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BackgroundBreast surgeons have a wide variety of intraoperative techniques available to help achieve low rates for positive margins of excision, with variable levels of evidence.MethodsA systematic review of the medical literature from 1995 to July 2016 was conducted, with 434 abstracts identified and evaluated. The analysis included 106 papers focused on intraoperative management of breast cancer margins and contained actionable data.ResultsUltrasound-guided lumpectomy for palpable tumors, as an alternative to palpation guidance, can lower positive margin rates, but the effect when used as an alternative to wire localization (WL) for nonpalpable tumors is less certain. Localization techniques such as radioactive seed localization and radioguided occult lesion localization were found potentially to lower positive margin rates as alternatives to WL depending on baseline positive margin rates. Intraoperative pathologic methods including gross histology, frozen section analysis, and imprint cytology all have the potential to lower the rates of positive margins. Cavity-shave margins and the Marginprobe device both lower rates of positive margins, with some potential for negative cosmetic effects. Specimen radiography and multiple miscellaneous techniques did not affect positive margin rates or provided too little evidence for formation of a conclusion.ConclusionsA systematic review of the literature showed evidence that several intraoperative techniques and actions can lower the rates of positive margins. These results are presented together with graded recommendations.

Background Malignant peripheral nerve sheath tumors (MPNST) are a rare form of soft tissue sarcoma with few studies reporting on patient outcomes and prognostic variables. Methods A retrospective review of 175 patients diagnosed with MPNST from 1985 to 2010 was performed. Patient, tumor, and treatment characteristics were evaluated to identify prognostic variables. Results The median age of our study population was 44 years, and 51% were female. Median tumor size was 6 cm, and 61% of patients had high-grade tumors. Tumors were most commonly located on the extremities (45%), then trunk (34%) and head/neck (19%). The majority of patients underwent surgical resection (95%) and adjuvant treatment with chemotherapy (6%), radiation (42%) or both (22%). Margin status was R0 in 69%, R1 in 2%, R2 in 9%, and unknown in 20%. The local recurrence rate was 22%, and 5- and 10-year disease-specific survival (DSS) were 60% and 45%, respectively. On univariate analysis, no predictors for local recurrence were identified. Tumor size ≥5 cm, high tumor grade, tumor location, presence of neurofibromatosis type 1, local recurrence, and adjuvant chemotherapy were all associated with DSS. On multivariate analysis, size ≥5 cm [hazard ratio (HR) = 6.1, 95% confidence interval (CI) 1.5–25.0], local recurrence (HR = 4.4, 95% CI 1.7–11.4), high tumor grade (HR = 3.8, 95% CI 1.1–13.2), and truncal location (HR = 3.7, 95% CI 1.1–12.7) were poor prognostic indicators for DSS. Conclusions High tumor grade and tumor size ≥5 cm predict adverse DSS for MPNST. In the context of a multidisciplinary treatment regimen, local recurrence and survival outcomes at 5 and 10 years were better than previously reported for MPNST.

PurposeTo evaluate the performance of contrast-enhanced spectral mammography (CESM) compared to MRI in the assessment of tumor response in breast cancer patients undergoing neoadjuvant systemic therapy (NST).MethodsThe institutional review board approved this study. From September 2014 to June 2017, we identified patients with pathologically confirmed invasive breast cancer who underwent NST. All patients had both CESM and MRI performed pre- and post-NST with pathological assessment after surgical management. Size of residual malignancy on post-NST CESM and MRI was compared with surgical pathology. Lin concordance and Pearson correlation coefficient were used to assess agreement. Bland–Altman plots were used to visualize the differences between tumor size on imaging and pathology.ResultsSixty-five patients were identified. Mean age was 52.7 (range 30–76) years. Type of NST included chemotherapy in 53 (82%) and endocrine therapy in 12 (18%). Mean tumor size after NST was 14.6 (range 0–105) mm for CESM and 14.2 mm (range 0–75 mm) for MRI compared with 19.6 (range 0–100) mm on final surgical pathology. Equivalence tests demonstrated that mean tumor size measured by CESM (p = 0.009) or by MRI (p = 0.01) was equivalent to the mean tumor size measured by pathology within − 1 and 1-cm range. Comparing CESM versus MRI for assessment of complete response, the sensitivity was 95% versus 95%, specificity 66.7% versus 68.9%, positive predictive value 55.9% versus 57.6%, and negative predictive value 96.7% versus 96.9% respectively.ConclusionsCESM was comparable to MRI in assessing residual malignancy after completion of NST.

Background Elevated PD-L1 expression on tumor cells, a context associated with an adaptive immune response, has been linked to the total burden of copy number variants (CNVs) in aneuploid tumors, to microsatellite instability (MSI), and to specific genomic driver lesions, including loss of PTEN , MYC amplification, and activating mutations in driver oncogenes such as KRAS and PIK3CA . Triple-negative breast cancers (TNBCs) typically have high levels of CNVs and diverse driver lesions in their genomes. Thus, there is significant interest in exploiting genomic data to develop predictive immunotherapy biomarkers for patients with TNBC. Methods Whole tissue samples from 55 resected TNBCs were screened by immunohistochemistry (IHC) for PD-1 and PD-L1 by using validated antibodies and established scoring methods for staining of tumor and non-tumor cells. In parallel, we interrogated biopsies from each resection with DNA content flow cytometry and sorted the nuclei of diploid, tetraploid, and aneuploid cell populations. CNVs were mapped with CNV oligonucleotide arrays by using purified (>95%) tumor populations. We generated whole exome data for 12 sorted tumor samples to increase the resolution within loci of interest and to incorporate somatic mutations into our genomic signatures. Results and Conclusions PD-L1 staining was detected on tumor cells in 29 out of 54 (54%) evaluable cases and was associated with increased overall survival ( P  = 0.0024). High levels of PD-1 and PD-L1 (IHC ≥4) were present in 11 out of 54 (20%) and 20 out of 54 (37%) cases with staining of PD-L1 primarily on tumor cells for 17 out of 20 (85%) cases. The latter included tumors with both high (>50) and low (<20) numbers of CNVs. Notably, homozygous deletion of PTEN ( n  = 6) or activating mutation in PIK3CA ( n  = 1) was not associated with increased expression of either immune checkpoint activator in TNBC. In contrast, two treatment-naïve cases with EGFR driver amplicons had high PD-L1 tumor staining. High mutational load and predicted neoepitopes were observed in MSI + and high CNV burden TNBCs but were not associated with high PD-L1 expression on tumor cells. Our results challenge current models of genomic-based immunotherapy signatures yet suggest that discrete genomic lesions may complement existing biomarkers to advance immune checkpoint therapies for patients with TNBC.

Background The influence of distance traveled for treatment on short- and long-term cancer outcomes is unclear. Methods Patients with colon, esophageal, liver, and pancreas cancer from 2003 to 2006 were identified from the National Cancer Data Base (NCDB). Distance traveled for surgical treatment was estimated using zip code centroids. Propensity scores were generated for probability of traveling farther for treatment. Mixed effects logistic regression for 90-day mortality and Cox regression for 5-year mortality were compared between patients treated regionally and those traveling from farther away. Results The mean distance traveled for all patients for surgical resection was 30.0 ± 227 miles, with a median distance of 7.5 (interquartile range 14.4) miles. Patients who were aged ≥80 years, on Medicaid, or African American were less likely to be in the fourth quartile of distance (Q4) traveled for surgery. Patients who were in Q4 had a lower risk-adjusted 90-day mortality compared to Q1 for colon [odds ratio (OR) 0.89, 95 % confidence interval (CI) 0.82–0.96], liver (OR 0.49, 95 % CI 0.3–0.78), and pancreatic (OR 0.74, 95 % CI 0.56–0.98) cancer. Similarly, patients in Q4 for all tumor types had a lower risk-adjusted 5-year mortality compared to patients in Q1; colon (hazard ratio (HR) 0.96, 95 % CI 0.93–0.99), esophagus (HR 0.84, 95 % CI 0.75–0.94), liver (HR 0.75, 95 % CI 0.62–0.89), and pancreas (HR 0.87, 95 % CI 0.80–0.95). Conclusions Greater travel distance for surgical resection of gastrointestinal cancers is associated with lower 90-day and 5-year mortality outcomes. This distance bias has implications for regionalization and reporting of cancer outcomes.

The burden of cancer continues to increase in society and negatively impacts the lives of numerous patients. Due to the high cost of current treatment strategies, there is a crucial unmet need to develop inexpensive preclinical platforms to accelerate the process of anti-cancer drug discovery to improve outcomes in cancer patients, most especially in female patients. Many current methods employ expensive animal models which not only present ethical concerns but also do not often accurately predict human physiology and the outcomes of anti-cancer drug responsiveness. Conventional treatment approaches for cancer generally include systemic therapy after a surgical procedure. Although this treatment technique is effective, the outcome is not always positive due to various complex factors such as intratumor heterogeneity and confounding factors within the tumor microenvironment (TME). Patients who develop metastatic disease still have poor prognosis. To that end, recent efforts have attempted to use 3D microengineered platforms to enhance the predictive power and efficacy of anti-cancer drug screening, ultimately to develop personalized therapies. Fascinating features of microengineered assays, such as microfluidics, have led to the advancement in the development of the tumor-on-chip technology platforms, which have shown tremendous potential for meaningful and physiologically relevant anti-cancer drug discovery and screening. Three dimensional microscale models provide unprecedented ability to unveil the biological complexities of cancer and shed light into the mechanism of anti-cancer drug resistance in a timely and resource efficient manner. In this review, we discuss recent advances in the development of microengineered tumor models for anti-cancer drug discovery and screening in female-related cancers. We specifically focus on female-related cancers to draw attention to the various approaches being taken to improve the survival rate of women diagnosed with cancers caused by sex disparities. We also briefly discuss other cancer types like colon adenocarcinomas and glioblastoma due to their high rate of occurrence in females, as well as the high likelihood of sex-biased mutations which complicate current treatment strategies for women. We highlight recent advances in the development of 3D microscale platforms including 3D tumor spheroids, microfluidic platforms as well as bioprinted models, and discuss how they have been utilized to address major challenges in the process of drug discovery, such as chemoresistance, intratumor heterogeneity, drug toxicity, etc. We also present the potential of these platform technologies for use in high-throughput drug screening approaches as a replacements of conventional assays. Within each section, we will provide our perspectives on advantages of the discussed platform technologies.

Folate receptor alpha (FOLR1) has been identified as a potential prognostic and therapeutic target in a number of cancers. A correlation has been shown between intense overexpression of FOLR1 in breast tumors and poor prognosis, yet there is limited examination of the distribution of FOLR1 across clinically relevant breast cancer subtypes. To explore this further, we used RNA-seq data from multiple patient cohorts to analyze the distribution of FOLR1 mRNA across breast cancer subtypes comprised of estrogen receptor positive (ER+), human epidermal growth factor receptor positive (HER2+), and triple negative (TNBC) tumors. FOLR1 expression varied within breast tumor subtypes; triple negative/basal tumors were significantly associated with increased expression of FOLR1 mRNA, compared to ER+ and HER2+ tumors. However, subsets of high level FOLR1 expressing tumors were observed in all clinical subtypes. These observations were supported by immunohistochemical analysis of tissue microarrays, with the largest number of 3+ positive tumors and highest H-scores of any subtype represented by triple negatives, and lowest by ER+ tumors. FOLR1 expression did not correlate to common clinicopathological parameters such as tumor stage and nodal status. To delineate the importance of FOLR1 overexpression in triple negative cancers, RNA-interference was used to deplete FOLR1 in overexpressing triple negative cell breast lines. Loss of FOLR1 resulted in growth inhibition, whereas FOLR1 overexpression promoted folate uptake and growth advantage in low folate conditions. Taken together, our data suggests patients with triple negative cancers expressing high FOLR1 expression represent an important population of patients that may benefit from targeted anti-FOLR1 therapy. This may prove particularly helpful for a large number of patients who would typically be classified as triple negative and who to this point have been left without any targeted treatment options.

Purpose Quantify in vivo biomechanical tissue properties in various breast densities and in average risk and high-risk women using Magnetic Resonance Imaging (MRI)/MRE and examine the association between breast biomechanical properties and cancer risk based on patient demographics and clinical data. Methods Patients with average risk or high-risk of breast cancer underwent 3.0 T breast MR imaging and elastography. Breast parenchymal enhancement (BPE), density (from most recent mammogram), stiffness, elasticity, and viscosity were recorded. Within each breast density group (non-dense versus dense), stiffness, elasticity, and viscosity were compared across risk groups (average versus high). Separately for stiffness, elasticity, and viscosity, a multivariable logistic regression model was used to evaluate whether the MRE parameter predicted risk status after controlling for clinical factors. Results 50 average risk and 86 high-risk patients were included. Risk groups were similar in age, density, and menopausal status. Among patients with dense breasts, mean stiffness, elasticity, and viscosity were significantly higher in high-risk patients ( N  = 55) compared to average risk patients ( N  = 34; all p  < 0.001). Stiffness remained a significant predictor of risk status (OR = 4.26, 95% CI [1.96, 9.25]) even after controlling for breast density, BPE, age, and menopausal status. Similar results were seen for elasticity and viscosity. Conclusion A structurally based, quantitative biomarker of tissue stiffness obtained from MRE is associated with differences in breast cancer risk in dense breasts. Tissue stiffness could provide a novel prognostic marker to help identify high-risk women with dense breasts who would benefit from increased surveillance and/or risk reduction measures.

BackgroundCytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has been associated with increased postoperative complications and a prolonged length of stay (LOS). We report on our experience following implementation of an Enhanced Recovery After Surgery (ERAS) program for CRS and HIPEC.MethodsPatients were divided into pre- and post-ERAS groups. Modifications in the ERAS group included routine use of transversus abdominis plane blocks, intra- and postoperative fluid restriction, and minimizing the use of narcotics, drains, and nasogastric tubes.ResultsOf a total of 130 procedures, 49 (38%) were in the pre-ERAS group and 81 (62%) were in the ERAS group. Mean LOS was reduced from 10.3 ± 8.9 days to 6.9 ± 5.0 days (p = 0.007) and the rate of grade III/IV complications was reduced from 24 to 15% (p = 0.243) following ERAS implementation. The ERAS group received less intravenous fluid during hospitalization (19.2 ± 18.7 L vs. 32.8 ± 32.5 L, p = 0.003) and used less opioids than the pre-ERAS group (median of 159.7 mg of oral morphine equivalents vs. 272.6 mg). There were no significant changes in the rates of 30-day readmission or acute kidney injury between the two groups (p = non-significant). On multivariable analyses, ERAS was significantly associated with a reduction in LOS (− 2.89 days, 95% CI − 4.84 to − 0.94) and complication rates (odds ratio 0.22, 95% CI 0.08–0.57).ConclusionsImplementation of an ERAS program for CRS and HIPEC is associated with a reduction in overall intravenous fluids, postoperative narcotic use, complication rates, and LOS.

BackgroundAlthough major cancer surgery at a high-volume hospital is associated with lower postoperative mortality, the use of such hospitals may not be equally distributed.ObjectiveOur aim was to study socioeconomic and racial differences in cancer surgery at Commission on Cancer (CoC)-accredited high-volume hospitals.MethodsThe National Cancer Database (NCDB) was used to identify patients undergoing surgery for colon, esophageal, liver, and pancreatic cancer from 2003 to 2012. Annual hospital volume for each cancer was categorized using quartiles of patient volume. Patient-level predictors of surgery at a high-volume hospital, trends in the use of a high-volume hospital, and adjusted likelihood of surgery at a high-volume hospital in 2012 versus 2003 were analyzed.ResultsAfrican American patients were less likely to undergo surgery at a high-volume hospital for esophageal (odds ratio [OR] 0.59, 95% confidence interval [CI] 0.49–0.73) and pancreatic cancer (OR 0.83, 95% CI 0.74–0.92), while uninsured patients and those residing in low educational attainment zip codes were less likely to undergo surgery at a high-volume hospital for esophageal, liver, and pancreatic cancer. In 2012, African Americans, uninsured patients, and those from low educational attainment zip codes were no more likely to undergo surgery at a high-volume hospital than in 2003 for any cancer type. These differences were not seen in colon cancer patients, for whom significant regionalization was not seen.ConclusionsDifferences in the use of CoC-accredited high-volume hospitals for major cancer surgery were seen nationwide and persisted over the duration of the study. Strategies to increase referrals and/or access to high-volume hospitals for African American and socioeconomically disadvantaged patients should be explored.