Metastatic melanoma - a review of current and future treatment options.

Despite advances in treatment and surveillance, melanoma continues to claim approximately 9,000 lives in the US annually (SEER 2013). The National Comprehensive Cancer Network currently recommends ipilumumab, vemurafenib, dabrafenib, and high-dose IL-2 as first line agents for Stage IV melanoma. Little data exists to guide management of cutaneous and subcutaneous metastases despite the fact that they are relatively common. Existing options include intralesional Bacillus Calmette-Guérin, isolated limb perfusion/infusion, interferon-α, topical imiquimod, cryotherapy, radiation therapy, interferon therapy, and intratumoral interleukin-2 injections. Newly emerging treatments include the anti-programmed cell death 1 receptor agents (nivolumab and pembrolizumab), anti-programmed death-ligand 1 agents, and oncolytic vaccines (talimogene laherparepevec). Available treatments for select sites include adoptive T cell therapies and dendritic cell vaccines. In addition to reviewing the above agents and their mechanisms of action, this review will also focus on combination therapy as these strategies have shown promising results in clinical trials for metastatic melanoma treatment.

Relative value units poorly correlate with measures of surgical effort and complexity.

BACKGROUND: The relationship between procedural relative value units (RVUs) for surgical procedures and other measures of surgeon effort are poorly characterized. We hypothesized that RVUs would poorly correlate with quantifiable metrics of surgeon effort. METHODS: Using the 2010 American College of Surgeons - National Surgical Quality Improvement Program (NSQIP) database, we selected 11 primary current procedural terminology codes associated with high volume surgical procedures. We then identified all patients with a single reported procedural RVU who underwent nonemergent, inpatient general surgical operations. We used linear regression to correlate length of stay (LOS), operative time, overall morbidity, frequency of serious adverse events (SAEs), and mortality with RVUs. We used multivariable logistic regression using all preoperative NSQIP variables to determine other significant predictors of our outcome measures. RESULTS: Among 14,481 patients, RVUs poorly correlated with individual LOS (R(2) = 0.05), operative time (R(2) = 0.10), and mortality (R(2) = 0.35). There was a moderate correlation between RVUs and SAEs (R(2) = 0.79) and RVUs and overall morbidity (R(2) = 0.75). However, among low- to mid-level RVU procedures (11-35) there was a poor correlation between SAEs (R(2) = 0.15), overall morbidity (R(2) = 0.05), and RVUs. On multivariable analysis, RVUs were significant predictors of operative time, LOS, and SAEs (odds ratio 1.06, 95% confidence interval: 1.05-1.07), but RVUs were not a significant predictor of mortality (odds ratio 1.02, 95% confidence interval: 0.99-1.05). CONCLUSIONS: For common, index general surgery procedures, the current RVU assignments poorly correlate with certain metrics of surgeon work, while moderately correlating with others. Given the increasing emphasis on measuring and tracking surgeon productivity, more objective measures of surgeon work and productivity should be developed.

Lactate Oxidase Disrupts Lactate-Activated RAS and PI3K Oncogenic Signaling.

LOX was recently shown to inhibit cancer cell proliferation and tumor growth. The mechanism of this inhibition, however, has been exclusively attributed to LOX depletion of TME lactate, a cancer cell energy source, and production of H2O2, an oxidative stressor. We report that TME lactate triggers the assembly of the lactate receptor hydroxycarboxylic acid receptor 1 (HCAR1)-associated protein complex, which includes GRB2, SOS1, KRAS, GAB1, and PI3K, for the activation of both the RAS and the PI3K oncogenic signaling pathways in breast cancer (BCa) cells. LOX treatment decreased the levels of the proteins in the protein complex via induction of their proteasomal degradation. In addition, LOX inhibited lactate-stimulated expression of the lactate transporters MCT1 and MCT4. Our data suggest that HCAR1 activation by lactate is crucial for the assembly and function of the RAS and PI3K signaling nexus. Shutting down lactate signaling by disrupting this nexus could be detrimental to cancer cells. HCAR1 is therefore a promising target for the control of the RAS and the PI3K signaling required for BCa progression. Thus, our study provides insights into lactate signaling regulation of cancer progression and extends our understanding of LOX's functional mechanisms that are fundamental for exploring its therapeutic potential.

Utilization of sentinel lymph node biopsy in patients with ductal carcinoma in situ undergoing mastectomy.

BACKGROUND: Current guidelines suggest consideration of sentinel lymph node biopsy (SLNB) for patients with ductal carcinoma in situ (DCIS) undergoing mastectomy. Our objective was to identify factors influencing the utilization of SLNB in this population. METHODS: We used the Surveillance Epidemiology and End Results database to identify all women with breast DCIS treated with mastectomy from 2000 to 2008. We excluded patients without histologic confirmation, those diagnosed at autopsy, those who had axillary lymph node dissections performed without a preceding SLNB, and those for whom the status of SLNB was unknown. We used multivariate logistic regression reporting odds ratios (OR) and 95% confidence intervals (CI) to evaluate the relationship of patient- and tumor-related factors to the likelihood of undergoing SLNB. RESULTS: Of 20,177 patients, 51% did not receive SLNB. Factors associated with a decreased likelihood of receiving a SLNB included advancing age (OR 0.66; 95% CI 0.62-0.71), Asian (OR 0.75; CI 0.68-0.83) or Hispanic (OR 0.84; 95% CI 0.74-0.96) race/ethnicity, and history of prior non-breast (OR 0.57; 95% CI 0.53-0.61). Factors associated with an increased likelihood of receiving a SLNB included treatment in the east (OR 1.28; 95% CI 1.17-1.4), intermediate (OR 1.25; 95% CI 1.11-1.41), high (OR 1.84; 95% CI 1.62-2.08) grade tumors, treatment after the year 2000, and DCIS size 2-5 cm (OR 1.54; 95% CI 1.42-1.68) and >5 cm (OR 2.43; 95% CI 2.16-2.75). CONCLUSIONS: SLNB is increasingly utilized in patients undergoing mastectomy for DCIS, but disparities in usage remain. Efforts at improving rates of SLNB in this population are warranted.

Combined analysis of phase III trials evaluating [99mTc]tilmanocept and vital blue dye for identification of sentinel lymph nodes in clinically node-negative cutaneous melanoma.

BACKGROUND: [(99m)Tc]Tilmanocept is a CD206 receptor-targeted radiopharmaceutical designed for sentinel lymph node (SLN) identification. Two nearly identical nonrandomized phase III trials compared [(99m)Tc]tilmanocept to vital blue dye. METHODS: Patients received [(99m)Tc]tilmanocept and blue dye. SLNs identified intraoperatively as radioactive and/or blue were excised and histologically examined. The primary end point, concordance, was the proportion of blue nodes detected by [(99m)Tc]tilmanocept; 90 % concordance was the prespecified minimum concordance level. Reverse concordance, the proportion of radioactive nodes detected by blue dye, was also calculated. The prospective statistical plan combined the data from both trials. RESULTS: Fifteen centers contributed 154 melanoma patients who were injected with both agents and were intraoperatively evaluated. Intraoperatively, 232 of 235 blue nodes were detected by [(99m)Tc]tilmanocept, for 98.7 % concordance (p < 0.001). [(99m)Tc]Tilmanocept detected 364 nodes, for 63.7 % reverse concordance (232 of 364 nodes). [(99m)Tc]Tilmanocept detected at least one node in more patients (n = 150) than blue dye (n = 138, p = 0.002). In 135 of 138 patients with at least one blue node, all blue nodes were radioactive. Melanoma was identified in the SLNs of 22.1 % of patients; all 45 melanoma-positive SLNs were detected by [(99m)Tc]tilmanocept, whereas blue dye detected only 36 (80 %) of 45 (p = 0.004). No positive SLNs were detected exclusively by blue dye. Four of 34 node-positive patients were identified only by [(99m)Tc]tilmanocept, so 4 (2.6 %) of 154 patients were correctly staged only by [(99m)Tc]tilmanocept. No serious adverse events were attributed to [(99m)Tc]tilmanocept. CONCLUSIONS: [(99m)Tc]Tilmanocept met the prespecified concordance primary end point, identifying 98.7 % of blue nodes. It identified more SLNs in more patients, and identified more melanoma-containing nodes than blue dye.

Assessing rural-urban disparities in the use of sentinel lymph node biopsy for melanoma.

BACKGROUND: We hypothesized that patients in urban areas with intermediate thickness cutaneous melanoma would have higher rates of sentinel lymph node biopsy (SLNB) relative to their rural-dwelling counterparts. METHODS: The Surveillance, Epidemiology, and End Results database was queried for patients who underwent surgery for intermediate thickness cutaneous melanoma from 2004-2008. Patients were categorized as coming from urban or rural counties based on a nine-point scale. We used multivariate logistic regression models to predict use of SLNB. Covariates examined included sex, race/ethnicity, age, T stage, tumor histology, tumor location, and ulceration. The likelihood of undergoing SLNB was reported as OR with 95% CI. RESULTS: Of 8441 patients, 8382 (99.3%) had complete information regarding use of SLNB. On multivariate analysis, patients from rural counties had a decreased likelihood of receiving a SLNB (OR 0.87, CI 0.78-0.97; P = 0.014). Additional factors associated with a decreased likelihood of receiving a SLNB included increasing age, Asian/Hispanic/Unknown race, and head and neck or overlapping primary tumor site. CONCLUSIONS: Patients in rural areas are less likely to receive a SLNB for intermediate thickness cutaneous melanoma than their urban-dwelling counterparts.

Age-related disparities in use of completion lymphadenectomy for melanoma sentinel lymph node metastasis.

BACKGROUND: Guidelines recommend that patients with melanoma metastatic to the sentinel lymph node (SLN) undergo a completion lymphadenectomy (CLND) of the affected lymph node basin. We have previously reported on decreased use of SLN biopsy among elderly patients. We hypothesized that elderly patients with SLN metastases would have lower rates of CLND relative to their younger counterparts. METHODS: The Surveillance, Epidemiology, and End Results database was queried for patients who underwent SLN biopsy for intermediate thickness cutaneous melanoma (Breslow thickness 1.01 mm-4.00 mm) from 2004 to 2008 and were found to have SLN metastasis. Patients were categorized according to age by decade. We then used multivariate logistic regression models to predict receipt of CLND. Additional covariates included sex, race/ethnicity, T stage, tumor histology, tumor location, and ulceration. The likelihood of receiving a CLND was reported as OR with 95% CI; significance was set at P ≤ 0.05. RESULTS: Entry criteria were met by 765 patients. Of these, 548 (71.6%) patients underwent CLND. On multivariate analysis, patients in the age groups 70-79 y old (OR 0.39, CI 0.20-0.78; P = 0.007) and ≥ 80 y old (OR 0.27, CI 0.12-0.61; P = 0.001) were less likely to undergo CLND than the youngest age group (1-39 y old). CONCLUSIONS: Elderly patients with SLN metastasis are less likely to receive CLND than their younger counterparts. A multi-center randomized clinical trial evaluating the potential survival benefit of CLND is ongoing. Further research to assess reasons why the elderly are less likely to receive CLND are needed.

Nomograms to predict risk of in-hospital and post-discharge venous thromboembolism after abdominal and thoracic surgery: an American College of Surgeons National Surgical Quality Improvement Program analysis.

BACKGROUND: Postoperative venous thromboembolism (VTE) is increasingly viewed as a quality of care metric, although risk-adjusted incident rates of postoperative VTE and VTE after hospital discharge (VTEDC) are not available. We sought to characterize the predictors of VTE and VTEDC to develop nomograms to estimate individual risk of VTE and VTEDC. METHODS: Using the American College of Surgeons National Surgical Quality Improvement Program database, we identified 471,867 patients who underwent inpatient abdominal or thoracic operations between 2005 and 2010. We excluded primary vascular and spine operations. We built logistic regression models using stepwise model selection and constructed nomograms for VTE and VTEDC with statistically significant covariates. RESULTS: The overall, unadjusted, 30-d incidence of VTE and VTEDC was 1.5% and 0.5%, respectively. Annual incidence rates remained unchanged over the study period. On multivariate analysis, age, body mass index, presence of preoperative infection, operation for cancer, procedure type (spleen highest), multivisceral resection, and non-bariatric laparoscopic surgery were significant predictors for VTE and VTEDC. Other significant predictors for VTE, but not VTEDC, included a history of chronic obstructive pulmonary disease, disseminated cancer, and emergent operation. We constructed and validated nomograms by bootstrapping. The concordance indices for VTE and VTEDC were 0.77 and 0.67, respectively. CONCLUSIONS: Substantial variation exists in the incidence of VTE and VTEDC, depending on patient and procedural factors. We constructed nomograms to predict individual risk of 30-d VTE and VTEDC. These may allow more targeted quality improvement interventions to reduce VTE and VTEDC in high-risk general and thoracic surgery patients.

Comparative morbidity and mortality from cervical or thoracic esophageal anastomoses.

BACKGROUND: In the modern era of esophagectomy, we hypothesized that perioperative morbidity and mortality from cervical or thoracic sites of anastomoses would not be different. METHODS: We used the American College of Surgeons National Surgical Quality Improvement Program database to identify patients who underwent esophagectomy for lower esophageal or gastroesophageal (GE) junction malignancies from 2005 to 2010. Patients were categorized as having either a cervical or thoracic anastomosis based on CPT codes. RESULTS: There were 601 (66%) cervical and 308 (34%) thoracic anastomoses. Cervical anastomoses were associated with greater than 2 units of blood transfusion in a higher proportion of patients (10% vs. 3%, P = 0.001), and higher superficial surgical site infections (13% vs. 7%, P = 0.003). There were no difference in rates of organ/space infections (6% vs. 7%, P = 0.70), overall morbidity (38% vs. 39%, P = 0.84), or mortality (3% vs. 4%, P = 0.34). Median length of stay was similar (11.5 days cervical vs. 11 days thoracic, P = 0.89), even among patients with organ/space infections (18 days cervical vs. 21 days thoracic, P = 0.49). On multivariate analysis thoracic anastomosis was not a significant predictor of increased overall morbidity (OR 1.13: 95%CI 0.83-1.54). CONCLUSION: After esophagectomy, the site of anastomosis does not predict an increased risk of perioperative morbidity or mortality.

Extremity soft tissue tumor surgery by surgical specialty: a comparison of case volume among oncology and non-oncology-designated surgeons.

INTRODUCTION: We sought to characterize the extent of extremity soft tissue tumor (ESTT) resections among surgical specialties, hypothesizing that substantial variation exists in the number of ESTT resections performed by specialty. METHODS: We queried the UHC-AAMC database for data from 85 institutions for years 2007-2009. We abstracted data on total number of musculoskeletal (MSK) procedures, number of subcutaneous (SQ), deep, and malignant ESTT resections, and anatomic site of resection. Data were available for 4,682 practitioners including the following specialties: general surgery (GS, N = 2,195), plastic surgery (PS, N = 792), surgical oncology (SO, N = 533), general orthopedics (GO, N = 1,079), and orthopedic oncology (OO, N = 83). RESULTS: The mean number of all MSK procedures performed per year was 19.0 ± 2.3 GS, 179.6 ± 3.0 PS, 32.4 ± 6.2 SO, 798.6 ± 115.4 GO, and 482.9 ± 6.5 OO (P = 0.001). SQ ESTT resections per year were similar among specialties (1.7 ± 0.3 GS, 2.7 ± 0.3 PS, 2.4 ± 0.4 SO, 1.7 ± 0.5 GO, 4.7 ± 0.2 OO), while deep and malignant resections were more likely performed by OO (combined deep and malignant: 0.9 ± 0.1 GS, 2.0 ± 0.4 PS, 9.9 ± 0.6 SO, 5.8 ± 0.3 GO, and 63.6 ± 8.1 OO, P = 0.001). Adjusting for number of physicians in the database, of the total deep and malignant ESTT resections, 9.4% were performed by GS, 7.7% by PS, 26.0% by SO, 30.8% by GO, and 26.0% by OO. CONCLUSION: Nearly 50% of deep and malignant ESTT resections are performed by non-oncology-designated surgeons. Approximately 17% are performed by practitioners who complete an average of one to two of these procedures per year. These findings may have significant implications for quality of care in soft tissue tumor surgery.

Do radiation use disparities influence survival in patients with advanced breast cancer?

BACKGROUND: The authors previously identified racial/ethnic disparities in the use of radiation therapy (RT) in patients with advanced breast cancer (BC). They hypothesized that disparities in the use of RT were associated with survival differences favoring white patients. METHODS: The authors used the Surveillance, Epidemiology, and End Results database to identify white, black, Hispanic, and Asian patients with BC associated with ≥ 10 metastatic lymph nodes diagnosed between 1988 and 2005. Multivariate analyses of overall survival (OS) and disease-specific survival (DSS) assessed age, sex, race, tumor size, histology, estrogen receptor status, progesterone receptor status, RT, and type of surgery. The authors further stratified for use of RT and type of surgery. Risk of mortality was reported as hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: Of 15,895 patients with advanced BC, 12,653 met entry criteria. On multivariate analysis, RT was associated with a decreased risk of all-cause (HR, 0.78; 95% CI 0.74-0.83; P < .001) and disease-specific (HR, 0.81; 95% CI, 0.76-0.86; P < .001) mortality; black race was associated with an increased risk of all-cause (HR, 1.54; 95% CI, 1.42-1.68; P < .001) and disease-specific (HR, 1.53; 95% CI, 1.39-1.68; P < .001) mortality. After stratifying by type of surgery and use of RT, blacks demonstrated poorer survival than their white counterparts, regardless of surgery type or receipt of RT. CONCLUSIONS: Only black patients had poorer OS and DSS relative to whites. When stratified by type of surgery and use of RT, blacks continued to demonstrate poorer survival. This survival disparity is unlikely to be because of lack of RT.

Influence of specialty and clinical experience on treatment sequencing in the multimodal management of soft tissue extremity sarcoma.

PURPOSE: Although multimodal management of extremity soft tissue sarcoma (STS) is the standard of care, considerable variation exists in the sequencing of radiotherapy (RT) or chemotherapy (CT). Our goal was to identify factors responsible for this variation. METHODS: Members of specialty societies with an interest in STS were emailed a questionnaire about multimodal treatment of STS. Survey responses were scored on a 5-point Likert scale (1 = always preoperative and 5 = always postoperative) and analyzed by specialty, years in practice, and percentage of practice consisting of STS. RESULTS: The questionnaire was completed by 320 (65%) of 490 physicians, including medical oncologists (18%), radiation oncologists (8%), orthopedic oncologists (22%), surgical oncologists (45%), and others (7%). Respondents were evenly split on the use of neoadjuvant RT (mean 3.03 ± 0.06) and showed a slight preference for neoadjuvant CT (2.89 ± 0.06). Radiation oncologists (2.52 ± 0.18), physicians with a >75% STS practice (2.58 ± 0.17), and those in practice <5 years (2.79 ± 0.12) preferred neoadjuvant RT. Neoadjuvant CT was preferred by orthopedic oncologists (2.62 ± 0.12) and physicians with >75% STS practice (2.51 ± 0.16). Factors influencing the choice for neoadjuvant RT were well-defined treatment volume, increased acute morbidity, and decreased late morbidity, while for CT, they were in-situ disease monitoring and early treatment of micrometastases. CONCLUSIONS: Treatment sequencing in STS is influenced by specialty and clinical experience, with no clear consensus. These patterns may reflect the recent trend toward regionalization of STS care.

Utilization of lymph node assessment in patients with ductal carcinoma in situ treated with lumpectomy.

BACKGROUND: Lymph node assessment (LNA), including sentinel lymph node biopsy (SLNB), is controversial in patients undergoing lumpectomy for ductal carcinoma in situ (DCIS). Our goal was to identify factors influencing LNA in these patients. METHODS: We used the Surveillance Epidemiology and End Results database to identify all female patients treated with lumpectomy for DCIS from 2000 to 2008. We excluded patients without histologic confirmation, including those diagnosed at autopsy, and those for whom LNA status was unknown. Multivariate logistic regression models predicted use of LNA. Likelihood of undergoing LNA was reported as odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: A total of 62,935 patients met inclusion criteria. Approximately 15% (N = 9726) had regional LNA at the time of lumpectomy, with 12% (N = 7294) undergoing SLNB. Factors associated with an increased likelihood of undergoing LNA included treatment in the Southeast (OR 1.25, CI 1.04-1.22); treatment after the year 2000; grade II (OR 2.71, CI 2.48-2.96), III (OR 2.38, CI 2.18-2.59), or IV (OR 2.61, CI 2.37-2.88) tumors; DCIS size 2-5 cm (OR 1.49, CI 1.37-1.62) or >5 cm (OR 2.16, CI 1.78-2.61), and estrogen receptor-negative (OR 1.29, CI 1.16-1.43) or progesterone receptor-negative (OR 1.22, CI 1.11-1.33) tumors. Factors associated with a decreased likelihood of undergoing regional LNA were age >60 (OR 0.83, CI 0.79-0.87), and Asian race (OR 0.88, CI 0.81-0.96). Factors predictive of LNA in general were also predictive of SLNB. CONCLUSIONS: Although LNA is controversial for patients undergoing lumpectomy for DCIS, it is used in 15% of cases. Further research establishing for the benefit of LNA in DCIS patients treated with lumpectomy is needed.

Histologic type predicts survival in patients with retroperitoneal soft tissue sarcoma.

BACKGROUND: Histologic grade, completeness of resection, and presence of metastases are traditionally regarded as the primary factors in predicting survival for retroperitoneal soft tissue sarcoma (RPSTS). We sought to examine the importance of histologic type as a prognostic factor among patients with RPSTS. METHODS: We identified 2337 cases of RPSTS in the Surveillance, Epidemiology, and End Results (SEER) database from 1988 to 2004. After excluding 273 cases of age <18, identification by autopsy only, or absence of histologic confirmation, we arrived at a final study cohort of 2064 patients. Overall survival (OS) and disease-specific survival (DSS) were estimated using the Kaplan-Meier method. Multivariate analysis was performed using a Cox proportional hazards model, adjusting for age, gender, race, histologic type, histologic grade, tumor size, extent of resection, and SEER summary stage. RESULTS: Among 33 histologic types, leiomyosarcoma (28.7%), well-differentiated/dedifferentiated liposarcoma (20.3%), liposarcoma not otherwise specified (NOS) (11.9%), malignant fibrous histiocytoma (MFH-11.0%), and sarcoma NOS (10.7%) were the most prevalent. Grade distribution was low, 24.2%; intermediate, 16%; high 34.3%, and unknown, 25.5%. Surgery was performed in 85.8%, and radiotherapy was administered to 22.8%. With a median follow-up of 38 mo, median OS was 78, 35, 25, 18, and 10 mo for liposarcoma, leiomyosarcoma, other histologies, MFH, and sarcoma NOS, respectively (P < 0.0001). Median DSS was 120, 53, not reached, 30, and 13 mo for liposarcoma, leiomyosarcoma, other histologies, MFH, and sarcoma NOS, respectively (P < 0.0001). On multivariate analysis, histologic type was associated with statistically significant differences in both OS and DSS. CONCLUSIONS: Histologic type is an important predictor of survival in RPSTS.

Predicting survival for well-differentiated liposarcoma: the importance of tumor location.

BACKGROUND: Although well-differentiated liposarcoma (WD Lipo) is a low grade neoplasm with a negligible risk of metastatic disease, it can be locally aggressive. We hypothesized that survival for WD Lipo varies significantly based on tumor location. METHODS: We identified 1266 patients with WD Lipo in the Surveillance, Epidemiology, and End Results database from 1988-2004. After excluding patients diagnosed by autopsy only, those lacking histologic confirmation, those lacking data on tumor location, and those with metastatic disease or unknown staging information, we arrived at a final study cohort of 1130 patients. Clinical, pathologic, and treatment variables were analyzed for their association with overall survival (OS) and disease-specific survival (DSS) using Kaplan-Meier analysis and Cox proportional hazards multivariate models. RESULTS: Mean age was 61 y (± 14.6), 72.2% were white, and 60.4% were male. Eighty-one percent of patients were treated with surgical therapy alone, 4.6% were treated with radiotherapy (RT) alone, and 12.9% were treated with both surgery and RT. Extremity location was most common (41.6%), followed by trunk (29%), retroperitoneal/intra-abdominal (RIA, 21.6%), thorax (4.2%), and head/neck (3.6%). With a median follow-up of 45 mo, median OS was 115 mo (95% confidence interval [CI] 92-138 mo) for RIA tumors compared to not reached for other tumor locations (P = 0.002). On multivariate analysis, increasing age and RIA location both predicted worse OS and DSS while tumor size, race, sex, receipt of RT, and Surveillance, Epidemiology, and End Results (SEER) stage did not. Tumor size became a significant predictor of worse DSS, but not OS, only when site, SEER stage, and extent of resection were removed from the multivariate model. Non-RIA locations, including extremity, experienced statistically similar OS, but 5-y DSS for trunk location was intermediate [92.3%, (95% CI 88.5%-96.1%) compared with 98.0% (95% CI, 96.2%-99.8%) for extremity and 86.6 (95% CI 81.1%-92.1%) for RIA, P < 0.001]. CONCLUSIONS: Among patients with WD Lipo, RIA location is associated with significantly worse outcomes independent of tumor size. Future studies should focus on the anatomic and biologic reasons for these differences.

Geographic variation in utilization of sentinel lymph node biopsy for intermediate thickness cutaneous melanoma.

BACKGROUND AND OBJECTIVES: Sentinel lymph node biopsy (SLNB) is the standard for evaluation of the draining lymphatic basin for intermediate thickness melanoma. Despite this, SLNB has not been uniformly adopted. We hypothesized that there are geographic areas of the United States where patients are less likely to receive SLNB. METHODS: The Surveillance, Epidemiology, and End Results database was queried for patients who underwent surgery for intermediate thickness cutaneous melanoma (Breslow thickness 1.00-4.00 mm) from 2004 to 2008. Patients were categorized according to geographic area based on the reporting registry. Multivariate logistic regression models predicted use of SLNB. RESULTS: Entry criteria were met by 8957 patients. On multivariate analysis, patients from the South were less likely (OR 0.54, CI 0.48-0.62; P < 0.001) to receive a SLNB. Additional factors associated with a decreased likelihood of receiving a SLNB included head and neck primary tumor site, high or unknown serum LDH, Asian, Hispanic, Native American or unknown race, and increasing age. CONCLUSIONS: Patients from the South were less likely to receive a SLNB for an intermediate thickness cutaneous melanoma. This report of geographic disparities on a national level should be confirmed locally to better guide interventions aimed at eliminating these disparities.

Identification of the Collagen Types Essential for Mammalian Breast Acinar Structures.

Modeling human breast tissue architecture is essential to study the pathophysiological conditions of the breast. We report that normal mammary epithelial cells grown in human breast extracellular matrix (ECM) hydrogel formed acini structurally similar to those of human and pig mammary tissues. Type I, II, III and V collagens were commonly identified in human, pig, and mouse breast ECM. Mammary epithelial cells formed acini on certain types or combinations of the four collagens at normal levels of breast tissue elasticity. Comparison of the collagen species in mouse normal breast and breast tumor ECM revealed common and distinct sets of collagens within the two types of tissues. Elevated expression of collagen type I alpha 1 chain (Col1a1) was found in mouse and human breast cancers. Collagen type XXV alpha 1 chain (Col25a1) was identified in mouse breast tumors but not in normal breast tissues. Our data provide strategies for modeling human breast pathophysiological structures and functions using native tissue-derived hydrogels and offer insight into the potential contributions of different collagen types in breast cancer development.

Nomogram to predict risk of 30-day morbidity and mortality for patients with disseminated malignancy undergoing surgical intervention.

OBJECTIVE: To estimate individual risk of 30-day surgical morbidity and mortality after surgical intervention for patients with disseminated malignancy (DMa). BACKGROUND: Patients with DMa frequently require surgical consultation for palliative operations. Although these patients are at high risk for surgical morbidity and mortality, limited data exist allowing individual risk stratification. METHODS: Using the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) from 2005 to 2007, we identified 7447 patients with DMa. Each of the 53 preoperative ACS NSQIP variables was analyzed to assess risk of morbidity and mortality. Logistic regression models were developed using stepwise model selection and generalized additive models. Covariates were evaluated for nonlinearity and interactions among variables. We constructed nomograms utilizing clinically and statistically significant covariates to predict 30-day risk of morbidity and mortality. RESULTS: Overall 30-day unadjusted morbidity and mortality rates were 28.3% and 8.9%, respectively. Mortality rates reached 18.4% for vascular procedures and 27.9% for emergent operations. Increasing age, impaired functional status, Do-Not-Resuscitate status, impaired respiratory function, ascites, hypoalbuminema, elevated creatinine, and abnormal WBC were all significant predictors (P < 0.0001) of increased morbidity and mortality on multivariate analysis. Nomograms to predict individual 30-day risk of complications and death based on preoperative factors were developed and validated by bootstrapping. Concordance indices were 0.704 and 0.861 for morbidity and mortality, respectively. CONCLUSIONS: Surgical intervention among patients with DMa is associated with substantial morbidity and mortality. We have constructed nomograms to predict individual risk of 30-day morbidity and mortality. These have significant implications for surgical decision-making in this group of patients.

Metaplastic breast cancer: to radiate or not to radiate?

BACKGROUND: The role of radiation therapy (RT) is unclear for metaplastic breast cancer (MBC). We hypothesized that RT would improve overall survival (OS) and disease-specific survival (DSS). MATERIALS AND METHODS: We used the Surveillance, Epidemiology, and End Results (SEER) database to identify MBC patients diagnosed from 1988 to 2006. Univariate analyses of patient, tumor, and treatment-specific factors on OS and DSS were performed using the Kaplan-Meier method and differences among survival curves assessed via log rank. Variables assessed included patient age, race/ethnicity, histologic subtype, tumor grade, T stage, N stage, M stage, hormone receptor status, surgery type, and use of RT. Cox proportional hazards models used all univariate covariates. Risks of mortality were reported as hazard ratios (HR) with 95% confidence intervals (95% CI); significance was set at P ≤ 0.05. RESULTS: Among 1501 patients, RT was given to 580 (38.6%). Ten-year OS and DSS were 53.2, and 68.3%, respectively. In the overall analysis, RT provided an OS (HR 0.64; 95% CI, 0.51-0.82; P < 0.001) and DSS (HR 0.74; CI, 0.56-0.96; P < 0.03) benefit. When patients were stratified according to type of surgery, RT provided an OS but not a DSS benefit to lumpectomy (HR 0.51; CI, 0.32-0.79, P < 0.01) and mastectomy patients (HR 0.67; CI, 0.49-0.90; P < 0.01). CONCLUSIONS: Our findings support the use of RT for patients with MBC following lumpectomy or mastectomy. These retrospective findings should be confirmed in a prospective clinical trial.

Tumor location predicts survival in cutaneous head and neck melanoma.

BACKGROUND: Prior studies documented poorer outcomes in patients with cutaneous head and neck melanoma (CHNM) relative to those with melanoma at other sites. We evaluated survival differences attributable to tumor location in patients with CHNM. METHODS: We queried the Surveillance, Epidemiology, and End Results (SEER) database for patients undergoing surgery for CHNM from 1988 to 2006, excluding patients without biopsy-proven diagnoses, those diagnosed at autopsy, and patients with distant metastases. Using the Kaplan-Meier method, we assessed patient, tumor, and treatment-specific factors on overall survival (OS) and melanoma specific survival (MSS). Cox proportional hazards models assessed the role of tumor location (ear, eyelid, face, lip, scalp/neck) on OS and MSS, while controlling for patient age, gender, race, tumor thickness, tumor ulceration, lymph node status, histologic subtype, type of surgery, and use of radiation. Risks of overall and melanoma-specific mortality were reported as hazard ratios (HR) with 95% confidence intervals (CI). RESULTS: Among 27,097 patients, 10-y rates of OS and MSS were 56.1% and 84.7%, respectively. On multivariate analysis, scalp/neck primary site was associated with an increased risk of overall (HR 1.20, CI 1.14-1.26; P < 0.001) and melanoma-specific mortality (HR 1.64, CI 1.49-1.80, P < 0.001) relative to melanomas of the face. Tumors of the lip had poorer MSS (HR 1.55; CI 1.05-2.28, P = 0.03) but not OS (HR 1.03, CI 0.80-1.34; P = 0.80). CONCLUSIONS: Patients with melanomas of the scalp/neck have poorer OS and MSS and those with lip melanomas have poorer MSS. These anatomic areas should not be overlooked when performing skin examinations.