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Publication Record


Minimally invasive surgery to treat embryonal tumors of childhood.
Phelps HM, Lovvorn HN
(2019) Cancer Metastasis Rev 38: 695-708
MeSH Terms: Child, Child, Preschool, Female, Humans, Infant, Male, Minimally Invasive Surgical Procedures, Neoadjuvant Therapy, Neoplasms, Germ Cell and Embryonal, Neuroblastoma
Show Abstract · Added November 30, 2020
Minimally invasive surgery (MIS) to resect primary and metastatic pediatric embryonal tumors offers the potential for reduced postoperative morbidity with smaller wounds, less pain, fewer surgical site infections, decreased blood loss, shorter hospital stays, and less disruption to treatment regimens. However, significant controversy surrounds the question of whether a high-fidelity oncologic resection of childhood embryonal tumors with gross total resection, negative margins, and appropriate lymph node sampling can be achieved through MIS. This review outlines the diverse applications of MIS to treat definitively pediatric embryonal malignancies, including this approach to metastatic deposits. It outlines specific patient populations and presentations that may be particularly amenable to the minimally invasive approach. This work further summarizes the current evidence supporting the efficacy of MIS to accomplish a definitive, oncologic resection without compromising relapse-free or overall survival. Finally, the review offers technical considerations to consider in order to achieve a safe and complete resection.
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Magnetization Transfer MRI of Breast Cancer in the Community Setting: Reproducibility and Preliminary Results in Neoadjuvant Therapy.
Virostko J, Sorace AG, Wu C, Ekrut D, Jarrett AM, Upadhyaya RM, Avery S, Patt D, Goodgame B, Yankeelov TE
(2019) Tomography 5: 44-52
MeSH Terms: Adult, Breast, Breast Neoplasms, Community Health Centers, Female, Humans, Image Interpretation, Computer-Assisted, Magnetic Resonance Imaging, Middle Aged, Neoadjuvant Therapy, Neoplasm, Residual, Pilot Projects, Reproducibility of Results, Treatment Outcome
Show Abstract · Added March 25, 2019
Repeatability and reproducibility of magnetization transfer magnetic resonance imaging of the breast, and the ability of this technique to assess the response of locally advanced breast cancer to neoadjuvant therapy (NAT), are determined. Reproducibility scans at 3 different 3 T scanners, including 2 scanners in community imaging centers, found a 16.3% difference (n = 3) in magnetization transfer ratio (MTR) in healthy breast fibroglandular tissue. Repeatability scans (n = 10) found a difference of ∼8.1% in the MTR measurement of fibroglandular tissue between the 2 measurements. Thus, MTR is repeatable and reproducible in the breast and can be integrated into community imaging clinics. Serial magnetization transfer magnetic resonance imaging performed at longitudinal time points during NAT indicated no significant change in average tumoral MTR during treatment. However, histogram analysis indicated an increase in the dispersion of MTR values of the tumor during NAT, as quantified by higher standard deviation ( = .005), higher full width at half maximum ( = .02), and lower kurtosis ( = .02). Patients' stratification into those with pathological complete response (pCR; n = 6) at the conclusion of NAT and those with residual disease (n = 9) showed wider distribution of tumor MTR values in patients who achieved pCR after 2-4 cycles of NAT, as quantified by higher standard deviation ( = .02), higher full width at half maximum ( = .03), and lower kurtosis ( = .03). Thus, MTR can be used as an imaging metric to assess response to breast NAT.
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14 MeSH Terms
Utility of Image Guidance in the Localization of Disappearing Colorectal Liver Metastases.
Pak LM, Gagnière J, Allen PJ, Balachandran VP, D'Angelica MI, DeMatteo RP, Jarnagin WR, Miga MI, Simpson AL, Kingham TP
(2019) J Gastrointest Surg 23: 760-767
MeSH Terms: Adult, Aged, Antineoplastic Agents, Colorectal Neoplasms, Female, Hepatectomy, Humans, Liver Neoplasms, Male, Metastasectomy, Middle Aged, Neoadjuvant Therapy, Neoplasm, Residual, Prospective Studies, Surgery, Computer-Assisted, Tomography, X-Ray Computed, Ultrasonography
Show Abstract · Added April 2, 2019
BACKGROUND - Colorectal liver metastases that demonstrate a complete radiographic response during chemotherapy are increasingly common with advances in chemotherapy regimens and are described as disappearing liver metastases (DLMs). However, these DLMs often continue to harbor residual viable tumor. If these tumors are found in the operating room with ultrasound (US), they should be treated. The intraoperative sonographic visualization of these lesions, however, can be hindered by chemotherapy-associated liver parenchyma changes. The objective of this study was to evaluate the use of an intraoperative image guidance system, Explorer (Analogic Corporation, Peabody, MA), to aid surgeons in the identification of DLMs initially undetected by US alone.
STUDY DESIGN - In a single-arm prospective trial, patients with colorectal liver metastases undergoing liver resection and/or ablation with one or more DLMs during neoadjuvant chemotherapy were enrolled. Intraoperatively, DLMs were localized with conventional US. Any DLM not found by conventional US was re-evaluated with the image guidance system. The primary outcome was the proportion of sonographically occult DLMs subsequently located by image-guided US.
RESULTS - Between April 2016 and November 2017, 25 patients with 61 DLMs were enrolled. Thirty-eight DLMs (62%) in 14 patients (56%) were not identified with US alone. Six (16%) DLMs in five patients (36%) were subsequently located with assistance of the image guidance system. The image guidance changed the intraoperative surgical plan in four of these patients.
CONCLUSIONS - Image guidance can aid surgeons in the identification of initially sonographically occult DLMs and facilitate the complete surgical clearance of all sites of liver disease.
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17 MeSH Terms
Genetic and Phenotypic Diversification of Heterogeneous Tumor Populations.
Elion DL, Cook RS
(2018) Trends Mol Med 24: 655-656
MeSH Terms: Antineoplastic Combined Chemotherapy Protocols, Drug Resistance, Neoplasm, Humans, Neoadjuvant Therapy, Triple Negative Breast Neoplasms
Show Abstract · Added April 15, 2019
Chemotherapy is the most commonly prescribed treatment for patients with aggressive and lethal triple negative breast cancers (TNBCs), which often develop chemoresistance. A recent study combined single nucleus sequencing, single cell RNA sequencing, and evolutionary biology to understand how tumor cells use genetic and phenotypic diversity to evade the selective pressures of neoadjuvant chemotherapy.
Copyright © 2018 Elsevier Ltd. All rights reserved.
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Maintaining oncologic integrity with minimally invasive resection of pediatric embryonal tumors.
Phelps HM, Ayers GD, Ndolo JM, Dietrich HL, Watson KD, Hilmes MA, Lovvorn HN
(2018) Surgery 164: 333-343
MeSH Terms: Child, Preschool, Early Diagnosis, Female, Humans, Infant, Male, Minimally Invasive Surgical Procedures, Neoadjuvant Therapy, Neoplasms, Germ Cell and Embryonal, Neuroblastoma, Registries, Tennessee, Tomography, X-Ray Computed, Treatment Outcome, Ultrasonography, Prenatal
Show Abstract · Added November 30, 2020
BACKGROUND - Embryonal tumors arise typically in infants and young children and are often massive at presentation. Operative resection is a cornerstone in the multimodal treatment of embryonal tumors but potentially disrupts therapeutic timelines. When used appropriately, minimally invasive surgery can minimize treatment delays. The oncologic integrity and safety attainable with minimally invasive resection of embryonal tumors, however, remains controversial.
METHODS - Query of the Vanderbilt Cancer Registry identified all children treated for intracavitary, embryonal tumors during a 15-year period. Tumors were assessed radiographically to measure volume (mL) and image-defined risk factors (neuroblastic tumors only) at time of diagnosis, and at preresection and postresection. Patient and tumor characteristics, perioperative details, and oncologic outcomes were compared between minimally invasive surgery and open resection of tumors of comparable size.
RESULTS - A total of 202 patients were treated for 206 intracavitary embryonal tumors, of which 178 were resected either open (n = 152, 85%) or with minimally invasive surgery (n = 26, 15%). The 5-year, relapse-free, and overall survival were not significantly different after minimally invasive surgery or open resection of tumors having a volume less than 100 mL, corresponding to the largest resected with minimally invasive surgery (P = .249 and P = .124, respectively). No difference in margin status or lymph node sampling between the 2 operative approaches was detected (p = .333 and p = .070, respectively). Advantages associated with minimally invasive surgery were decreased blood loss (P < .001), decreased operating time (P = .002), and shorter hospital stay (P < .001). Characteristically, minimally invasive surgery was used for smaller volume and earlier stage neuroblastic tumors without image-defined risk factors.
CONCLUSION - When selected appropriately, minimally invasive resection of pediatric embryonal tumors, particularly neuroblastic tumors, provides acceptable oncologic integrity. Large tumor volume, small patient size, and image-defined risk factors may limit the broader applicability of minimally invasive surgery.
Copyright © 2018 Elsevier Inc. All rights reserved.
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Modeling Continuous Prognostic Factors in Survival Analysis: Implications for Tumor Staging and Assessing Chemotherapy Effect in Osteosarcoma.
Cates JMM
(2018) Am J Surg Pathol 42: 485-491
MeSH Terms: Adolescent, Adult, Age Factors, Aged, Aged, 80 and over, Bone Neoplasms, Chemotherapy, Adjuvant, Child, Databases, Factual, Decision Support Techniques, Female, Humans, Male, Middle Aged, Models, Statistical, Necrosis, Neoadjuvant Therapy, Neoplasm Staging, Orthopedic Procedures, Osteosarcoma, Predictive Value of Tests, Risk Assessment, Risk Factors, Time Factors, Treatment Outcome, Tumor Burden, United States, Young Adult
Show Abstract · Added November 1, 2018
Extent of response to neoadjuvant chemotherapy, tumor size, and patient age are important prognostic variables for patients with osteosarcoma, but applying information from these continuous variables in survival models is difficult. Dichotomization is usually inappropriate and alternative statistical techniques should be considered instead. Nonlinear multivariable regression methods (restricted cubic splines and fractional polynomials) were applied to data from the National Cancer Database to model continuous prognostic factors for overall survival from localized, high-grade osteosarcoma of the appendicular and nonspinal skeleton following neoadjuvant chemotherapy and surgical resection (N=2493). The assumption that log hazard ratios were linear in relation to these continuous prognostic factors was tested using likelihood ratio tests of model deviance and Wald tests of spline coefficients. Log hazard ratios for increasing patient age were linear over the range of 4 to 80 years, but showed evidence for variation in the coefficient over elapsed follow-up time. Tumor size also showed a linear relationship with log hazard over the range of 1 to 30 cm. Hazard ratios for chemotherapy effect profoundly deviated from log-linear (P<0.004), with significantly decreased hazard for death from baseline for patients with ≥90% tumor necrosis (hazard ratio, 0.32; 95% confidence interval, 0.20-0.52; P<0.0001). Important implications of these results include: (1) ≥90% tumor necrosis defines good chemotherapy response in a clinically useful manner; (2) staging osteosarcoma by dichotomizing tumor size is inappropriate; and (3) patient age can be modeled as a linear effect on the log hazard ratio in prognostic models with the caveat that risk may change over duration of the analysis.
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28 MeSH Terms
Nodal Disease in Rectal Cancer Patients With Complete Tumor Response After Neoadjuvant Chemoradiation: Danger Below Calm Waters.
Baucom RB, Maguire LH, Kavalukas SL, Geiger TM, Ford MM, Muldoon RL, Hopkins MB, Hawkins AT
(2017) Dis Colon Rectum 60: 1260-1266
MeSH Terms: Adenocarcinoma, Case-Control Studies, Chemoradiotherapy, Combined Modality Therapy, Female, Humans, Lymphatic Metastasis, Male, Middle Aged, Neoadjuvant Therapy, Neoplasm Invasiveness, Neoplasm Staging, Neoplasm, Residual, Rectal Neoplasms, Retrospective Studies, Risk Factors, Survival Rate, Treatment Outcome, United States
Show Abstract · Added December 14, 2017
BACKGROUND - A subset of patients with rectal cancer who undergo neoadjuvant chemoradiation therapy will develop a complete pathologic tumor response. Complete nodal response is not universal in these patients and is difficult to assess clinically. Quantifying the risk of nodal disease would allow for targeted therapy with either radical resection or "watchful waiting."
OBJECTIVE - This study aimed to identify risk factors for residual nodal disease in ypT0 rectal adenocarcinoma.
DESIGN - This is a retrospective case control study.
SETTINGS - The National Cancer Database 2006 to 2014 was used to identify patients for this study.
PATIENTS - Patients with stage II/III rectal adenocarcinoma who completed chemoradiation therapy followed by resection and who had ypT0 tumors were included. Patients with metastatic disease and <2 lymph nodes evaluated were excluded. Patients were divided into 2 groups: node positive and node negative.
MAIN OUTCOME MEASURES - The main outcome was nodal disease. The secondary outcome was overall survival.
RESULTS - A total of 42,257 patients with stage II/III rectal cancer underwent chemoradiation therapy and radical resection; 4170 (9.9%) patients had ypT0 tumors and 395 (9.5%) were node positive. Of patients with clinically node-negative disease (ie, pretreatment imaging), 6.2% were node positive after chemoradiation therapy and resection. In multivariable analysis, factors predictive of nodal disease included increasing (pretreatment) clinical N-stage, high tumor grade (3/4), perineural invasion, and lymphovascular invasion. Higher clinical T-stage was inversely associated with residual nodal disease. Overall 5-year survival was significantly different between patients with ypN0, ypN1, and ypN2 disease (87.4%, 82.2%, and 62.5%, p = 0.002).
LIMITATIONS - This study was limited by the lack of clinical detail in the database and the inability to assess recurrence.
CONCLUSIONS - Ten percent of patients with ypT0 tumors had positive nodes after chemoradiation therapy and resection. Factors associated with residual nodal disease included clinical nodal disease at diagnosis and poor histologic features. Patients with any of these features should consider radical resection regardless of tumor response. Others could be suitable for "watchful waiting" strategies. See Video Abstract at http://links.lww.com/DCR/A458.
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19 MeSH Terms
Preoperative Chemotherapy and Survival for Large Anorectal Gastrointestinal Stromal Tumors: A National Analysis of 333 Cases.
Hawkins AT, Wells KO, Krishnamurty DM, Hunt SR, Mutch MG, Glasgow SC, Wise PE, Silviera ML
(2017) Ann Surg Oncol 24: 1195-1201
MeSH Terms: Adult, Age Factors, Aged, Aged, 80 and over, Antineoplastic Agents, Anus Neoplasms, Chemotherapy, Adjuvant, Female, Gastrointestinal Stromal Tumors, Humans, Imatinib Mesylate, Male, Middle Aged, Neoadjuvant Therapy, Rectal Neoplasms, Survival Rate, Tumor Burden, United States, Young Adult
Show Abstract · Added March 21, 2017
PURPOSE - Anorectal gastrointestinal stromal tumors (GISTs) are exceedingly rare, and management remains controversial in regard to local resection (LR) and preoperative chemotherapy.
METHODS - The National Cancer Data Base was queried from 1998 to 2012 for cases of GIST resection in the rectum or anus. Patient demographics, type of surgery (LR vs. radical excision [RE]), short-term outcomes, and overall survival (OS) were analyzed. Preoperative chemotherapy was recorded following the US FDA approval of imatinib in 2002.
RESULTS - Overall, 333 patients with resection of anorectal GISTs were included. Mean age at presentation was 62.3 years (range 22-90), and median tumor size was 4.0 cm (interquartile range 2.2-7.0). Five-year OS for all patients was 77.6%. In a multivariable survival analysis, only age and tumor size >5 cm (hazard ratio 2.48, 95% confidence interval 1.50-4.01; p = 0.004) were associated with increased mortality. One hundred and sixty-three (49.0%) patients underwent LR, compared with 158 (47.4%) who underwent RE. For tumors smaller than 5 cm, no difference in 5-year survival by surgical approach was observed (LR 82.3% vs. RE 82.6%; p = 0.71). Fifty-nine patients (17.7%) received preoperative chemotherapy; for patients undergoing RE with tumors >5 cm, there was decreased mortality in the group who received preoperative chemotherapy (5-year OS with chemotherapy 79.2% vs. no chemotherapy 51.2%; p = 0.03).
CONCLUSIONS - Size is the most important determinant in survival following resection. Local excision is common, with resection split between LR and RE. For smaller tumors, LR may be adequate therapy. Preoperative chemotherapy may result in improved survival for large tumors treated with radical resection, but the data are imperfect.
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19 MeSH Terms
Refinement of Triple-Negative Breast Cancer Molecular Subtypes: Implications for Neoadjuvant Chemotherapy Selection.
Lehmann BD, Jovanović B, Chen X, Estrada MV, Johnson KN, Shyr Y, Moses HL, Sanders ME, Pietenpol JA
(2016) PLoS One 11: e0157368
MeSH Terms: Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Computational Biology, Datasets as Topic, Disease Progression, Female, Gene Expression, Gene Expression Profiling, Humans, Immunohistochemistry, Laser Capture Microdissection, Lymphocytes, Tumor-Infiltrating, Microarray Analysis, Neoadjuvant Therapy, Neoplasm Grading, Neoplasm Proteins, Retrospective Studies, Stromal Cells, Survival Analysis, Triple Negative Breast Neoplasms
Show Abstract · Added April 9, 2017
Triple-negative breast cancer (TNBC) is a heterogeneous disease that can be classified into distinct molecular subtypes by gene expression profiling. Considered a difficult-to-treat cancer, a fraction of TNBC patients benefit significantly from neoadjuvant chemotherapy and have far better overall survival. Outside of BRCA1/2 mutation status, biomarkers do not exist to identify patients most likely to respond to current chemotherapy; and, to date, no FDA-approved targeted therapies are available for TNBC patients. Previously, we developed an approach to identify six molecular subtypes TNBC (TNBCtype), with each subtype displaying unique ontologies and differential response to standard-of-care chemotherapy. Given the complexity of the varying histological landscape of tumor specimens, we used histopathological quantification and laser-capture microdissection to determine that transcripts in the previously described immunomodulatory (IM) and mesenchymal stem-like (MSL) subtypes were contributed from infiltrating lymphocytes and tumor-associated stromal cells, respectively. Therefore, we refined TNBC molecular subtypes from six (TNBCtype) into four (TNBCtype-4) tumor-specific subtypes (BL1, BL2, M and LAR) and demonstrate differences in diagnosis age, grade, local and distant disease progression and histopathology. Using five publicly available, neoadjuvant chemotherapy breast cancer gene expression datasets, we retrospectively evaluated chemotherapy response of over 300 TNBC patients from pretreatment biopsies subtyped using either the intrinsic (PAM50) or TNBCtype approaches. Combined analysis of TNBC patients demonstrated that TNBC subtypes significantly differ in response to similar neoadjuvant chemotherapy with 41% of BL1 patients achieving a pathological complete response compared to 18% for BL2 and 29% for LAR with 95% confidence intervals (CIs; [33, 51], [9, 28], [17, 41], respectively). Collectively, we provide pre-clinical data that could inform clinical trials designed to test the hypothesis that improved outcomes can be achieved for TNBC patients, if selection and combination of existing chemotherapies is directed by knowledge of molecular TNBC subtypes.
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20 MeSH Terms
Proximal location in extremity long bones is a poor prognostic factor for osteosarcoma: A retrospective cohort study of 153 patients.
Cates JM, Schoenecker JG
(2016) Acta Oncol 55: 1036-9
MeSH Terms: Adolescent, Adult, Bone Neoplasms, Cohort Studies, Disease-Free Survival, Female, Humans, Humerus, Male, Neoadjuvant Therapy, Osteosarcoma, Prognosis, Proportional Hazards Models, Retrospective Studies, Tibia, Young Adult
Show Abstract · Added November 1, 2018
BACKGROUND - Osteosarcomas arising in the proximal femur, humerus, and tibia appear to have poorer outcomes than those arising in distal long bones. However, the strength of this association is uncertain, particularly in light of other prognostic factors. Therefore, this retrospective cohort study was performed to compare patient outcomes between proximal and distal tumor location within extremity long bones.
MATERIAL AND METHODS - A total of 153 patients with conventional high-grade osteosarcoma of the extremity long bones, pelvis, or axial skeleton who had undergone neoadjuvant chemotherapy and surgical resection between 1985 and 2010 were identified in the Surgical Pathology files at Vanderbilt Medical Center. Effect of anatomic location within a proximal long bone was assessed using multivariable Cox proportional hazard regression.
RESULTS - Proximal tumor location was a strong predictor of poor prognosis in univariate survival analysis. Multivariate regression analysis showed that after controlling for American Joint Committee on Cancer (AJCC) stage, histologic response to chemotherapy, surgical resection margin status, and histologic type, location in the proximal femur, tibia, and humerus were independent risk factors for death due to osteosarcoma, but not event-free survival.
CONCLUSION - Osteosarcomas of the proximal extremity long bones are associated with decreased disease-specific survival compared to tumors of the distal long bones, even after accounting for other key prognostic covariates.
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