Sustained Virologic Suppression Reduces HIV-1 DNA Proviral Levels and HIV Antibodies in Perinatally HIV-Infected Children Followed from Birth.

The extent to which perinatally HIV-infected children, following cART initiation, develop a low proviral reservoir burden over time, as measured by HIV DNA droplet-digital polymerase chain reaction (ddPCR) and the effect on HIV antibody is not well characterized. We measured proviral HIV DNA and plasma RNA virus load (VL) in 37 perinatally HIV-infected children at 6 months of age who initiated stable cART. At 6-11 years of age, HIV proviral DNA, HIV VL (RNA), and HIV antibody by Western Blot (WB) were assessed. CART was initiated before 6 months of age in 13 children and after 6 months in 24. At school age, the HIV DNA levels did not differ by the timing of cART, and the HIV DNA levels were lower in children with negative/indeterminate WB (p = 0.0256). Children with undetectable HIV RNA VL > 50% of the time since cART initiation had lower median DNA VL than children with undetectable VL < 50% of the time (p = 0.07). Long-term viral suppression in perinatally HIV-infected children is associated with a decrease in HIV antibodies and reduced HIV reservoirs.

Inflammatory Marker Testing Identifies CD74 Expression in Melanoma Tumor Cells, and Its Expression Associates with Favorable Survival for Stage III Melanoma.

PURPOSE: Inflammatory marker expression in stage III melanoma tumors was evaluated for association with outcome, using two independent cohorts of stage III melanoma patients' tumor tissues. EXPERIMENTAL DESIGN: Fifteen markers of interest were selected for analysis, and their expression in melanoma tissues was determined by immunohistochemistry. Proteins associating with either overall survival (OS) or recurrence-free survival (RFS) in the retrospective discovery tissue microarray (TMA; n = 158) were subsequently evaluated in an independent validation TMA (n = 114). Cox proportional hazards regression models were used to assess the association between survival parameters and covariates, the Kaplan-Meier method to estimate the distribution of survival, and the log-rank test to compare distributions. RESULTS: Expression of CD74 on melanoma cells was unique, and in the discovery TMA, it associated with favorable patient outcome (OS: HR, 0.53; P = 0.01 and RFS: HR, 0.56; P = 0.01). The validation data set confirmed the CD74 prognostic significance and revealed that the absence of macrophage migration inhibitory factor (MIF) and inducible nitric oxide synthase (iNOS) was also associated with poor survival parameters. Consistent with the protein observation, tumor CD74 mRNA expression also correlated positively (P = 0.003) with OS in the melanoma TCGA data set. CONCLUSIONS: Our data validate CD74 as a useful prognostic tumor cell protein marker associated with favorable RFS and OS in stage III melanoma. Low or negative expression of MIF in both TMAs and of iNOS in the validation set also provided useful prognostic data. A disease-specific investigation of CD74's functional significance is warranted, and other markers appear intriguing to pursue. Clin Cancer Res; 22(12); 3016-24. ©2016 AACR.

Clinical Benefit from Ipilimumab Therapy in Melanoma Patients may be Associated with Serum CTLA4 Levels.

Stage IV metastatic melanoma patients historically have a poor prognosis with 5-10% 5-year survival. Ipilimumab, a monoclonal antibody against cytotoxic T-lymphocyte antigen 4 (CTLA4), is one of the first treatments to provide beneficial durable responses in advanced melanoma. However, less than 25% of those treated benefit, treatment is expensive, and side effects can be fatal. Since soluble (s) CTLA4 may mediate inhibitory effects previously ascribed to the membrane-bound isoform (mCTLA4), we hypothesized patients benefiting from ipilimumab have higher serum levels of sCTLA4. We found that higher sCTLA4 levels correlated both with response and improved survival in patients treated with ipilimumab in a small patient cohort [patients with (n = 9) and without (n = 5) clinical benefit]. sCTLA4 levels were statistically higher in ipilimumab-treated patients with response to ipilimumab. In contrast, sCTLA4 levels did not correlate with survival in patients who did not receive ipilimumab (n = 11). These preliminary observations provide a previously unrecognized link between serum sCTLA4 levels and response to ipilimumab as well as to improved survival in ipilimumab-treated melanoma patients and a potential mechanism by which ipilimumab functions.

Staging of regional lymph nodes in melanoma: a case for including nonsentinel lymph node positivity in the American Joint Committee on Cancer staging system.

IMPORTANCE: Survival varies widely in patients with stage III melanoma. The existence of clinical significance for positive nonsentinel lymph node (NSLN) status would warrant consideration for incorporation into the American Joint Committee on Cancer staging system and better prediction of survival. OBJECTIVE: To evaluate whether disease limited to sentinel lymph nodes (SLNs) represents different clinical significance than disease spread into NSLNs. DESIGN, SETTING, AND PARTICIPANTS: The database of the John Wayne Cancer Institute at Saint John's Health Center, Santa Monica, California, was queried for all patients with SLNs positive for cutaneous melanoma who subsequently underwent completion lymph node dissection. MAIN OUTCOMES AND MEASURES: Disease-free survival, melanoma-specific survival (MSS), and overall survival. RESULTS: A total of 4223 patients underwent SLN biopsy from 1986 to 2012. Of these patients, 329 had a tumor-positive SLN. Of the 329, 250 patients (76.0%) had no additional positive nodes and 79 (24.0%) had a tumor-positive NSLN. Factors predictive of NSLN positivity included older age (P = .04), greater Breslow thickness (P < .001), and ulceration (P < .02). Median overall survival was 178 months for the SLN-only positive group and 42.2 months for the NSLN positive group (5-year overall survival, 72.3% and 46.4%, respectively). Median MSS was not reached for the SLN-only positive group and was 60 months for the NSLN positive group (5-year MSS, 77.8% and 49.5%, respectively). On multivariate analysis, NSLN positivity had a strong association with recurrence (hazard ratio [HR], 1.75; 95% CI, 1.23-2.50; P = .002), shorter overall survival (HR, 2.24; 95% CI, 1.48-3.40; P < .001), and shorter MSS (HR, 2.23; 95% CI, 1.46-3.07; P < .001). To further control for the effects of total positive lymph nodes, comparison was done for patients with only N2 disease (2-3 total positive lymph nodes); the results of this comparison confirmed the independent effect of NSLN status (MSS; P = .04). CONCLUSIONS AND RELEVANCE: Nonsentinel lymph node positivity is one of the most significant prognostic factors in patients with stage III melanoma. Subclassification of melanoma by NSLN tumor status should be considered for the American Joint Committee on Cancer staging system.

Management of popliteal sentinel nodes in melanoma.

BACKGROUND: Although most melanomas on the distal lower extremity drain exclusively to inguinal lymph nodes, a small percentage (<5%) drain to interval nodes in the popliteal basin. We investigated a possible relationship between tumor-draining popliteal and inguinal nodes in patients with lower-extremity melanoma. STUDY DESIGN: We queried our melanoma database to identify patients who underwent sentinel node biopsy (SNB) for an infrapopliteal melanoma. Patterns of nodal drainage and nodal metastasis were analyzed. RESULTS: Of 461 patients who underwent SNB for a primary infrapopliteal melanoma, 15 (3.2%) had drainage to the popliteal basin. Thirteen melanomas were on the posterior leg and foot, and 2 were on the anterior lower leg. Mean Breslow thickness was 2.4 mm. All 15 patients with popliteal drainage also had inguinal drainage and therefore underwent concurrent inguinal and popliteal SNB. The average number of popliteal sentinel nodes was 1.4 (range 1 to 3). Eight patients (53%) had a tumor-positive popliteal sentinel node, and 6 of the 8 underwent completion popliteal lymphadenectomy. Four of the 8 patients (50%) also had tumor-positive inguinal sentinel nodes; all underwent complete inguinal lymphadenectomy. We also identified 9 additional patients who underwent SNB for locoregional recurrent melanomas of the infrapopliteal leg. Three (33%) of these patients had concurrent inguinal and popliteal SNB, with 1 isolated tumor-positive popliteal node found. CONCLUSIONS: In our series, a high percentage of popliteal sentinel lymph nodes contained metastases, and these patients frequently also had inguinal metastases. In our patients, all inguinal metastases were associated with concomitant popliteal metastases. Although it is anatomically separate, the inguinal basin appears to be a functional extension of the popliteal basin.