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.

Landscape of mutations in early stage primary cutaneous melanoma: An InterMEL study.

It is unclear why some melanomas aggressively metastasize while others remain indolent. Available studies employing multi-omic profiling of melanomas are based on large primary or metastatic tumors. We examine the genomic landscape of early-stage melanomas diagnosed prior to the modern era of immunological treatments. Untreated cases with Stage II/III cutaneous melanoma were identified from institutions throughout the United States, Australia and Spain. FFPE tumor sections were profiled for mutation, methylation and microRNAs. Preliminary results from mutation profiling and clinical pathologic correlates show the distribution of four driver mutation sub-types: 31% BRAF; 18% NRAS; 21% NF1; 26% Triple Wild Type. BRAF mutant tumors had younger age at diagnosis, more associated nevi, more tumor infiltrating lymphocytes, and fewer thick tumors although at generally more advanced stage. NF1 mutant tumors were frequent on the head/neck in older patients with severe solar elastosis, thicker tumors but in earlier stages. Triple Wild Type tumors were predominantly male, frequently on the leg, with more perineural invasion. Mutations in TERT, TP53, CDKN2A and ARID2 were observed often, with TP53 mutations occurring particularly frequently in the NF1 sub-type. The InterMEL study will provide the most extensive multi-omic profiling of early-stage melanoma to date. Initial results demonstrate a nuanced understanding of the mutational and clinicopathological landscape of these early-stage tumors.

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.

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.

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.

An open source automated tumor infiltrating lymphocyte algorithm for prognosis in melanoma.

Assessment of tumor infiltrating lymphocytes (TILs) as a prognostic variable in melanoma has not seen broad adoption due to lack of standardization. Automation could represent a solution. Here, using open source software, we build an algorithm for image-based automated assessment of TILs on hematoxylin-eosin stained sections in melanoma. Using a retrospective collection of 641 melanoma patients comprising four independent cohorts; one training set (N = 227) and three validation cohorts (N = 137, N = 201, N = 76) from 2 institutions, we show that the automated TIL scoring algorithm separates patients into favorable and poor prognosis cohorts, where higher TILs scores were associated with favorable prognosis. In multivariable analyses, automated TIL scores show an independent association with disease-specific overall survival. Therefore, the open source, automated TIL scoring is an independent prognostic marker in melanoma. With further study, we believe that this algorithm could be useful to define a subset of patients that could potentially be spared immunotherapy.

Novel Methylated DNA Markers Discriminate Advanced Neoplasia in Pancreatic Cysts: Marker Discovery, Tissue Validation, and Cyst Fluid Testing.

OBJECTIVES: Pancreatic cystic lesions (PCLs) may be precancerous. Those likely to harbor high-grade dysplasia (HGD) or pancreatic cancer (PC) are targets for surgical resection. Current algorithms to predict advanced neoplasia (HGD/PC) in PCLs lack diagnostic accuracy. In pancreatic tissue and cyst fluid (CF) from PCLs, we sought to identify and validate novel methylated DNA markers (MDMs) that discriminate HGD/PC from low-grade dysplasia (LGD) or no dysplasia (ND). METHODS: From an unbiased whole-methylome discovery approach using predefined selection criteria followed by multistep validation on case (HGD or PC) and control (ND or LGD) tissues, we identified discriminant MDMs. Top candidate MDMs were then assayed by quantitative methylation-specific polymerase chain reaction on archival CF from surgically resected PCLs. RESULTS: Of 25 discriminant MDMs identified in tissue, 13 were selected for validation in 134 CF samples (21 cases [8 HGD, 13 PC], 113 controls [45 ND, 68 LGD]). A tree-based algorithm using 2 CF-MDMs (TBX15, BMP3) achieved sensitivity and specificity above 90%. Discrimination was significantly better by this CF-MDM panel than by mutant KRAS or carcinoembryonic antigen, with areas under the receiver operating characteristic curve of 0.93 (95% confidence interval: 0.86-0.99), 0.71 (0.57-0.85), and 0.72 (0.60-0.84), respectively. Cutoffs for the MDM panel applied to an independent CF validation set (31 cases, 56 controls) yielded similarly high discrimination, areas under the receiver operating characteristic curve = 0.86 (95% confidence interval: 0.77-0.94, P = 0.2). DISCUSSION: Novel MDMs discovered and validated in tissue accurately identify PCLs harboring HGD/PC. A panel of 2 MDMs assayed in CF yielded results with potential to enhance current risk prediction algorithms. Prospective studies are indicated to optimize and further evaluate CF-MDMs for clinical use.

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.

Standardization of epidermal growth factor receptor (EGFR) measurement by quantitative immunofluorescence and impact on antibody-based mutation detection in non-small cell lung cancer.

Challenges in measurement of epidermal growth factor receptor (EGFR) protein expression have led to conflicting data on its prognostic value and discontinuation of its use for prediction of response. Herein is described a quantitative standardized assay for EGFR and its use in a series of retrospective cohorts of patients with non-small cell lung cancer (NSCLC). The AQUA technology of quantitative immunofluorescence was used in conjunction with Western blot analysis to calculate the absolute concentration of EGFR in two independent NSCLC cohorts (170 from Yale New Haven Hospital and 335 from Sotiria and Patras Hospitals in Greece). EGFR and mutated EGFR were measured using D38B1 antibody and two mutation-specific antibodies. All patients positive or borderline for mutation-specific antibody were genotyped. A threshold for reproducible detection of EGFR was defined as 0.85 ng/µg total protein. EGFR expression demonstrated no prognostic value in either cohort. The mutation rate was 1.79% in the Yale cohort, and 1.52% in the Sotiria/Patras cohort, with no antibody detection-based false-positive cases. No mutations were detected for EGFR concentrations <1.46 ng/µg total protein. In summary, accurate measurement of EGFR still shows no prognostic value in NSCLC. In these two population-based cohorts, the antibody-based EGFR mutation rate was lower than has been frequently reported.

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.