Deborah Kuk

OBJECTIVE: The aim of this study was to evaluate and validate the proposed 8th edition American Joint Committee on Cancer (AJCC) system for T and N staging of pancreatic adenocarcinoma. SUMMARY OF BACKGROUND DATA: Investigators have questioned the clinical relevance and reproducibility of previous AJCC staging for pancreatic adenocarcinoma. METHODS: Prospective databases at Memorial Sloan Kettering (MSK), Massachusetts General Hospital (MGH), and Johns Hopkins Hospital (JHH) were queried for patients who had undergone resection for pancreatic adenocarcinoma. Patients who underwent a margin-negative (R0) resection, and who had previously undergone pathologic review, were included. Patients were staged according to 7th edition AJCC criteria, as well as the proposed 8th edition system that includes different definitions of tumor size (T) and nodal status (N). The dataset was randomly split into training and test sets. RESULTS: Two thousand three hundred eighteen patients were identified who met inclusion criteria. Recursive partitioning on the training set (n = 1551) identified statistically appropriate cutoffs for tumor size (<2.2 cm, ≥4.8 cm,) and nodal status (no positive nodes, 1 to 3 positive nodes, ≥4 positive nodes) that supported the proposed 8th edition changes. Median survival in patients staged as T3, N0 by the 7th edition definitions was different between institutions (median Center 1, 24 mo; Center 2, 37 mo; Center 3, 29 mo; P = 0.054). This difference was not observed when patients were staged as T3, N0 by 8th edition criteria. Stage, and stage-specific outcome (7th edition), on the test set revealed a predominance of patients (68%) within the IIB subgroup, and a concordance probability estimate (CPE) of 0.57 for stage-specific survival. When assessed with 8th edition criteria, no stage subgroup had a majority of patients, and the CPE was 0.58. CONCLUSIONS: The proposed 8th edition changes for T and N classification were statistically valid and may allow a more reproducible system of T staging. This system also stratifies patients more evenly across stages without sacrificing prognostic accuracy.

OBJECTIVE: To determine the prognostic significance of histologic type/subtype in a large series of patients with primary resected retroperitoneal sarcoma. BACKGROUND: The histologic diversity and rarity of retroperitoneal sarcoma has hampered the ability to predict patient outcome. METHODS: From a single-institution, prospective database, 675 patients treated surgically for primary, nonmetastatic retroperitoneal sarcoma during 1982 to 2010 were identified and histologic type/subtype was reviewed. Clinicopathologic variables were analyzed for association with disease-specific death (DSD), local recurrence (LR), and distant recurrence (DR). RESULTS: Median follow-up for survivors was 7.5 years. The predominant histologies were well-differentiated liposarcoma, dedifferentiated liposarcoma, and leiomyosarcoma. Five-year cumulative incidence of DSD was 31%, and factors independently associated with DSD were R2 resection, resection of 3 or more contiguous organs, and histologic type. Five-year cumulative incidence for LR was 39% and for DR was 24%. R1 resection, age, tumor size, and histologic type were independently associated with LR; size, resection of 3 or more organs, and histologic type were independently associated with DR. Liposarcoma and leiomyosarcoma were associated with late recurrence and DSD (as long as 15 years from diagnosis). For solitary fibrous tumor, LR was uncommon (<10%), but early distant recurrence was common (36% at 5 years). Nomograms were developed to predict DSD, LR, and DR. CONCLUSIONS: Histologic type/subtype is the most important independent predictor of DSD, LR, and DR in primary retroperitoneal sarcoma. Histology predicts the pattern and incidence of LR and DR and will aid in more accurate patient counseling and selection of patients for adjuvant therapy trials.

Ipilimumab, a monoclonal antibody against cytotoxic T lymphocyte antigen 4 (CTLA-4), has been shown to improve survival in patients with advanced metastatic melanoma. It also enhances immunity to NY-ESO-1, a cancer/testis antigen expressed in a subset of patients with melanoma. To characterize the association between immune response and clinical outcome, we first analyzed NY-ESO-1 serum antibody by ELISA in 144 ipilimumab-treated patients with melanoma and found 22 of 140 (16%) seropositive at baseline and 31 of 144 (22%) seropositive following treatment. These NY-ESO-1-seropositive patients had a greater likelihood of experiencing clinical benefit 24 wk after ipilimumab treatment than NY-ESO-1-seronegative patients (P = 0.02, relative risk = 1.8, two-tailed Fisher test). To understand why some patients with NY-ESO-1 antibody failed to experience clinical benefit, we analyzed NY-ESO-1-specific CD4(+) and CD8(+) T-cell responses by intracellular multicytokine staining in 20 NY-ESO-1-seropositive patients and found a surprising dissociation between NY-ESO-1 antibody and CD8 responses in some patients. NY-ESO-1-seropositive patients with associated CD8(+) T cells experienced more frequent clinical benefit (10 of 13; 77%) than those with undetectable CD8(+) T-cell response (one of seven; 14%; P = 0.02; relative risk = 5.4, two-tailed Fisher test), as well as a significant survival advantage (P = 0.01; hazard ratio = 0.2, time-dependent Cox model). Together, our data suggest that integrated NY-ESO-1 immune responses may have predictive value for ipilimumab treatment and argue for prospective studies in patients with established NY-ESO-1 immunity. The current findings provide a strong rationale for the clinical use of modulators of immunosuppression with concurrent approaches to favor tumor antigen-specific immune responses, such as vaccines or adoptive transfer, in patients with cancer.

BACKGROUND: Therapeutic antibodies against programmed cell death receptor 1 (PD-1) are considered front-line therapy in metastatic melanoma. The efficacy of PD-1 blockade for patients with biologically distinct melanomas arising from acral and mucosal surfaces has not been well described. METHODS: A multi-institutional, retrospective cohort analysis identified adults with advanced acral and mucosal melanoma who received treatment with nivolumab or pembrolizumab as standard clinical practice through expanded access programs or published prospective trials. Objective responses were determined using investigator-assessed Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Progression-free survival and overall survival were assessed using the Kaplan-Meier method. RESULTS: Sixty individuals were identified, including 25 (42%) with acral melanoma and 35 (58%) with mucosal melanoma. Fifty-one patients (85%) had received previous therapy, including 77% who had previously received ipilimumab. Forty patients (67%) received pembrolizumab at a dose of 2 mg/kg or 10 mg/kg, and 20 (33%) received nivolumab at a doses ranging from 0.3 to 10 mg/kg every 2 to 3 weeks. The objective response rate was 32% (95% confidence interval, 15%-54%) in patients with acral melanoma and 23% (95% confidence interval, 10%-40%) in those with mucosal melanoma. After a median follow-up of 20 months in the acral melanoma group and 10.6 months in the mucosal melanoma group, the median progression-free survival was 4.1 months and 3.9 months, respectively. Only 2 patients (3%) discontinued treatment because of toxicity. CONCLUSIONS: Response rates to PD-1 blockade in patients with acral and mucosal melanomas were comparable to the published rates in patients with cutaneous melanoma and support the routine use of PD-1 blockade in clinical practice. Further investigation is needed to identify the mechanisms of response and resistance to therapy in these subtypes. Cancer 2016;122:3354-3362. © 2016 American Cancer Society.