Ki67-Adjusted Mitotic Score (KAMS): a novel prognostic metric in well-differentiated pancreatic neuroendocrine tumors Public

Abstract

Introduction: The grading of PanNETs presents numerous diagnostic challenges and limits our ability to accurately predict their clinical behavior. The current WHO grading system uses Ki67 index (KI) and/or mitotic count (MC) to obtain a histological grade (G1, G2, G3) for tumors. However, there are numerous ambiguities in this grading system, including different scales of measurement of Ki67 and mitosis, sub-optimal categorical cut-offs and lack of consensus on best counting methodologies. To fully exploit the prognosticating power of both KI and MC, we rationally integrated them and derived a new metric, Ki67-adjusted mitotic score (KAMS), which represents the proportion of mitotic cells amongst cycling Ki67-positive tumor cells.

Methods: Among 97 PanNETs KAMS was calculated by transforming monotonic ordinal MC into % mitotic cells and dividing it by % Ki67. Survival stratification was done via Kaplan-Meier estimator based on KAMS and KI.

Results: Using current established thresholds in PanNET grading, the survival stratification for KI showed significance between high (Grade 3) and low (Grade 1) Ki67 survival percentages (p=0.02). However, KAMS was able to stratify patients into two statistically significant survival groups (p= 0.04): The "above-threshold KAMS" group had 74% survival while the "below-threshold KAMS" group had a 53% survival. The ideal threshold of KAMS was .0033.

Conclusion: This study underscores the significance of our new metric, KAMS, to provide a more accurate risk prediction in PanNETs. Low KAMS significantly predict poor prognosis in PanNETs and is superior to Ki67 in survival stratification. Although validation of the KAMS score in other larger datasets is warranted, it appears that KAMS could significantly improve PanNETs prognostic risk determination by identifying individuals at higher risk of progressing to metastatic disease.

Table of Contents

CHAPTER 1: Literature Review and Introduction: .................1

Epidemiology in the United States .....................1

Global Burden.................................................4

Clinical Background.........................................8

Treatment Options..........................................9

Grading and Related Issues.............................10

Research Question .........................................13

CHAPTER 2: Manuscript...................................................14

Abstract.......................................................15

Introduction..................................................16

Methods........................................................18

Results..........................................................19

Discussion.....................................................,24

References......................................................27

CHAPTER 3: Public Health Implications..............................28

REFERENCES.................................................................30

About this Master's Thesis

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School	Rollins School of Public Health
Department	Hubert Department of Global Health
Degree	MPH
Submission	Master's Thesis
Language	English
Research Field	Health Sciences, Public Health Biology, Molecular Health Sciences, Oncology
Mot-clé	WHO Grade KI-67
Committee Chair / Thesis Advisor	Lobelo, Roberto L, Emory University
Partnering Agencies	Hospital or other health care provider University, college or educational institution (other than Emory)

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