Cancer is a disease of aging, and aged cancer patients have a poorer prognosis. This may be due to accumulated cellular damage, decreases in adaptive immunity, and chronic inflammation. However, the effects of the aged microenvironment on tumor progression have been largely unexplored. Since dermal fibroblasts can have profound impacts on melanoma progression1–4 we examined whether age-related changes in dermal fibroblasts could drive melanoma metastasis and response to targeted therapy. We find that aged fibroblasts secrete a Wnt antagonist, sFRP2, which activates a multi-step signaling cascade in melanoma cells that results in a decrease in β-catenin and MITF, and ultimately the loss of a key redox effector, APE1. Loss of APE1 attenuates the response of melanoma cells to ROS-induced DNA damage, rendering them more resistant to targeted therapy (vemurafenib). Age-related increases in sFRP2 also augment both angiogenesis and metastasis of melanoma cells. These data provide an integrated view of how fibroblasts in the aged microenvironment contribute to tumor progression, offering new paradigms for the design of therapy for the elderly.

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BACKGROUND: Although studies of metastasectomy have been limited primarily to institutional experiences, reports of favorable long-term outcomes have generated increasing interest. In the current study, the authors attempted to define the national practice patterns in metastasectomy for 4 common malignancies with varying responsiveness to systemic therapy. METHODS: The National (Nationwide) Inpatient Sample was used to estimate the national incidence of metastasectomy for colorectal cancer, lung cancer, breast cancer, and melanoma from 2000 through 2011. Incidence-adjusted rates were determined for liver, lung, brain, small bowel, and adrenal metastasectomies. The average annual percentage change (AAPC) in metastasectomy by cancer type was calculated using joinpoint regression. RESULTS: Colorectal cancer was the most common indication for metastasectomy (87,407 cases; 95% confidence interval [95% CI], 86,307-88,507 cases) followed by lung cancer (58,245 cases; 95% CI, 57,453-59,036 cases), breast cancer (26,271 cases; 95% CI, 25,672-26,870 cases), and melanoma (20,298 cases; 95% CI, 19,897-20,699 cases). Metastasectomy increased significantly for all cancer types over the study period: colorectal cancer (AAPC, 6.83; 95% CI, 5.7-7.9), lung cancer (AAPC, 5.8; 95% CI, 5.1-6.4), breast cancer (AAPC, 5.5; 95% CI, 3.7-7.3), and melanoma (AAPC, 4.03; 95% CI, 2.1-6.0). Despite an increasing number of comorbidities in patients undergoing metastasectomy (P<.05 for each cancer type), inpatient mortality rates after metastasectomy fell for all cancer types, most significantly for colorectal (AAPC, 25.49; 95% CI, 28.2 to 22.7) and lung (AAPC, 26.2; 95% CI, 211.7 to 20.3) cancers. The increasing performance of metastasectomy was largely driven by high-volume institutions, in which patients had a lower mean number of comorbidities (P<.01 for all cancer types) and lower inpatient mortality (P<.01 for all cancers except melanoma). CONCLUSIONS: From 2000 through 2011, the performance of metastasectomy increased substantially across common cancer types, notwithstanding various advances in systemic therapies. Metastasectomy was performed more safely, despite increasing patient comorbidity. High-volume institutions appeared to drive practice patterns. Cancer 2015;121:747-57. V C 2014 American Cancer Society.KEYWORDS: metastasectomy, colorectal cancer metastasectomy, lung cancer metastasectomy, breast cancer metastasectomy, melanoma metastasectomy, surgical trends. INTRODUCTIONHistorically, the role of surgery in patients with metastatic cancer was predominately limited to palliative or emergent operations. By the 1980s, however, a few centers were consistently performing surgical resections for select patients with metastatic cancer and reporting promising results. [1][2][3] In addition, theories of cancer biology began to suggest that in a subset of patients, oligometastatic disease might indeed represent the entire clinically relevant disease burden. 4 In these cases, complete resection was associated with prolonged disease-free s...

Background An elevated neutrophil‐to‐lymphocyte ratio (NLR) is associated with poor survival in patients with cancer, including those who receive immunotherapies. The authors sought to investigate NLR as a biomarker of treatment outcomes in patients with melanoma who were treated with PD‐1 inhibition. Methods Patients undergoing initial treatment with PD‐1 inhibitor monotherapy for stage IV melanoma at a single center from 2012 to 2015 were included. Clinical characteristics and the NLR at baseline and before subsequent treatment cycles were collected. The time to treatment failure (TTF) and overall survival (OS) were evaluated using Kaplan‐Meier and landmark analyses. Results Among 224 study patients, 63 (28%) had a baseline NLR ≥5. The baseline NLR was significantly associated with Eastern Cooperative Oncology Group performance status and the number of involved metastatic sites. With a median follow‐up of 39 months in survivors, a baseline NLR ≥5 was independently associated with shorter OS (hazard ratio, 2.0; 95% CI, 1.3‐2.9) and TTF (hazard ratio, 1.7; 95% CI, 1.2‐2.4). An NLR increase ≥30% during the first 2 cycles of treatment was associated with worse OS (median, 47 vs 13.5 months; P < .001) and a trend toward shorter TTF (12.8 vs 5.9 months; P = .05). A combined baseline NLR ≥5 and an NLR increase ≥30% identified a small cohort with markedly shortened OS (median, 5.8 months) and TTF (median, 1.8 months). Conclusions Elevated baseline NLR and an increased NLR early during treatment are prognostic for TTF and OS in patients who have melanoma treated with PD‐1 inhibitor monotherapy. Combined, these biomarkers can widely risk‐stratify patients for treatment failure and survival.

IMPORTANCEPatients with advanced sarcoma have limited treatment options. Talimogene laherparepvec (T-VEC) has been shown to increase tumor-specific immune activation via augmenting antigen presentation and T-cell priming.OBJECTIVE To examine whether T-VEC in combination with pembrolizumab is associated with increased tumor-infiltrating lymphocyte infiltration and programmed death-ligand 1 expression and thus with increased antitumor activity in patients with locally advanced or metastatic sarcoma. DESIGN, SETTING, AND PARTICIPANTSThis open-label, single-institution phase 2 interventional trial of T-VEC plus pembrolizumab enrolled 20 patients with locally advanced or metastatic sarcoma between March 16 and December 4, 2017, for whom at least 1 standard systemic therapy had failed. The median duration of therapy was 16 weeks (range, 7-67 weeks). Reported analyses include data through December 14, 2018.INTERVENTION Patients received pembrolizumab (200-mg flat dose) intravenously and T-VEC (first dose, Յ4 mL × 10 6 plaque-forming units [PFU]/mL; second and subsequent doses, Յ4 mL × 10 8 PFU/mL) injected into palpable tumor site(s) on day 1 of each 21-day cycle. MAIN OUTCOMES AND MEASURESThe primary end point was objective response rate (ORR; complete response and partial response) at 24 weeks determined by Response Evaluation Criteria In Solid Tumors (RECIST), version 1.1, criteria. Secondary end points included best ORR by immune-related RECIST criteria, progression-free survival rate at 24 weeks, overall survival, and safety. RESULTSAll 20 patients (12 women [60%]; median age, 63.5 years [range, 24-90 years]) were evaluable for response. The study met its primary end point of evaluating the best ORR at 24 weeks determined by RECIST, version 1.1, criteria; the best ORR was 30% (95% CI, 12%-54%; n = 6). The ORR overall was 35% (95% CI, 15%-59%; n = 7). The incidence of grade 3 treatment-related adverse events was low (4 patients [20%]). There were no grade 4 treatment-related adverse events or treatment-related deaths. CONCLUSIONS AND RELEVANCEIn this phase 2 clinical trial, treatment with T-VEC plus pembrolizumab was associated with antitumor activity in advanced sarcoma across a range of sarcoma histologic subtypes, with a manageable safety profile. This combination therapy met its predefined primary study end point; further evaluation of T-VEC in combination with pembrolizumab for patients with select sarcoma subtypes is planned.

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Leiomyosarcomas of the IVC present a technical challenge to the surgeon. Careful preoperative workup and a collaborative team consisting of experienced cardiac and vascular surgeons and surgical oncologists can allow for a safe and successful operation despite extensive tumor involvement.