Oncology hospitalist impact on hospice utilization.

BACKGROUND: Unplanned hospitalizations among patients with advanced cancer are often sentinel events prompting goals of care discussions and hospice transitions. Late referrals to hospice, especially those at the end of life, are associated with decreased quality of life and higher total health care costs. Inpatient management of patients with solid tumor malignancies is increasingly shifting from oncologists to oncology hospitalists. However, little is known about the impact of oncology hospitalists on the timing of transition to hospice. OBJECTIVE: To compare hospice discharge rate and time to hospice discharge on an inpatient oncology service led by internal medicine-trained hospitalists and a service led by oncologists. METHODS: At Smilow Cancer Hospital, internal medicine-trained hospitalists were integrated into one of two inpatient medical oncology services allowing comparison between the new, hospitalist-led service (HS) and the traditional, oncologist-led service (TS). Discharges from July 26, 2021, through January 31, 2022, were identified from the electronic medical record. The odds ratio for discharge disposition by team was calculated by logistic regression using a multinomial distribution. Adjusted length of stay before discharge was assessed using multivariable linear regression. RESULTS: The HS discharged 47/400 (11.8%) patients to inpatient hospice, whereas the TS service discharged 18/313 (5.8%), yielding an adjusted odds ratio of 1.94 (95% CI, 1.07-3.51; p = .03). Adjusted average length of stay before inpatient hospice disposition was 6.83 days (95% CI, 4.22-11.06) for the HS and 16.29 days (95% CI, 7.73-34.29) for the TS (p = .003). CONCLUSIONS: Oncology hospitalists improve hospice utilization and time to inpatient hospice referral on an inpatient medical oncology service. PLAIN LANGUAGE SUMMARY: Patients with advanced cancer are often admitted to the hospital near the end of life. These patients generally have a poor chance of long-term survival and may prefer comfort-focused care with hospice. In this study, oncology hospitalists discharged a higher proportion of patients to inpatient hospice with less time spent in the hospital before discharge.

InterMEL: An international biorepository and clinical database to uncover predictors of survival in early-stage melanoma.

INTRODUCTION: We are conducting a multicenter study to identify classifiers predictive of disease-specific survival in patients with primary melanomas. Here we delineate the unique aspects, challenges, and best practices for optimizing a study of generally small-sized pigmented tumor samples including primary melanomas of at least 1.05mm from AJTCC TNM stage IIA-IIID patients. We also evaluated tissue-derived predictors of extracted nucleic acids' quality and success in downstream testing. This ongoing study will target 1,000 melanomas within the international InterMEL consortium. METHODS: Following a pre-established protocol, participating centers ship formalin-fixed paraffin embedded (FFPE) tissue sections to Memorial Sloan Kettering Cancer Center for the centralized handling, dermatopathology review and histology-guided coextraction of RNA and DNA. Samples are distributed for evaluation of somatic mutations using next gen sequencing (NGS) with the MSK-IMPACTTM assay, methylation-profiling (Infinium MethylationEPIC arrays), and miRNA expression (Nanostring nCounter Human v3 miRNA Expression Assay). RESULTS: Sufficient material was obtained for screening of miRNA expression in 683/685 (99%) eligible melanomas, methylation in 467 (68%), and somatic mutations in 560 (82%). In 446/685 (65%) cases, aliquots of RNA/DNA were sufficient for testing with all three platforms. Among samples evaluated by the time of this analysis, the mean NGS coverage was 249x, 59 (18.6%) samples had coverage below 100x, and 41/414 (10%) failed methylation QC due to low intensity probes or insufficient Meta-Mixed Interquartile (BMIQ)- and single sample (ss)- Noob normalizations. Six of 683 RNAs (1%) failed Nanostring QC due to the low proportion of probes above the minimum threshold. Age of the FFPE tissue blocks (p<0.001) and time elapsed from sectioning to co-extraction (p = 0.002) were associated with methylation screening failures. Melanin reduced the ability to amplify fragments of 200bp or greater (absent/lightly pigmented vs heavily pigmented, p<0.003). Conversely, heavily pigmented tumors rendered greater amounts of RNA (p<0.001), and of RNA above 200 nucleotides (p<0.001). CONCLUSION: Our experience with many archival tissues demonstrates that with careful management of tissue processing and quality control it is possible to conduct multi-omic studies in a complex multi-institutional setting for investigations involving minute quantities of FFPE tumors, as in studies of early-stage melanoma. The study describes, for the first time, the optimal strategy for obtaining archival and limited tumor tissue, the characteristics of the nucleic acids co-extracted from a unique cell lysate, and success rate in downstream applications. In addition, our findings provide an estimate of the anticipated attrition that will guide other large multicenter research and consortia.

Outcomes on an inpatient oncology service after the introduction of hospitalist comanagement.

BACKGROUND: Smilow Cancer Hospital (SCH) introduced hospitalist comanagement to the inpatient oncology service to address long lengths of stay and oncologist burnout. OBJECTIVE: To determine the impact of hospitalists on inpatient quality outcomes and oncologist experience. INTERVENTIONS: Hospitalists were introduced to one of two inpatient oncology services at SCH. Patients were assigned to teams equally based on capacity. Outcomes on the oncologist-led, traditional service (TS) were compared with outcomes on the hospitalist service (HS) 6 months after program implementation. MAIN OUTCOMES AND MEASURES: Outcomes included patient volume, length of stay (LOS), early discharge, discharge time, and 30-day readmission rate. Mixed linear or Poisson models that accounted for multiple admissions during the study duration were used. Oncologist experience was measured by survey. RESULTS: During the study period, there were 713 discharges, 400 from the HS and 313 from the TS (p = .0003). There was no difference in demographics or severity of illness (SOI) between services. Following adjustment for age, sex, race/ethnicity, cancer type, and discharge disposition, the average LOS was 4.71 on the HS and 5.47 on the TS (p = .01). Adjusted early discharge rate was 6.22% on the HS and 2.06% on the TS (p = .01). Adjusted mean discharge time was 3:45 p.m. on HS and 4:16 p.m. on TS (p = .009). There was no difference in readmission rates. Oncologists reported less stress (p = .001) and a better ability to manage competing responsibilities (p < .0001) while working on the HS. CONCLUSIONS: Hospitalist comanagement significantly improved LOS, early discharge, time of discharge, and oncologist experience without an increase in 30-day readmissions.

APOBEC mutagenesis and selection for NFE2L2 contribute to the origin of lung squamous-cell carcinoma.

Lung squamous-cell carcinoma originates as a consequence of oncogenic molecular variants arising from diverse mutagenic processes such as tobacco, defective homologous recombination, aging, and cytidine deamination by APOBEC proteins. Only some of the many variants generated by these processes actually contribute to tumorigenesis. Therefore, molecular investigation of mutagenic processes such as cytidine deamination by APOBEC should also determine whether the mutations produced by these processes contribute substantially to the growth and survival of cancer. Here, we determine the processes that gave rise to mutations of 681 lung squamous-cell carcinomas, and quantify the probability that each mutation was the product of each process. We then calculate the contribution of each mutation to increases in cellular proliferation and survival. We performed in vitro experiments to determine cytidine deamination activity of APOBEC3B against oligonucleotides corresponding with genomic sequences that give rise to variants of high cancer effect size. The largest APOBEC-related cancer effects are attributable to mutations in PIK3CA and NFE2L2. We demonstrate that APOBEC effectively deaminates NFE2L2 at the locations that confer high cancer effect. Overall, we demonstrate that APOBEC activity can lead to mutations in NFE2L2 that have large contributions to cancer cell growth and survival, and that NFE2L2 is an attractive potential target for therapeutic intervention.

Oncologic emergencies and urgencies: A comprehensive review.

Patients with advanced cancer generate 4 million visits annually to emergency departments (EDs) and other dedicated, high-acuity oncology urgent care centers. Because of both the increasing complexity of systemic treatments overall and the higher rates of active therapy in the geriatric population, many patients experiencing acute decompensations are frail and acutely ill. This article comprehensively reviews the spectrum of oncologic emergencies and urgencies typically encountered in acute care settings. Presentation, underlying etiology, and up-to-date clinical pathways are discussed. Criteria for either a safe discharge to home or a transition of care to the inpatient oncology hospitalist team are emphasized. This review extends beyond familiar conditions such as febrile neutropenia, hypercalcemia, tumor lysis syndrome, malignant spinal cord compression, mechanical bowel obstruction, and breakthrough pain crises to include a broader spectrum of topics encompassing the syndrome of inappropriate antidiuretic hormone secretion, venous thromboembolism and malignant effusions, as well as chemotherapy-induced mucositis, cardiomyopathy, nausea, vomiting, and diarrhea. Emergent and urgent complications associated with targeted therapeutics, including small molecules, naked and drug-conjugated monoclonal antibodies, as well as immune checkpoint inhibitors and chimeric antigen receptor T-cells, are summarized. Finally, strategies for facilitating same-day direct admission to hospice from the ED are discussed. This article not only can serve as a point-of-care reference for the ED physician but also can assist outpatient oncologists as well as inpatient hospitalists in coordinating care around the ED visit.

Impact of a Dedicated Cancer Urgent Care Center on Acute Care Utilization.

PURPOSE: Acute care imposes a significant burden on patients and cancer care costs. We examined whether an advanced practice provider-driven, cancer-specific urgent care center embedded within a large tertiary academic center decreased acute care use among oncology patients on active therapy. MATERIALS AND METHODS: We conducted a quasi-experimental study anchored around the Oncology Extended Care Clinic (OECC) opening date. We evaluated two parallel 4-month periods: a post-OECC period that followed a 5-month run-in phase, and the identical calendar period 1 year earlier. Our primary outcomes included all emergency department (ED) presentations and hospital admissions during the 3-month window following the index provider visit. We used Poisson models to calculate absolute pre-OECC v post-OECC rate differences. RESULTS: Our cohort included 2,095 patients in the pre-OECC period and 2,188 in the post-OECC period. We identified 32.6 ED visits/100 patients and 41.2 hospitalizations/100 patients in the pre-OECC period, versus 28.2 ED visits/100 patients and 26.1 hospitalizations/100 patients post-OECC. After adjusting for age, sex, race and ethnicity, and practice location, we observed a significant decrease of 4.6 ED visits/100 patients during the post-OECC period (95% CI, -8.92/100 to -0.28/100; P = .04) compared with the pre-OECC period. There was no significant association between the OECC opening and hospitalization rate (rate difference: -3.29 admissions/100 patients; 95% CI, -8.24/100 to 1.67/100; P = .19). CONCLUSION: Establishing a cancer-specific urgent care center was significantly associated with a modest decrease in emergency room utilization but not with hospitalization rate. Barriers included clinic capacity, patient awareness, and physician comfort with advanced practice provider autonomy. Optimizing workflow and standardizing clinical pathways can create benchmarks useful for value-based payments.

Genomic and evolutionary classification of lung cancer in never smokers.

Lung cancer in never smokers (LCINS) is a common cause of cancer mortality but its genomic landscape is poorly characterized. Here high-coverage whole-genome sequencing of 232 LCINS showed 3 subtypes defined by copy number aberrations. The dominant subtype (piano), which is rare in lung cancer in smokers, features somatic UBA1 mutations, germline AR variants and stem cell-like properties, including low mutational burden, high intratumor heterogeneity, long telomeres, frequent KRAS mutations and slow growth, as suggested by the occurrence of cancer drivers' progenitor cells many years before tumor diagnosis. The other subtypes are characterized by specific amplifications and EGFR mutations (mezzo-forte) and whole-genome doubling (forte). No strong tobacco smoking signatures were detected, even in cases with exposure to secondhand tobacco smoke. Genes within the receptor tyrosine kinase-Ras pathway had distinct impacts on survival; five genomic alterations independently doubled mortality. These findings create avenues for personalized treatment in LCINS.

Biomarkers for prognosis in pancreatic neuroendocrine tumors.

Pancreatic neuroendocrine tumors (PNETs) encompass a diverse group of malignancies marked by histological heterogeneity and highly variable clinical outcomes. We performed a systematic review on potential prognostic biomarkers in PNETs by searching the PubMed database. A total of 472 manuscripts were reviewed in detail, of which 52 multivariate studies met the inclusion criteria proposed by the Reporting Recommendations for Tumor Marker Prognostic Studies. These altogether analyzed 53 unique targets, and 36 of them were statistically associated with survival.

Microsatellitosis in Patients with Melanoma.

BACKGROUND: Microsatellitosis (mS) in melanoma has been considered a marker of unfavorable tumor biology, leading to the current American Joint Committee on Cancer staging of IIIB/C/D disease, despite few investigative studies of this entity limited by the small sample sizes and incomplete nodal microstaging. We sought to better characterize outcomes and prognostic factors in a multi-institutional cohort of patients with mS and nodal microstaging. METHODS: The Sentinel Lymph Node Working Group cohort included 414 mS patients who underwent sentinel lymph node (SLN) biopsy. Cox regression analysis was used to evaluate the prognostic significance of established clinicopathologic characteristics. Melanoma-specific survival (MSS) of patients with mS was compared with 3002 similarly staged patients from the Surveillance, Epidemiology, and End Results (SEER) Program registry. RESULTS: The median age of the mS cohort was 64.9 years; 39.6% were female. Median thickness was 3 mm, 40.6% of cases were ulcerated, and the SLN positivity rate was 46.7%. Increasing thickness, male sex, and SLN positivity were significantly associated with poorer MSS. Stage IIIB/C/D 5-year MSS rates were 86.3% (95% confidence interval [CI] 79.4-93.3%), 54.1% (95% CI 45.4-59.7%), and 44.2% (95% CI 25.4-63.0%), respectively. MSS survival for the stage IIIB mS cohort was significantly better than a similarly staged SEER cohort (5-year MSS of 70.1%, 95% CI 66.0-74.2%), while no significant difference was observed for the stage IIIC or D cohorts. CONCLUSIONS: SLN metastases are common and are a significant prognostic factor in patients with mS. Survival in stage IIIB patients with mS was considerably more favorable than their stage would otherwise suggest, which has important implications for decisions regarding adjuvant therapy for patients with mS.

Intratumoral multinucleated giant cells are not a prognostic pathologic feature in cutaneous melanoma.

BACKGROUND: Histopathologic diagnostic features such as tumor thickness, ulceration, mitoses, microsatellitosis and nodal metastases are principal pathologic staging components of cutaneous melanomas. We chose to focus on evaluating the presence of multinucleated giant cells in microscopic sections as a putative novel prognosticating diagnostic feature of melanoma. METHODS: We assembled a retrospective cohort comprised of 562 cases of melanoma. We annotated each case for a multitude of known clinicopathologic variables to allow robust statistical evaluation of our cohort. RESULTS: Only 37 cases (6.6%) exhibited the multinucleated giant cells phenotype. Virtually all multinucleated giant cells were localized in the reticular dermis. Of interest, melanomas with multinucleated giant cells were roughly twice more likely to occur on head and neck sites (p = 0.04). Melanomas with multinucleated giant cells phenotype had both comparable melanoma recurrence (p = 0.12) and similar melanoma-specific mortality when compared with melanomas without multinucleated giant cells phenotype (p = 0.26). CONCLUSION: Despite prior anecdotal reports possibly linking multinucleated giant cells phenotype to more aggressive clinical course, we find that melanomas with multinucleated giant cells phenotype is not associated with shorter survival.

Red meat and fruit intake is prognostic among patients with localized cutaneous melanomas more than 1mm thick.

BACKGROUND: As the 10-year mortality for localized cutaneous melanoma more than 1.00 mm thick approaches 40% following complete resection, non-therapeutic interventions that can supplement recommended active surveillance are needed. Although guidelines recommending nutrition, physical activity and tobacco cessation for cancer survivors have been published, data describing their associations with melanoma survivorship are lacking. METHODS: Analysis of modifiable lifestyle behaviors collected on the 249 cases with melanomas more than 1.00 mm thick enrolled in the Connecticut Case-Control Study of Skin Self-Examination study was conducted. Independent associations with melanoma-specific survival were evaluated through Cox proportional hazards modeling adjusting for age, gender, Breslow thickness, ulceration and the presence of microsatellites. Independently significant variables were then combined into a single model and backwards elimination was employed until all remaining variables were significant at p<0.05. RESULTS: Following adjustment for age, Breslow thickness and anatomic site of the index melanoma, daily fruit consumption was associated with improved melanoma-specific survival (HR=0.54; 95% CI: 0.34-0.86) whereas at least weekly red meat consumption was associated with worse outcomes (HR=1.84; 95% CI: 1.02-3.30). Natural red (HR=0.44; 95% CI: 0.22-0.88) or blond (HR=0.52; 95% CI: 0.29-0.94) hair were also favorably prognostic. Higher fish consumption was of borderline significance for improved survival only when considered independently (HR=0.65; 95% CI: 0.40-1.05); no association was seen following adjustment for red meat and fruit consumption (p>0.10). CONCLUSIONS: Dietary choices at the time of diagnosis are associated with melanoma-specific survival in patients with melanomas more than 1.00 mm thick. Further validation of our findings in larger cohorts with repeated post-diagnostic measures is warranted to further evaluate whether dietary modification during the survivorship period can improve melanoma-specific survival.

Learning curve to lymph node resection in minimally invasive esophagectomy for cancer.

OBJECTIVE: Minimally invasive esophagectomy (MIE) is a safe alternative to open approaches, yet the impact of the minimally invasive approach on oncologic efficacy is unclear. The objectives of the current study were to compare lymph node yields and surgical margins during a single-surgeon series to examine the learning curve to oncologic aspects of MIE. METHODS: A retrospective review of a prospectively maintained institutional database was performed. The sequential MIE experience for esophageal cancer was subcategorized into terciles (first 25 MIEs as early, next 24 as middle, and most recent 24 as later). RESULTS: Seventy-three patients underwent MIE for cancer between 2008 and 2013. Complete resections (R0) were performed in 71 cases (93%), and there were no significant differences in the number of complete resections with negative margins during the MIE experience (P = 0.54). The number of lymph nodes harvested during MIE increased significantly with progressive experience, with a mean of 22, 29, and 28 nodes recovered in the early, middle, and late subgroups, respectively (P = 0.038). On multivariate analysis, only increasing surgeon experience (1.4-fold increase in nodal yield for the latter two thirds relative to the first third, P = 0.0011) and histology of high-grade dysplasia (0.54-fold decrease in nodal yield relative to adenocarcinoma or squamous cell carcinoma, P = 0.025) were significant predictors of lymph node yield. CONCLUSIONS: The ability to execute a complete lymphadenectomy during MIE is affected by surgeon experience and improves over time, plateauing after the first 25 cases.

Marginal and joint distributions of S100, HMB-45, and Melan-A across a large series of cutaneous melanomas.

CONTEXT: The distribution of the standard melanoma antibodies S100, HMB-45, and Melan-A has been extensively studied. Yet, the overlap in their expression is less well characterized. OBJECTIVES: To determine the joint distributions of the classic melanoma markers and to determine if classification according to joint antigen expression has prognostic relevance. DESIGN: S100, HMB-45, and Melan-A were assayed by immunofluorescence-based immunohistochemistry on a large tissue microarray of 212 cutaneous melanoma primary tumors and 341 metastases. Positive expression for each antigen required display of immunoreactivity for at least 25% of melanoma cells. Marginal and joint distributions were determined across all markers. Bivariate associations with established clinicopathologic covariates and melanoma-specific survival analyses were conducted. RESULTS: Of 322 assayable melanomas, 295 (91.6%), 203 (63.0%), and 236 (73.3%) stained with S100, HMB-45, and Melan-A, respectively. Twenty-seven melanomas, representing a diverse set of histopathologic profiles, were S100 negative. Coexpression of all 3 antibodies was observed in 160 melanomas (49.7%). Intensity of endogenous melanin pigment did not confound immunolabeling. Among primary tumors, associations with clinicopathologic parameters revealed a significant relationship only between HMB-45 and microsatellitosis (P = .02). No significant differences among clinicopathologic criteria were observed across the HMB-45/Melan-A joint distribution categories. Neither marginal HMB-45 (P = .56) nor Melan-A (P = .81), or their joint distributions (P = .88), was associated with melanoma-specific survival. CONCLUSIONS: Comprehensive characterization of the marginal and joint distributions for S100, HMB-45, and Melan-A across a large series of cutaneous melanomas revealed diversity of expression across this group of antigens. However, these immunohistochemically defined subclasses of melanomas do not significantly differ according to clinicopathologic correlates or outcome.

ß-catenin signaling controls metastasis in Braf-activated Pten-deficient melanomas.

Malignant melanoma is characterized by frequent metastasis, however, specific changes that regulate this process have not been clearly delineated. Although it is well known that Wnt signaling is frequently dysregulated in melanoma, the functional implications of this observation are unclear. By modulating ß-catenin levels in a mouse model of melanoma that is based on melanocyte-specific Pten loss and Braf(V600E) mutation, we demonstrate that ß-catenin is a central mediator of melanoma metastasis to the lymph nodes and lungs. In addition to altering metastasis, ß-catenin levels control tumor differentiation and regulate both MAPK/Erk and PI3K/Akt signaling. Highly metastatic tumors with ß-catenin stabilization are very similar to a subset of human melanomas. Together these findings establish Wnt signaling as a metastasis regulator in melanoma.

Gestational weight gain and subsequent postpartum weight loss among young, low-income, ethnic minority women.

OBJECTIVE: Document weight change trajectories that lead to gestational weight gain or postpartum weight loss outside clinical recommendations established by the Institute of Medicine. STUDY DESIGN: Women aged 14-25 receiving prenatal care and delivering singleton infants at term (n = 427). Medical record review and 4 structured interviews conducted: second and third trimester, 6- and 12-months postpartum. Longitudinal mixed modeling to evaluate weight change trajectories. RESULTS: Only 22% of participants gained gestational weight within Institute of Medicine guidelines. There were 62% that exceeded maximum recommendations-more common among those overweight/obese (body mass index ≥25.0; P < .0001). 52% retained ≥10 lb 1-year postpartum. Increased weight gain and retention documented among smokers and women with pregnancy-induced hypertension; breastfeeding promoted postpartum weight loss (all P < .02). Body mass index by race interaction suggested healthier outcomes for Latinas (P = .02). CONCLUSION: Excessive pregnancy weight gain and inadequate postpartum weight loss are highly prevalent among young low-income ethnic minority women. Pregnancy and postpartum are critical junctures for weight management interventions.

Biomarkers: the useful and the not so useful--an assessment of molecular prognostic markers for cutaneous melanoma.

Among individuals with localized (Stage I-II) melanoma, stratifying patients by a number of phenotypic variables (e.g., depth of invasion, ulceration) yields a wide range of 10-year melanoma-specific survival rates. With the possible exception of Ki-67, no molecular assessment is routinely used. However, there have been a tremendous number of studies assessing protein expression by immunohistochemistry toward the goal of better prediction of recurrence. In a previous systematic review, which required publication of multivariable prognostic models as a strict inclusion criterion, we identified 37 manuscripts that collectively reported on 62 proteins. Data for 324 proteins extracted from 418 manuscripts did not meet our inclusion criteria for that study, but are revisited here, emphasizing trends of protein expression across either melanocytic lesion progression or gradations of tumor thickness. These identified 101 additional proteins that stratify melanoma, organized according to the Hanahan and Weinberg functional capabilities of cancer.

Melanoma prognostic model using tissue microarrays and genetic algorithms.

PURPOSE: As a result of the questionable risk-to-benefit ratio of adjuvant therapies, stage II melanoma is currently managed by observation because available clinicopathologic parameters cannot identify the 20% to 60% of such patients likely to develop metastatic disease. Here, we propose a multimarker molecular prognostic assay that can help triage patients at increased risk of recurrence. METHODS: Protein expression for 38 candidates relevant to melanoma oncogenesis was evaluated using the automated quantitative analysis (AQUA) method for immunofluorescence-based immunohistochemistry in formalin-fixed, paraffin-embedded specimens from a cohort of 192 primary melanomas collected during 1959 to 1994. The prognostic assay was built using a genetic algorithm and validated on an independent cohort of 246 serial primary melanomas collected from 1997 to 2004. RESULTS: Multiple iterations of the genetic algorithm yielded a consistent five-marker solution. A favorable prognosis was predicted by ATF2 ln(non-nuclear/nuclear AQUA score ratio) of more than -0.052, p21(WAF1) nuclear compartment AQUA score of more than 12.98, p16(INK4A) ln(non-nuclear/nuclear AQUA score ratio) of < or = -0.083, beta-catenin total AQUA score of more than 38.68, and fibronectin total AQUA score of < or = 57.93. Primary tumors that met at least four of these five conditions were considered a low-risk group, and those that met three or fewer conditions formed a high-risk group (log-rank P < .0001). Multivariable proportional hazards analysis adjusting for clinicopathologic parameters shows that the high-risk group has significantly reduced survival on both the discovery (hazard ratio = 2.84; 95% CI, 1.46 to 5.49; P = .002) and validation (hazard ratio = 2.72; 95% CI, 1.12 to 6.58; P = .027) cohorts. CONCLUSION: This multimarker prognostic assay, an independent determinant of melanoma survival, might be beneficial in improving the selection of stage II patients for adjuvant therapy.

The semaphorin 7A receptor Plexin C1 is lost during melanoma metastasis.

The transformation of normal melanocytes, or melanocyte stem cells, to melanoma, is a complex process involving multiple mechanisms. Loss of tumor suppressor proteins, which function as brakes on cell growth, migration, or cell survival, was recognized early on as an important mechanism for initiation and progression of melanoma. Semaphorins and their cognate receptors, Plexins and neuropilins, are involved in neuronal pathfinding, immune function, and tumor progression through effects on blood vessel growth and cell migration. Semaphorin 7A (Sema7A) is a membrane-linked semaphorin that is expressed by human keratinocytes, and we have shown that Sema7A binds to human melanocytes through beta1-integrins and the Plexin C1 receptor. Functional studies showed that Sema7A stimulates cytoskeletal reorganization in human melanocytes, resulting in adhesion and dendrite formation. Downstream targets of Plexin C1 signaling in human melanocytes include cofilin and LIM kinase II, both of which are critical mediators of cell adhesion and migration. In this report, we analyzed the expression of Plexin C1 using immunohistochemistry on sections of primary and matched metastatic lesions from 19 subjects and in a large melanoma tumor microarray. Our data show a significant loss of Plexin C1 in metastatic melanoma compared with primary melanoma, suggesting the possibility that the Plexin C1 receptor is a tumor suppressor protein for melanoma.

Tissue biomarkers for prognosis in cutaneous melanoma: a systematic review and meta-analysis.

In the clinical management of early-stage cutaneous melanoma, it is critical to determine which patients are cured by surgery alone and which should be treated with adjuvant therapy. To assist in this decision, many groups have made an effort to use molecular information. However, although there are hundreds of studies that have sought to assess the potential prognostic value of molecular markers in predicting the course of cutaneous melanoma, at this time, no molecular method to improve risk stratification is part of recommended clinical practice. To help understand this disconnect, we conducted a systematic review and meta-analysis of the published literature that reported immunohistochemistry-based protein biomarkers of melanoma outcome. Three parallel search strategies were applied to the PubMed database through January 15, 2008, to identify cohort studies that reported associations between immunohistochemical expression and survival outcomes in melanoma that conformed to the REMARK criteria. Of the 102 cohort studies, we identified only 37 manuscripts, collectively describing 87 assays on 62 distinct proteins, which met all inclusion criteria. Promising markers that emerged included melanoma cell adhesion molecule (MCAM)/MUC18 (all-cause mortality [ACM] hazard ratio [HR] = 16.34; 95% confidence interval [CI] = 3.80 to 70.28), matrix metalloproteinase-2 (melanoma-specific mortality [MSM] HR = 2.6; 95% CI = 1.32 to 5.07), Ki-67 (combined ACM HR = 2.66; 95% CI = 1.41 to 5.01), proliferating cell nuclear antigen (ACM HR = 2.27; 95% CI = 1.56 to 3.31), and p16/INK4A (ACM HR = 0.29; 95% CI = 0.10 to 0.83, MSM HR = 0.4; 95% CI = 0.24 to 0.67). We further noted incomplete adherence to the REMARK guidelines: 14 of 27 cohort studies that failed to adequately report their methods and nine studies that failed to either perform multivariable analyses or report their risk estimates were published since 2005.