostic factors in PDAC. METHODS: 106 patients for whom there was tissue available at time of surgical resection for PDAC were included. A tissue microarray was constructed using surgical specimens, stained with antibodies to 53BP1, and scored for expression intensity. Univariate and multivariate statistical analyses were performed to investigate the association between 53BP1 and patient survival with known prognostic factors for survival. RESULTS: The association of 53BP1 with several established prognostic factors was examined, including stage, tumor grade, surgical margin, peripancreatic extension, lymph node ratio (LNR), and CA 19–9. We found that 53BP1 modified the effects of known prognostic variables including LNR and CA 19–9 on survival outcomes. When 53BP1 intensity was low, increased LNR was associated with decreased OS (HR 4.84, 95% CI (2.26, 10.37), p<0.001) and high CA19-9 was associated with decreased OS (HR 1.72, 95% CI (1.18, 2.51), p=0.005). When 53BP1 intensity was high, LNR and CA19-9 were no longer associated with OS (p=0.958 and p=0.606, respectively). CONCLUSIONS: In this study, 53BP1, a key player in DNA damage response and repair, was found to modify the prognostic value of two established prognostic factors, LNR and CA 19–9, suggesting 53BP1 may alter tumor behavior and ultimately impact how we interpret the value of other prognostic factors

Perception Is Reality: quality metrics in pancreas surgery – a Central Pancreas Consortium (CPC) analysis of 1399 patients

Several groups have defined pancreatic surgery quality metrics that identify centers delivering quality care. Although these metrics are perceived to be associated with good outcomes, their relationship with actual outcomes has not been established

Association of Preoperative Risk Factors With Malignancy in Pancreatic Mucinous Cystic Neoplasms: A Multicenter Study

Pancreatic mucinous cystic neoplasms (MCNs) harbor malignant potential, and current guidelines recommend resection. However, data are limited on preoperative risk factors for malignancy (adenocarcinoma or high-grade dysplasia) occurring in the setting of an MCN

The diagnosis of pancreatic mucinous cystic neoplasm and associated adenocarcinoma in males: An eight‐institution study of 349 patients over 15 years

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137278/1/jso24582_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137278/2/jso24582.pd

Adjuvant Chemoradiation Therapy for Pancreatic Adenocarcinoma: Who Really Benefits?

The role of adjuvant chemoradiation therapy (CRT) in pancreatic cancer remains controversial. The primary aim of this study was to determine if CRT improved survival in patients with resected pancreatic cancer in a large, multiinstitutional cohort of patients

Multi-institutional analysis of pancreatic adenocarcinoma demonstrating the effect of diabetes status on survival after resection

The effect of diabetes on survival after resection pancreatic ductal carcinoma (PDAC) is unclear. The present study was undertaken to determine whether pre-operative diabetes has any predictive value for survival