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PURPOSE: This study aimed to explore the association of β-catenin expression pattern with pathological response after neoadjuvant chemotherapy in breast cancer (BC) patients.MATERIALS AND METHODS: In this retrospective exploratory study, data for 50 BC patients who received neoadjuvant chemotherapy were recorded. β-catenin expression in tumours was assessed using immunohistochemistry and classified as either membranous or cytoplasmic according to the pattern of staining. Distributions of different clinico-pathological parameters according to β-catenin expression were assessed using the Chi-square test. Logistic regression analysis was used to assess any relation of the pattern of β-catenin expression with the pathological response.RESULTS: Cytoplasmic β-catenin expression was detected in 34% of BCs. Among our cases, 52% were hormonal receptor (HR)-positive, 24% were HER2-positive, 74% were clinical stage III and 74% received both anthracycline and taxane-based chemotherapy. Patients with cytoplasmic expression were more commonly younger than 40 years at diagnosis (cytoplasmic, 41.2% vs. no cytoplasmic expression, 12.1%, p=0.03). By doing t-test, cytoplasmic β-catenin expression was linked with a higher body mass index compared to membranous-only expression (mean± SD 33.0 ± 4.47 vs. 29.6 ±6.01, respectively, p=0.046). No significant associations were found between β-catenin expression and other parameters such as HR and HER2 status, or clinical stage. Complete pathological response (pCR) rate was twice as great in patients with membranous expression but without statistical signi cance (membranous- only, 33.3% vs. cytoplasmic, 17.6%, OR=2.3, 95% CI= 0.55-9.87, p=0.24).CONCLUSIONS: This study suggests that cytoplasmic β-catenin expression may be linked with lower probability of achieving pCR after neoadjuvant chemotherapy. These data need to be validated in a larger cohort of patients.

Smaglo B.,Oncology | Mok H.,Baylor College of Medicine
Annals of Cardiothoracic Surgery | Year: 2017

Resection techniques for esophageal carcinoma continue to evolve, from endoscopic mucosal resection or endoscopic submucosal dissection for early stage disease to standard and robot-assisted minimally invasive esophagectomy as part of multimodal therapy for locally advanced disease. Though currently limited to assessing conduit perfusion and sentinel lymph nodes, embedded technology in the robotic surgical platform will likely play an expanded role during esophagectomy in the future. The use of targeted therapies, checkpoint inhibitors, engineered immune cell therapy, and cancer vaccines show promise in the treatment of systemic disease. Radiation therapy techniques are becoming increasingly sophisticated and they may play a more active role in stage IV disease in the future. © Annals of Cardiothoracic Surgery. All rights reserved.

Rosti G.,Oncology
Supportive Care in Cancer | Year: 2017

Improving patient-physician communication is an area of medicine that deserves greater attention. Narrative medicine can be considered as one tool that can aid in fostering better communication. Current medical practice is dominated by evidence-based medicine, and dictates what therapies the clinician will offer in a given circumstance, ideally supported by (evidence-based) guidelines. However, when taken alone it tends to decentralize the patient. There are many different approaches that can be used to understand the patient and what he or she is experiencing as a result of their illness. While time constraints are often mentioned as a barrier to improved communication, in reality the time required to listen to patients is not excessive, and all caregivers should reflect on the possibility to give patients greater freedom from time constraints during consultation, and encourage them to narrate their experiences. Moreover, use of narrative-based medicine may be associated with better diagnosis and treatment of pain. Narrative-based medicine is not just for end-of-life care, but something for all caregivers to give greater consideration to in daily practice in order to form a strong frame of alliance. © 2017 The Author(s)

Rodel C.,Goethe University Frankfurt | Liersch T.,University of Gottingen | Becker H.,University of Gottingen | Fietkau R.,Friedrich - Alexander - University, Erlangen - Nuremberg | And 19 more authors.
The Lancet Oncology | Year: 2012

Background: Preoperative chemoradiotherapy, total mesorectal excision surgery, and adjuvant chemotherapy with fluorouracil is the standard combined modality treatment for rectal cancer. With the aim of improving disease-free survival (DFS), this phase 3 study (CAO/ARO/AIO-04) integrated oxaliplatin into standard treatment. Methods: This was a multicentre, open-label, randomised, phase 3 study in patients with histologically proven carcinoma of the rectum with clinically staged T3-4 or any node-positive disease. Between July 25, 2006, and Feb 26, 2010, patients were randomly assigned to two groups: a control group receiving standard fluorouracil-based combined modality treatment, consisting of preoperative radiotherapy of 50·4 Gy plus infusional fluorouracil (1000 mg/m2 days 1-5 and 29-33), followed by surgery and four cycles of bolus fluorouracil (500 mg/m2 days 1-5 and 29; fluorouracil group); and an experimental group receiving preoperative radiotherapy of 50·4 Gy plus infusional fluorouracil (250 mg/m2 days 1-14 and 22-35) and oxaliplatin (50 mg/m2 days 1, 8, 22, and 29), followed by surgery and eight cycles of adjuvant chemotherapy with oxaliplatin (100 mg/m2 days 1 and 15), leucovorin (400 mg/m2 days 1 and 15), and infusional fluorouracil (2400 mg/m2 days 1-2 and 15-16; fluorouracil plus oxaliplatin group). Randomisation was done with computer-generated block-randomisation codes stratified by centre, clinical T category (cT1-4 vs cT4), and clinical N category (cN0 vs cN1-2) without masking. DFS is the primary endpoint. Secondary endpoints, including toxicity, compliance, and histopathological response are reported here. Safety and compliance analyses included patients as treated, efficacy endpoints were analysed according to the intention-to-treat principle. This study is registered with ClinicalTrials.gov, number NCT00349076. Findings: Of the 1265 patients initially enrolled, 1236 were evaluable (613 in the fluorouracil plus oxaliplatin group and 623 in the fluorouracil group). Preoperative grade 3-4 toxic effects occurred in 140 (23%) of 606 patients who actually received fluorouracil and oxaliplatin during chemoradiotherapy and in 127 (20%) of 624 patients who actually received fluorouracil chemoradiotherapy. Grade 3-4 diarrhoea was more common in those who received fluorouracil and oxaliplatin during chemoradiotherapy than in those who received fluorouracil during chemoradiotherapy (73 patients [12%] vs 52 patients [8%]), as was grade 3-4 nausea or vomiting (23 [4%] vs nine [1%]). 516 (85%) of the 606 patients who received fluorouracil and oxaliplatin-based chemoradiotherapy had the full dose of chemotherapy, and 571 (94%) had the full dose of radiotherapy; as did 495 (79%) and 601 (96%) of 624 patients who received fluorouracil-based chemoradiotherapy, respectively. A pathological complete response was achieved in 103 (17%) of 591 patients who underwent surgery in the fluorouracil and oxaliplatin group and in 81 (13%) of 606 patients who underwent surgery in the fluorouracil group (odds ratio 1·40, 95% CI 1·02-1·92; p=0·038). In the fluorouracil and oxaliplatin group, 352 (81%) of 435 patients who began adjuvant chemotherapy completed all cycles (with or without dose reduction), as did 386 (83%) of 463 patients in the fluorouracil group. Interpretation: Inclusion of oxaliplatin into modified fluorouracil-based combined modality treatment was feasible and led to more patients achieving a pathological complete response than did standard treatment. Longer follow-up is needed to assess DFS. Funding: German Cancer Aid (Deutsche Krebshilfe). © 2012 Elsevier Ltd.

Mathew J.,Oncology
Diseases of the Esophagus | Year: 2011

Summary: Obesity is a risk factor for the development of esophageal malignancy. We report a case of the development of esophageal adenocarcinoma after placement of an adjustable gastric band for obesity. A 66-year-old male was referred to our clinic for findings of an obstructing mass at the gastroesophageal junction after previously undergoing a laparoscopic adjustable gastric band placement. Investigations confirmed a locally advanced poorly differentiated esophageal adenocarcinoma. The patient underwent chemotherapy and gastric band removal with improvement of his dysphagia. However, his disease progressed and he died of metastatic disease. We discuss the diagnosis of esophageal carcinoma after gastric banding procedure. © 2010 © the Authors. Journal compilation © 2010, Wiley Periodicals, Inc. and the International Society for Diseases of the Esophagus.

Demetri G.D.,Dana-Farber Cancer Institute | Reichardt P.,Oncology | Kang Y.-K.,University of Ulsan | Blay J.-Y.,University of Lyon | And 20 more authors.
The Lancet | Year: 2013

Background Until now, only imatinib and sunitinib have proven clinical benefi t in patients with gastrointestinal stromal tumours (GIST), but almost all metastatic GIST eventually develop resistance to these agents, resulting in fatal disease progression. We aimed to assess effi cacy and safety of regorafenib in patients with metastatic or unresectable GIST progressing after failure of at least imatinib and sunitinib. Methods We did this phase 3 trial at 57 hospitals in 17 countries. Patients with histologically confi rmed, metastatic or unresectable GIST, with failure of at least previous imatinib and sunitinib were randomised in a 2:1 ratio (by computergenerated randomisation list and interactive voice response system; preallocated block design (block size 12); stratifi ed by treatment line and geographical region) to receive either oral regorafenib 160 mg daily or placebo, plus best supportive care in both groups, for the fi rst 3 weeks of each 4 week cycle. The study sponsor, participants, and investigators were masked to treatment assignment. The primary endpoint was progression-free survival (PFS). At disease progression, patients assigned placebo could crossover to open-label regorafenib. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01271712. Results From Jan 4, to Aug 18, 2011, 240 patients were screened and 199 were randomised to receive regorafenib (n=133) or matching placebo (n=66). Data cutoff was Jan 26, 2012. Median PFS per independent blinded central review was 4.8 months (IQR 1.4-9.2) for regorafenib and 0.9 months (0.9-1.8) for placebo (hazard ratio [HR] 0.27, 95% CI 0.19-0.39; p7lt;0.0001). After progression, 56 patients (85%) assigned placebo crossed over to regorafenib. Drug-related adverse events were reported in 130 (98%) patients assigned regorafenib and 45 (68%) patients assigned placebo. The most common regorafenib-related adverse events of grade 3 or higher were hypertension (31 of 132, 23%), hand-foot skin reaction (26 of 132, 20%), and diarrhoea (seven of 132, 5%). Interpretation The results of this study show that oral regorafenib can provide a signifi cant improvement in progression-free survival compared with placebo in patients with metastatic GIST after progression on standard treatments. As far as we are aware, this is the fi rst clinical trial to show benefi t from a kinase inhibitor in this highly refractory population of patients.

Ardini E.,Oncology | Galvani A.,Oncology
Frontiers in Oncology | Year: 2012

In 2007, the ALK tyrosine kinase was described as a potential therapeutic target for a subset of non-small-cell lung cancer patients. Clinical proof of concept, culminating in the recent approval by the Food and Drug Administration of the Pfizer drug crizotinib followed in record time. The drug was approved together with a companion diagnostic for detection of patients eligible for therapy. This remarkable example of the coming of age of personalized medicine in cancer therapy is hopefully only an auspice of things to come in a rapidly developing field. Perhaps unsurprisingly, however, the appearance of clinical acquired resistance to crizotinib was observed early on in clinical testing, with the identification of several ALK secondary point mutations which diminish drug efficacy and which open the way for development of second-generation inhibitors. It is also emerging that acquired resistance to crizotinib may additionally occur through ALK-independent mechanisms, which still need to be elucidated in detail. Here we discuss the factors that led to such a rapid approval of a targeted agent, and we describe the second-generation compounds currently in development. © 2012 Ardini and Galvani.

Scabini M.,Oncology | Stellari F.,Oncology | Cappella P.,Oncology | Rizzitano S.,Oncology | And 2 more authors.
Apoptosis | Year: 2011

In vivo imaging of apoptosis in a preclinical setting in anticancer drug development could provide remarkable advantages in terms of translational medicine. So far, several imaging technologies with different probes have been used to achieve this goal. Here we describe a bioluminescence imaging approach that uses a new formulation of Z-DEVD-aminoluciferin, a caspase 3/7 substrate, to monitor in vivo apoptosis in tumor cells engineered to express luciferase. Upon apoptosis induction, Z-DEVD-aminoluciferin is cleaved by caspase 3/7 releasing aminoluciferin that is now free to react with luciferase generating measurable light. Thus, the activation of caspase 3/7 can be measured by quantifying the bioluminescent signal. Using this approach, we have been able to monitor caspase-3 activation and subsequent apoptosis induction after camptothecin and temozolomide treatment on xenograft mouse models of colon cancer and glioblastoma, respectively. Treated mice showed more than 2-fold induction of Z-DEVD-aminoluciferin luminescent signal when compared to the untreated group. Combining D-luciferin that measures the total tumor burden, with Z-DEVD-aminoluciferin that assesses apoptosis induction via caspase activation, we confirmed that it is possible to follow non-invasively tumor growth inhibition and induction of apoptosis after treatment in the same animal over time. Moreover, here we have proved that following early apoptosis induction by caspase 3 activation is a good biomarker that accurately predicts tumor growth inhibition by anti-cancer drugs in engineered colon cancer and glioblastoma cell lines and in their respective mouse xenograft models. © 2010 Springer Science+Business Media, LLC.

Guiley K.Z.,University of California at Santa Cruz | Liban T.J.,University of California at Santa Cruz | Felthousen J.G.,Oncology | Felthousen J.G.,Virginia Commonwealth University | And 4 more authors.
Genes and Development | Year: 2015

The DREAM complex represses cell cycle genes during quiescence through scaffolding MuvB proteins with E2F4/5 and the Rb tumor suppressor paralog p107 or p130. Upon cell cycle entry, MuvB dissociates from p107/p130 and recruits B-Myb and FoxM1 for up-regulating mitotic gene expression. To understand the biochemical mechanisms underpinning DREAM function and regulation, we investigated the structural basis for DREAM assembly. We identified a sequence in the MuvB component LIN52 that binds directly to the pocket domains of p107 and p130 when phosphorylated on the DYRK1A kinase site S28. A crystal structure of the LIN52–p107 complex reveals that LIN52 uses a suboptimal LxSxExL sequence together with the phosphate at nearby S28 to bind the LxCxE cleft of the pocket domain with high affinity. The structure explains the specificity for p107/p130 over Rb in the DREAM complex and how the complex is disrupted by viral oncoproteins. Based on insights fromthe structure, we addressed how DREAM is disassembled upon cell cycle entry. We found that p130 and B-Myb can both bind the core MuvB complex simultaneously but that cyclin-dependent kinase phosphorylation of p130 weakens its association. Together, our data inform a novel target interface for studying MuvB and p130 function and the design of inhibitors that prevent tumor escape in quiescence. © 2015 Guiley et al.

Finn R.S.,Oncology | Bengala C.,University of Modena and Reggio Emilia | Ibrahim N.,University of Houston | Roche H.,Institute Claudius Regaud | And 5 more authors.
Clinical Cancer Research | Year: 2011

Purpose: Dasatinib is a potent, oral SRC-family kinase inhibitor with preclinical antiproliferative, antimetastatic, and antiosteoclastic activity suggesting dasatinib sensitivity in triple-negative, or basal-like, breast cancer cell lines. This phase 2 trial assessed efficacy and safety of single-agent dasatinib in patients with advanced triple-negative breast cancer (TNBC). Experimental Design: Female patients with measurable, locally advanced or metastatic TNBC initially received dasatinib 100 mg twice daily (BID); to improve tolerability, the protocol was amended and subsequent patients received 70 mg BID. Primary endpoint was Response Evaluation Criteria in Solid Tumors-defined objective response rate (ORR); secondary endpoints included progression-free survival (PFS), disease control rate (DCR), safety, and limited pharmacokinetics. Results: Of the 44 treated patients, 43 were response evaluable. ORR was 4.7%: two patients had confirmed partial responses lasting 14 and 58 weeks, respectively. Of 11 patients with stable disease, two continued for more than 16 weeks, thus protocol-defined DCR was 9.3%. Median PFS was 8.3 weeks (95% CI: 7.3-15.3). Five patients discontinued before first tumor assessment. No grade 4 adverse events (AE) were reported; grade 3 AEs occurring in more than 5% of patients were fatigue (9.1%), diarrhea, pleural effusion, and dyspnea (all 6.8%). Laboratory abnormalities were uncommon. Dasatinib at 100 mg BID was not well tolerated; rates of treatment interruption, dose reduction, and serious AEs were lower with dasatinib 70 mg BID. Conclusions: Single-agent dasatinib has limited activity in unselected patients with TNBC. Dasatinib 70 mg BID was better tolerated than 100 mg BID. Future studies will investigate dasatinib in other breast cancer settings, including chemotherapy combinations. ©2011 AACR.

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