Recent evidence highlights the potential prognostic and predictive value of BRAF and K‐RAS gene alterations in patients with colorectal cancer. However, a comprehensive evaluation of BRAF and K‐RAS mutations and their specific clinicopathological features, histomorphological presentation and effect on protein expression have not been systematically analyzed. The aim of this study was to characterize the clinicopathological, histomorphological and protein expression profiles of BRAF‐ and K‐RAS‐mutated colorectal cancers and determine their impact on patient survival. Molecular analysis for microsatellite instability (MSI), K‐RAS and BRAF was carried out on paraffin‐embedded samples from 404 patients with primary colorectal cancer. Using tissue microarrays, 36 tumor‐associated and 14 lymphocyte/inflammatory‐associated markers were evaluated by immunohistochemistry. BRAF mutation was associated with right‐sided tumor location (p < 0.001), higher tumor grade (p = 0.029), absence of peritumoral lymphocytic inflammation (p = 0.026) and MSI‐H (p < 0.001). In right‐sided tumors, loss of CDX2 expression was observed in 23 of 24 cases (95.8%). BRAF mutation was a poor prognostic indicator in patients with right‐sided disease (p = 0.01). This result was maintained in multivariable analysis (p < 0.001; HR = 2.82; 95% CI: 1.5–5.5) with pT, pN and vascular invasion and independent of CDX2 expression. K‐RAS mutation, in contrast, was not associated with any of the features analyzed. BRAF gene mutation is an adverse prognostic factor in right‐sided colon cancer patients independent of MSI status and, moreover, in patients with lymph node‐negative disease. These results indicate that molecular analysis for BRAF may be a useful biomarker for identifying patients with right‐sided colon cancer with poor outcome who may benefit from a more individualized course of therapy.

The ideal anticoagulant is oral, has a wide therapeutic range, predictable pharmacokinetics and pharmacodynamics, a rapid onset of action, an available antidote, minimal side effects and minimal interactions with other drugs or food. With the development of the novel direct oral anticoagulants (DOAC), we now have an alternative to the traditional vitamin K antagonists (VKA) for the prevention and treatment of thrombosis. DOACs have limited monitoring requirements and very predictable pharmacokinetic profiles. They were shown to be non-inferior or superior to VKA in the prophylaxis or treatment of thromboembolic events. Particularly in terms of safety they were associated with less major bleeding, including intracranial bleeding, thus providing a superior benefit for the prevention of stroke in patients with atrial fibrillation. Despite these advantages, there are remaining limitations with DOACs: their dependence on renal and hepatic function for clearance and the lack of an approved reversal agent, whereas such antidotes are successively being made available. DOACs do not need regular monitoring to assess the treatment effect but, on the other hand, they interact with other drugs and interfere with functional coagulation assays. From a practical point of view, the properties of oral administration, simple dosing without monitoring, a short half-life allowing for the possibility of uncomplicated switching or bridging, and proven safety overwhelm the disadvantages, making them an attractive option for short- or long-term anticoagulation.

The combination of lenalidomide (Revlimid , R) and dexamethasone (d) is a standard regimen for patients with relapsed/refractory multiple myeloma (rrMM). With this regimen, only a small fraction of patients will achieve high quality responses [≥ very good partial response (VGPR)]. The combination of bendamustine (B), lenalidomide and dexamethasone (BRd) has shown high efficacy in patients with advanced rrMM. However, dose-limiting haematotoxicity restricted its use in extensively pre-treated patient populations. This prospective, multicentre Phase II study evaluated the efficacy and safety of BRd in rrMM patients with one prior line of therapy. Fifty patients were enrolled (median age 68·5 years [range 46-83]) and were treated with B 75 mg/m days 1, 2; R 25 mg days 1-21 and d (40/20 mg) days 1, 8, 15 and 22, for 6 28-day induction cycles, followed by 12 cycles with Rd alone. Pegfilgrastim was administered according to protocol-defined criteria. The study aimed to demonstrate a complete response (CR)/VGPR rate of >40% after induction therapy. Of 45 evaluable patients, 23 (51%) achieved a CR/VGPR. Grade 4 neutropenia or thrombocytopenia occurred in 17 (34%) and 8 (16%) of patients, respectively. BRd is a safe and efficacious regimen as a second line treatment for rrMM, leading to high quality responses in a considerable proportion of patients.

Dasatinib produced high metabolic response rates in TKI-naive patients with FDG-PET/CT-positive GIST. Cancer 2018;124:1449-54. © 2018 American Cancer Society.

Background High quality response [very good partial remission (VGPR), complete remission (CR)] is associated with improved long-term outcome in multiple myeloma (MM) therapy. Lenalidomide (Len)/ dexamethasone (Dex) (Rd) is considered a standard 2nd-line regimen. However, after 1st-line MM therapy containing a “novel agent” like thalidomide, only a relatively small fraction (21.3%) of patients (pts) achieved VGPR or better when RD was used in relapsed/refractory MM (RRMM)1. Bendamustine (Ben) is an alkylating agent with superior activity compared to melphalan/prednisone. The combination of Ben, Len and Dex (BRd) in pts with advanced RRMM resulted in dose-limiting hematotoxicity, which restricted its efficacy in extensively pretreated pts2. However, recent phase I experience demonstrated the feasibility of BRd as 2nd- and 3rd-line myeloma therapy3. We therefore evaluated the efficacy and toxicity of the BRd-regimen as 2nd line therapy for RRMM. Patients and methods This multicenter Phase II study was designed to enroll 50 pts with RRMM undergoing 2nd-line MM therapy [including also pts with prior autologous stem cell transplantation (ASCT)]. Pts had to have measurable disease, ECOG performance status 0-2, adequate hematological values and a creatinine clearance > 50 ml/min. Study treatment consisted of Ben 75 mg/m2 i.v. day (d) 1 & 2 and Len 25 mg p.o. d 1-21 for a total of six 28-day induction cycles. Dex (40 and 20 mg p.o. for pts <= or > 75 years of age, respectively) was given on d 1, 8, 15, and 22. Pegfilgrastim 6 mg s.c. was administered on d 3 in case of severe neutropenia, treatment delay due to neutropenia or febrile neutropenia according to predefined application rules. Induction treatment was followed by 12 cycles (28 d) of maintenance therapy with Rd at the same dose. The primary study endpoint was the CR/VGPR rate after induction therapy, based on standard IMWG criteria. A Simon's two stage design was used to differentiate between 20% (considered uninteresting) vs 40 % (considered promising, power of 80%, p=5%) of high quality responses. At least 13 pts with VGPR or better after induction therapy were required to meet the statistical threshold predefined for promising activity of the BRd regimen in this study. Results 50 pts were enrolled between 04/2012 and 07/2014 (median age 68 years [46-84y], 73% men). 49% pts had ISS stage II/III, 42.5% had undergone prior SCTs, and 13% had known high risk cytogenetic aberrations. 91% of pts had received novel agents (thalidomide, bortezomib) during 1st-line therapy. At the time of abstract submission, data from 38 pts having completed induction treatment were available. Final analysis of the primary study endpoint including all patients will be updated and presented at the meeting. Of the currently 38 evaluable pts, 20 (52.6%, Table 1) achieved a CR/VGPR after a median of 3.3 induction cycles. Only 1 patient experienced disease progression (PD) during induction phase. 77% of pts received pegfilgrastim. Dose reduction during induction therapy was required in 7.7% of pts. 42.5% received < 6 scheduled induction cycles (50% due to toxicities, 50% for other reasons). 49% had treatment-related SAEs. Grade 3/ 4 neutropenia and thrombocytopenia occurred in 51%/25.5% and 23.4%/8.5% of pts, respectively. Only 1 patient developed CTC grade 3 febrile neutropenia. Most common grade 3/4 non-hematologic toxicities were infections (14%), rash (9.5%), and diarrhea (9.5%). Anaphylactic reaction grade 4 related to Ben and pulmonary embolism grade 3 occurred in 1 patient each. A cerebral insult grade 4 occurred in a patient non-compliant with the anti-thrombotic prophylaxis required per protocol. One death due to respiratory failure (considered to be unlikely related to study treatment) was reported for an 83 year old male. Conclusion BRd is a safe and efficacious regimen for 2nd line treatment of RRMM patients whose 1st-line therapy included thalidomide or bortezomib. High quality responses (>= VGPR) can be achieved in a considerable proportion (52.6%) of these pts. Our study suggests that the fraction of patients achieving VGPR or better after BRd treatment may be substantially higher than attainable with Rd alone. References 1 Wang et al. Blood, 2008, 112: 4445-51 2 Lentzsch et al. Blood, 2012, 119: 4608-13 3 Poenisch et al., Br J Haematol, 2013, 162, 202–9 Table 1 Best response after induction CR VGPR PR MR SD total (n=38) 3 17 15 1 2 prior ASCT (n=16) 2 6 7 1 0 no prior ASCT (n=22) 1 11 8 0 2 Disclosures Mey: Mundipharma: Honoraria, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Use of Bendamustine in relapsed/refractory Multiple Myekoma. To investigate the efficacy and safety of Bendamustine in combination with the standard backbone of Lenalidomide/ Dexamethasone in patients with replaced/refractory MM.. Bargetzi:Celgene: Membership on an entity's Board of Directors or advisory committees. Taverna:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Schmid:Celgene: Honoraria. Knauf:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. von Moos:Amgen: Consultancy, Honoraria, Research Funding. Hiendlmeyer:Celgene: Research Funding; Mundipharma: Research Funding; Amgen: Research Funding. Hitz:Celgene: Research Funding. Driessen:Mundipharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees.