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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.
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.
BACKGROUND - The impact of re-resection of a positive intraoperative bile duct margin on clinical outcomes for resectable hilar cholangiocarcinoma (HCCA) remains controversial. We sought to define the impact of re-resection of an initially positive frozen-section bile duct margin on outcomes of patients undergoing surgery for HCCA.
METHODS - Patients who underwent curative-intent resection for HCCA between 2000 and 2014 were identified at 10 hepatobiliary centers. Short- and long-term outcomes were analyzed among patients stratified by margin status.
RESULTS - Among 215 (83.7%) patients who underwent frozen-section evaluation of the bile duct, 80 (37.2%) patients had a positive (R1) ductal margin, 58 (72.5%) underwent re-resection, and 29 ultimately had a secondary negative margin (secondary R0). There was no difference in morbidity, 30-day mortality, and length of stay among patients who had primary R0, secondary R0, and R1 resection (all p > 0.10). Median and 5-year survival were 22.3 months and 23.3%, respectively, among patients who had a primary R0 resection compared with 18.5 months and 7.9%, respectively, for patients with an R1 resection (p = 0.08). In contrast, among patients who had a secondary R0 margin with re-resection of the bile duct margin, median and 5-year survival were 30.6 months and 44.3%, respectively, which was comparable to patients with a primary R0 margin (p = 0.804). On multivariable analysis, R1 margin resection was associated with decreased survival (R1: hazard ratio [HR] 1.3, 95% confidence interval [CI] 1.0-1.7; p = 0.027), but secondary R0 resection was associated with comparable long-term outcomes as primary R0 resection (HR 0.9, 95% CI 0.4-2.3; p = 0.829).
CONCLUSIONS - Additional resection of a positive frozen-section ductal margin to achieve R0 resection was associated with improved long-term outcomes following curative-intent resection of HCCA.
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.
Multiple different schemes are used to assess surgical resection margins in orthopedic pathology, but which is optimal for reporting resection margin status of osteosarcoma is uncertain. Moreover, the minimum tumor clearance (metric width of resection margin) necessary for local control is not well defined. In this investigation, the American Joint Committee on Cancer (AJCC) R system, Musculoskeletal Tumor Society (MSTS) system, and margin distance method for reporting resection margin status were compared in a series of 186 high-grade osteosarcomas. Hazard ratios for local recurrence for each resection margin category were compared with other categories within each margin assessment scheme to assess discriminatory ability. Cross-model comparisons of regression coefficients from parametric survival and logistic regression models were also performed. Predictive accuracy of each margin assessment scheme for determining 2-year local recurrence-free survival was evaluated by comparing the areas under receiver-operating characteristic curves generated from logistic regression analyses. Concordance with clinical outcomes was also calculated. Both the MSTS and margin distance schemes showed significantly greater predictive accuracy and concordance with observed outcomes than the AJCC R system. A margin distance of ≥2 mm significantly decreased the risk of local recurrence. Results were similar after adjustment for confounding prognostic factors (anatomic site, macroscopic lymphovascular invasion, and chemotherapy status). Therefore, surgical resection margins for osteosarcoma should be reported using either the MSTS or margin distance method instead of the AJCC R system.
OBJECTIVES - To determine the utility and necessity of submitting tissue sections from the biopsy tracts of osteosarcoma resection specimens.
METHODS - The prevalence of residual tumor in representative sections of osteosarcoma biopsy tracts was assessed in a series of 97 osteosarcoma resection specimens.
RESULTS - No residual tumor cells were identified in 97 sampled biopsy tracts (0%; 95% confidence interval, 0%-2.5%).
CONCLUSIONS - Pathologists do not need to submit sections of resected biopsy tracts unless there is clinical or gross evidence that would warrant further examination.
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INTRODUCTION - In this multi-institutional study of patients undergoing pancreaticoduodenectomy for pancreatic adenocarcinoma, we sought to identify factors associated with perioperative transfusion requirement as well as the association between blood transfusion and perioperative and oncologic outcomes.
METHODS - The surgical databases across six high-volume institutions were analyzed to identify patients who underwent pancreaticoduodenectomy for pancreatic adenocarcinoma from 2005 to 2010. For statistical analyses, patients were then stratified by transfusion volume according to whether they received 0, 1-2, or >2 units of packed red blood cells.
RESULTS - Among 697 patients identified, 42 % required blood transfusion. Twenty-three percent received 1-2 units, and 19 % received >2 units. Factors associated with an increased transfusion requirement included older age, heart disease, diabetes, longer operative time, higher blood loss, tumor size, and non-R0 margin status (all p < 0.05). The median disease-free survival (13.8 vs. 18.3 months, p = 0.02) and overall survival (14.0 vs. 21.0 months, p < 0.0001) durations of transfused patients were shorter than those of transfusion-free patients. Multivariate modeling identified intraoperative transfusion of >2 units (hazard ratio, 1.92, p = 0.009) and postoperative transfusions as independent factors associated with decreased disease-free survival.
CONCLUSIONS - This multi-institutional study represents the largest series to date analyzing the effects of perioperative blood transfusion on patient outcomes following pancreaticoduodenectomy for pancreatic adenocarcinoma. While blood transfusion was not associated with increased rate of infectious complications, allogeneic blood transfusion did confer a negative impact on disease-free and overall survival.
UNLABELLED - Neoadjuvant chemotherapy (NAC) induces a pathologic complete response (pCR) in approximately 30% of patients with triple-negative breast cancers (TNBC). In patients lacking a pCR, NAC selects a subpopulation of chemotherapy-resistant tumor cells. To understand the molecular underpinnings driving treatment-resistant TNBCs, we performed comprehensive molecular analyses on the residual disease of 74 clinically defined TNBCs after NAC, including next-generation sequencing (NGS) on 20 matched pretreatment biopsies. Combined NGS and digital RNA expression analysis identified diverse molecular lesions and pathway activation in drug-resistant tumor cells. Ninety percent of the tumors contained a genetic alteration potentially treatable with a currently available targeted therapy. Thus, profiling residual TNBCs after NAC identifies targetable molecular lesions in the chemotherapy-resistant component of the tumor, which may mirror micrometastases destined to recur clinically. These data can guide biomarker-driven adjuvant studies targeting these micrometastases to improve the outcome of patients with TNBC who do not respond completely to NAC.
SIGNIFICANCE - This study demonstrates the spectrum of genomic alterations present in residual TNBC after NAC. Because TNBCs that do not achieve a CR after NAC are likely to recur as metastatic disease at variable times after surgery, these alterations may guide the selection of targeted therapies immediately after mastectomy before these metastases become evident.
In a significant fraction of breast cancer patients, distant metastases emerge after years or even decades of latency. How disseminated tumour cells (DTCs) are kept dormant, and what wakes them up, are fundamental problems in tumour biology. To address these questions, we used metastasis assays in mice and showed that dormant DTCs reside on microvasculature of lung, bone marrow and brain. We then engineered organotypic microvascular niches to determine whether endothelial cells directly influence breast cancer cell (BCC) growth. These models demonstrated that endothelial-derived thrombospondin-1 induces sustained BCC quiescence. This suppressive cue was lost in sprouting neovasculature; time-lapse analysis showed that sprouting vessels not only permit, but accelerate BCC outgrowth. We confirmed this surprising result in dormancy models and in zebrafish, and identified active TGF-β1 and periostin as tumour-promoting factors derived from endothelial tip cells. Our work reveals that stable microvasculature constitutes a dormant niche, whereas sprouting neovasculature sparks micrometastatic outgrowth.
PURPOSE - Patients with triple-negative breast cancer (TNBC) and residual disease after neoadjuvant chemotherapy generally have worse outcome; however, some patients with residual tumor after neoadjuvant chemotherapy do not relapse. We hypothesize that there are subgroups of patients with chemoresistant TNBC with different prognosis.
EXPERIMENTAL DESIGN - Forty-nine chemoresistant cases from 111 patients with TNBC treated with neoadjuvant chemotherapy (M.D. Anderson Cancer Center, Houston, TX) constituted the discovery cohort, and 25 chemoresistant samples from 47 neoadjuvant chemotherapy-treated TNBC (The Methodist Hospital, Houston, TX) were chosen for validation. Extended validation was carried out in 269 operable TNBC predicted to be chemoresistant by expression pattern from published datasets.
RESULTS - We established a seven-gene prognostic signature using dChip and gene set enrichment analyses. In the independent validation cohort, the classifier predicted correctly with positive predictive value of 75.0% and negative predictive value (i.e., relapse-free survival; RFS) of 76.9% at 3 years. Those predicted to relapse had a HR of 4.67 [95% confidence interval (CI): 1.27-17.15] for relapse in 3 years. In extended validation, patients predicted not to relapse exhibited 3-year RFS of 78.9%, whereas the 3-year RFS was 48.5% for patients predicted to relapse, with HR of 2.61 (95% CI: 1.52-4.49). The TNBC subgroup that predicted to have relatively favorable prognosis was characterized by high expression of "luminal-like" genes [androgen-receptor (AR) and GATA3], whereas the subgroup with worse prognosis was characterized by expression of cancer stem-cell markers.
CONCLUSION - We developed a clinically relevant signature for patients with chemoresistant TNBC. For these women, new therapeutic strategies like targeting AR activation or cancer stem cells may need to be developed.