Search

Abbreviated magnetic resonance imaging (Ab-MRI) has been evaluated for elevated breast cancer risk or dense breasts but has not been evaluated across all risk profiles.Patients selected underwent Ab-MRI from February 2020 to September 2021. Women were older than aged 30 years, up to date with screening mammography, and paid $299 cash.A total of 93 patients were identified with a mean age of 52 years; 92.5% were Caucasian, 0% black, and 97.9% were from high socioeconomic status. Mean Gail score was 14.2, and 83.3% had a lifetime risk of breast cancer20%. Reasons for Ab-MRI: dense breasts (36.6%); family history (24.7%); palpable mass (12.9%). Providers ordering: OBGYN (49.5%); breast surgeon (39.1%); primary care (6.6%). Thirteen biopsies (14%) detected one breast cancer. 31.1% had a change in follow-up screening: 58.6% 6-month MRI, 20.7% 6-month mammogram, and 10.3% 6-month ultrasound. Negative predictive value was 100% (95% confidence interval [CI]: 95-100%, p0.0001). Sensitivity was 100% (95% CI: 2.5-100%, p0.0001), and specificity was 87% (95% CI: 78.3-93.1%, p0.0001) compared with 77.6% and 98.8% for mammography. Only one cancer was detected: cost of $27,807 plus cost of 13 MRI or ultrasound (US)-guided biopsies and additional follow-up imaging. Historically 20% of abnormalities detected on full MRI are malignant; however, 7.7% of ab-MRI abnormalities were malignant CONCLUSIONS: One third of women were recommended a change in follow-up, which predominantly included a 6-month MRI. Ab-MRI may introduce average risk women to unnecessary follow-up and increased biopsies with a lower cancer detection rate. Ab-MRI should be evaluated closely before implementation.

BACKGROUND There has been a growing trend toward minimally invasive surgery (MIS) for colon cancer. Pathological analysis of a minimum of 12 lymph nodes (LNs) is a benchmark for adequate resection. Here, we present a comparison of surgical techniques in achieving a full oncologic resection. METHODS Patients undergoing surgery for Stage I-III colon cancer (2010-2016) were identified from the National Cancer Database. Cases were stratified by surgical approach. Trends in approach were assessed, including whether the 12-LN benchmark was met. Uni- and multivariate regression was used to assess overall survival (OS). RESULTS A total of 290,776 colectomies were analyzed. MIS increased from 32.8% to 57.2% from 2010 to 2016 (p

Background Philadelphia and its suburbs were an epicenter for the initial COVID-19 outbreak. Accordingly, alterations were made in breast cancer care at a community hospital. Methods The authors developed a prospective database of all the patients with invasive or in situ breast cancer between March 1 and June 15 at their breast center. Any change in a breast cancer plan due to the pandemic was documented, and the patients were grouped into two cohorts according to whether a change was made (CTX) or no change was made (NC) in their care. The patients were asked a series of questions about their care, including those in the Generalized Anxiety Disorder two-item questionnaire (GAD-2), via telephone. Results The study enrolled 73 patients: 41 NC patients (56%) and 32 CTX patients (44%). The two cohorts did not differ in terms of age, race, or stage. Changes included delay in therapy (15.1%) and use of neoadjuvant endocrine therapy (NET, 28.8%). The median time to surgery was 24 days (interequartile range [IQR], 16–45 days) for the NC patients and 82 day s (IQR, 52–98 days) for the CTX patients (p ≤ 0.001). The median duration of NET was 78 days. The GAD-2 showed anxiety positivity to be 29.6% for the CTX patients and 32.4% for the NC patients (p = 1.00). More than half (55.6%) of the CTX patients believed COVID-19 affected their treatment outlook compared with 25.7% of the NC patients (p = 0.021). Conclusions A prospective database captured changes in breast cancer care at a community academic breast center during the initial phase of the COVID-19 pandemic. 44% of patients experienced a change in breast cancer care due to COVID-19. The same level of anxiety and depression was seen in both change in therapy (CTX) and no change (NC). 55.6% of CTX cohort believed COVID-19 affected their treatment outlook.

Metabolic syndrome (MS) is defined by having at least 3 of 4 components: obesity, dyslipidemia, hypertension (HTN), and diabetes. Prior studies analyzed the individual components of MS for all breast cancers which are predominantly hormone positive. Our study is the first to evaluate MS in triple-negative breast cancer (TNBC). A retrospective review of TNBC from 2007 to 2013 identified 177 patients with complete information for statistical analysis. Cox proportional hazards models were used to test the association between MS, disease-free survival (DFS), and overall survival (OS). 48 (27%) patients had MS. After controlling for age, race, pathologic stage, surgery type, and additional comorbidities outside of MS, MS was significantly associated with poorer DFS (adjusted HR: 2.24, p = 0.030), but not associated with OS (adjusted HR: 1.92, p = 0.103). HTN was significantly associated with poorer DFS (adjusted HR: 3.63, p = 0.006) and OS (adjusted HR: 3.45, p = 0.035) in the univariable and multivariable analyses. Diabetes was not associated with worse OS or DFS. The 5-year age-adjusted OS rates for 60-year-old patients with and without diabetes were 85.8% and 87.3%, respectively. The age-adjusted 5-year OS rate for 60-year old patients was higher in patients with a body mass index (BMI) > 30 (90.2%) versus BMIs of 25–29.9 (88.2%) or

Male breast cancer (MBC) is often diagnosed at a later stage and with a more unfavorable tumor-to-breast ratio compared to women, prompting lower rates of breast conservation (BCT). We sought to assess the practice patterns of neoadjuvant therapy (NT) in MBC patients and the impact on BCT.Men with nonmetastatic, invasive breast cancer were identified from the National Cancer Database. Patients were categorized as having small (cT1/2) or locally advanced (cT3/4) tumors and by whether they received NT (which included endocrine or chemotherapy). Univariate and multivariable analyses were performed to assess patterns of NT use and rates BCT.Of 15,151 male patients, 4.8% received NT and 21.6% underwent BCT. NT was more common among males with cT3/4 tumors than those with cT1/2 tumors (8.2 vs. 2.1%, P.001). Overall, unadjusted rates of BCT were higher for patients receiving NT in the cT3/4 subgroup (19.0 vs. 12.5%, P.001), a difference which persisted on multivariable analysis. For all patients analyzed, overall survival (OS) did not differ between males who underwent NT and those who did not (110 vs. 122 months, P = .67), but NT was associated with poorer OS in both univariate and multivariate analyses for patients with cT3/4 tumors (both P.01).Men with invasive breast cancer have an expected low rate of BCT, but NT appears to reduce the use of mastectomy in patients with locally advanced cancers. More work is needed to understand the impacts of BCT on locoregional recurrence and disease-free and overall survival for MBC.

Many quality measures in cancer care are process measures. The rates of compliance for these measures over time have not been well described, and the relationships between measure compliance and survival are not well understood. The National Cancer Database, representing cancer registry data from approximately 1500 Commission on Cancer (CoC) cancer programs, was queried to determine the rates of compliance, with the CoC’s colon cancer quality measure requiring 12 regional lymph nodes be removed at resection. Data were assessed in 2003, before the measure was reported to programs, through 2015. Measure compliance and risk-adjusted survival were examined by hospital type. From 2003 to 2015, 544,018 cases of colon cancer were analyzed for number of nodes removed. In 2003, compliance was 52.8% and National Cancer Institute (NCI) centers had the highest compliance rate (69.0%), followed by academic cancer centers (61.9%), comprehensive community hospitals (50.9%), and community hospitals (44.0%). Between 2003 and 2015, compliance improved for all hospital types, although differences remained. Risk-adjusted survival in 2009 was better at NCI centers [hazard ratio (HR) 0.76] than at academic cancer centers (HR 0.90), which had better survivals than comprehensive community programs (HR 0.93) when compared with patients treated at community hospitals. After introduction of this quality measure, performance at CoC-accredited hospitals improved over the subsequent 13 years, and survival by hospital type paralleled measure compliance by hospital type. This demonstrated measurement may be associated with improvements in performance, and that there are differences in performance and outcome by hospital type.

Many studies have demonstrated disparities in breast cancer (BC) incidence and mortality among Black women. We hypothesized that in Pennsylvania (PA), a large economically diverse state, BC diagnosis and mortality would be similar among races when stratified by a municipality's median income.We collected the frequencies of BC diagnosis and mortality for years 2011-2015 from the Pennsylvania Cancer Registry and demographics from the 2010 US Census. We analyzed BC diagnoses and mortalities after stratifying by median income, municipality size, and race with univariable and multivariable logistic regression models.In this cohort, of 5,353,875 women there were 54,038 BC diagnoses (1.01% diagnosis rate) and 9,828 BC mortalities (0.18% mortality rate). Unadjusted diagnosis rate was highest among white women (1.06%) but Black women had a higher age-adjusted diagnosis rate (1.06%) than white women (1.02%). Race, age and income were all significantly associated with BC diagnosis, but there were no differences in BC diagnosis between white and Black women across all levels of income in the multivariable model. BC mortality was highest in Black women, a difference which persisted when adjusted for age. Black women 35 years and older had a higher mortality rate in all income quartiles.We found that in PA, age, race and income are all associated with BC diagnosis and mortality with noteworthy disparities for Black women. Continued surveillance of differences in both breast cancer diagnosis and mortality, and targeted interventions related to education, screening and treatment may help to eliminate these socioeconomic and racial disparities.

The National Accreditation Program of Breast Centers (NAPBC) certifies institutions that provide quality breast care. Whereas low socioeconomic status (SES) has a negative impact on patient outcomes, it is unknown whether an institution's patient SES mix is associated with meeting NAPBC standards.All institutions submitting at least 100 breast cancer patients to the National Cancer Database (2006-2017) were ranked based on the patients' insurance status, income, and education. The 10% treating the largest proportion of low-SES patients were termed low-SES institutions (LSES). Patient cohorts were created based on the 2018 NAPBC standards. Uni- and multivariate comparisons of patient, tumor, and treatment factors were made to calculate adjusted odds of meeting each standard between low- and non-low-SES institutions.The analysis included 1319 institutions. Both the LSES and non-LSES reached the benchmark rate of 50% lumpectomies (61.2 vs 62.9%; p0.001), but the unadjusted and adjusted rates of lumpectomy were lower in LSES. The rate for sentinel lymphadenectomy was lower for LSES (49.2 vs 53.7%; p0.001). Similarly, the unadjusted and adjusted rates of adjuvant chemotherapy and endocrine therapy were lower at LSES. Although the unadjusted rate of adjuvant radiation was higher at LSES, adjusted odds demonstrated that patients treated at LSES were less likely to undergo adjuvant radiation when appropriate.Small but significant differences in achieving multidisciplinary standards for quality breast cancer care exist between LSES and non-LSES and may exacerbate disparities already faced by patients of low SES.

Metabolic syndrome (MS) is defined by having at least 3 of 4 components: obesity, dyslipidemia, hypertension (HTN), and diabetes. Prior studies analyzed the individual components of MS for all breast cancers which are predominantly hormone positive. Our study is the first to evaluate MS in triple-negative breast cancer (TNBC).A retrospective review of TNBC from 2007 to 2013 identified 177 patients with complete information for statistical analysis. Cox proportional hazards models were used to test the association between MS, disease-free survival (DFS), and overall survival (OS).48 (27%) patients had MS. After controlling for age, race, pathologic stage, surgery type, and additional comorbidities outside of MS, MS was significantly associated with poorer DFS (adjusted HR: 2.24, p = 0.030), but not associated with OS (adjusted HR: 1.92, p = 0.103). HTN was significantly associated with poorer DFS (adjusted HR: 3.63, p = 0.006) and OS (adjusted HR: 3.45, p = 0.035) in the univariable and multivariable analyses. Diabetes was not associated with worse OS or DFS. The 5-year age-adjusted OS rates for 60-year-old patients with and without diabetes were 85.8% and 87.3%, respectively. The age-adjusted 5-year OS rate for 60-year old patients was higher in patients with a body mass index (BMI) 30 (90.2%) versus BMIs of 25-29.9 (88.2%) or 25 (83.5%).In the TNBC population, MS was significantly associated with poorer DFS, but not associated with OS. HTN was the only component of MS that was significantly associated with both DFS and OS. Obesity has a potential small protective benefit in the TNBC population.

Background: Breast cancers are traditionally viewed as immunologically silent. However, recent research has demonstrated that the triple-negative breast cancer (TNBC) and HER-2 positive (HER2) are capable of stimulating the immune system. In contrast, the most commonly diagnosed subtype, the luminal A (hormone receptor positive (HR+)/HER-2 negative), is associated with a lower degree of tumor infiltrating lymphocytes (TILs) and low expression level of immune checkpoint regulators such as programmed death-ligand-1 (PD-L1). Cryoablation, the destruction of cells by ultra-low temperatures, has been used to treat benign breast disease and clinical trials have been conducted to determine its utility for invasive breast cancers. The primary endpoint has been the rate of complete tumor ablation with no assessment of immunological responses. We hypothesized that neoantigens released during cryoablation might be sufficient to trigger immune responses that could aid in the prevention/reduction of metastatic spread and relapse of breast cancers.In this pilot study we evaluated biopsy material, cryoablated specimens and sentinel lymph nodes (SLN) from patients enrolled in the ACOSOG Z1072 trial at Lankenau Medical Center (LMC) [N=18] with cancers < 2 cm. Responses were compared to patients treated with surgical resection.Methods: After obtaining IRB approval for retrospective analyses of specimens from the ACOSOG Z1072 trial, immunohistochemical staining of archival specimens was performed. An on-going biomarker study protocol was amended to include immune markers and used to select control patients of similar age and tumor characteristics. Per trial protocol, tumors had to be be surgically removed within 28 days of cryoablation, but the exact time was left to the surgeons discretion. Participating surgeons at LMC preferred to remove tumors on average 24.7 days after ablation resulting in an average time from diagnosis to surgical removal of 43.3 days (range 25- 56 days). Although most breast surgeries are performed within two weeks of diagnosis; some patients defer their surgery for personal reasons. This allowed us to identify patients (N=26) with a comparable average time from diagnosis to surgery of 37 days (range 21 - 66 days). Sections were stained for CD4, CD8, CD20, CD21, and CD1c to assess possible changes in immune repertoire due to cryoablation. We also evaluated presence of immune check-point regulators such as PD-L1 and CTLA-4 in biopsy, surgical material and SLN together with the immune modulator IDO1 using commercially available antibodies and standard techniques. Results: Cryoablation transformed tumors in patients into a gelatinous mass surrounded by a fibrotic capsule. The ACOSOG trial demonstrated an effective cryoablation-induced destruction of ER+ invasive ductal carcinoma lesions in 92% of patients (N=86). Sections from cryoablation patients displayed a necrotic core and infiltrating lymphocytes in the microenvironment. These masses had a slightly higher presence of CD8+ lymphocytes compared to CD4+. The inverse relation was observed in non-cryoblated specimens. SLNs from cryoablated patients had an elevated presence of CD20+ B cells compared to patients treated by surgery. Follicular dendritic cells (CD21+) were also present at higher numbers in SLNs from cryoablated patients. We detected positive staining for both PD-L1 and IDO1 among surgical and cryoablated patients. Sporadic presence of CTLA-4 was identified with a slight preference for cryoabalted patients. Conclusion: Cryoablation of breast cancer lesions can induce immune responses in vivo with possible anti-tumor activity in immunologically silent tumors such as HR+ breast cancers. All local cryo patients in the clinical trial are currently disease-free (F/U 5 - 13years), while 1 surgical patient is alive with late recurrence (11 years post-surgery). Citation Format: Margaretha Wallon, Jonah D Klein, Zachary Aukers, Nolan Metz, Vibha Ahudja, Laura Mandik-Nayak, Vincenzo Ciocca, Vlasta Zemba-Palko, Robin M Ciocca, Jennifer L Sabol, Ned Z Carp. Development of unique immune responses triggered by cryoablation of breast cancers [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-04-05.

Background: Breast cancer is traditionally not considered as a highly immunogenic disease. Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer with reported high genomic instability and high mutation rate, indicating the possible presence of neoantigens. Cryoablation, the destruction of cells by ultra-low temperatures, can release these neoantigens and induce a tumor specific immune response. We hypothesized these neoantigens might be sufficient to trigger a robust immune response to prevent and/or reduce spread and relapse of TNBC. In this pilot study we cryoablated orthotopical 4T1 tumors in immune competent Balb/c mice and compared the results to surgery to evaluate 1) possible induction of immune responses and 2) effects on metastases formation. Methods: We used 4T1 mammary carcinoma cells to initiate tumor growth in the mammary fatpad. Tumors were treated by cryoablation, cryoablation followed by surgery (cryo-surgery), or surgery alone. Tumor growth was followed and allowed to reach 3-4mm in largest dimension. Animals were euthanized 7 days post-treatment and tissues were collected to assess cytokine levels and presence of dissociated 4T1 cells. Single-cell suspensions of tumor, tumor-draining lymph node [TDLN], and spleen were tested for secretion of mouse Th1/Th2 cytokines using a bead array and measured by flow cytometery. Possible metastatic spread was assessed by a clonogenic assay using cells from venous blood, lung, and brain. Cell suspensions were seeded in growth medium supplemented with the selection agent 6-thioguanine, allowing only resistant 4T1 cells to form colonies. Results: Cryoablation transformed tumors into a gelatinous mass surrounded by a fibrotic capsule, as typically seen in the clinic. Frozen sections of tumors revealed a necrotic core and infiltrating lymphocytes in the microenvironment. These animals displayed robust increases of Th1 and Th2 cytokines in both spleen and TDLN compared to animals with cryo-surgery treatment. TDLN of animals with surgically excised tumors secreted only IL-2. Circulating tumor cells were found in animals prior to treatment, while no 4T1 colonies formed from cell suspensions of lung and brain tissue [N=8]. At end-point, the surgery alone group had more 4T1 foci formed from lung and brain [mean foci /animal = 6.25 and 0.75, respectively; N=6] than the other two groups. Two animals in this group progressed and were euthanized early due to numerous lung metastases. The cryoablated group had the lowest number of foci formed in the lung and brain [2.25 and 0 respectively; N=8], and all animals were healthy at the predetermined end-point. Mean foci formation in the cryo-surgery group [N=7] was in-between the two other groups and one animal was euthanized early due to metastatic burden 5 days after surgery. Conclusion: Cryoablation of TNBC can induce stimulatory immune responses in vivo. These immune responses might explain why animals treated with cryoablation, though having circulating tumor cells at the time of treatment, exhibited fewer micro metastatic growths compared to surgery alone and the cryo-surgery combination. On-going experiments aim to identify long-term effects of cryoablation on the formation of metastatic foci and growth. Citation Format: Klein JD, Aukers Z, Kennedy J, Ciocca RM, Sabol JL, Carp NZ, Wallon UM. Cryoablation of murine mammary tumors induce robust immune response [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-06-11.

The definition of a community hospital has been highly variable based on teaching versus non-teaching, proximity to a major metropolitan area, number of hospital beds, governance structure, partnered or not partnered with a larger center, or simply its role as a care hub for the local population. For the purpose of this chapter, the term community hospital will refer to the American Hospital Associations definition as a non-federal, short-term, general, and/or specialty hospitals. This excludes university centers, but includes university affiliates and can be teaching or non-teaching. In 1980, 16% of outpatient surgeries took place at community hospitals. In 2015, this number increased to 66% (National Center for Health Statistics, Center for Disease Control, 2017). Similar trends are being seen in cancer care. Since clinical trials (inclusive of pharmaceutical trials, device trials, quality of life trials, and others) are the means by which the medical and surgical community evaluate and improve care for patients, it is imperative that the population of patients who receive their care at community centers have the opportunity to enroll in clinical trials. Similarly, surgeons in these settings must be armed with the tools needed to participate in clinical trials. This chapter outlines the community surgeon’s involvement in clinical trials. Discussed are the historic perspective (including community participation in practice changing trials), the logistic challenges and barriers in the community hospital, and the unique elements of trials in the community setting compared to the university-based academic settings.

Background: Cryoablation, the destruction of cells by ultra-low temperatures, has been used to treat benign breast disease and two clinical trials (ACOSOG Z1072 and FROST) have been conducted to determine its utility in invasive breast cancers. The focus of the trials has been the rate of complete tumor ablation with no assessment of immunological responses. We hypothesize that neoantigens released during cryoablation might be sufficient to trigger a robust immune response to prevent and/or reduce spread and relapse of breast cancers. In this pilot study we 1) evaluated biopsy material, cryoablated specimens and axillary lymph nodes from patients with cancers smaller than 2cm enrolled in the ACOSOG Z1072 trial at Lankenau Medical Center [N=18] and 2) assessed immune responses and effects on metastases formation in the classical mouse mammary tumor model 4T1 in immune competent Balb/c mice. In both settings responses were compared to patients/mice treated with surgical resection alone. Methods: After obtaining IRB approval for retrospective analyses of specimens from the ACOSOG Z1072 trial, immunohistochemical staining of surgical specimens was performed. Sections were stained for CD4, CD8, CD20, CD21, and CD1c. In the IACUC approved animal experiments, 4T1 cells were injected orthotopically in the mammary fatpad to initiate tumor growth. Small tumors were treated by cryoablation or surgery alone. Animals were euthanized 7 days post-treatment and tissues were collected to assess cytokine levels and presence of dissociated 4T1 cells. Single-cell suspensions of tumor, tumor-draining lymph node [TDLN], and spleen were tested for secretion of mouse Th1/Th2 cytokines using a bead array and measured by flow cytometry. Possible metastatic spread was assessed by a clonogenic assay using cells from venous blood, lung and brain. Cell suspensions were seeded in growth medium with the selection agent 6-thioguanine, allowing only resistant 4T1 cells to form colonies. Results: Cryoablation transformed tumors in both patients and mice into a gelatinous mass surrounded by a fibrotic capsule. Sections of tumors from both humans and mice displayed a necrotic core and infiltrating lymphocytes in the microenvironment. The cryoablated human tumors had slightly higher presence of lymphocytes positive for CD8+ compared to CD4+. The inverse relation was observed in non-cryoblated specimens. No significant difference was observed for CD20+ lymphocytes. Tumor-draining lymph nodes from cryoablated patients had an elevated presence of CD20+ B cells compared to patients treated by surgery alone. Follicular dendritic cells (CD21+) were also present at higher numbers in TDLN from cryoablated patients. Animals treated with cryoablation displayed robust increases of Th1 and Th2 cytokines in both spleen and TDLN compared to animals with surgery treatment. In the animals, circulating tumor cells were found prior to treatment, while no 4T1 colonies formed from cell suspensions of lung and brain tissue [N=8]. At end-point, the surgery group had more 4T1 foci formed from lung and brain [mean foci /animal = 6.25 and 0.75, respectively; N=6] than the cryo group that had 2.25 and 0 foci in lung and brain, respectively [N=8]. Conclusion: Cryoablation of breast cancer lesions can induce stimulatory immune responses in vivo. These immune responses might explain why animals treated with cryoablation, though having circulating tumor cells at the time of treatment, exhibited fewer micro metastatic growths compared to surgery alone. The presence of elevated numbers of CD20+ in TDLN has been associated with improved disease-free survival. All local patients in the clinical trial are currently disease-free (5 to 9-year F/U) which is higher than expected recurrence rate at ~15% at 9 years post treatment. Citation Format: Allison A Campoverde, Jonah D Klein, Zachary Aukers, John Kennedy, Vlasta Zemba-Palko, Vincenzo Ciocca, Robin M Ciocca, Jennifer L Sabol, Ned Z Carp, Margaretha Wallon. Immune responses triggered by cryoablation of breast cancers [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-04-22.

BACKGROUND – Tissue inhibitor of metalloproteinase-4 (TIMP-4) is a secreted multi-functional protein associated with poor survival prognosis among early-stage triple-negative breast cancers (TNBC). TNBC represent a highly aggressive form of this disease with an unmet need for effective predictive markers and targeted therapy. Extracellular TIMP-4 binds to the membrane bound tetraspanin CD63 and induces the activation of the tumor promoting PI3K/AKT/mTOR pathway. Here we report that TIMP-4 induced aggressive tumor growth and metastasis can be adverted by directly targeting TIMP-4 using a newly developed monoclonal antibody (mAb) to sequester TIMP-4 and the varied responses to common chemotherapy (CTX) regimen. METHODS – The role of elevated TIMP-4 in TNBC cell behavior was tested in cell culture and animal experiments using the human breast cancer line MDA-MB-468. Cells with or without TIMP-4 added to the medium were used to determine the effects on growth, clonogenic survival and response to chemotherapeutic agents such as adriamycin, Taxol, and the new TIMP-4 mAb. The same cell-line was used to induce tumor growth in nude mice with or without TIMP-4 containing slow-release pellets implanted into the mammary fatpad (mfp). Tumor growth and response to therapy was followed over a six-week period. Lungs, liver, spleen and mfp were collected and analyzed for presence of human cells using a specific anti-human MHC I mAb. Prospectively collected patient samples, in accordance with the IRB approved protocol, were tested for circulating levels of TIMP-4 using a commercially available ELISA assay in samples collected prior to chemotherapy and at each treatment cycle. The medical oncology staff recommended therapy without knowledge of TIMP-4 status. RESULTS – Augmentation of TIMP-4 levels in cell culture medium or the mfp of mice resulted in similar tumor phenotype as in the clinic; fast growing tumors with accelerated disease progression. Elevated TIMP-4 levels in the tumor environment resulted in a 1.5-fold increased growth rate with liver and/or lung metastasis in 25% of animals (N=16). No metastases were found in animals with normal TIMP-4 levels. Treating cell cultures or tumor-bearing mice (i.p. injections) with our TIMP-4 mAb resulted in decelerated growth rate and no detectable metastatic disease in the animals. Results from patient samples demonstrated that circulating TIMP-4 levels in breast cancer patients remain elevated after definitive surgery, indicating that TIMP-4 might continuously stimulate any remaining disseminated tumor cells. Adriamycin containing regiments was the only CTX to suppress the TIMP-4 levels independent of primary tumor size and nodal status. CONCLUSIONS – Based on these clinical and experimental data we suggest that TIMP-4 may represent a prognostic and predictive marker, and a therapeutic target for TNBC patients at highest risk. The presence of TIMP-4 identifies a patient population likely to recur quickly due to continuous activation of the PI3K/AKT/mTOR pathway. Though adriamycin therapy can reduce the TIMP-4 levels, the toxicity of this agent suggests that targeted therapy of the PI3K/AKT pathway and/or a biological therapeutic approach directed against TIMP-4 may be of benefit in this subset of pts and should be further explored. Citation Format: U Margaretha Wallon, Jennifer L Sabol, Vlasta Zemba-Palko, James S DuHadaway, Erica Sutanto-Ward, Zonera A Ali, Paul B Gilman, Robin M Ciocca, Ned Z Carp, George C Prendergast. TIMP-4 is a prognostic and predictive marker in triple-negative breast cancers [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-08-54.

BACKGROUND: Triple-negative breast cancers (TNBC) represent a highly aggressive form of this disease with few treatment options available. Currently, even the smallest node negative cancers are considered by many to warrant treatment with chemotherapy (CTX). While many recur early (within 2–3 years), there is a subset of long-term survivors illustrating the heterogeneity within this group. Here we report our ongoing effort to establish tissue inhibitor of metalloproteinase-4 (TIMP-4) as a prognostic marker in all early breast cancers a. While the canonical function of TIMPs is to inhibit tissue degradation, numerous reports have established that TIMPs exert tumor promoting activity. In our prospective study, we evaluated TIMP-4 as prognostic marker for TNBC and its role in disease progression. METHODS: Specimens from our retrospective and prospective cohorts were assessed by immunohistochemical staining using standard techniques and a monoclonal antibody for TIMP-4b in accordance with the IRB approved protocol. Staining intensity was documented on a scale of 0–3. No data was released to the treating physicians at the time of collection. Outcome data from a total of 240 pts was obtained through tumor registry and clinician practices. Staining intensity was then correlated with outcome to calculate sensitivity and specificity of the marker. To determine the role of TIMP-4 in TNBC cell behavior we have performed microarray analyses. The effects of TIMP-4-induced signaling were tested using invasion and clonogenic survival assays under normal growth conditions and after exposure to gamma radiation. RESULTS: Elevated TIMP-4 expression identified a high risk of relapse and short survival time with 75% sensitivity and 80% specificity. No discernable differences were noted between retrospective and prospective cohorts. Array analyses revealed activation of the PI3K/AKT pathway in the presence of TIMP-4. Furthermore, elevated TIMP-4 increased the invasive behavior of breast cancer cells in Matrigel™-coated invasion chambers and reduced sensitivity to gamma irradiation. These effects were reversible by addition of either a PI3K inhibitor or an anti-TIMP-4 antibody, suggesting their use as potential therapeutic strategies. CONCLUSIONS: On the basis of these clinical data we suggest that TIMP-4 may offer a simple prognostic marker for TNBC patients at highest risk. The presence of TIMP-4 identifies a patient population likely to recur quickly despite standard CTX treatment. Our research suggests that targeted therapy of the PI3K/AKT pathway and/or a biological therapeutic approach directed against TIMP-4 may be of benefit in this subset of pts and should be explored. Therefore, TIMP-4 testing of TNBC patients could aid in the selection of a treatment regimen to improve survival outcome. a Liss, M et.al. Am. J. Pathol. 2009 b Donover, P et.al. J. Cell. Biochem. 2010 Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-09-21.

Background: Patients have traditionally been considered candidates for sentinel node biopsy (SNBx) only at the time of wide local excision (WLE). We hypothesized that patients with prior WLE may also be staged accurately with SNBx. Methods: Seventy-six patients, including 18 patients from the University of Virginia and 58 from a multicenter study of SNBx led by investigators at the University of Vermont, who had previous WLE for clinically localized melanoma underwent lymphoscintigraphy with SNBx. Median follow-up time was 38 months. Results: Intraoperative identification of at least 1 sentinel node was accomplished in 75 patients (98.6%). The mean number of sentinel nodes removed per patient was 2.0. Eleven patients (15%) had positive sentinel nodes. Among the 64 patients with negative SNBx, 3 (4%) developed nodal recurrences in a sentinel node–negative basin simultaneous with systemic metastasis, and 1 (1%) developed an isolated first recurrence in a lymph node. Conclusions:This multicenter study more than doubles the published experience with SNBx after WLE and provides much-needed outcome data on recurrence after SNBx in these patients. These outcomes compare favorably with the reported literature for patients with SNBx at the time of WLE, suggesting that accurate staging of the regional lymph node bed is possible in patients after WLE.

A 46-year-old female who had been experiencing severe diarrhea and marked weight loss underwent exploratory laparotomy because of a mass near the tail of the pancreas noted on CT scan. Pathologic examination revealed a mucinous cystadenoma of the pancreas occurring in heterotopic pancreatic tissue. This is the second reported case of mucinous cystadenoma occurring in heterotopic pancreatic tissue.

The relationship between DNA content, TNM stage, tumor size, grade, histology, and disease-free survival was assessed in a retrospective study of patients with non-small cell lung cancer who had undergone resection and complete mediastinal lymph node dissection. Flow cytometric analysis was performed on paraffin-embedded tissue of 90 consecutive patients. The patients were analyzed both as a group and by individual stage. Median follow-up was 11 months (range, 1 to 35 months). Aneuploid tumors were not significantly different from diploid tumors with regard to pathologic TNM stage (p = 0.34), size (p = 0.5), grade (p = 0.5), or histology (p = 0.34). Disease-free survival of patients with aneuploid tumors was not significantly different than that of patients whose tumors had normal DNA content (p = 0.69). DNA content did not correlate with established prognostic factors in patients with non-small cell lung cancer who underwent resection and complete mediastinal lymph node dissection.

Overexpression of the glutathione S-transferases (GSTs) and their involvement in the detoxification of anticancer agents has prompted numerous investigations of the enzyme activity of human tumor tissue. This study represents an in-depth evaluation of the contribution of patient history and pathological status to the GST activity of various human tissues. GST activity was elevated significantly in tumors of the lung, breast and colon as compared to unmatched and matched normal tissue from the same organ. The GST activity of primary breast tumors varied significantly with the stage of the tumor. Breast tumors previously treated with both radiation and chemotherapy had significantly lower levels of GST activity than untreated tumors. Neither progesterone nor estrogen receptor content was associated with the GST activity in primary breast tumors. Colon metastases possessed higher levels of GST activity than primary colon tumors but enzyme activity was independent of the Duke's classification of the tumor. Only tumors of the left colon had levels of GST activity that were higher than those of adjacent normal mucosa. No relationship was evident between either age or sex and the GST activity of any of the tissues examined. GST activity levels may reflect the site-specific ability of tissues to provide cellular protection against xenobiotics.

e12511 Background: While BRCA1 and BRCA2 are high penetrance genes accounting for a significant proportion of hereditary breast and ovarian cancers (HBOC), many other genes have been associated wit...

The goal of this pilot study was to determine in patients with operable breast cancer the incidence of breast cancer cells present in the blood, the clearance rate after surgical resection of the primary tumor, and the incidence of patients with persistent cancer cells in the blood after the primary tumor was removed. Twenty-one patients with operable breast cancer had 15 ml venous blood obtained twice prior to surgery and after surgery at 2, 4, 8, 12, 24, and 48 hours and also on days 7 and 14. Immunomagnetic selection of malignant cells was performed on each sample. Cells were then fixed on slides and immunocytochemistry performed on the collected cells. Cells that had a rosette of magnetic beads, cytoplasmic staining for keratin, and malignant morphology were counted as breast cancer cells. Eighteen of 19 of patients had cancer cells detected in at least one of the two blood samples preceding surgical removal of the primary tumor. The incidence of cancer cells in the blood of patients rapidly declined during the 48 hours postsurgery. The incidence of cancer cells in the blood remained stable in approximately 30% of patients to 14 days. The majority of breast cancer patients in this pilot study (even with small tumors and negative nodes) had detectable cancer cells in the blood prior to resection of the primary tumor. These findings justify further investigation. Successful application of this methodology may serve as a powerful indicator of which patients need systemic adjuvant therapy, the effectiveness of systemic adjuvant therapy, tumor recurrence, and early detection of breast cancer.

• We examined the possibility that tumor-released products inhibit lymphokine-activated killer cell activation. Lymphokineactivated killer cells from human peripheral blood lymphocytes were activated with recombinant interleukin 2 for 4 days in the presence of malignant effusions or conditioned media from cultured cell lines (10% vol/vol). Eight of 10 malignant effusions/media suppressed the induction of lymphokine-activated killer cell cytotoxicity, as measured in a 4-hour sodium chromate release assay. Seven of 10 effusions/media inhibited lymphokine-activated killer cell proliferation. Suppression was both dose and time dependent. A representative suppressive effusion was fractionated by agarose gel chromatography, treated with detergents disruptive of ionic bonds and lipids, and refractionated using polyacrylamide gel chromatography. Seven suppressive fractions ranging in molecular weight from 1 × 10 5 to 3× 10 5 d were isolated. It is speculated that this suppressor factor may represent a large multimeric structure with ionic-bonded individual suppressive components. ( Arch Surg . 1991;126:476-480)

Malignant mesothelioma of the tunica vaginalis is an extremely rare tumor. Appropriate treatment consists of inquinai orchiectomy with close followup. Treatment of locally recurrent malignant mesothelioma of the tunica vaginalis has not been standardized. We recommend radical resection for the initial presentation of locally recurrent disease rather than saving surgical resection as salvage therapy after other treatment modalities have failed. We report case 37 of malignant mesothelioma of the tunica vaginalis and review the literature.

This report describes a recent case in which colonoscopy of a patient with the presenting complaint of rectal bleeding revealed the right colon to be carpeted with 50-100 pseudopolyps, each 3-4 mm in diameter. Biopsy specimens taken during colonoscopy revealed the presence of Strongyloides stercoralis in the bowel wall. This diagnosis should be considered in any patient with gastrointestinal complaints and a history of travel to an endemic area.

• An infrequently reported cause of small-bowel obstruction, but one with increasingly important implications in today's diet-conscious society, is bran. This report describes a patient with no history of abdominal operation who developed complete obstruction of the small bowel after the ingestion of two bowls of bran cereal. The obstructing mass of bran was removed by enterotomy and found to be an inspissated, toothpastelike plug. The patient recovered fully. ( Arch Surg 1988;123:98-100)

Abstract #5078 Background: Breast cancer significantly impacts girls' lives: it affects 1:8 women and directly impacts those most influential in girls' lives (e.g. mothers, friends' mothers, teachers, coaches). Plus, girls are often exposed to powerful media messages meant to raise breast cancer awareness. Our hypothesis is that these factors could generate significant fear and misunderstanding in adolescent and pre-adolescent girls. Methods: To better understand the impact of breast cancer fear in girls, the nonprofit organization Breastcancer.org and the Taking Care of Your “Girls” book project, together with the Lankenau Hospital Health Education Center, conducted an in-school online survey in girls ages 8 to 18 years (median 15), prior to the delivery of a Breast Health Assembly in 7 Philadelphia and Atlanta areas schools. 2450 girls attended the assemblies, of which 1709 participated in the survey (about 70% question completion rate). Results: In total, 73% of girls had a relative or close acquaintance who had had breast cancer (most often: a friend's mother [49% n=580/1201]). Although only 3.34% (n=40/1196) of girls' mothers had had breast cancer, girls were most fearful of breast cancer affecting their mothers. While only 46% (n=768/1573) thought breast cancer was common in grandmothers, 76% (n=1192/1572) reported it was most common in mothers. Although only 3.35 % (n=53/1580) believed that breast cancer was common in teens, 26% (477/1554) said that they've already feared having breast cancer themselves. The most common triggers for this fear were a misinterpretation of a normal breast finding, a news report on breast cancer, or a new breast cancer diagnosis in someone they knew. Over 20% believed that infection, drug use, stress, and tanning could cause breast cancer; and 10-20% reported their belief that caffeine, getting bumped or bruised in the breast, and antiperspirants could cause it. In addition, 8.5% thought that breast-feeding increased breast cancer risk. Discussion: 73% of the girls in this study have one or more women close to them who've had breast cancer and all girls are sensitive to the media. These factors seem to contribute to their fear of the disease and their tendency to overestimate breast cancer risk (in themselves and their mothers). Furthermore, they were un- or misinformed about true breast cancer risk factors and effective breast health measures. The impact of a girl's unrealistic fear of breast cancer is unknown. We are concerned that it may deter rather than motivate healthy behaviors. Breast health programs are necessary to replace fear and inaccurate information with facts and reassurance. These results might be useful in the design of education and intervention strategies to improve psychological wellbeing and the achievement of long-term public health goals. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5078.