Performance of a prognostic 31-gene expression profile in an independent cohort of 523 cutaneous melanoma patients.

BACKGROUND: The heterogeneous behavior of patients with melanoma makes prognostication challenging. To address this, a gene expression profile (GEP) test to predict metastatic risk was previously developed. This study evaluates the GEP's prognostic accuracy in an independent cohort of cutaneous melanoma patients. METHODS: This multi-center study analyzed primary melanoma tumors from 523 patients, using the GEP to classify patients as Class 1 (low risk) and Class 2 (high risk). Molecular classification was correlated to clinical outcome and assessed along with AJCC v7 staging criteria. Primary endpoints were recurrence-free (RFS) and distant metastasis-free (DMFS) survival. RESULTS: The 5-year RFS rates for Class 1 and Class 2 were 88% and 52%, respectively, and DMFS rates were 93% versus 60%, respectively (P < 0.001). The GEP was a significant predictor of RFS and DMFS in univariate analysis (hazard ratio [HR] = 5.4 and 6.6, respectively, P < 0.001 for each), along with Breslow thickness, ulceration, mitotic rate, and sentinel lymph node (SLN) status (P < 0.001 for each). GEP, tumor thickness and SLN status were significant predictors of RFS and DMFS in a multivariate model that also included ulceration and mitotic rate (RFS HR = 2.1, 1.2, and 2.5, respectively, P < 0.001 for each; and DMFS HR = 2.7, 1.3 and 3.0, respectively, P < 0.01 for each). CONCLUSIONS: The GEP test is an objective predictor of metastatic risk and provides additional independent prognostic information to traditional staging to help estimate an individual's risk for recurrence. The assay identified 70% of stage I and II patients who ultimately developed distant metastasis. Its role in consideration of patients for adjuvant therapy should be examined prospectively.

Clinical impact of a 31-gene expression profile test for cutaneous melanoma in 156 prospectively and consecutively tested patients.

OBJECTIVE: DecisionDx-Melanoma * is a 31-gene expression profile test that predicts the risk of metastasis in patients with primary cutaneous melanoma (CM). This study was designed to ascertain clinical management changes determined by the test outcome, which classifies CM patients being at low (Class 1) or high (Class 2) risk for recurrence. RESEARCH DESIGN AND METHODS: Medical charts were reviewed from 156 CM patients from six institutions (three dermatology and three surgical oncology practices) who were consecutively tested between May 2013 and December 2015. Clinical management data that were compiled and compared before and after receipt of the 31-gene expression test result included frequency of physical exams, frequency and modality of imaging, and referrals to surgical and medical oncologists. RESULTS: Forty-two percent of patients were Stage I, 47% were Stage II and 8% were Stage III. Overall, 95 patients (61%) were Class 1 and 61 (39%) were Class 2. Documented changes in management were observed in 82 (53%) patients, with the majority of Class 2 patients (77%) undergoing management changes compared to 37% of Class 1 patients (p < 0.0001 by Fisher's exact test). The majority (77/82, 94%) of these changes were concordant with the risk indicated by the test result (p < 0.0001 by Fisher's exact test), with increased management intensity for Class 2 patients and reduced management intensity for Class 1 patients. CONCLUSIONS: Molecular risk classification by gene expression profiling has clinical impact and influences physicians to direct clinical management of CM patients. The vast majority of the changes implemented after the receipt of test results were reflective of the low or high recurrence risk associated with the patient's molecular classification. Because follow-up data was not collected for this patient cohort, the study is limited for the assessment of the impact of gene expression profile based management changes on healthcare resource utilization and patient outcome.

Activating mutation in MET oncogene in familial colorectal cancer.

BACKGROUND: In developed countries, the lifetime risk of developing colorectal cancer (CRC) is 5%, and it is the second leading cause of death from cancer. The presence of family history is a well established risk factor with 25-35% of CRCs attributable to inherited and/or familial factors. The highly penetrant inherited colon cancer syndromes account for approximately 5%, leaving greater than 20% without clear genetic definition. Familial colorectal cancer has been linked to chromosome 7q31 by multiple affected relative pair studies. The MET proto-oncogene which resides in this chromosomal region is considered a candidate for genetic susceptibility. METHODS: MET exons were amplified by PCR from germline DNA of 148 affected sibling pairs with colorectal cancer. Amplicons with altered sequence were detected with high-resolution melt-curve analysis using a LightScanner (Idaho Technologies). Samples demonstrating alternative melt curves were sequenced. A TaqMan assay for the specific c.2975C >T change was used to confirm this mutation in a cohort of 299 colorectal cancer cases and to look for allelic amplification in tumors. RESULTS: Here we report a germline non-synonymous change in the MET proto-oncogene at amino acid position T992I (also reported as MET p.T1010I) in 5.2% of a cohort of sibling pairs affected with CRC. This genetic variant was then confirmed in a second cohort of individuals diagnosed with CRC and having a first degree relative with CRC at prevalence of 4.1%. This mutation has been reported in cancer cells of multiple origins, including 2.5% of colon cancers, and in <1% in the general population. The threonine at amino acid position 992 lies in the tyrosine kinase domain of MET and a change to isoleucine at this position has been shown to promote metastatic behavior in cell-based models. The average age of CRC diagnosis in patients in this study is 63 years in mutation carriers, which is 8 years earlier than the general population average for CRC. CONCLUSIONS: Although the MET p.T992I genetic mutation is commonly found in somatic colorectal cancer tissues, this is the first report also implicating this MET genetic mutation as a germline inherited risk factor for familial colorectal cancer. Future studies on the cancer risks associated with this mutation and the prevalence in different at-risk populations will be an important extension of this work to define the clinical significance.

The satisfaction of Latina breast cancer survivors with their healthcare and health-related quality of life.

OBJECTIVE: The aim of this study was to evaluate the relationship of satisfaction with the cancer care doctor and health-related quality of life (HRQOL) among Latina breast cancer survivors (BCS) by (1) assessing whether satisfaction would be positively correlated with HRQOL and (2) assessing whether satisfaction would significantly influence HRQOL while controlling for covariates. METHODS: The cross-sectional study used self-report data from 117 Latina BCS. Satisfaction was measured with the Hall Satisfaction Index, and HRQOL was measured with the Functional Assessment of Cancer Therapy-General (FACT-G). Analyses included calculation of descriptive statistics, t tests, bivariate correlations, analyses of variance (ANOVAs), and multivariate analyses. RESULTS: Latina BCS had high satisfaction and generally good HRQOL. The Hall Satisfaction Index total score was positively associated with FACT-G functional well-being (r=0.265, p=0.004). Multivariate analyses showed that the Hall Satisfaction Index total score was a significant predictor of FACT-G functional well-being (p=0.012). Employment status was also a significant predictor, where being employed or retired resulted in better functional well-being than being unemployed. CONCLUSIONS: Latina BCS were quite satisfied with their cancer care doctors, and high levels of satisfaction with the cancer care doctor influenced functional well-being when confounding variables were controlled. Despite reportedly high satisfaction, Latina BCS did report barriers to satisfaction that could be considered cultural. Implications are discussed.

The religiosity/spirituality of Latina breast cancer survivors and influence on health-related quality of life.

OBJECTIVE: The study evaluated the association of religiosity/spirituality (R/S) and health-related quality of life (HRQOL) among Latina breast cancer survivors (BCS) in order to determine whether R/S would be positively correlated with HRQOL and whether R/S would significantly influence HRQOL. METHODS: The cross-sectional study utilized self-report data from 117 Latina BCS survivors. R/S was measured with the Systems of Belief Inventory-15 Revised (SBI-15R) and HRQOL was measured with the Functional Assessment of Cancer Therapy-General (FACT-G). Analyses included calculation of descriptive statistics, t-tests, bivariate correlations, and multivariate analyses. RESULTS: Latina BCS had very high levels of R/S and generally good HRQOL. The SBI-15R total score was positively correlated with FACT-G social well-being (SWB) (r=0.266, p=0.005), relationship with doctor (RWD) (r=0.219, p=0.020), and functional well-being (FWB) (r=0.216, p=0.022). Multivariate analyses revealed that SBI-15R was a significant predictor of FACT-G FWB (p=0.041) and satisfaction with the relationship with the doctor (p=0.050), where higher levels of R/S predicted higher levels of well-being. CONCLUSIONS: Latina BCS had very high levels of R/S, which were significantly, positively correlated with dimensions of HRQOL (SWB, FWB, RWD). Furthermore, these high levels of R/S predicted better FWB and satisfaction with the patient-doctor relationship while controlling for potentially confounding variables. Implications are discussed.

Common familial colorectal cancer linked to chromosome 7q31: a genome-wide analysis.

Present investigations suggest that approximately 30% of colorectal cancer cases arise on the basis of inherited factors. We hypothesize that the majority of inherited factors are moderately penetrant genes, common in the population. We use an affected sibling pair approach to identify genetic regions that are coinherited by siblings with colorectal cancer. Individuals from families with at least two siblings diagnosed with colorectal adenocarcinoma or high-grade dysplasia were enrolled. Known familial colorectal cancer syndromes were excluded. A genome-wide scan on 151 DNA samples from 70 kindreds was completed using deCODE 1100 short tandem repeat marker set at an average 4-cM density. Fine mapping on a total of 184 DNAs from 83 kindreds was done in regions suggesting linkage. Linkage analysis was accomplished with Merlin analysis package. Nonparametric linkage analysis revealed three genetic regions with logarithm of the odds (LOD) scores >or=2.0: Ch. 3q29, LOD 2.61 (P = 0.0003); Ch. 4q31.3, LOD 2.13 (P = 0.0009); and Ch. 7q31.31, LOD 3.08 (P = 0.00008). Affected siblings with increased sharing at the 7q31 locus have a 3.8-year (+/- 3.5) earlier age of colorectal cancer onset although this is not statistically significant (P = 0.11). No significant linkage was found near genes causing known syndromes or regions previously reported (8q24, 9q22, and 11q23). The chromosome 3q21-q24 region reported to be linked in colorectal cancer relative pairs is supported by our study, albeit a minor peak (LOD 0.9; P = 0.02). No known familial cancer genes reside in the 7q31 locus, and thus the identified region may contain a novel susceptibility gene responsible for common familial colorectal cancer.

Testing three different cancer genetics registry recruitment methods with Hispanic cancer patients and their family members previously registered in local cancer registries in Texas.

OBJECTIVE: To increase accrual among Hispanics to the Cancer Genetics Network national cancer genetics registry. METHODS: Drawing from South Texas cancer registries, 444 Hispanic men and women were randomly assigned to one of three experimental conditions: standard direct-mailed procedures (X1), X1 plus culturally tailored materials (X2), and X2 plus interpersonal phone contact (X3). Participants were also surveyed about the effectiveness of the education materials and the phone contact. A refusal survey was provided for those who declined to join the study. RESULTS: A total of 154 individuals joined the Cancer Genetics Network. The X3 condition yielded the greatest accrual (43.2%) compared to X1 (30.9%) and X2 (29.9%; p < 0.05). Tailored materials appeared to have no effect but were highly regarded. The main reasons for not participating were a lack of interest and time requirements. CONCLUSION: Interpersonal communication can have a powerful effect on recruitment. However, more research is needed to determine the cost-efficacy of more labor-intensive approaches to registry accrual.

Case report and summary of literature: giant perineal keloids treated with post-excisional radiotherapy.

BACKGROUND: Keloids are common benign tumors of the dermis, typically arising after insult to the skin. While typically only impinging on cosmesis, large or recurrent keloids may require therapeutic intervention. While no single standardized treatment course has been established, several series report excellent outcomes for keloids with post-surgery radiation therapy. CASE PRESENTATION: We present a patient with a history of recurrent keloids arising in the absence of an ascribed trauma and a maternal familial history of keloid formation, whose physical examination several large perineal keloids of 6-20 cm in the largest dimension. The patient was treated with surgical extirpation and adjuvant radiation therapy. Radiotherapy was delivered to the scar bed to a total dose of 22 Gy over 11 daily fractions. Acute radiotherapy toxicity necessitated a treatment break due to RTOG Grade III acute toxicity (moderate ulceration and skin breakdown) which resolved rapidly during a 3-day treatment break. The patient demonstrated local control and has remained free of local recurrence for more than 2 years. CONCLUSION: Radiotherapy for keloids represents a safe and effective option for post-surgical keloid therapy, especially for patients with bulky or recurrent disease.

Assessing BRCA carrier probabilities in extended families.

PURPOSE: Carrier prediction models estimate the probability that a person has a BRCA mutation. We evaluated the accuracy of the BOADICEA model and compared its performance with that of other models (BRCAPRO, Myriad I and II, Couch, and Manchester Scoring System). We also studied the effect of extended family information on risk estimation using BOADICEA. METHODS: We compared the area under receiver operating characteristic curves generated from 472 families with one member tested for BRCA mutations. We calculated sensitivity, specificity, and predictive values at an estimated probability of 10% and explored the biases of carrier prediction. RESULTS: BOADICEA performed better than the other models in Ashkenazi Jewish (AJ) families, BRCAPRO performed slightly better in non-AJ families, and Myriad II performed comparably well in both groups. Including extended family information in BOADICEA yielded slightly better performance than did limiting the information to second-degree relatives. Using a 10% cutoff point, BOADICEA and Myriad II were most sensitive in predicting BRCA1/2 mutations in AJ families, and Myriad II was most sensitive in non-AJ families. The Manchester Scoring System was the most sensitive and least specific in a subgroup of non-AJ families. BOADICEA and BRCAPRO tended to underestimate the observed risk at low estimated probabilities and overestimate it at higher probabilities. CONCLUSION: The BOADICEA, BRCAPRO, and Myriad II models performed similarly. Including second-degree relatives slightly improved carrier prediction by BOADICEA. The Myriad II model was the easiest to implement.

Interest, awareness, and perceptions of genetic testing among Hispanic family members of breast cancer survivors.

OBJECTIVE: To provide a preliminary description of the interest, awareness, and perceptions of genetic testing among Hispanics with a family history of breast cancer DESIGN: This cross-sectional pilot study used interpersonal structured interviews for data collection. PARTICIPANTS: We interviewed 48 Hispanics without breast cancer but who had a family member with breast cancer; participants lived in San Antonio and the surrounding area. MAIN OUTCOME: The outcomes were interest in breast cancer genetic testing, awareness about genetic testing, perceived risk of carrying a breast cancer susceptibility gene, and the perceived benefits and risks associated with a genetic test. MEASURES: Items previously used in research regarding interest and perceived genetic risk and a previously validated benefits and risks-limitations scale for genetic testing commonly used by other researchers were used to measure the outcomes. RESULTS: Awareness of genetic testing for breast cancer susceptibility was very low, yet most (82%) participants were interested in a genetic test for breast cancer susceptibility. Participants were more likely to identify with the benefits than the potential risks of genetic testing. The most highly endorsed benefits were to know to take better care of one's self and to undergo more frequent screening. CONCLUSIONS: Hispanics seem to have positive perceptions about genetic testing for breast cancer susceptibility. However, the high level of interest in genetic testing may be driven by a lack of knowledge about genetic testing. Culturally sensitive and appropriate educational programs about breast cancer genetic testing and the surrounding issues are needed for the Hispanic population.

Locally advanced duodenal gangliocytic paraganglioma treated with adjuvant radiation therapy: case report and review of the literature.

BACKGROUND: Gangliocytic paraganglioma are rare neoplasms that predominantly arise in periampulary region. Though considered benign the disease can spread to regional lymphatics. CASE PRESENTATION: A 49 year old woman presented with melena and was found to have a periampullary mass. Endoscopic evaluation and biopsy demonstrated a periampullary paraganglioma. The tumor was resected with pylorus-preserving pancreaticoduodenectomy and was found to represent a gangliocytic paraganglioma associated with nodal metastases. In a controversial decision, the patient was treated with adjuvant external beam radiation therapy. She is alive and well one year following resection. The authors have reviewed the current literature pertaining to this entity and have discussed the biologic behavior of the tumor as well as the rationale for treatment strategies employed. CONCLUSION: Paraganglioma is a rare tumor that typically resides in the gastrointestinal tract and demonstrates low malignant potential. Due to rarity of the disease there is no consensus on the adjuvant treatment even though nearly 5% of the lesions demonstrate the malignant potential.

Positive margins following surgical resection of breast carcinoma: analysis of pathologic correlates.

BACKGROUND AND OBJECTIVES: Histologic margin positivity represents a significant source of adverse clinical outcome affecting breast conservation therapy for in situ or invasive malignancy. Elucidation of factors associated with positive margin status might clarify and improve local therapy strategies. In order to define our experience with margin positivity and to identify relevant pathologic criteria, we retrospectively analyzed the cases of 143 patients who underwent resections for carcinoma with intent of breast conservation between 1995 and 1999. METHODS: Histologic features and indices of biologic aggressiveness were compared among tumors resected with positive versus negative margins in order to determine whether such markers could be used to anticipate outcome. RESULTS: Twenty-eight pathologic specimens were identified to possess histologically positive margins. Twenty-six patients underwent additional operative procedures. Of the 26 re-excision specimens, 17 (65%) contained residual malignancy. Statistical analysis demonstrated that margin positivity correlated with in situ histology and with Her 2/neu positivity. CONCLUSIONS: These data suggest certain pathologic factors that may portend difficulty in achieving negative resection margins in patients in whom breast conservation therapy is considered.

Metastatic seminoma presenting with pulmonary embolus, inferior vena caval thrombosis, and gastrointestinal bleeding.

Testicular cancer metastasis to the retroperitoneum can be associated with a variety of complications due to obstruction or invasion of adjacent structures. In this case report, we present an unusual patient with invasion of the duodenum from germ cell cancer and discuss the management of this challenging scenario.

Pathologic review of atypical hyperplasia identified by image-guided breast needle core biopsy. Correlation with excision specimen.

CONTEXT: Management of breast needle core biopsies diagnosed as atypical ductal hyperplasia, atypical lobular hyperplasia, and lobular carcinoma in situ is controversial. Current recommendations involve excisional biopsy to rule out ductal carcinoma in situ and/or invasive carcinoma, which have been reported in more than 50% of cases in some series. OBJECTIVE: To determine how frequently these diagnoses made on needle core biopsy are ultimately found to represent in situ or invasive carcinoma based on excisional biopsy specimens, in order to identify predictive factors. DESIGN: One thousand eight hundred thirty-six image-guided needle core biopsies were performed between January 1, 1995 and May 1, 2001. Fifty-four (2.9%) patients diagnosed with atypical ductal hyperplasia (n = 36), atypical lobular hyperplasia (n = 12), atypical ductal hyperplasia + atypical lobular hyperplasia (n = 3), or lobular carcinoma in situ (n = 3) subsequently underwent breast excisions. Pathologic features were reviewed in each of the needle core biopsies using Page's criteria and were then correlated with excision specimens. SETTING: University medical center. RESULTS: Review of the needle core biopsy cases with either ductal carcinoma in situ or invasive carcinoma + ductal carcinoma in situ on final excision showed that nucleoli were evident in most of the needle core cases, with foci of nuclear pleomorphism and individual cell necrosis or apoptosis. CONCLUSION: A more precise diagnosis can be made by using strict criteria for atypical ductal hyperplasia versus ductal carcinoma in situ on needle core biopsy. Cytologic atypia, even if in a small area, particularly when there is apoptosis/individual cell necrosis, correlates with the finding of a more serious lesion on excision.

Pain and quality of life after treatment in patients with locally recurrent rectal cancer.

PURPOSE: Because survival in patients with locally recurrent rectal cancer (LRRC) is limited, pain control and quality of life (QOL) are important parameters. The purpose of this study was to assess the prevalence of posttreatment pain and QOL of patients with LRRC treated with nonsurgical palliation or resection and identify predictors of poor outcome. PATIENTS AND METHODS: Posttreatment pain severity and QOL were prospectively assessed in 45 patients with LRRC using the Brief Pain Inventory and Functional Assessment of Cancer Therapy-Colorectal questionnaire. RESULTS: Fifteen patients received nonsurgical palliation, and 30 patients underwent resection of their pelvic tumors. There was a significant association between higher posttreatment pain scores and worse QOL (P <.001). Patients treated with nonsurgical palliation reported moderate to severe pain beyond the third month of treatment. Resected patients reported comparable levels of pain during the first 3 postoperative years, particularly after bony resections; long-term survivors (beyond 3 years), however, reported minimal pain and good QOL. Female sex, pelvic/sciatic pain at presentation, total pelvic exenteration, and bony resection were associated with higher rates of moderate to severe posttreatment pain (P =.04, P <.001, P =.04, and P =.02, respectively). Pain at presentation was an independent predictor of posttreatment pain (odds ratio, 7.4 [95% confidence interval, 1.8 to 30.3]; P =.006). CONCLUSION: Patients with LRRC treated with nonsurgical palliation or resection experience significant levels of pain after treatment. Close posttreatment pain monitoring is warranted in patients presenting with pelvic pain, and more aggressive pain management strategies may improve posttreatment QOL.

Irofulven (6-hydroxymethylacylfulvene, MGI 114)-induced apoptosis in human pancreatic cancer cells is mediated by ERK and JNK kinases.

BACKGROUND: Pancreatic carcinoma resists chemotherapeutic mediation of apoptosis. Irofulven (MGI 114, 6-hydroxymethylacylfulvene) is a novel illudin S analogue that we have shown to induce caspase-mediated apoptosis in pancreatic carcinoma cell lines. MATERIALS AND METHODS: Westem blot analysis and kinase assays were used to demonstrate the activation of Erk 1/2 and JNK1 kinases following Irofulven administration in the presence and absence of selective kinase inhibitors. RESULTS: Irofulven activates JNK1 and Erk1/2, but not p38. The addition of the MAPK inhibitors, SB202190 and PD98059 (targeting JNK1 and Erk1/2 activation, respectively), prevents kinase activation and blocks Irofulven-induced activation of caspases -3, -7, -8 and -9. Blockade of either JNK1 or Erk1/2 results in a 50% decrease in apoptosis in MiaPaCa-2 cells treated with Irofulven. CONCLUSION: Our data demonstrated that JNK1 and Erk1/2 are activated by Irofulven treatment and that blockade of either MAPK subfamily decreases apoptosis by rendering Irofulven incapable of inducing caspase activation.

Analysis of sentinel lymph node mapping with immediate pathologic review in patients receiving preoperative chemotherapy for breast carcinoma.

BACKGROUND: Sentinel lymph node mapping (SLNM) and neoadjuvant chemotherapy are becoming established components of therapy for selected patients with breast carcinoma. However, neoadjuvant therapy has been considered a relative contraindication to SLNM. In an effort to learn whether patients who have received preoperative chemotherapy can undergo accurate SLNM, we evaluated our experience with this technique. METHODS: From January 1997 to June 2000, SLNM and axillary lymph node dissection were concurrently performed in 35 patients who received preoperative chemotherapy. Mapping was performed with (99m)Tc sulfur colloid only in one patient and Lymphazurin dye only in 15 patients, and the two methods were combined in the remainder. RESULTS: SLNM successfully identified a sentinel lymph node in 30 (86%) patients. Metastatic disease was identified in the sentinel lymph nodes of four patients during surgery. The intraoperative pathologic diagnosis proved to be correct in 19 (79%) of 24 patients. The final pathologic diagnosis of the sentinel lymph node reflected the status of the axillary contents in all patients in whom it was identified. CONCLUSIONS: These results demonstrate that SLNM can be consistently performed in patients receiving preoperative chemotherapy for breast cancer, suggesting the utility of this technique in this patient population.