Older age impacts radiotherapy-related outcomes in soft tissue sarcoma.

BACKGROUND: Radiation therapy (RT) is a standard component in the multimodality management of localized soft tissue sarcoma (STS). Increasing studies are focusing on biological modifiers that may influence the host's response to RT, including immunologic mechanisms known to change with the aging process. We hypothesized that the effects of RT would be influenced by age, contributing to differences in treatment outcome. METHODS: Using Surveillance, Epidemiology, and End Results (1990-2011), we identified 30,898 adult patients (>18 y) with nonmetastatic STS undergoing initial surgery. We compared patient demographics, tumor characteristics, and treatments by age. Multivariable analyses were used to analyze overall survival (OS) and disease-specific survival (DSS). Hazard ratios (HRs) were calculated based on multivariable Cox proportional hazards models. RESULTS: Mean age at diagnosis was 56.6 ± 16.8 y, and 33.6% of patients were ≥65 y. Of the total, 52.1% of patients were male and 67% were white; 59.9% of patients underwent surgery alone, 33.3% received adjuvant RT, and 6.8% neoadjuvant RT. On multivariable analysis, age, sex, year of diagnosis, histology, grade, size, marital status, and RT predicted OS, whereas age, year of diagnosis, ethnicity, histology, site, grade, RT, size, and marital status predicted DSS. In all patients, RT was associated with improved OS and DSS compared to surgery alone (median OS 136 ± 13 mo with RT versus 118 ± 9 mo without RT and 5-y OS 63.2 ± 1.4% with RT versus 60.5 ± 1.2% without, P < 0.01). Patients ≥65 y derived greater improvements in OS and DSS compared with patients <65 y. These benefits were most notable after neoadjuvant RT with patients ≥65 y having significantly better OS (HR = 0.63; 95% confidence interval = 0.53-0.75), whereas patients <65 y did not (HR = 0.96; 95% confidence interval = 0.83-1.10). In addition, interaction testing demonstrated a significant modifier effect between RT and age (P < 0.05). CONCLUSIONS: RT is associated with improved survival in patients with STS undergoing surgical treatment, but improvements in oncologic outcome with RT were greatest among older patients. Further studies into the mechanism of these age-related effects are needed.

Immunity to the melanoma inhibitor of apoptosis protein (ML-IAP; livin) in patients with malignant melanoma.

Therapeutic targeting of melanoma antigens frequently focuses on the melanocyte differentiation or cancer-testis families. Antigen-loss variants can often result, as these antigens are not critical for tumor cell survival. Exploration of functionally relevant targets has been limited. The melanoma inhibitor of apoptosis protein (ML-IAP; livin) is overexpressed in melanoma, contributing to disease progression and treatment resistance. Improved understanding of the significance of ML-IAP immune responses in patients has possible therapeutic applications. We found ML-IAP frequently expressed in melanoma metastases by immunohistochemistry. To assess spontaneous immunity to ML-IAP, an overlapping peptide library representing full-length protein was utilized to screen cellular responses in stage I-IV patients and healthy controls by ELISPOT. A broad array of CD4(+) and CD8(+) cellular responses against ML-IAP was observed with novel class I and class II epitopes identified. Specific HLA-A*0201 epitopes were analyzed further for frequency of reactivity. The generation of specific CD4(+) and cytotoxic T cells revealed potent functional capability including cytokine responsiveness to melanoma cell lines and tumor cell killing. In addition, recombinant ML-IAP protein used in an ELISA demonstrated high titer antibody responses in a subset of patients. Several melanoma patients who received CTLA-4 blockade with ipilimumab developed augmented humoral immune responses to ML-IAP as a function of treatment which was associated with beneficial clinical outcomes. High frequency immune responses in melanoma patients, associations with favorable treatment outcomes, and its essential role in melanoma pathogenesis support the development of ML-IAP as a disease marker and therapeutic target.

Imatinib targeting of KIT-mutant oncoprotein in melanoma.

PURPOSE: Melanoma subtypes based on anatomic location and UV light exposure can be further classified based on genetic alterations recently identified. Mutations and gene amplification in KIT have been described in a significant percentage of mucosal and acral melanomas. We recently reported a patient with metastatic mucosal melanoma harboring a known KIT mutation treated with imatinib mesylate who experienced a major response. Biological effects of KIT inhibition in these melanomas remain poorly understood. We sought to investigate further the effects of imatinib in these melanoma subsets. EXPERIMENTAL DESIGN: Mucosal melanoma cells were analyzed for KIT aberrations by genomic sequencing, quantitative PCR, and single nucleotide polymorphism analyses. Imatinib effects were assayed by viability measurements and apoptotic cytotoxicity. Tumor cell lysates were assayed by Western blots to determine effects on multiple signaling pathways after imatinib exposure. RESULTS: Mucosal melanoma cells exhibited imatinib sensitivity correlating with KIT mutational status. Imatinib dramatically decreased proliferation and was cytotoxic to a KIT mutated and amplified cell culture. Exposure to drug affected the mitogen-activated protein kinase, phosphatidylinositol 3-kinase/AKT, JAK-STAT, and antiapoptotic pathways. CONCLUSIONS: Rational targeting of KIT in melanoma offers a unique and potent clinical opportunity. In vitro analyses revealed major sensitivity to KIT kinase inhibition by imatinib, with potent induction of melanoma cell apoptosis. Biochemical studies identified changes in signaling molecules regulating proliferation and survival responses, which may serve as mediators and/or biomarkers of in vivo treatment efficacy. Pathways affected by KIT inhibition provide a model for understanding components in effective melanoma cell death and insights into targeting for resistance mechanisms.

Concerted potent humoral immune responses to autoantigens are associated with tumor destruction and favorable clinical outcomes without autoimmunity.

PURPOSE: The therapeutic importance of immune responses against single versus multiple antigens is poorly understood. There also remains insufficient understanding whether responses to one subset of antigens are more significant than another. Autoantibodies are frequent in cancer patients. They can pose no biological significance or lead to debilitating paraneoplastic syndromes. Autoreactivity has been associated with clinical benefits, but the magnitude necessary for meaningful results is unknown. Autologous tumor cells engineered to secrete granulocyte macrophage colony-stimulating factor generate immune infiltrates in preexisting metastases with associated tumor destruction. We sought to identify targets of responses from this vaccination strategy. EXPERIMENTAL DESIGN: Postvaccination sera used in screening a cDNA expression library prepared from a densely infiltrated metastasis of a long-term surviving melanoma patient identified several autoantigens. Additional autoantigens were identified through similar screenings in non-small cell lung cancer and murine models, and proteins implicated in cancer propagation. ELISAs for several targets were established using recombinant proteins, whereas others were evaluated by petit serologies. RESULTS: Eleven gene products were identified through serologic screening from two patients showing highly favorable clinical outcomes. A subset of antigens revealed significant changes in antibody titers compared with weak responses to other proteins. Time course analyses showed coordinated enhanced titers against several targets as a function of vaccination in responding patients. CONCLUSIONS: This study shows the range of biologically significant antigens resulting from a whole-cell vaccine. Targets include autoantigens that are components of cell cycle regulation. Potent antibody responses against multiple autoantigens are associated with effective tumor destruction without clinical autoimmunity.

Hyperparathyroidism of Renal Disease.

Renal hyperparathyroidism (rHPT) is a common complication of chronic kidney disease characterized by elevated parathyroid hormone levels secondary to derangements in the homeostasis of calcium, phosphate, and vitamin D. Patients with rHPT experience increased rates of cardiovascular problems and bone disease. The Kidney Disease: Improving Global Outcomes guidelines recommend that screening and management of rHPT be initiated for all patients with chronic kidney disease stage 3 (estimated glomerular filtration rate, < 60 mL/min/1.73 m(2)). Since the 1990s, improving medical management with vitamin D analogs, phosphate binders, and calcimimetic drugs has expanded the treatment options for patients with rHPT, but some patients still require a parathyroidectomy to mitigate the sequelae of this challenging disease.

Older Age Modifies Oncologic Outcome Following Radiotherapy in Soft-tissue Sarcoma: A Subtype-specific SEER Analysis.

BACKGROUND: Given the immune-mediated mechanisms of radiotherapy (RT), we hypothesized that age would affect response to RT in patients with soft-tissue sarcoma (STS) undergoing surgery. MATERIALS AND METHODS: Using the Surveillance, Epidemiology, and End Results Program (1990-2011), we identified 15,380 patients with non-metastatic STS. Stratified by age (≥65 years) and histological subtype, we assessed predictors of overall (OS) and disease-specific survival (DSS). RESULTS: Treatment with RT was associated with improved OS and DSS compared to surgery alone (p<0.05). Multivariate analysis also demonstrated that older patients obtained significant improvements in OS following RT, while younger patients did not. Results for DSS were similar, with older patients with leiomyosarcoma, sarcoma not otherwise specified, and myxoid liposarcoma, in particular, showing greater improvements in DSS after RT than younger patients (p<0.05). Interaction testing demonstrated an impact of year of diagnosis on outcomes but not receipt of RT. CONCLUSION: Among patients with STS undergoing surgery, age appears to impact oncological outcomes after RT.