Role of imatinib in the management of early, operable, and advanced GI stromal tumors (GISTs)

Gastrointestinal stromal tumors (GISTs), the most common sarcoma of the GI tract, have unique kinase mutations that serve as targets for medical therapy. This article reviews the data supporting the use of the tyrosine kinase inhibitor (TKI) imatinib in GIST patients, and how this treatment should be combined with surgical resection (when possible) to optimize patient outcomes. Although surgical resection remains the mainstay of treatment for these tumors, patients with resected GISTs have high relapse rates that can be reduced by 1 year of adjuvant imatinib. Data also support the use of imatinib for patients with recurrent or unresectable GIST. In these patients the drug should be continued until progression, intolerance, or the patients are rendered resectable. Patients with advanced GIST who are successfully resected after imatinib treatment should be placed back on imatinib postoperatively. Patients who develop generalized progression (progression at 2 or more sites) on imatinib should move to other treatments, such as newer TKIs or other targeted approaches currently under study. Genotyping of the tumor should be considered in all pediatric GISTs and high risk adult GISTs, especially if there is progression on imatinib. Quality of life and the cost/benefit of new therapies are important issues for further study in patients with GIST

Guidance of sentinel lymph node biopsy decisions in patients with T1-T2 melanoma using gene expression profiling.

AIM: Can gene expression profiling be used to identify patients with T1-T2 melanoma at low risk for sentinel lymph node (SLN) positivity? PATIENTS & METHODS: Bioinformatics modeling determined a population in which a 31-gene expression profile test predicted \u3c5% SLN positivity. Multicenter, prospectively-tested (n = 1421) and retrospective (n = 690) cohorts were used for validation and outcomes, respectively. RESULTS: Patients 55-64 years and ≥65 years with a class 1A (low-risk) profile had SLN positivity rates of 4.9% and 1.6%. Class 2B (high-risk) patients had SLN positivity rates of 30.8% and 11.9%. Melanoma-specific survival was 99.3% for patients ≥55 years with class 1A, T1-T2 tumors and 55.0% for class 2B, SLN-positive, T1-T2 tumors. CONCLUSION: The 31-gene expression profile test identifies patients who could potentially avoid SLN biopsy

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Vitreo-Retinal Traction and Anastrozole Use

Purpose—This study tested a prediction stemming from the hypothesis that anastrozole users experience heightened vitreo-retinal traction. This hypothesis was based on the knowledge that menopause increases the risk of intraocular tractional events such as posterior vitreous detachments (PVDs). Methods—Retinal thickness was measured for 3 groups of amenorrheic women: (1) anastrozole users and (2) tamoxifen users undergoing adjuvant therapy for early-stage breast cancer, and (3) control subjects not using hormonal medication. Foveal shape indices were derived for subjects without PVDs. Results—For anastrozole users, the distance to the temporal side of the fovea became less than the distance to the nasal side at a sufficient height above the foveal base. This effect did not exist for control subjects; the between-group difference was appreciable. Results concerning tamoxifen users were inconclusive. Conclusions—The foveas of women using anastrozole appear to be subjected to more tractional force than are the foveas of women not using any hormonal medication