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The standard of care for resectable gastric or gastroesophageal (GE) junction cancer for patients who can tolerate a surgical procedure is surgical resection, but surgery alone is not optimal treatment for patients at high risk for relapse. For patients with lower-risk lesions (confined to gastric wall, nodes negative; T1-2N0M0), local-regional relapse risks are low, and adjuvant radiotherapy is usually not recommended, except in select instances. Since both local-regional and systemic relapses are common after resection of high-risk gastric or GE junction cancers (beyond wall, nodes positive, or both; T3-4N0, TanyN+), adjuvant treatment is indicated for these patients. The results of phase III trials that demonstrate a survival benefit for adjuvant preoperative radiotherapy, postoperative chemoradiation, or preoperative chemoradiation vs. surgery alone will be presented and compared with the results of adjuvant perioperative chemotherapy. Results of Surveillance, Epidemiology, and End Results (SEER) analyses and meta-analyses that support the role of adjuvant radiotherapy or chemoradiation will be summarized.

Treatment options for women with newly diagnosed breast cancer include breast conservation therapy and mastectomy with or without reconstruction, which provide equivalent cancer outcomes in properly selected patients. Although multiple studies have evaluated breast surgery quality-of-life outcomes, the data are inconsistent. This factor is important to consider when counseling patients and defining surgical quality measures.

Background In the era of breast conservation therapy, preoperative imaging is imperative in planning a single definitive surgical treatment. Methods We performed a retrospective review of a prospectively collected database of patients treated at a single institution for invasive breast cancer over 5 years. Clinical and pathologic variables were analyzed with respect to magnetic resonance imaging (MRI) and pathologic tumor size using analysis of variance F tests and chi-square tests. Results Of 190 patients, 53% had concordance of MRI and pathologic cancer size within .5 cm. MRI overestimated 33% and underestimated 15% of tumors. Neoadjuvant chemotherapy and lymph node status were associated with discordance. Among tumors overestimated by MRI, 65% had additional significant findings in the breast tissue around the main lesion: satellite lesions, ductal carcinoma in situ, and/or lymphovascular invasion. Conclusions Breast MRI is concordant with pathologic tumor size within .5 cm among 53% of patients. Most patients with tumors overestimated by MRI have significant findings in the surrounding breast tissue, the excision of which would be expected to benefit the patient.

We report the occurrence of a refractory infection caused by the “rapidly growing” nontuberculous mycobacterium, Mycobacterium fortuitum, after incisional hernia repair using synthetic mesh. The patient had previously undergone three herniorrhaphies incorporating polypropylene mesh. Multiple surgical debridements were required, along with complete removal of all the mesh, to eradicate the infection. Prolonged antimicrobial therapy with sulfamethoxazole, an agent active against the patient's isolate, was also used. Although this atypical mycobacterium has been reported to cause a variety of infections, including many types of periprosthetic infections, this case represents successful treatment of M. fortuitum infecting abdominal wall mesh.

OBJECTIVE. The purpose of this pictorial essay is to illustrate several clinical situations in which SPECT/CT can be effectively applied in nuclear radiology practice.CONCLUSION. SPECT/CT has recently emerged as a valuable adjunct to standard techniques in clinical nuclear radiology. This technique provides significantly improved scintigraphic localization and characterization of disease, increasingly important in this era of minimally invasive surgery and targeted radiotherapy.

Desmoplastic melanoma is a rare subtype of malignant melanoma, which is unusual in that it is more often associated with local recurrence than with lymph node or distant metastatic spread. The histologic architecture of this melanoma subtype differs from conventional melanoma in that the melanoma cells are interspersed within an abundant collagenous stroma. We present a case that demonstrates both true positive and false negative findings on F-18 FDG PET/CT imaging in a case of recurrent desmoplastic melanoma.

Malignant melanoma presents a substantial clinical challenge. Current diagnostic methods are limited in their ability to diagnose early disease and accurately predict individual risk of disease progression and outcome. The lack of adequate approaches to properly define disease subgroups precludes rational treatment design and selection. Better tools are urgently needed to provide more accurate and personalized melanoma patient management. Recent progress in the understanding of the molecular aberrations that underlie melanoma oncogenesis will likely advance the diagnosis, prognosis, and treatment of melanoma. The emerging pattern of molecular complexity in melanoma tumors mirrors the clinical diversity of the disease and highlights the notion that melanoma, like other cancers, is not a single disease but a heterogeneous group of disorders that arise from complex molecular changes. Understanding of molecular aberrations involving important cellular processes, such as cellular signaling networks, cell cycle regulation, and cell death, will be essential for better diagnosis, accurate assessment of prognosis, and rational design of effective therapeutics. Defining an individual patient's unique tumor characteristics may lead to personalized prediction of outcomes and selection of therapy. We review the emerging molecular landscape of melanoma and its implications for better management of patients with melanoma.

BACKGROUND: Whether time between biopsy and surgery for malignant melanoma affects clinical outcomes is sparsely defined. This study evaluated factors influencing surgical interval and surgical interval effect on outcomes. METHODS: We performed a review of a prospective 10-year, single-institution database. RESULTS: There were 473 patients treated for 478 malignant melanomas. The mean surgical interval was 30.5 days. The mean thickness was 2.1 mm; 46% of patients had a surgical interval of more than 28 days whereas 8% had a surgical interval of more than 56 days. Residual melanoma was found at excision in 170 (36%) patients. Age, sex, and referral source significantly affected surgical interval, however, lesion thickness, sentinel lymph node status, ulceration, and residual melanoma at excision did not. In univariate Cox models, neither a surgical interval of 28 or less nor less than 56 days showed better overall survival (OS) or disease-free survival (DFS). In multivariate Cox models of OS and DFS including lesion thickness, sentinel lymph node status, ulceration, and residual melanoma at excision, neither a surgical interval of 28 days or fewer nor a surgical interval of 56 days or fewer significantly affected outcomes. CONCLUSIONS: Age, sex, referral source, and lesion thickness were associated with surgical interval. Immediate surgery for malignant melanoma does not significantly impact OS or DFS.

Successful systemic management of stage IV melanoma continues to be elusive because of the paucity of effective therapies. This has fueled the continued interest in surgical resection. Several single-institution studies and a current, large, multi-institutional phase III trial have demonstrated a survival benefit for patients who underwent surgical resection for melanoma metastases. Incorporating these results into new approaches using multimodality treatment may enhance survival in patients with stage IV melanoma. J. Surg. Oncol. 2008;97:462–468. © 2008 Wiley-Liss, Inc.

This study aims to validate radioactive seed localization (RSL) as an alternative to wire localization (WL) in the operative excision of nonpalpable breast lesions. Eligible patients were recruited sequentially. A sample of 99 patients treated with WL was compared to the next 383 patients treated with RSL. Margins were considered "negative" if > or =2 mm from in-situ and invasive disease. Pain and convenience scores were recorded on a 10-point scale. Patient characteristics and histology were similar. The lesion and localization device were retrieved in all patients. Margins of the first specimen were negative in 73% of RSL patients, versus 54% of WL patients (p < 0.001). A second operation was required in 8% of RSL patients to achieve negative margins, versus 25% of WL patients (p < 0.001). Pain scores were not statistically different. However, the RSL group had higher convenience scores (p = 0.015). RSL is safe, effective, and compared to WL, reduces the rates of intraoperative re-excision and reoperation for positive margins by 68%. Patient satisfaction is improved with RSL. We strongly favor RSL over WL.

Background A subset of triple negative breast cancers (TNBC) has somatic amplification of chromosome 9p24.1, encoding PD-L1, PD-L2, and JAK2 (the "PDJ" amplicon). The JAK/STAT pathway promotes malignant transformation and proliferation, and the JAK1/JAK2 inhibitor ruxolitinib is being evaluated in early phase clinical trials in breast cancer. This study was designed to measure the frequency of PDJ copy number gain in existing TNBC cell lines, and determine the impact of targeted JAK2 inhibition on cellular proliferation. Methods: Copy number alterations were measured in nine TNBC cell lines (MDA-MB-453, MDA-MB-436, BT549, MDA-MB231, MFM-223, MDA-MB-468, H5578T, MDA-MB-157, HCC1937) by array comparative genomic hybridization (aCGH). JAK2 and pSTAT3 expression was measured by immunoblot in four of the TNBC lines (HCC1937, MDA-MB-468, MDA-MB-231, MDA-MB-436) and compared with MCF10A, SK-BR3, and T47D. To selectively inhibit JAK2, lentiviral vectors encoding five different shRNA targeting JAK2 were generated. Ruxolitinib treatment was performed at 25 uM for 48 hrs and 72 hrs. Cell proliferation was measured by CellTiter-Glo. Results: All TNBC cell lines had an elevated level of baseline protein expression of JAK2 and pSTAT3 compared to SK-BR3, T47D, and MCF10A. Of the nine TNBC cell lines, only MDA-MB-436 and BT549 had copy number gain of 9p24.1 (log2ratio Conclusion These results demonstrate that existing TNBC cell lines have varying copy number alterations of chromosome 9p24.1 encoding JAK2, and targeted JAK2 inhibition in TNBC inhibits cell proliferation. Citation Format: Chen M, Andreozzi M, Gonzalez-Malerva L, Eaton S, Pockaj B, Barrett MT, Anderson KS. JAK2 copy number and targeted JAK2 inhibition of TNBC cell lines. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-04-19.

Introduction: Triple negative breast carcinoma (TNBC) is a subtype of breast cancer with a paucity of therapeutic targets and a poor prognostic phenotype. In a retrospective cohort, we sought to determine the prevalence of the amplicon targeting the 9p24.1 locus, resulting in over-expression of PD-L1, PD-L2, and JAK2 (PDJ), and potentially actionable therapeutic targets. We then probed the genomic landscape of these PDJ positive tumors and identified co-occurring copy number aberrations, including focal amplifications and homozygous deletions. The presence of the PDJ amplicon and selected co-occurring aberrations provide a unique description of a clinically relevant subtype of TNBC. Methods: We evaluated fresh frozen and formalin-fixed paraffin embedded tumor samples from 64 patients with triple negative breast cancer whom underwent definitive surgical resection. Clinical annotation was available in 60 of the samples. Tumor populations (diploid, tetraploid, and aneuploidy) were sorted from each biopsy using DNA content flow cytometry. Each sorted sample was interrogated with oligonucleotide array comparative genomic hybridization (aCGH). All microarray slides were scanned using an Agilent 2565C DNA scanner and the images were analyzed with Agilent Feature Extraction version 10.7. The aCGH data was assessed with a series of QC metrics then analyzed using an aberration detection algorithm. Results: We detected a high level (log2ratio greater than or equal to 2) amplicon targeting 9p24.1 in 18 of 64 patients (28%) genomic profiles with triple negative breast carcinoma. In the PDJ positive population, we detected 8 of 18 patients (44%) with co-amplification targeting myc at 8q24, 3 of 18 patients (17%) with co-amplifications targeting EGFR at 7p11, 3 of 18 patients (17%) with co-amplifications targeting PIK3CA. These co-occurring genomic events in PDJ positive tumors may provide clinically actionable targets. Other selected amplifications detected included NOTCH3, KRAS, RUNX1, TUBAL3, FGFR2, AKT1, AKT2, YPEL2, PBXL7, KIT. We detected PTEN homozygous deletion in 2 of 18 patients (11%) PDJ positive tumors. Other homozygous deletions identified in the genomic landscape included FAT1, SOX3, Park2, TNFAIP3, GPC3, RB1, and CREBBP. Conclusions: In our retrospective analysis, the amplification of chromosome 9p24.1 involving PD-L1, PD-L2, and JAK2 is present in approximately 28% of triple negative breast cancer patients. The genomic landscape of these PDJ positive TNBCs include recurring high-level focal amplifications and targeted homozygous deletions of clinically relevant genes. The clinical implications of these data are under current investigation using model systems and are in early phase clinical trials. The efficacy of immune checkpoint inhibitors including nivolumab, pembrolizumab, and JAK2 inhibitors including ruxolitinib, in PDJ positive triple negative breast carcinoma is intriguing and remains to be elucidated. Citation Format: Gawryletz CD, Anderson KS, Cunliffe HE, Northfelt DW, McCullough AE, Lenkiewicz E, Malasi S, Pockaj BA, Barrett MT. The genomic landscape of PD-L1, PD-L2, Jak2 (PDJ) amplified triple negative breast carcinoma. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-03-13.

Introduction: In a pilot study, we recently described amplification of chromosome 9p24 encoding PD-L1, PD-L2, and JAK2 (the PDJ amplicon) in 29% of early stage triple negative breast cancers (TNBC). Amplification was associated with poor DFS and OS. The impact of this amplicon on immune function is not known. Methods: Fresh frozen tumor samples from 36 subjects with newly-diagnosed TNBC (stages I-III) were evaluated for copy number aberrations using DNA-based flow cytometry to enrich nuclei based on ploidy status (tetraploidy or aneuploidy), followed by oligonucleotide CGH arrays. Targeted immune expression profiling was performed using the Nanostring PanCancer Immune Profiling Panel (n=770 genes). Results: 23 samples had measurable abnormal ploidy (evidence of sufficient tumor content) for CGH analysis; the remaining samples were omitted from analysis. High level (log2ratio >1) amplification was detected in 6/23 (26.1%) of TNBCs, and low-level copy number gain (CN log2ratio >0 and-1 and Conclusion: Amplification of chromosome 9p24.1 involving PD-L1, PD-L2, and JAK2 is present in a significant proportion of TNBCs. This amplicon is associated with altered gene expression of the tumor microenvironment. Citation Format: Anderson KS, Andreozzi M, Pockaj BA, Hopper M, McCullough AE, Barrett MT. Amplification of chromosome 9p24 targeting PD-L1 and JAK2 correlates with altered tumor microenvironment expression profiles in triple negative breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-04-02.

An estimated 73870 people will be diagnosed with melanoma in the United States in 2015, resulting in 9940 deaths. The majority of patients with cutaneous melanomas are cured with wide local excision. However, current evidence supports the use of sentinel lymph node biopsy (SLNB) given the 15%-20% of patients who harbor regional node metastasis. More importantly, the presence or absence of nodal micrometastases has been found to be the most important prognostic factor in early-stage melanoma, particularly in intermediate thickness melanoma. This review examines the development of SLNB for melanoma as a means to determine a patient's nodal status, the efficacy of SLNB in patients with melanoma, and the biology of melanoma metastatic to sentinel lymph nodes. Prospective randomized trials have guided the development of practice guidelines for use of SLNB for melanoma and have shown the prognostic value of SLNB. Given the rapidly advancing molecular and surgical technologies, the technical aspects of diagnosis, identification, and management of regional lymph nodes in melanoma continues to evolve and to improve. Additionally, there is ongoing research examining both the role of SLNB for specific clinical scenarios and the ways to identify patients who may benefit from completion lymphadenectomy for a positive SLN. Until further data provides sufficient evidence to alter national consensus-based guidelines, SLNB with completion lymphadenectomy remains the standard of care for clinically node-negative patients found to have a positive SLN.

Introduction The transverse rectus abdominus muscle (TRAM) flap is one of the treatment options for breast reconstruction. TRAM flap reconstruction donor site herniation rates range from 1% to 8.8%. Traditionally, these hernias were treated by an open primary repair with or without the addition of onlay mesh. We report laparoscopic approach to treat TRAM and deep inferior epigastric perforator flap (DIEP) harvest site hernias with mesh. Cases We treated 5 patients, 4 from TRAM and 1 from DIEP flap harvest site hernias during the period of October 2003 to January 2006. Two of these patients underwent previous open mesh repair with recurrence. All of these patients underwent laparoscopic hernia repair using polytetrafluoroethylene dual mesh. Follow-up ranged 6 to 31 months without any recurrences. Conclusions Laparoscopic mesh repair of ventral hernias located at TRAM and DIEP flap harvest sites can be performed safely and with a low rate of recurrence.

Purpose To evaluate clinical characteristics and survival outcomes among patients with locally advanced or metastatic colorectal cancer who achieve a complete response (CR) to systemic treatment either alone or with multimodality approach. Patients and Methods Data were collected retrospectively from CRC patients enrolled onto the phase III trial N9741, a National Cancer Institute–funded and Gastrointestinal Cancer Intergroup–sponsored study coordinated by the North Central Cancer Treatment Group. Patients were randomly assigned to combinations of oxaliplatin, fluorouracil (FU)/leucovorin (LV) and irinotecan. The three treatment arms consist of IFL (irinotecan + FU/LV), FOLFOX4 (oxaliplatin + FU/LV), and IROX (irinotecan + oxaliplatin). Median follow-up was 42.6 months. Results Sixty-two (4%) of 1,508 patients had a CR to chemotherapy alone, and an additional 32 (2%) had a CR after multimodality treatment. Factors associated with achieving CR with systemic chemotherapy alone included FOLFOX4 treatment, patients with assessable disease, or a single site of metastasis. Continuing protocol treatment beyond two cycles after documentation of CR was not associated with improved survival. The rate of curative intent resection was significantly higher for patients treated with oxaliplatin-containing regimens (P = .02). Median survival was similar between patients with CR after chemotherapy alone (44.3 months) or after multimodality approach (47.4 months; P = .81). Conclusion FOLFOX4 was more likely to produce a CR than were IFL or IROX. Oxaliplatin regimens were more likely to result in successful surgical resections. Patients who have CR to systemic chemotherapy alone can achieve impressive survival outcomes similar to those seen among patients who attained a CR status after multimodality treatment.

Background Many women with nipple discharge undergo operative duct excision with few actually having carcinoma. Methods We reviewed all patients with nipple discharge at our institution from 2001 to 2005. Clinical findings were analyzed to determine an appropriate treatment algorithm. Results Nipple discharge was present in 204 patients. Carcinoma was identified in 7 patients (3% of all, 9% of those undergoing biopsy). Age ≥50 years, abnormal mammography, and abnormal sonography were the only significant predictors of carcinoma. Among patients with unilateral, spontaneous, bloody, or serous discharge with a negative mammogram, the carcinoma risk was 3%. Among patients with unilateral, spontaneous, bloody, or serous discharge with a negative mammogram and subareolar ultrasound, the carcinoma risk was 0%. Conclusions Patients with nipple discharge can be divided into risk groups by combining clinical and radiologic findings. Low-risk patients can be offered close clinical follow-up rather than operation. A recommended management algorithm is presented.

Context Symptomatic arm lymphedema as the presenting symptom of invasive breast carcinoma is a rare occurrence. Design We report a case of invasive breast cancer presenting with unilateral arm swelling. The patient was initially thought to have venous thrombosis. A thorough physical examination and a mammogram revealed the presence of breast cancer and associated subclinical axillary lymphadenopathy. Conclusion Failure to recognize this presentation can lead to misdiagnosis or a significant delay in diagnosis and treatment.

Critical to the clinical management of a patient with malignant melanoma is an understanding of its natural history. As with most malignant disorders, prognosis is highly dependent on the clinical stage (extent of tumor burden) at the time of diagnosis. The patient's clinical stage at diagnosis dictates selection of therapy. We review the state of the art in melanoma staging, prognosis, and therapy. Substantial progress has been made in this regard during the past 2 decades. This progress is primarily reflected in the development of sentinel lymph node biopsies as a means of reducing the morbidity associated with regional lymph node dissection, increased understanding of the role of neoangiogenesis in the natural history of melanoma and its potential as a treatment target, and emergence of innovative multimodal therapeutic strategies, resulting in significant objective response rates in a disease commonly believed to be drug resistant. Although much work remains to be done to improve the survival of patients with melanoma, clinically meaningful results seem within reach.

Malignant melanoma is an aggressive, therapy-resistant malignancy of melanocytes. The incidence of melanoma has been steadily increasing worldwide, resulting in an increasing public health problem. Exposure to solar UV radiation, fair skin, dysplastic nevi syndrome, and a family history of melanoma are major risk factors for melanoma development. The interactions between genetic and environmental risk factors that promote melanomagenesis are currently the subject of ongoing research. Avoidance of UV radiation and surveillance of high-risk patients have the potential to reduce the population burden of melanoma. Biopsies of the primary tumor and sampling of draining lymph nodes are required for optimal diagnosis and staging. Several clinically relevant pathologic subtypes have been identified and need to be recognized. Therapy for early disease is predominantly surgical, with a minor benefit noted with the use of adjuvant therapy. Management of systemic melanoma is a challenge because of a paucity of active treatment modalities. In the first part of this 2-part review, we discuss epidemiology, risk factors, screening, prevention, and diagnosis of malignant melanoma. Part 2 (which will appear in the April 2007 issue) will review melanoma staging, prognosis, and treatment.

6 Background: Traditional screening mammography (MG) enables early detection of breast cancer and therefore results in decreased mortality. Mammography, however, is an imperfect tool and limited by an overall sensitivity of 75-85%. Specificity is limited as well resulting in many false-positive examinations and unnecessary follow-up examinations. The recent development of contrast-enhanced digital mammography (CEDM) has made the usage of IV contrast enhancement with mammography a possibility. CEDM is an angiographic technique that uses digital subtraction, which removes the normal mammary gland on images in order to detect breast tumors and visualize their vascularity. The literature is promising with regard to CEDM as studies have found that CEDM achieves increased sensitivity without reductions in specificity in comparison to MG, US and/or MRI. Methods: In this multi-reader study we compared the diagnostic accuracy of CEDM as an adjunct to MG/US in patients with suspicious findings (BI-RADS 4). The study population included 31 patients who were imaged with CEDM prior to their scheduled US or stereotactic-guided biopsy. We compared the relative performance of MG/US alone versus MG/US/CEDM in determining the probability of malignancy. Histology served as the gold standard. Results: See table below. Conclusions: The addition of CEDM to the workup of suspected lesions on MG and/or US preliminarily decreases the number of false-positive MG thereby with potential to reduce cost and unnecessary patient harm. [Table: see text]

Background: Next generation sequencing (NGS) has revealed that the genetic profiles of individual tumors are highly heterogeneous due to their subclonal composition. Tumor heterogeneity has profound clinical implications affecting differences in treatment response and therapeutic resistance. Methods: An estrogen receptor positive, Her2 normal breast cancer patient underwent definitive surgical treatment with modified radical mastectomy. Multiple samples were obtained from the primary cancer and metastatic lymph nodes. Flow cytometry based methods were used to isolate and classify distinct cell subpopulations according to their ploidy, and samples were processed for whole exome sequencing (WES). Comparative Genomic Hybridization (CGH) methods were used to identify somatic unique copy-number alterations (CNAs). WES-Single Nucleotide Variations (SNVs) were used to infer subclonal phylogenetic relationships using Maximum Parsimony methods and annotated with variation-cluster-barcodes (vc-barcodes) generated using a variation Bayesian mixture model (VBMM) approach that focuses on copy-number neutral sequence variations for subclone identification (SciClone). Our comparative phylogenetic-VBMM clustering method was used to identify CNA and/or SNV drivers that are key in differentiating subclonal populations at multiple tumor sites. Results: CNA-neutral WES-SNVs from 25 subclonal populations (isolated from 4 distinct sites) clustered into 6 major groups and were used to generate vc-barcodes. A phylogenetic reconstruction of subclonal architecture annotated with vc-barcode information expedited identification of key variations underlying the differentiation of subclones at distinct tumor sites. For example, we identified an amplification event involving the Anaplastic Lymphoma Kinase (ALK) gene that was more frequent in primary biopsy subclones (12/17, ∼71%) in comparison to metastatic subclones (2/6, ∼34%). As the ALK amplification is lost, we find that most of the metastatic subclones also acquire a predicted damaging mutation in this oncogene (4/6, ∼67%). In addition, we identified a potential driver metastatic cell lineage that carries the ALK amplification in the absence of the nonsynonymous mutation. Conclusions: We developed a hybrid clustering methodology and used it to reconstruct the subclonal architecture in primary and metastatic tumors from a single breast cancer patient. Our methods have identified several CNAs and/or SNVs underlying subclonal differentiation, as well as potential biomarkers of disease progression and indicators of emerging resistance. Application of these methods to larger cohorts and types of tumors should be conducted to ascertain more precise estimates of the predictive accuracy of our processes. Citation Format: Mia D. Champion, Princy Francis, Barbara A. Pockaj, Michael T. Barrett. Hybrid clustering methodologies to distinguish CNAs and/or SNVs that drive subclonal differentiation in samples from a breast cancer patient primary tumor and metastatic lymph nodes. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4861. doi:10.1158/1538-7445.AM2015-4861

Background: The development of novel chemotherapeutic agents has significantly improved the prognosis and survival of patients with breast cancer. ER positive or luminal tumors represent around two thirds of all breast cancers and these cancers are comprised of different histologies including differing gene expression and mutational profiles. This study examined biomarkers involved in immune evasion including PD-L1 and its association with other biological pathways as potential treatment options for luminal breast cancer patients. Methods: We analyzed 1311 breast samples using a multiplatform approach including whole genome mRNA expression (HumanHT-12 v4 BeadChip Illumina Inc., San Diego, CA), protein expression (immunohistochemistry), gene copy number changes (in situ hybridization) and gene sequencing and an additional 304 breast samples were tested for PD-1 and PD-L1 by IHC. The mRNA expression data was based on whole tumor and represents cell type heterogeneity. Heat map analysis was done to look at differential gene expression between the PD-L1 high vs low luminal breast cancers. Results: Based on expression of ER, PR and HER2 by IHC, we subdivided the data into sub- cohorts. Elevated mRNA expression of immune markers including PD-L1, CTLA4, B7H-3, and IDO1 was noted in the ER+HER2- luminal population including ER+ PR- and ER+PR+ cohort. Positive correlation was found between PD-L1 and other immune regulators including CTLA-4, B7-H3 and IDO1 (Spearman correlations of 0.49, 0.36 and 0.46). Protein expression of PD-L1 was found to be specific to the HER2 negative cohort with no expression in the HER2 positive cohort regardless of ER status. Within the ER+HER2- cohort, PD-L1 expression was 5% {ER+PR+ was 5% (4/81) and the ER+PR- was 6% (2/34)}. In contrast, PD-L1 expression was higher in the triple negative cohort, 17% (13/75). The expression of PD-1 on the other hand was present throughout the different cohorts. PD-1 expression ranged from 43% in the ER+HER2- cohort {41% (14/34) in ER+PR-HER2-; 43% (35/81) in ER+PR+HER2-} to 33% in the ER+HER2+ cohort {44% (4/9) in ER+PR-Her2+; and 17% (1/6) in ER+PR+HER2+}. In the ER-HER2+ cohort PD-L1 expression was 75%{6/8 in ER-PR-HER2+ and 0/0 in ER-PR+HER+} and 63%(47/75) in the triple negative cohort. Pathway analysis of the PD-L1 negative vs positive luminal population identified 127 genes involved in various cancer pathways including EGFR and VEGF signaling network (P=7.47e-09). Conclusions: The expression of immune regulatory targets in the breast cancer population suggests that immune- targeted therapies with anti PD-1/PD-L1, CTLA4, B7-H3 and IDO1 may be effective especially in the luminal cohort. Our study further shows that ER+HER2- breast cancer patients may be better candidates for immunotherapy with checkpoint inhibitors as compared to ER+HER2+ due to lack of PD-L1 expression in the HER2 positive cohort. Further validation of our findings is ongoing. Citation Format: Gargi D Basu, Anatole Ghazalpour, Randal Vader, Sandeep Reddy, Karen Anderson, Ann McCullough, Barbara Pockaj. Expression of novel immunotherapeutic targets in luminal breast cancer patients [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 P5-04-08.

Background: Patients diagnosed with melanoma of the foot have been reported to have a poor prognosis. We reviewed our experience at a tertiary-care medical clinic to determine the disease course in patients diagnosed with melanoma of the foot. Methods: A retrospective review was performed of 38 patients with a diagnosis of primary or locally recurrent melanoma of the foot treated between January, 1988, and July, 2004. The main outcome measures included methods of diagnosis, clinical and histopathologic features, and patterns of recurrence. Results: The mean age at diagnosis was 61 years; most were women (58%) and Caucasian (95%). The average time to diagnosis was 17 months. Initial clinical diagnosis had been considered benign in 12 (32%). The median Breslow thickness was 1.75 mm, T1 lesions were the most common, and acral lentiginous melanoma accounted for 42%. Thirteen patients (34%) had ulcerated lesions. Sentinel lymph node biopsy specimens of 25 patients identified four (16%) with metastatic disease. Surgical complications occurred in 12 patients, usually after skin graft or soft-tissue flap reconstruction. Systemic recurrence developed in six patients, four of whom also had regional recurrence. Conclusions: Most patients were elderly Caucasian women and most presented with early-stage disease, but diagnosis can be difficult and a subgroup presented with thick melanomas. Reconstructive surgical procedures had a high rate of complications; however, overall functional outcomes were good. Stage of cancer at diagnosis was associated with systemic metastases.

To determine the impact of sentinel lymph node (SLN) status and other risk factors on recurrence and overall survival in head and neck melanoma patients.The SLN Working Group, based in San Francisco, Calif, with its 11 member centers, the John Wayne Cancer Institute, and The University of Texas M. D. Anderson Cancer Center pooled data on 629 primary head and neck melanoma patients who had selective sentinel lymphadenectomy. A total of 614 subjects were analyzable. All centers obtained internal review board approval and adhered to the Health Insurance Portability and Accountability Act of 1996 regulations. A Cox proportional hazards model was used to identify factors associated with overall and disease-free survival.Tertiary care medical centers.Clinical outcome of head and neck melanoma patients undergoing selective sentinel lymphadenectomy.Overall, 10.1% (n = 62) of the subjects had at least 1 positive node. Subjects with positive SLN status had significantly thicker tumors (mean thickness, 2.8 vs 2.1 mm; P.001), and were more likely to have ulcerated tumors (P = .004). During the median follow-up of 3.3 years, the overall mortality from head and neck melanoma was 10%, with more than 20% experiencing at least 1 recurrence. Multivariate analysis showed that tumor site was an independent predictor of mortality; location on the scalp had a more than 3-fold (P.001) greater mortality than tumors on the face. Tumor thickness was also an independent predictor of overall survival, and SLN status was the most important predictor of disease-free survival in the multivariate model (P.001). Tumors on the scalp had the highest rate of recurrence, while those on the neck had the lowest. Tumor ulceration was the significant predictor of time to recurrence or disease-free survival (P.001).In this multicenter study, SLN status and other risk factors have an effect on recurrence and/or overall survival.

Every year in the United States, breast cancer is diagnosed in more than 200,000 women. Because of the prevalence of breast cancer, treatment-related sequelae are of importance to many survivors of the disease. One such sequela is upper extremity lymphedema, which occurs when fluid accumulates in the interstitial space and causes enlargement and usually a feeling of heaviness in the limb. Axillary surgery contributes considerably to the incidence of lymphedema, with the incidence and severity of swelling related to the number of lymph nodes removed. Lymph-edema after standard axillary lymph node dissection can occur in up to approximately 50% of patients. However, the risk of lymph-edema is decreased substantially with newer sentinel lymph node sampling procedures. Adjuvant radiotherapy to the breast or lymph nodes increases the risk of lymphedema, which has been reported in 9% to 40% of these patients. Management of lymph-edema requires a multidisciplinary approach to minimize the effect on the patient's quality of life. This review presents an overview of the pathophysiology, diagnosis, prevention, and treatment of breast cancer-related lymphedema.

Hormone replacement therapy (HRT) is contraindicated in women with a history of breast cancer or a high risk of breast cancer development. Recent results from large clinical trials, such as the Women's Health Initiative, have demonstrated increased risks of thromboembolic events and a moderate increased risk of breast cancer in women using conjugated estrogens and progestogens. There is a need for viable non-hormonal alternative treatments to HRT, such as nutritional and botanical therapies, in this population of women, who tend to experience more significant vasomotor symptoms. Safe and effective therapies that do not stimulate breast cell proliferation could prove extremely useful for the management of such symptoms for women in both low- and high-risk breast cancer populations. As a non-hormonal treatment, anti-depressants, such as selective serotonin reuptake inhibitors (SSRIs), have been shown to improve hot flash symptoms in women. The proposed mechanism is related to an increase in serotonin allowing for an increase in the set point of the brain's thermoregulator. In small clinical studies, the administration of tryptophan and 5-hydroxytryptophan (5HTP), the precursors of serotonin, have been shown to reduce depressive symptoms, possibly by enhancing the synthesis of serotonin. Thus, increased serotonin levels may have the ability to decrease hot flashes in a mechanism similar to that of SSRIs without the risks of breast cell stimulation. This would be particularly desirable for menopausal women with breast cancer or with risks of breast cancer. This article discusses the background information on hot flashes, SSRIs, tryptophan, and 5HTP, and possible clinical application of 5HTP for menopausal women with breast cancer risk.

Background Breast cancer incidence and survival varies by race and ethnicity. There are limited data regarding breast cancer in Native American women. Methods A retrospective chart review was performed of 139 women diagnosed with breast cancer and treated at Phoenix Indian Medical Center in Phoenix, AZ between January 1, 1982 and December 31, 2003. Data points included tribal affiliation, and quantum (percentage American Indian Heritage) along with patient, tumor, and treatment characteristics. Results Most patients (79%) presented initially with physical symptoms. There were no significant differences based on tribal affiliation; however, higher quantum predicted both larger tumor size and more advanced stage at diagnosis. Obesity also significantly correlated with larger tumor size and more advanced stage. Treatment was inadequate in 21%; this was attributed to traditional beliefs, patient refusal, or financial issues. Conclusions When compared to national averages, Native American women presented at a later stage, underutilized screening, and had greater delays to treatment.

Hot flashes cause significant morbidity in postmenopausal women, including women with breast cancer. We undertook a pilot study to estimate the effectiveness of black cohosh to reduce hot flashes.Women who reported significant hot flashes (or = 14 per week) were enrolled. Black cohosh was given in the form of the commercial product Remifemin. The first week was a no-treatment baseline period, and therapy was given for the subsequent 4 weeks. Hot flash data were collected by daily questionnaires during baseline and treatment weeks. Adverse effects were recorded.Twenty-one women completed the study. Their mean age was 56 years (range, 38-80). Thirteen patients had a history of breast cancer. Six patients were taking tamoxifen or raloxifene. Patients reported an average of 8.3 hot flashes per day during the baseline week. The reduction in mean daily hot flash frequency was 50% (95% CI, 34%-65%), while weekly hot flash scores were reduced 56% (95% CI, 40%-71%) at completion of the study. Overall, patients reported less trouble with sleeping, less fatigue, and less abnormal sweating. No patients stopped therapy because of adverse effects.Black cohosh appeared to reduce hot flashes and had a low toxicity. The efficacy found in this trial seems to be more than would be expected by a placebo effect (20%-30% hot flash reduction in previous trials). These results suggest that further evaluation of this black cohosh preparation with a phase III randomized trial is indicated.

The significance of breast cancer sentinel lymph node (SLN) metastases detected only by immunohistochemistry staining (IHC) remains poorly understood. This study attempted to quantify the risk of non-SLN metastases.A prospectively collected database of 750 consecutive SLN biopsy procedures in breast cancer patients was reviewed. Medical records were reviewed to supplement the database.SLNs were identified in 738 (98.4%) of these procedures in 723 patients. Of these, 151 patients (20.5%) had metastases detected by hematoxylin and eosin staining (HE), and 33 (4.6%) of the 718 with known IHC staining results had metastases detected by IHC only. Twenty-eight (84.8%) of 33 patients with IHC-detected metastases underwent complete axillary lymph node dissection (CALND). The median primary tumor size was 2.0 cm among those undergoing CALND and 0.9 cm among the five patients treated without CALND (P = .10). Two of the 28 patients (7.1%) had additional metastases detected with CALND. These patients had a T3 or T4 invasive lobular primary tumor. Of 24 patients with T1 or T2 primary tumors and IHC-detected metastases who underwent CALND, none had additional metastases detected. Median follow-up was 14.5 months. All patients with IHC-detected SLN metastases were treated with adjuvant systemic therapy. None of the five patients with IHC-detected metastases not undergoing CALND has subsequently manifested clinical axillary disease.CALND could have been or was safely omitted in 29 of 29 patients with T1 or T2 primary tumors and metastases detected by IHC. Such patients should be counseled about this low risk before CALND is recommended.

This prospective, single-arm, pilot clinical trial, developed to evaluate the efficacy and tolerability of mirtazapine for alleviating hot flashes, was conducted between May 2001 and January 2002. Patients' baseline characteristics were collected during the first week of the study. At the beginning of the second week, patients were started on mirtazapine at a dose of 7.5 mg at bedtime. The dose of mirtazapine was then increased to 15 mg at week 3 and to 30 mg at week 4. For week 5, patients could choose whether to take 15 mg/d or 30 mg/d. Data were obtained primarily from patient-completed questionnaires. Data from 22 evaluable women were available. For the 16 patients who completed the study, the median reductions in total daily hot flashes and weekly hot-flash scores from their baselines were 52.5% and 59.5%, respectively. Patients reported improvements in tension, trouble sleeping, abnormal sweating, distress from hot flashes, satisfaction with hot-flash control, overall quality of life, and impact of hot flashes on quality of life. Patients also reported increases in appetite and dry mouth. Although data from a double-blind, placebo-controlled clinical trial would be necessary to more definitively elucidate the efficacy and toxicity of mirtazapine in patients with hot flashes, the available data suggest that mirtazapine is a reasonable treatment to consider in patients with hot flashes, particularly in those with anxiety and sleep disturbances.

A retrospective review of the treatment of 15 breast cancer patients who received postoperative radiotherapy after a mastectomy and transverse rectus abdominis myocutaneous (TRAM) flap breast reconstruction was undertaken to determine the effects of postoperative irradiation on flap viability and cosmesis. Fourteen patients had pedicle TRAM flaps, and one patient had a free TRAM flap. Surgical complications, acute and chronic side effects of radiotherapy, and cosmetic outcome were evaluated. The median interval between the TRAM flap procedure and radiotherapy was 7 months. The median total radiation dose was 60 Gy. All patients underwent three-dimensional radiotherapy treatment planning to determine the optimal dose distribution. Mild erythema developed in 9 patients (60%), moderate erythema developed in 2 (13%), and severe erythema developed in 1 (7%). Dry desquamation developed in 6 patients (40%), whereas moist desquamation developed in none. At median follow-up of 26.4 months, only 2 (13%) of the 15 patients had fat necrosis within the TRAM flap that was not present before radiotherapy. Fourteen patients (93%) retained their flap, and 13 patients (87%) rated their cosmetic outcome as "good" to "excellent." We conclude that TRAM flaps can be irradiated with few complications and acceptable cosmetic results.

Background We investigated whether the timing of injection of 99m Tc-labeled sulfur colloid (radiocolloid) significantly influenced the success of breast cancer sentinel lymph node (SLN) mapping. Methods Review of a prospective SLN database. Five hundred forty-six consecutive breast SLN mapping patients were analyzed. A dual radiocolloid/blue dye technique was used in all patients. Results The SLN identification rate was similar among those patients injected the day prior (100%) and those injected the day of operation (99%, P = 0.14). A “hot” SLN was identified in 99% of patients injected the day prior and in 97% ( P = 0.17) injected the day of operation. The mean number of SLNs was greater among those injected the day prior (2.71) than among those injected the day of operation (2.33, P = 0.01). There were no differences in the rates of SLN metastases. Conclusions Radiocolloid injection the day before operation is an acceptable and logistically advantageous technique for breast cancer SLN mapping.

Background The current study sought to validate radioactive seed localization (RSL) as an alternative to wire localization (WL) to facilitate the operative excision of nonpalpable breast lesions. Methods One hundred consecutive patients underwent preoperative WL and the next 100 RSL. Margins were considered negative if ≥2 mm from in situ and invasive disease. Results RSL resulted in 100% retrieval of the seeds and lesions. Sixty-eight percent of patients underwent RSL at least 1 day before surgery. RSL resulted in a 35% relative improvement in the rate of negative margins in the first specimen ( P = 0.01) and a 62% relative improvement in the rate of reoperation for positive margins ( P = 0.01). The sentinel lymph node (SLN) identification rate was 100% in both groups. Conclusions RSL is effective and safe, and this procedure significantly improved the rate of negative margins in the first specimen and the rate of reoperation for positive margins compared to WL. We highly favor RSL over WL.

Background Breast-conserving therapy (BCT) is reported to result in a significant rate of complications and local recurrences in patients with prior implant breast augmentation. The role of sentinel lymph node (SLN) biopsy in these patients is unknown. Methods Retrospective review of patients with prior breast augmentation treated with BCT or SLN biopsy. Results Nineteen breast cancers were treated with BCT. Of 17 breasts undergoing adjuvant radiotherapy, 11 (64.7%) retained favorable aesthetic results. Of 9 subpectoral implants, capsular contracture developed in only 1 (11.1%). During follow-up (median 3 years), 1 local recurrence (5.3%) occurred in a patient who refused adjuvant radiotherapy and systemic therapy. Eleven patients underwent SLN biopsy with an identification rate of 100% and a false-negative rate of 0%. Conclusions Breast-conserving therapy inclusive of radiotherapy after implant breast augmentation produced acceptable cosmetic results in nearly two-thirds of patients. Sentinel lymph node mapping in the setting of prior implant augmentation was highly successful and accurate.

Simultaneous deregulation of both Wnt and ErbB growth factors has previously been shown to result in the cooperative induction of mammary gland tumors. Using the murine mammary tumor virus (MMTV)-Wnt-1 transgenic model of mammary carcinoma, we have identified an unvarying association between beta-catenin and epidermal growth factor receptor/c-Neu (ErbB1/ErbB2) heterodimers in mammary gland tumors, indicating a requirement for ErbB signaling in Wnt-mediated tumorigenesis. Expansion of these observations to a second transgenic model, MMTV-c-Neu, demonstrated similar tumor-specific interactions, including an ErbB1 ligand-inducible phosphorylation of both beta-catenin and c-Neu. Direct relevance of these findings to human breast cancer was established upon examination of a set of human infiltrating ductal breast adenocarcinoma and lymph node metastasis tissues taken at surgery. These data revealed increased levels of beta-catenin in tumors and metastases versus normal breast as well as an association between beta-catenin and c-Neu that measurably occurs only in neoplasia, most strongly in metastatic lesions. These studies have identified a seemingly indispensable interaction between beta-catenin and epidermal growth factor receptor/c-Neu heterodimers in Wnt-1-mediated breast tumorigenesis that may indicate a fundamental signaling event in human metastatic progression.

Background: Despite advances in the staging and surgical therapy of melanoma, patients with high-risk resected melanoma still have 5-year recurrence rates of 55% to 80% and 5-year survival rates as low as 25% to 70%. Effective adjuvant therapy is needed for this patient population. Methods: The authors review the literature regarding the use of interferon for the adjuvant therapy of resected melanoma. Results: Low-dose adjuvant interferon regimens have not affected overall survival and have had an inconsistent effect on disease-free survival across different stage groupings. High-dose adjuvant interferon improved disease- free and overall survival in the E1684 and Intergroup E1694 trials. High-dose interferon regimens cause significant morbidity, but quality-adjusted years of life are greater with this therapy. Conclusions: Adjuvant high-dose interferon should be considered standard therapy for all high-risk melanoma patients expected to be able to tolerate the interferon and treated off protocol. In addition, this regimen should serve as the active control in future trials of alternative adjuvant therapies for these patients.

1001 Background: Triple negative breast cancer (TNBC) is an aggressive form of breast cancer that lacks expression of ER, PR and HER2. Targeted treatment options for TNBC are limited, and novel pot...

1095 Background: Nipple-sparing mastectomy (NSM) has been accepted as a risk reducing procedure and for treatment of select breast cancers. The purpose of this study was to detail the types of post...

Dieulafoy's lesion is a submucosal artery associated with a minute mucosal defect, and it is an extremely rare cause of profuse but intermittent gastrointestinal bleeding. Most cases have occurred in the proximal stomach within 6 cm of the gastroesophageal junction. Less commonly, cases are encountered in the antrum, duodenum, jejunum, colon, and rarely the rectum. Only three cases of rectal Dieulfoy's lesion have been reported in the English medical literature: one in a child and two in otherwise healthy young men. We report a case of a rectal Dieulafoy's lesion in an elderly man with a mucous fistula. Successful treatment was administered with a combination of injection therapy and heater-probe coagulation followed by elective surgical oversewing. Rectal Dieulafoy's lesions should be included in the differential diagnosis of unexplained rectal bleeding in the elderly.