Julie R. Lange

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in the management of peritoneal surface malignancies of colonic origin: A consensus statement

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in the management of peritoneal surface malignancies of colonic origin : a consensus statement

Quantitative Multiplex Methylation-Specific PCR Assay for the Detection of Promoter Hypermethylation in Multiple Genes in Breast Cancer

If detected early, breast cancer is eminently curable. To detect breast cancer in samples with little cellularity, a high level of sensitivity is needed. Tumor-specific promoter hypermethylation has provided such a valuable tool for detection of cancer cells in biological samples. To accurately assess promoter hypermethylation for many genes simultaneously in small samples, we developed a novel method, quantitative multiplex-methylation-specific PCR (QM-MSP). QM-MSP is highly sensitive (1 in 104–105 copies of DNA) and linear over 5 orders of magnitude. For RASSF1A, TWIST, Cyclin D2, and HIN1, we observed significant differences in both the degree (P < 0.003) and incidence (P < 0.02) of hypermethylation between normal and malignant breast tissues. Evaluation of the cumulative hypermethylation of the four genes within each sample revealed a high level of sensitivity (84%) and specificity (89%) of detection of methylation. We demonstrate the application of this technique for detecting hypermethylated RASSF1A, TWIST, Cyclin D2, HIN1, and RARB in 50–1000 epithelial cells collected from breast ducts during endoscopy or by lavage. Such an approach could be used in a variety of small samples derived from different tissues, with these or different biomarkers to enhance detection of malignancy.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in the management of peritoneal surface malignancies of colonic origin: a consensus statement. Society of Surgical Oncology.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in the management of peritoneal surface malignancies of colonic origin : a consensus statement

Detection of Cancer DNA in Plasma of Patients with Early-Stage Breast Cancer

Purpose: Detecting circulating plasma tumor DNA (ptDNA) in patients with early-stage cancer has the potential to change how oncologists recommend systemic therapies for solid tumors after surgery. Droplet digital polymerase chain reaction (ddPCR) is a novel sensitive and specific platform for mutation detection. Experimental Design: In this prospective study, primary breast tumors and matched pre- and postsurgery blood samples were collected from patients with early-stage breast cancer (n = 29). Tumors (n = 30) were analyzed by Sanger sequencing for common PIK3CA mutations, and DNA from these tumors and matched plasma were then analyzed for PIK3CA mutations using ddPCR. Results: Sequencing of tumors identified seven PIK3CA exon 20 mutations (H1047R) and three exon 9 mutations (E545K). Analysis of tumors by ddPCR confirmed these mutations and identified five additional mutations. Presurgery plasma samples (n = 29) were then analyzed for PIK3CA mutations using ddPCR. Of the 15 PIK3CA mutations detected in tumors by ddPCR, 14 of the corresponding mutations were detected in presurgical ptDNA, whereas no mutations were found in plasma from patients with PIK3CA wild-type tumors (sensitivity 93.3%, specificity 100%). Ten patients with mutation-positive ptDNA presurgery had ddPCR analysis of postsurgery plasma, with five patients having detectable ptDNA postsurgery. Conclusions: This prospective study demonstrates accurate mutation detection in tumor tissues using ddPCR, and that ptDNA can be detected in blood before and after surgery in patients with early-stage breast cancer. Future studies can now address whether ptDNA detected after surgery identifies patients at risk for recurrence, which could guide chemotherapy decisions for individual patients. Clin Cancer Res; 20(10); 2643–50. ©2014 AACR.

Melanoma in Children and Teenagers: An Analysis of Patients From the National Cancer Data Base

PURPOSE This study examines the demographics, presentation, and outcomes of children and teenagers with melanoma using a US hospital-based oncology database. PATIENTS AND METHODS Data from the National Cancer Data Base from 1985 through 2003 were examined for demographics, presentation, and survival of patients aged 1 to 19 years, as well as a comparison group of patients aged 20 to 24 years. Two-sided linear and Pearson chi2 tests were calculated to examine associations. Proportions were compared using two-sided z tests. Five-year overall observed survival was evaluated using the Kaplan-Meier method and the log-rank test. Cox proportional hazards regression was used to estimate risk of mortality. RESULTS Of 3,158 patients aged 1 to 19 years, 96.3% had cutaneous melanoma, 3.0% had ocular melanoma, and 0.7% had an unknown primary tumor. Cutaneous melanoma in patients aged 1 to 19 years was more common in girls (55.5%) and patients older than 10 years (90.5%). The demographics and presentation of cutaneous melanoma were age related; younger children were significantly more likely to be nonwhite and male and more likely to present with a head and neck primary tumors and with regional or distant metastases (linear chi2, P < .001 for sex, race, and extent of disease). Poorer survival was associated with higher stage and younger age. In contrast to patients aged 20 to 24 years, survival was not related to thickness in patients aged 1 to 19 years with localized invasive melanoma. CONCLUSION Melanoma in children and teenagers differs from melanoma in young adults in demographics, presentation, and survival. Further investigation is warranted to elucidate possible biologic correlates of the unique aspects of melanoma in children and teenagers.

Quantitative multiplex methylation-specific PCR analysis doubles detection of tumor cells in breast ductal fluid

Purpose: The challenges of cytology for accurate diagnosis of breast cancer are well recognized. We previously showed that normal and tumor tissue can be distinguished using a technique called quantitative multiplex methylation-specific PCR (QM-MSP). We hypothesized that quantitative analysis of methylated genes will provide enhanced detection of cancer cells present in cytologic specimens. Experimental Design: QM-MSP was done on ductal lavage cells from a set of 37 ductal lavage samples from women undergoing mastectomy (27 with cancer and 3 without). Duct histology information was available for each lavaged duct. QM-MSP data was assessed by measuring cumulative methylation index and by receiver operating characteristic threshold analysis. To determine the baseline level of methylation for each gene in this population, cells from 60 ducts of women at high risk of developing breast cancer were analyzed. Results: QM-MSP findings on a panel of nine genes were correlated to duct histology and ductal lavage cytology. Cytology detected cancer in 33% (7 of 21 ducts) with a specificity of 99% (92 of 93). QM-MSP detected cancer as calculated by cumulative methylation index with a sensitivity of 62% (13 of 21) and specificity of 82% (62 of 76) and by receiver operating characteristic threshold analysis with a sensitivity of 71% (15 of 21) and specificity of 83% (63 of 76). Conclusions: Compared with cytology, QM-MSP doubled the sensitivity of detection of cancer. This study provides proof of principle by showing the advantages of using methylation analyses to query cytologic specimens and indicates its potential use in diagnosis and in stratifying risk.

Identification of Biomarkers for Breast Cancer in Nipple Aspiration and Ductal Lavage Fluid

Purpose: To establish a comprehensive proteomic approach for biomarker discovery and validation in breast fluid. Experimental Design: A total of 95 specimens from three institutions were used including 10 nipple aspiration fluid (5 stage I/II cancerous breasts and 5 age-matched healthy controls), 42 ductal lavage fluid from 14 patients with unilateral stage I/II cancer (25 from 9 cancerous breasts and 17 from 7 contralateral breasts), and 42 ductal lavage fluid from 14 high-risk women (multiple ducts repeated lavage). Differentially expressed protein/peptides were discovered by proteomic analysis of training sample, using ProteinChip arrays and surface-enhanced laser desorption ionization (SELDI) time-of-flight mass spectrometry, and validated on independently collected testing samples. After protein identification, ELISA was done to confirm the SELDI findings. Results: We were able to obtain reproducible protein profiles using minimal amount of protein (1 μg) by applying an optimized chip protocol and SELDI. We were able to select cancer-associated biomarkers despite large individual variability by applying both unsupervised and supervised cluster analysis. Furthermore, we were able to train and test candidate biomarkers on independently collected samples and identified one component of a multimarker panel as human neutrophil peptides 1 to 3. Conclusions: Breast fluid is a rich source of breast cancer biomarkers. In combination with high-throughput novel proteomic profiling technology and multicenter study design, markers that are highly specific to breast cancer can be discovered and validated. Our observations also suggest that persistent elevation of human neutrophil peptide in high-risk women may imply early onset of cancer not yet detectable by current detection method. Proof of this hypothesis requires follow-up on a larger study population.

Health Care System and Socioeconomic Factors Associated With Variance in Use of Sentinel Lymph Node Biopsy for Melanoma in the United States

PURPOSE Guidelines recommend sentinel lymph node biopsy (SLNB) for patients with clinical stage IB/II melanomas, but not clinical stage IA melanoma. This study examines factors associated with SLNB use for clinically node-negative melanoma. METHODS Patients diagnosed with clinically node-negative invasive melanoma in 2004 and 2005 were identified from the National Cancer Data Base. Regression models were developed to assess the association of clinicopathologic (sex, age, race/ethnicity, comorbidities, T stage), socioeconomic (insurance status, educational level, income), and hospital (hospital type, geographic area) factors with SLNB use. RESULTS A total of 16,598 patients were identified: 8,073 patients with clinical stage IA and 8,525 patients with clinical stage IB/II melanoma. For clinical stage IB/II melanoma, SLNB use was reported in 48.7% of patients. Patients with clinical stage IB/II melanoma were less likely to undergo SLNB if they were older than 75 years; had T1b tumors, no tumor ulceration, or head/neck or truncal lesions; were covered by Medicaid or Medicare; or lived in the Northeast, South, or West census regions. SLNB use was reported in 13.3% of patients with clinical stage IA melanoma and was more likely in patients who were younger than 56 years or lived in the Mountain or Pacific census regions. Patients treated at National Comprehensive Cancer Network-or National Cancer Institute-designated hospitals were most likely to undergo SLNB in adherence with national consensus guidelines. CONCLUSION SLNB use was associated with clinicopathologic factors but also with health system factors, including type of insurance, geographic area, and hospital type. These findings have implications for provider education and health policy.

The Role of Ultrasound-Guided Fine-Needle Aspiration of Axillary Nodes in the Staging of Breast Cancer

BackgroundAs a complement to sentinel node dissection (SLND), we evaluated ultrasound-guided fine-needle aspiration (USFNA) of normal and abnormal axillary nodes in breast cancer patients. We hypothesized that USFNA would be accurate for primary breast tumors larger than 2 cm.MethodsWe retrospectively reviewed 68 patients who underwent 69 preoperative USFNAs from 2003 to 2005. The results of 65 preoperative USFNA were compared with the results of SLND or axillary node dissection (ALND) for concordance. Four USFNAs were excluded from analysis because of a complete response to neoadjuvant therapy. We evaluated whether primary tumor features (histology, size, grade, vascular invasion, estrogen/progesterone receptor status and Her-2-neu status) predicted concordance of USFNA results and the final lymph node pathology.ResultsOf 65 axillae analyzed, 39 (60%) were positive, four (6%) were non-diagnostic, and 22 (34%) were negative by USFNA. USFNA had 89% sensitivity, 100% specificity, and 100% positive predictive value (PPV) in patients with palpable or ultrasonographically suspicious nodes. USFNA sensitivity dropped significantly for nonpalpable, ultrasonographically normal nodes (54%), while specificity and PPV remained 100%. None of the primary tumor features predicted concordance of USFNA and SLND/ALND.ConclusionsUSFNA of axillary nodes has a high specificity and PPV in clinically or radiologically suspicious nodes. Sensitivity of USFNA is low for nodes of normal appearance, but positive USFNA may allow definitive management of the axilla without a SLND. Thus, USFNA of normal appearing nodes might be beneficial in cases where decisions regarding neoadjuvant chemotherapy would be affected by the results.

Melanoma, version 4.2014: Featured updates to the NCCN guidelines

The NCCN Guidelines for Melanoma provide multidisciplinary recommendations on the clinical management of patients with melanoma. This NCCN Guidelines Insights report highlights notable recent updates. Foremost of these is the exciting addition of the novel agents ipilimumab and vemurafenib for treatment of advanced melanoma. The NCCN panel also included imatinib as a treatment for KIT-mutated tumors and pegylated interferon alfa-2b as an option for adjuvant therapy. Also important are revisions to the initial stratification of early-stage lesions based on the risk of sentinel lymph node metastases, and revised recommendations on the use of sentinel lymph node biopsy for low-risk groups. Finally, the NCCN panel reached clinical consensus on clarifying the role of imaging in the workup of patients with melanoma.