Citations

Purpose To determine the pathologic complete response (pCR) rate in estrogen receptor (ER) –positive primary breast cancer triaged to chemotherapy when the protein encoded by the MKI67 gene (Ki67) level was > 10% after 2 to 4 weeks of neoadjuvant aromatase inhibitor (AI) therapy. A second objective was to examine risk of relapse using the Ki67-based Preoperative Endocrine Prognostic Index (PEPI). Methods The American College of Surgeons Oncology Group (ACOSOG) Z1031A trial enrolled postmenopausal women with stage II or III ER-positive (Allred score, 6 to 8) breast cancer whose treatment was randomly assigned to neoadjuvant AI therapy with anastrozole, exemestane, or letrozole. For the trial ACOSOG Z1031B, the protocol was amended to include a tumor Ki67 determination after 2 to 4 weeks of AI. If the Ki67 was > 10%, patients were switched to neoadjuvant chemotherapy. A pCR rate of > 20% was the predefined efficacy threshold. In patients who completed neoadjuvant AI, stratified Cox modeling was used to assess whether time to recurrence differed by PEPI = 0 score (T1 or T2, N0, Ki67 < 2.7%, ER Allred > 2) versus PEPI > 0 disease. Results Only two of the 35 patients in ACOSOG Z1031B who were switched to neoadjuvant chemotherapy experienced a pCR (5.7%; 95% CI, 0.7% to 19.1%). After 5.5 years of median follow-up, four (3.7%) of the 109 patients with a PEPI = 0 score relapsed versus 49 (14.4%) of 341 of patients with PEPI > 0 (recurrence hazard ratio [PEPI = 0 v PEPI > 0], 0.27; P = .014; 95% CI, 0.092 to 0.764). Conclusion Chemotherapy efficacy was lower than expected in ER-positive tumors exhibiting AI-resistant proliferation. The optimal therapy for these patients should be further investigated. For patients with PEPI = 0 disease, the relapse risk over 5 years was only 3.6% without chemotherapy, supporting the study of adjuvant endocrine monotherapy in this group. These Ki67 and PEPI triage approaches are being definitively studied in the ALTERNATE trial (Alternate Approaches for Clinical Stage II or III Estrogen Receptor Positive Breast Cancer Neoadjuvant Treatment in Postmenopausal Women: A Phase III Study; clinical trial information: NCT01953588).

SummarySimtuzumab, a monoclonal antibody inhibitor of extracellular matrix enzyme lysyl oxidase‐like‐2, showed preclinical promise and was well tolerated in clinical studies. A phase 2, open‐label study of simtuzumab was conducted in patients with primary myelofibrosis (MF), post‐polycythaemia vera MF and post‐essential thrombocythaemia MF. Fifty‐four patients were randomized to receive simtuzumab alone (200 or 700 mg [n = 12 each group]) or simtuzumab (200 or 700 mg) with ruxolitinib (n = 15 each group) for 24 weeks. Simtuzumab alone or in combination with ruxolitinib showed no clinical benefit at 24 weeks. The mean serum simtuzumab trough concentrations appeared to increase dose‐proportionally between the 200‐mg and 700‐mg treatment groups. Therapy‐related serious adverse events were pyrexia, pain in extremity (both in 1 patient) and infusion reaction (in another patient). Bone marrow fibrosis (BMF) score was reduced at 24 weeks in 2 patients (16·7%) in the simtuzumab 700‐mg group, 1 (6·7%) in the simtuzumab 200‐mg + ruxolitinib group, and 2 (13·3%) in the simtuzumab 700‐mg + ruxolitinib group; similar numbers of patients had increased BMF. Simtuzumab alone or with ruxolitinib was well tolerated but did not produce clinical benefit nor consistently reduce BMF in patients with MF by 24 weeks.

BACKGROUND AND OBJETIVESDue to the potential risks associated with stent placement, European Society Gastrointestinal Endoscopy does not recommend prophylactic insertion of stents in patients without symptoms. The aim was to compare complication rates, need of surgery, colostomy formation, and survival between stent placement prior to start of chemotherapy (SEMS group) and upfront ChT (ChT group) in patients with endoscopically non‐transverable metastatic left‐sided colorectal cancer.METHODSGender, age, CEA, tumor location, sites of metastatic disease, peritoneal involvement, liver involvement, and angiogenesis inhibitors administration, were recorded. Complication rates, need of surgery, stoma creation, and survival were compared between both groups by univariate and multivariate test. Complications of SEMS placement in both groups were compared.RESULTSWe studied 75 men and 40 women, with a mean age of 66.3 years. Overall complication and perforation rates were similar but patients in the ChT group had a significant higher need of surgery and subsequent stoma creation. Perforation after SEMS placement rates were higher in patients receiving ChT than in patients without ChT. Survival was related to peritoneal carcinomatosis and administration of biological agents.CONCLUSIONSSEMS placement prior to ChT administration dismissed the need of subsequent surgery and decreased the rates of permanent stoma formation.

Key Points An international panel established the first ever diagnostic criteria for iMCD based on review of 244 clinical cases and 88 tissue samples. The criteria require multicentric lymphadenopathy with defined histopathology, ≥2 clinical/laboratory changes, and exclusion of iMCD mimics.

AbstractDisease overviewPolycythemia Vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms respectively characterized by erythrocytosis and thrombocytosis; other disease features include leukocytosis, splenomegaly, thrombosis, bleeding, microcirculatory symptoms, pruritus, and risk of leukemic or fibrotic transformation.DiagnosisPV is defined by aJAK2mutation, whose absence, combined with normal or increased serum erythropoietin level, makes the diagnosis unlikely.JAK2,CALR, andMPLmutations are the mutually exclusive “driver” mutations in ET with respective incidences of 55%, 25%, and 3%; approximately 17% are triple‐negative. However, the same molecular markers might also be present in prefibrotic myelofibrosis, whose morphological distinction from ET is prognostically relevant.Survival and leukemic/fibrotic transformationMedian survivals are approximately 14 years for PV and 20 years for ET; the corresponding values for younger patients (age <60 years) are 24 and 33 years. Life‐expectancy in ET is inferior to the control population. Driver mutational status has not been shown to affect survival in ET whereas the presence ofJAK2/MPLmutations has been associated with higher risk of arterial thrombosis and that ofMPLwith higher risk of fibrotic progression. Risk factors for overall survival in both ET and PV include advanced age, leukocytosis and thrombosis. Leukemic transformation rates at 20 years are estimated at <10% for PV and 5% for ET; fibrotic transformation rates are slightly higher. Most recently,ASXL1,SRSF2, andIDH2mutations have been associated with inferior overall, leukemia‐free or fibrosis‐free survival in PV; similarly adverse mutations in ET includedSH2B3,SF3B1,U2AF1,TP53,IDH2, andEZH2.Thrombosis risk stratificationCurrent risk stratification in PV and ET is designed to estimate the likelihood of recurrent thrombosis. Accordingly, PV includes two risk categories: high‐risk (age >60 years or thrombosis history) and low‐risk (absence of both risk factors). In ET, risk stratification includes four categories: very low risk (age ≤60 years, no thrombosis history,JAK2/MPLun‐mutated), low risk (age ≤60 years, no thrombosis history,JAK2/MPLmutated), intermediate risk (age >60 years, no thrombosis history,JAK2/MPLun‐mutated), and high risk (thrombosis historyorage >60 years withJAK2/MPLmutation). In addition, presence of extreme thrombocytosis (platelets >1000 × 10(9)/L) might be associated with acquired von Willebrand syndrome (AvWS) and, therefore, risk of bleeding.Risk‐adapted therapyThe main goal of therapy in PV and ET is to prevent thrombohemorrhagic complications. All patients with PV require phlebotomy to keep hematocrit below 45% and once‐daily aspirin (81 mg). In addition, high‐risk patients with PV require cytoreductive therapy. Very low risk ET patients might not require any form of therapy while low‐risk patients require at least once‐daily aspirin therapy. Cytoreductive therapy is also recommended for high‐risk ET patients but it is not mandatory for intermediate‐risk patients. First‐line drug of choice for cytoreductive therapy, in both ET and PV, is hydroxyurea and second‐line drugs of choice are interferon‐α and busulfan. We currently do not recommend treatment with ruxolutinib or otherJAK2inhibitors in PV or ET, unless in the presence of severe and protracted pruritus or marked splenomegaly that is not responding to the aforementioned drugs. Screening for AvWS is recommended before administrating aspirin, in the presence of extreme thrombocytosis. Am. J. Hematol. 92:95–108, 2017. © 2016 Wiley Periodicals, Inc.

Key Points More than half of patients with PV or ET harbor DNA mutations/variants other than JAK2/CALR/MPL. The presence of some of these mutations adversely affects overall, leukemia-free, or myelofibrosis-free survival.

Abstract Existing antiangiogenic approaches to treat metastatic hepatocellular carcinoma (HCC) are weakly effectual, prompting further study of tumor angiogenesis in this disease setting. Here, we report a novel role for sulfatase 2 (SULF2) in driving HCC angiogenesis. Sulf2-deficient mice (Sulf2 KO) exhibited resistance to diethylnitrosamine-induced HCC and did not develop metastases like wild-type mice (Sulf2 WT). The smaller and less numerous tumors formed in Sulf2 KO mice exhibited a markedly lower microvascular density. In human HCC cells, SULF2 overexpression increased endothelial proliferation, adhesion, chemotaxis, and tube formation in a paracrine fashion. Mechanistic analyses identified the extracellular matrix protein periostin (POSTN), a ligand of αvβ3/5 integrins, as an effector protein in SULF2-induced angiogenesis. POSTN silencing in HCC cells attenuated SULF2-induced angiogenesis and tumor growth in vivo. The TGFβ1/SMAD pathway was identified as a critical signaling axis between SULF2 and upregulation of POSTN transcription. In clinical HCC specimens, elevated levels of SULF2 correlated with increased microvascular density, POSTN levels, and relatively poorer patient survival. Together, our findings define an important axis controlling angiogenesis in HCC and a mechanistic foundation for rational drug development. Cancer Res; 77(3); 632–45. ©2016 AACR.