Markovic, Svetomir N.

The serum immunoglobulin free light chain (FLC) assay quantitates free kappa (κ) and lambda (λ) light chains. FLC elevations in patients with diffuse large B‐cell lymphoma (DLBCL), Hodgkin lymphoma (HL), and chronic lymphocytic leukemia (CLL) are associated with an inferior survival. These increases in FLC can be monoclonal (as in myeloma) or polyclonal. The goal was to estimate the frequency of these elevations within distinct types of B‐cell and T‐cell non‐Hodgkin lymphoma (NHL) and whether the FLC measurements are associated with event‐free survival (EFS). We studied serum for FLC abnormalities using normal laboratory reference ranges to define an elevated κ or λ FLC. Elevations were further classified as polyclonal or monoclonal. Four hundred ninety‐two patients were studied: 453 B‐cell and 34 T‐cell NHL patients. Twenty‐nine % (142/453) of patients had an elevated FLC of which 10% were monoclonal elevations. Within B‐cell NHL, FLC abnormalities were most common in lymphoplasmacytic (79%), mantle cell (68%), and lymphomas of mucosa associated lymphoid tissue (31%); they were least common in follicular (15%). The hazard ratio (HR) for EFS in all patients was 1.41 (95% CI; 1.11–1.81); in all B‐cell NHL the HR was 1.44 (95% CI 1.11–1.96); in all T‐cell NHL the HR was 1.17 (95% CI 0.55–2.49). FLC abnormalities predicted an inferior OS (HR = 2.75, 95% CI: 1.93–3.90, P < 0.0001). The serum FLC assay is useful for prognosis in both B‐cell and T‐cell types of NHL. In B‐cell NHL further discrimination between a monoclonal and polyclonal elevation may be helpful and should be analyzed in prospective clinical trials. Am. J. Hematol. 89:1116–1120, 2014. © 2014 Wiley Periodicals, Inc.

Abstract Background: The prognosis for stage III melanoma is variable, with the 5-year survival ranging from 23-87%. Previous studies have demonstrated both immune cell activation and dysfunction within the sentinel lymph node (SLN) of melanoma patients. We hypothesize that differences within the host response, specifically the immune cell profile of the SLN, may predict the heterogeneous behavior of stage III melanoma. Methods: A retrospective review of clinically node negative patients undergoing a SLN biopsy at our institution was undertaken. Thirty four SLN positive cases in which the patients also underwent a complete lymph node dissection were identified and the archived FFPE SLN blocks were obtained. A single tumor positive SLN was selected and immunohistochemistry was performed for dendritic cell markers (CD123, CD86, CD11c and HLA-DR), cytotoxic T cells (CD8), anergic T cells (PD-1) and regulatory T cells (Foxp3). Slides were digitized and analyzed for percent of the SLN staining positive for each respective marker using IHCscore. These findings were correlated with risk of further non-SLN disease in the same nodal basin as well as effect on disease-free and overall survival. Results: The SLN exhibited expression of both immune activation (CD8, CD86, and CD11c) and immune suppressive (CD123, PD-1 and Foxp3) markers. HLA-DR expression was significantly higher in females (52.07% vs. 42.32%, p=0.02). No other immune marker was associated with any baseline demographic or clinical variable. Median disease-free survival and overall survival was 6 months and not yet reached and 16 months and not yet reached for patients with and without non-SLN involvement, respectively; however, no difference was noted in any of the SLN immune markers between patients with and without non-SLN involvement. Increased CD8 expression in the SLN was associated with an improvement in disease-free survival (HR 0.94 p = 0.048) but not overall survival (HR 0.93 p = 0.07). In two variable multivariate analyses, CD8 expression remained independent for disease-free survival when adjusted for Breslow depth but not non-SLN involvement. The median disease-free survival for patients with low CD8 expression within the SLN was 19.5 months and median disease-free survival has not been reached in those with high CD8 expression in the SLN after a median of 59 months follow up (log-rank p = 0.05). Conclusion: Previous reports suggest T cell infiltration of melanoma tumors is an important prognostic factor. In this study we found that CD8 T cell accumulation within the SLN was associated with a disease-free survival advantage. Cytotoxic T cell accumulation within the SLN declines early in melanoma and the degree of CD8 depletion corresponds to the risk of disease recurrence. These findings support a key role for effector T cells in the control of melanoma progression. Citation Format: Travis E. Grotz, Aaron S. Mansfield, James W. Jakub, Svetomir N. Markovic, Tina J. Hieken. Immune cell profile of the SLN has prognostic value in stage III melanoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1266. doi:10.1158/1538-7445.AM2013-1266

ProblemSeveral pregnancy complications have disparities based on the sex of the fetus. It is unknown whether the sex of the fetus differentially alters the maternal immune milieu, potentially contributing to the observed differences.Method of studyUsing maternal plasma collected during 38 uncomplicated pregnancies (19 males, 19 females), we compared levels of cytokines, sex hormones, and angiogenic factors throughout gestation and postpartum.ResultsMale fetal sex was associated with higher levels of proinflammatory cytokines (G‐CSF, IL‐12p70, IL‐21, and IL‐33) and angiogenic factors (PlGF and VEGF‐A) compared with female fetal sex at multiple timepoints. Female fetal sex was associated with higher levels of regulatory cytokines (IL‐5, IL‐9, IL‐17, and IL‐25). IL‐27 increased throughout pregnancy regardless of fetal sex. There was no fetal sex‐based difference in analyte concentrations at the postpartum measurement.ConclusionWomen carrying a male fetus exhibit a more proinflammatory/proangiogenic immune milieu than women carrying a female fetus.

Abstract Monocytes may contribute to tumor progression in part by mediating tumor-induced immunosuppression. Alterations to the monocyte populations and functions in untreated patients with late-stage melanoma are not fully understood. To characterize these alterations, we compared the frequency, phenotype, and functional capacity of peripheral blood monocytes and other myeloid cells in untreated, newly diagnosed stage IV melanoma patients (n = 18) with those in healthy volunteers. Stage IV untreated melanoma patients exhibited a sizeable decrease in the percentage of monocytes (P &lt; 0.0001) that included a drop in the percentage of the CD14+CD16− classical monocyte pool (P = 0.006). Although there was not a significant difference in the CD14+HLA-DRlow/− monocyte population between the patients with melanoma and the healthy volunteers, the HLA-DR levels were considerably lower in the patients' CD14+CD16+ intermediate (P &lt; 0.0001) and CD14lowCD16+ nonclassical monocyte populations (P = 0.001). Decreased surface expression of CD86 (P = 0.0006) and TNFRII (P = 0.0001) and increased expression of tissue factor and PD-L1 (P = 0.003) were identified on monocytes from patients with melanoma. Furthermore, these monocytes had decreased ability to upregulate CD80 expression and cytokine production following stimulation with agonist of Toll-like receptor 3 (TLR3). Peripheral blood dendritic cell subsets were decreased in untreated stage IV melanoma patients. Our study demonstrates that untreated late-stage melanoma patients exhibit monocytopenia in addition to phenotypic and functional deficiencies that may negatively affect their immune function. These findings open new avenues into examining the role of monocyte populations in melanoma development. Cancer Immunol Res; 2(3); 241–8. ©2013 AACR.

BACKGROUNDThe management of pediatric melanoma (PM) has largely been extrapolated from adult data. However, the behavior of PM appears to differ from its adult counterparts. Therefore, an international PM registry was created and analyzed.METHODSTwelve institutions contributed deidentified clinicopathologic and outcome data for patients diagnosed with PM from 1953 through 2008.RESULTSOverall survival (OS) data were reported for 365 patients with invasive PM who had adequate follow‐up data. The mean age of the patients was 16 years (range 1 year‐21 years). The 10‐year OS rate, 80.6%, tended to vary by patient age: 100% for those aged birth to 10 years, 69.7% for those aged > 10 years to 15 years, and 79.5% for those aged > 15 years to 20 years (P = .147). Patients with melanomas measuring ≤ 1 mm had a favorable prognosis (10‐year OS rate of 97%), whereas survival was lower but similar for patients with melanomas measuring > 1 mm to 2 mm, > 2 mm to 4 mm, and > 4 mm (70%, 78%, and 80%, respectively; P = .0077). Ulceration and lymph node metastasis were found to be correlated with worse survival (P = .022 and P = .017, respectively). The 10‐year OS rate was 94.1% for patients with American Joint Committee on Cancer stage I disease, 79.6% for those with stage II disease, and 77.1% for patients with stage III disease (P < .001).CONCLUSIONSTumor thickness, ulceration, lymph node status, and stage were found to be significant predictors of survival in patients with PM, similar to adult melanoma. There is a trend toward increased survival in children aged ≤ 10 years versus adolescents aged > 10 years. Further analyses are needed to probe for potential biological and behavioral differences in pediatric versus adult melanoma. Cancer 2013;119:4012–4019. © 2013 American Cancer Society.

Day 100 prognostic factors of postautologous peripheral blood hematopoietic stem cell transplantation (APBHSCT) to predict clinical outcome in classical Hodgkin lymphoma (cHL) patients have not been evaluated. Thus, we studied if the day 100 peripheral blood absolute lymphocyte/monocyte ratio (Day 100 ALC/AMC) affects clinical outcomes by landmark analysis from day 100 post-APBHSCT. Only cHL patients achieving a complete remission at day 100 post-APBHSCT were studied. From 2000 to 2010, 131 cHL consecutive patients qualified for the study. The median followup from day 100 was 4.1 years (range: 0.2–12.3 years). Patients with a Day 100 ALC/AMC ≥ 1.3 experienced superior overall survival (OS) and progression-free survival (PFS) compared with Day 100 ALC/AMC < 1.3 (from day 100: OS, median not reached versus 2.8 years; 5 years OS rates of 93% (95% CI, 83%–97%) versus 35% (95% CI, 19%–51%), resp.,P<0.0001; from day 100: PFS, median not reached versus 1.2 years; 5 years PFS rates of 79% (95% CI, 69%–86%) versus 27% (95% CI, 14%–45%), resp.,P<0.0001). Day ALC/AMC ratio was an independent predictor for OS and PFS. Thus, Day 100 ALC/AMC ratio is a simple biomarker that can help to assess clinical outcomes from day 100 post-APBHSCT in cHL patients.