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Key PointsTherapy with an IL-15 superagonist resulted in immune and clinical responses in a transplant recipient with PML.

Estrogen receptor-positive (ER+) breast cancer represents the majority of breast cancer diagnoses and is the leading cause of cancer death in women. Endocrine therapy is the principal treatment strategy for ER+ breast cancer. However, resistance to endocrine therapy, either de novo or acquired, is commonly observed, resulting in disease relapse and progression. This review will focus on recent progress in our understanding of ER biology and the implications for treatments. Advances in genomic technology and laboratory investigations have led to the identification of somatic mutations, including treatment-emergent ESR1 mutations, and aberrant activation of growth factor receptor signaling pathways and cell cycle machinery that are associated with estrogen-independent proliferation and resistance to endocrine therapy. A plethora of molecularly targeted agents are being developed to overcome these resistance mechanisms, among which inhibitors against the mammalian target of rapamycin (mTOR) and cyclin-dependent kinases (CDK) 4/6 are now in clinical use. Advances in our understanding of ER biology have impacted the treatment landscape of ER+ breast cancer. Ongoing biomarker research on tumor specimens and cell-free tumor DNA will continue to generate important biological insight toward improving individualized treatment strategies for patients with ER+ breast cancer.

BACKGROUND: The standard of care for unresectable intrahepatic cholangiocarcinoma (ICC) is palliative systemic chemotherapy with cisplatin and gemcitabine. The use of hepatic arterial infusion (HAI) floxuridine (FUDR) with systemic chemotherapy may improve outcomes. We conducted a phase 1 study of HAI FUDR with systemic gemcitabine and oxaliplatin. METHODS: We enrolled patients in three cohorts: FUDR 0.16 mg/kg/day ×14 days (Cohort 1), FUDR 0.12 mg/kg/day ×14 days with gemcitabine 1,000 mg/m(2) on days 1, 8, 15 (Cohort 2), and FUDR 0.10 mg/kg/day ×14 days with gemcitabine 800 mg/m(2) days 1, 15 and oxaliplatin 85 mg/m(2) days 1, 15 (Cohort 3). The primary endpoint was the recommended phase 2 dose (RP2D). Dose limiting toxicities (DLTs) were assessed during cycle 1. Secondary objectives were response rate and survival. RESULTS: We enrolled 24 patients, 6 male, age range 42–81 years (median 64). No DLTs were observed in Cohort 1. In Cohort 2, the addition of gemcitabine 1,000 mg/m(2) days 1, 8, 15 resulted in grade 3 LFT elevation in 2 patients; for subsequent patients, the gemcitabine dose was reduced to 800 mg/m(2). No DLT were observed in Cohort 3. Most patients experienced stable disease (SD) or partial response (PR). Conversion to resectable disease occurred in all cohorts. CONCLUSIONS: Administration of FUDR via HAI pump in combination with systemic gemcitabine and oxaliplatin is well-tolerated in patients with unresectable cholangiocarcinoma. Preliminary analysis suggests a high rate of response and disease control, with some patients proceeding to resection. Based on Cohort 3, the RP2D is FUDR 0.10 mg/kg/day ×14 days, with gemcitabine 800 mg/m(2) days 1, 15 and oxaliplatin 85 mg/m(2) days 1, 15 for future studies. Future studies of this promising regimen will utilize this dosing schedule.

e16542Background: Germ cell tumor (GCT) is the most common cancer effecting males aged 15 to 35. With the implementation of cisplatin-based chemotherapy and/or surgery, the cure rate in early-stage...

It is uncertain whether pathologically prolonged international normalized ratio (INR) seen in chronic liver disease (CLD) protects against venous thromboembolism (VTE). Previous studies reported VTE incidence of 0.5% to 1.9% in patients with CLD. We sought to evaluate VTE incidence among hospitalized patients with CLD according to INR levels.This was a retrospective cohort study performed at a tertiary university hospital. We included all adult patients admitted with a primary diagnosis of CLD over a 7-year period. The primary outcome was the development of VTE during hospital stay. Patients were divided into quartiles according to their highest admission INR. VTE events and prophylaxis rates were compared among INR quartiles.During the allotted 7-year period, we included 190 patients. Of these, 12 developed VTE events, yielding a VTE incidence of 6.3%. There was no significant difference in the incidence of VTE between INR quartiles. Hospital mortality rates were higher in the higher INR quartiles than in the lower ones (P.001), but hospital length of stay was not significantly different. Of the patients with documented VTE, one (4.2%) was Child-Pugh stage A, three (4.6%) were stage B, and eight (8.0%) were stage C (P = .602). VTE prophylaxis was not used in 75% of patients.An elevated INR in the setting of CLD does not appear to protect against the development of hospital-acquired VTE. The notion that "auto-anticoagulation" protects against VTE is unfounded. Use of DVT prophylaxis was extremely low in this population.

746 Background: Peritoneal carcinomatosis (PC) is the intraperitoneal spread of cancer. Optimal treatment for PC is controversial. Systemic chemotherapy offers limited benefit (Franko, 2011). Intraperitoneal (IP) chemotherapy following cytoreductive surgery (CRS) improves outcomes (Verwaal, 2008). Oxaliplatin (Ox), capecitabine, and bevacizumab are standard agents for the treatment of metastatic colorectal cancer (CRC). Evidence suggests benefit of IP Ox at high doses. However, the optimal dose of IP Ox combined with standard systemic therapy is unclear. Methods: We conducted an IRB-approved phase I dose-escalation study of IP Ox D1 at 25mg/m2-100mg/m2, with systemic bevacizumab D1 at 5mg/kg, and capecitabine 850mg/m2 BID for 7 days (cycle = 14 days), in patients with PC from appendiceal or CRC after CRS. The primary aim was to determine the recommended phase II dose (RP2D)/maximum tolerated dose (MTD) for this regimen. Dose limiting toxicities (DLTs) were assessed during cycle 1. DLTs included grade 3 or 4 non-hematological toxicities, or grade 4 hematological toxicities. Results: 18 patients (12 females, median age 56) were enrolled on the study. No DLTs were observed during cycle 1 in the first 4 cohorts. One DLT (abdominal pain) was observed in cohort 5. Another patient in cohort 5 experienced grade 3 abdominal pain soon after cycle 2, thus limiting repeated treatment for this cohort. Other toxicities included fatigue (72%), nausea (61%), peripheral neuropathy (50%), constipation (50%), mucositis (39%) and dizziness (39%). See table below for average # of cycles per cohort and responses. Conclusions: IP Ox combined with capecitabine and bevacizumab is feasible. Our recommended dose for IP Ox is 85 mg/m2 with systemic therapy (cohort 4). An expansion cohort is underway for this dose level. Based on these data, further investigation of IP Ox with systemic chemotherapy for PC is warranted. Clinical trial information: NCT01061515. [Table: see text]