By Ripal T. Gandhi, MD, and Suvranu Ganguli, MD Spring 2017
J Hepatol. 2016 Nov 2. pii: S0168-8278(16)30638-9. doi: 10.1016/j.jhep.2016.10.029. [Epub ahead of print]
Duffy AG1, Ulahannan SV1, Makorova-Rusher O1, Rahma O1, Wedemeyer H2, Pratt D3, Davis JL4, Hughes MS4, Heller T5, ElGindi M1, Uppala A1, Korangy F1, Kleiner DE3, Figg WD6, Venzon D7, Steinberg SM7, Venkatesan AM8, Krishnasamy V8, Abi-Jaoudeh N8, Levy E8, Wood BJ8, Greten TF9.
BACKGROUND/AIMS: Tremelimumab is a fully human monoclonal antibody that binds to cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) on the surface of activated T lymphocytes. Ablative therapies induce a peripheral "immune response which may enhance the effect of anti-CTLA4 treatment in patients with advanced hepatocellular carcinoma (HCC). This study aimed to demonstrate whether tremelimumab could be combined safely and feasibly with ablation.
METHODS: Thirty-two patients with HCC were enrolled: male:female, 28:4; median age, 62 (range 36–76). Patients were given tremelimumab at two dose levels (3.5 and 10mg/kg i.v.) every 4 weeks for six doses, followed by 3-monthly infusions until off-treatment criteria were met. On day 36, patients underwent subtotal radiofrequency ablation or chemoablation. Staging was performed by contrast-enhanced CT or MRI scan every 8 weeks.
RESULTS: No dose-limiting toxicities were encountered. The most common toxicity was pruritus. Of the 19 evaluable patients, five (26.3 percent; 95 percent CI: 9.1–51.2 percent) achieved a confirmed partial response. Twelve of 14 patients with quantifiable HCV experienced a marked reduction in viral load. Six-week tumor biopsies showed a clear increase in CD8+ T cells in patients showing a clinical benefit only. Six- and 12-month probabilities of tumor progression free survival for this refractory HCC population were 57.1 percent and 33.1 percent, respectively, with median time to tumor progression of 7.4 months (95 percent CI 4.7 to 19.4 months). Median overall survival was 12.3 months (95 percent CI 9.3–15.4 months).
CONCLUSIONS: Tremelimumab in combination with tumor ablation is a potential new treatment for patients with advanced HCC and leads to the accumulation of intratumoral CD8+ T cells. Positive clinical activity was seen, with a possible surrogate reduction in HCV viral load.
LAY SUMMARY: Studies have shown that the killing of tumors by direct methods (known as ablation) can result in the immune system being activated or switched on. The immune system could potentially also recognize and kill the cancer that is left behind. There are new drugs available known as immune checkpoint inhibitors which could enhance this effect. Here, we test one of these drugs (tremelimumab) together with ablation.
J Vasc Surg. 2016 Dec;64(6):1633-1644.e1. doi: 10.1016/j.jvs.2016.05.098. Epub 2016 Aug 27.
Soden PA1, Zettervall SL1, Ultee KH1, Landon BE2, O'Malley AJ3, Goodney PP4, DeMartino RR5, Arya S6, Schermerhorn ML7; Society for Vascular Surgery Vascular Quality Initiative.
BACKGROUND: Dual antiplatelet therapy (DAPT) after coronary stenting prolongs survival by preventing both in-stent thrombosis and other cardiovascular atherothrombotic events. Patients with peripheral artery disease (PAD) typically have a heavy burden of unrevascularized coronary artery disease and also stand to benefit from increased atherothrombotic protection with DAPT. The potential benefit of DAPT compared with aspirin alone in patients with PAD is not well described.
METHODS: We identified all patients undergoing an initial elective lower extremity revascularization (bypass or endovascular) from 2003 to 2016 in the Vascular Quality Initiative registry discharged on aspirin or aspirin plus a thienopyridine antiplatelet agent (DAPT). We first estimated models predicting the likelihood of receiving DAPT and then used inverse probability weighting to account for baseline differences in the likelihood of receiving DAPT and compared late survival. For sensitivity analysis, we also performed Cox proportion hazard modeling on the unweighted cohorts and generated adjusted survival curves.
RESULTS: We identified 57,041 patients undergoing lower extremity revascularization (28 percent bypass). Of 15,985 bypasses (69 percent for critical limb ischemia [CLI]), 38 percent were discharged on DAPT. Of 41,056 endovascular interventions (39 percent for CLI), 69 percent were discharged on DAPT. Analyses using inverse probability weighting demonstrated a small survival benefit to DAPT at 1 year for bypass (93 percent vs. 92 percent [P = .001]) and endovascular interventions (93 percent vs. 92 percent [P = .005]) that was sustained through 5 years of follow-up (bypass, 80 percent vs. 78 percent [P = .004]; endovascular, 76 percent vs. 73 percent [P = .002]). When stratified by severity of PAD, DAPT had a survival benefit for patients with CLI undergoing bypass (5 years, 70 percent vs. 66 percent [P = .04]) and endovascular intervention (5 years, 71 percent vs. 67 percent [P = .01]) but not for patients with claudication (bypass, 89 percent vs. 88 percent [P = .36]; endovascular, 87 percent vs. 85 percent [P = .46]). The protective effect of DAPT was similar when using Cox proportional hazard models after bypass (hazard ratio, 0.81 [95 percent confidence interval, 0.72-0.90]) and endovascular intervention (hazard ratio, 0.89 [95 percent confidence interval, 0.83–0.95]).
CONCLUSIONS: DAPT at time of discharge was associated with prolonged survival for patients with CLI undergoing lower extremity revascularization but not for those with claudication. Further research is needed to quantify the risks associated with DAPT and to identify subgroups at increased risk of thrombotic and bleeding complications to guide medical management of patients with PAD.
Lancet p. 2366–2374, 12 November 2016
BACKGROUND: Short-term survival benefits of endovascular aneurysm repair (EVAR) versus open repair of intact abdominal aortic aneurysms have been shown in randomized trials, but this early survival benefit is lost after a few years. We investigated whether EVAR had a long-term survival benefit compared with open repair.
METHODS: We used data from the EVAR randomized controlled trial (EVAR trial 1), which enrolled 1,252 patients from 37 centers in the U.K. between Sept. 1, 1999, and Aug. 31, 2004. Patients had to be aged 60 years or older, have aneurysms of at least 5.5 cm in diameter, and deemed suitable and fit for either EVAR or open repair. Eligible patients were randomly assigned (1:1) using computer-generated sequences of randomly permuted blocks stratified by center to receive either EVAR (n=626) or open repair (n=626). Patients and treating clinicians were aware of group assignments, no masking was used. The primary analysis compared total and aneurysm-related deaths in groups until mid 2015 in the intention-to-treat population. This trial is registered at ISRCTN (ISRCTN55703451).
FINDINGS: We recruited 1,252 patients between Sept. 1, 1999, and Aug. 31, 2004. 25 patients (four for mortality outcome) were lost to follow-up by June 30, 2015. Over a mean of 12.7 years (SD 1.5; maximum 15.8 years) of follow-up, we recorded 9.3 deaths per 100 person-years in the EVAR group and 8.9 deaths per 100 person-years in the open-repair group (adjusted hazard ratio [HR] 1.11, 95 percent CI 0.97–1.27, p=0·14). At 0–6 months after randomization, patients in the EVAR group had a lower mortality (adjusted HR 0.61, 95 percent CI 0.37–1.02 for total mortality; and 0.47, 0.23–0.93 for aneurysm-related mortality, p=0.031), but beyond 8 years of follow-up open-repair had a significantly lower mortality (adjusted HR 1.25, 95 percent CI 1.00–1.56, p=0.048 for total mortality; and 5.82, 1.64–20.65, p=0.0064 for aneurysm-related mortality). The increased aneurysm-related mortality in the EVAR group after 8 years was mainly attributable to secondary aneurysm sac rupture (13 deaths [7 percent] in EVAR vs. two [1 percent] in open repair), with increased cancer mortality also observed in the EVAR group.
INTERPRETATION: EVAR has an early survival benefit but an inferior late survival compared with open repair, which needs to be addressed by lifelong surveillance of EVAR and re-intervention if necessary.
JAMA Surg. 2016;151(9):e161770. doi:10.1001/jamasurg.2016.1770
IMPORTANCE: Deep vein thrombosis (DVT) isolated to the calf veins (distal to the popliteal vein) is frequently detected with duplex ultrasonography and may result in proximal thrombosis or pulmonary embolism (PE).
OBJECTIVE: To evaluate whether therapeutic anticoagulation is associated with a decreased risk for proximal DVT or PE after diagnosis of an isolated calf DVT.
DESIGN, SETTING AND PARTICIPANTS: All adult patients with ultrasonographic detection of an isolated calf DVT from Jan. 1, 2010, to Dec. 31, 2013, at the Vascular Laboratory of the University of California, Davis, Medical Center were included. Patients already receiving therapeutic anticoagulation and those with a chronic calf DVT, a contraindication to anticoagulation, prior venous thromboembolism within 180 days or diagnosis of a PE suspected at the time of calf DVT diagnosis were excluded. Data were analyzed from Aug. 18, 2015, to Feb. 14, 2016.
EXPOSURES: Intention to administer therapeutic anticoagulation.
MAIN OUTCOMES AND MEASURES: Proximal DVT or PE within 180 days of the diagnosis of the isolated calf DVT.
RESULTS: From 14,056 lower-extremity venous duplex studies, we identified 697 patients with an isolated calf DVT and excluded 313 of these. The remaining 384 patients were available for analysis (222 men [57.8 percent]; 162 women [42.2 percent]; mean [SD] age, 60  years). The calf DVT involved an axial vein (anterior tibial, posterior tibial, or peroneal) in 243 patients (63.2 percent) and a muscular branch (soleus or gastrocnemius) in 215 (56.0 percent). Physicians attempted to administer therapeutic anticoagulation in 243 patients (63.3 percent), leaving 141 control participants. Proximal DVT occurred in 7 controls (5.0 percent) and 4 anticoagulation recipients (1.6 percent); PE, in 6 controls (4.3 percent) and 4 anticoagulation recipients (1.6 percent). Therapeutic anticoagulation was associated with a decreased risk for proximal DVT or PE at 180 days (odds ratio [OR], 0.34; 95 percent CI, 0.14–0.83) but an increased risk for bleeding (OR, 4.35; 95 percent CI, 1.27–14.9), findings that persisted after adjustment for confounding factors (ORs, 0.33 [95 percent CI, 0.12–0.87] and 4.87 [95 percent CI, 1.37–17.3], respectively) and sensitivity analyses.
CONCLUSIONS AND RELEVANCE: Rates of proximal DVT or PE are low after isolated calf DVT. Therapeutic anticoagulation is associated with a reduction of these outcomes but an increase in bleeding.