Browsing by Author "Garman, Katherine S"

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    An integrated approach to the prediction of chemotherapeutic response in patients with breast cancer.
    (PLoS One, 2008-04-02) Salter, Kelly H; Acharya, Chaitanya R; Walters, Kelli S; Redman, Richard; Anguiano, Ariel; Garman, Katherine S; Anders, Carey K; Mukherjee, Sayan; Dressman, Holly K; Barry, William T; Marcom, Kelly P; Olson, John; Nevins, Joseph R; Potti, Anil
    BACKGROUND: A major challenge in oncology is the selection of the most effective chemotherapeutic agents for individual patients, while the administration of ineffective chemotherapy increases mortality and decreases quality of life in cancer patients. This emphasizes the need to evaluate every patient's probability of responding to each chemotherapeutic agent and limiting the agents used to those most likely to be effective. METHODS AND RESULTS: Using gene expression data on the NCI-60 and corresponding drug sensitivity, mRNA and microRNA profiles were developed representing sensitivity to individual chemotherapeutic agents. The mRNA signatures were tested in an independent cohort of 133 breast cancer patients treated with the TFAC (paclitaxel, 5-fluorouracil, adriamycin, and cyclophosphamide) chemotherapy regimen. To further dissect the biology of resistance, we applied signatures of oncogenic pathway activation and performed hierarchical clustering. We then used mRNA signatures of chemotherapy sensitivity to identify alternative therapeutics for patients resistant to TFAC. Profiles from mRNA and microRNA expression data represent distinct biologic mechanisms of resistance to common cytotoxic agents. The individual mRNA signatures were validated in an independent dataset of breast tumors (P = 0.002, NPV = 82%). When the accuracy of the signatures was analyzed based on molecular variables, the predictive ability was found to be greater in basal-like than non basal-like patients (P = 0.03 and P = 0.06). Samples from patients with co-activated Myc and E2F represented the cohort with the lowest percentage (8%) of responders. Using mRNA signatures of sensitivity to other cytotoxic agents, we predict that TFAC non-responders are more likely to be sensitive to docetaxel (P = 0.04), representing a viable alternative therapy. CONCLUSIONS: Our results suggest that the optimal strategy for chemotherapy sensitivity prediction integrates molecular variables such as ER and HER2 status with corresponding microRNA and mRNA expression profiles. Importantly, we also present evidence to support the concept that analysis of molecular variables can present a rational strategy to identifying alternative therapeutic opportunities.
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    In Memoriam: Dawn Tranchino Provenzale, MD, MS (August 18, 1955-April 20, 2021).
    (Gastroenterology, 2021-12-22) Dominitz, Jason A; Fisher, Deborah A; Garman, Katherine S; Hunt, Christine M; Lieberman, David; Muir, Andrew J; Onken, Jane E; Robertson, Douglas J; Sandler, Robert S; Sultan, Shahnaz
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    Inconsistencies in Colonic Tattooing Practice: Differences in Reported and Actual Practices at a Tertiary Medical Center.
    (Southern medical journal, 2019-04) Spaete, Joshua P; Zheng, Jiayin; Chow, Shein-Chung; Burbridge, Rebecca A; Garman, Katherine S
    OBJECTIVES:Accurate localization of a colonic lesion is crucial to successful resection. Although colonic tattooing is a widely accepted technique to mark lesions for future identification surgery or repeat colonoscopy, no consensus guidelines exist. The objective of this study was to determine whether the current tattooing practice at a tertiary medical center differs from recommendations in the literature and self-reported provider practice. METHODS:The study consisted of an observational retrospective chart review of patients who received colonic tattoos, as well as a provider survey of reported tattooing practices at a tertiary academic medical center. A total of 747 patients older than 18 years of age who underwent colonoscopy with tattoo were included. Forty-four gastroenterologists performing endoscopy were surveyed on tattooing techniques. RESULTS:In the majority of cases, neither the number of tattoos, location of the tattoo nor the distance from the lesion was specified within the report. Following the index procedure, a tattoo was detected in 75% of surgical resections and 73% of endoscopies. At the time of surgery, however, the tattoo and/or the lesion was detected approximately 94% of the time. Twenty-five endoscopists (56.8%) completed the survey. Differences were seen the between the chart review and reported practice. Most providers report placing ≥2 marks (87.2%); however, chart review revealed that only 56.2 % were tattooed with ≥2 marks. CONCLUSIONS:Variation exists between the reported tattooing practice and actual practice. Despite this, most tattoos are identified at the time of surgery or repeat endoscopy. Further research is needed to determine whether a standardized approach to tattooing and reporting could improve localization at repeat endoscopy.
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    Orthotopic Transplantation of the Full-length Porcine Intestine After Normothermic Machine Perfusion.
    (Transplantation direct, 2022-11) Abraham, Nader; Ludwig, Elsa K; Schaaf, Cecilia R; Veerasammy, Brittany; Stewart, Amy S; McKinney, Caroline; Freund, John; Brassil, John; Samy, Kannan P; Gao, Qimeng; Kahan, Riley; Niedzwiecki, Donna; Cardona, Diana M; Garman, Katherine S; Barbas, Andrew S; Sudan, Debra L; Gonzalez, Liara M
    Successful intestinal transplantation is currently hindered by graft injury that occurs during procurement and storage, which contributes to postoperative sepsis and allograft rejection. Improved graft preservation may expand transplantable graft numbers and enhance posttransplant outcomes. Superior transplant outcomes have recently been demonstrated in clinical trials using machine perfusion to preserve the liver. We hypothesized that machine perfusion preservation of intestinal allografts could be achieved and allow for transplantation in a porcine model.

    Methods

    Using a translational porcine model, we developed a device for intestinal perfusion. Intestinal samples were collected at the time of organ procurement, and after 6 h of machine perfusion for gross and histologic evaluation, hourly chemistry panels were performed on the perfusate and were used for protocol optimization. Following transplantation, porcine recipient physical activity, systemic blood parameters, and vital signs were monitored for 2 d before sacrifice.

    Results

    In initial protocol development (generation 1, n = 8 grafts), multiple metabolic, electrolyte, and acid-base derangements were measured. These factors coincided with graft and mesenteric edema and luminal hemorrhage and were addressed with the addition of dialysis. In the subsequent protocol (generation 2, n = 9 grafts), differential jejunum and ileum perfusion were observed resulting in gross evidence of ileal ischemia. Modifications in vasodilating medications enhanced ileal perfusion (generation 3, n = 4 grafts). We report successful transplantation of 2 porcine intestinal allografts after machine perfusion with postoperative clinical and gross evidence of normal gut function.

    Conclusions

    This study reports development and optimization of machine perfusion preservation of small intestine and successful transplantation of intestinal allografts in a porcine model.
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    Pleiotrophin regulates the ductular reaction by controlling the migration of cells in liver progenitor niches.
    (Gut, 2016-04) Michelotti, Gregory A; Tucker, Anikia; Swiderska-Syn, Marzena; Machado, Mariana Verdelho; Choi, Steve S; Kruger, Leandi; Soderblom, Erik; Thompson, J Will; Mayer-Salman, Meredith; Himburg, Heather A; Moylan, Cynthia A; Guy, Cynthia D; Garman, Katherine S; Premont, Richard T; Chute, John P; Diehl, Anna Mae
    OBJECTIVE: The ductular reaction (DR) involves mobilisation of reactive-appearing duct-like cells (RDC) along canals of Hering, and myofibroblastic (MF) differentiation of hepatic stellate cells (HSC) in the space of Disse. Perivascular cells in stem cell niches produce pleiotrophin (PTN) to inactivate the PTN receptor, protein tyrosine phosphatase receptor zeta-1 (PTPRZ1), thereby augmenting phosphoprotein-dependent signalling. We hypothesised that the DR is regulated by PTN/PTPRZ1 signalling. DESIGN: PTN-GFP, PTN-knockout (KO), PTPRZ1-KO, and wild type (WT) mice were examined before and after bile duct ligation (BDL) for PTN, PTPRZ1 and the DR. RDC and HSC from WT, PTN-KO, and PTPRZ1-KO mice were also treated with PTN to determine effects on downstream signaling phosphoproteins, gene expression, growth, and migration. Liver biopsies from patients with DRs were also interrogated. RESULTS: Although quiescent HSC and RDC lines expressed PTN and PTPRZ1 mRNAs, neither PTN nor PTPRZ1 protein was demonstrated in healthy liver. BDL induced PTN in MF-HSC and increased PTPRZ1 in MF-HSC and RDC. In WT mice, BDL triggered a DR characterised by periportal accumulation of collagen, RDC and MF-HSC. All aspects of this DR were increased in PTN-KO mice and suppressed in PTPRZ1-KO mice. In vitro studies revealed PTN-dependent accumulation of phosphoproteins that control cell-cell adhesion and migration, with resultant inhibition of cell migration. PTPRZ1-positive cells were prominent in the DRs of patients with ductal plate defects and adult cholestatic diseases. CONCLUSIONS: PTN, and its receptor, PTPRZ1, regulate the DR to liver injury by controlling the migration of resident cells in adult liver progenitor niches.