Cognitive flexibility in women who recovered from anorexia nervosa - a model-based approach.

Research findings on cognitive flexibility (CF) functioning in women who recovered from anorexia nervosa (RAN) were found to be inconsistent. This was attributed to the multiple definitions of CF and the diverse measuring tools used to assess it. Applying a deductive approach to explore CF function may address these inconsistencies; thus, we used a model that divides CF into three subtypes, namely, stimulus-response mapping, switching sets and task switching. Additionally, we explored the association between CF subtypes and the disorder's clinical measures to assess the relation of CF to recovery. Forty-three RAN and 54 healthy controls performed tasks designed to assess CF subtypes based on the model's division, and the RAN group completed the Eating Disorder Examination Questionnaire. The results showed that the RAN group performed significantly worse than controls only in the stimulus-response mapping subtype. Additionally, there were no correlations between CF subtypes and clinical symptoms or the disorder measures - current and nadir body mass index, age of onset, time since recovery, and disorder duration. In conclusion, the study revealed CF impairment after recovery from AN, specifically in stimulus-response mapping. The variability in performance of the CF subtypes supports the application of a theory-driven perspective viewing CF as a modular ability in RAN. Additionally, CF is unrelated to clinical measures post-recovery and thus may not be used as a criterion for evaluating recovery.

Effects of EGFR driver mutations on pathologic regression in resectable locally advanced non-small cell lung cancer treated with neoadjuvant chemoradiation and completion surgery.

OBJECTIVE: We hypothesized that driver mutations in epidermal growth factor receptor (EGFR) are associated with decreased pathologic response to neoadjuvant chemoradiation (NA-ChRT) in locally advanced non-small cell lung cancer (LA-NSCLC). METHODS: Patients with Stage IIB-IIIA NSCLC treated with NA-ChRT, completion surgery, and underwent molecular profile testing were identified in a lung cancer database. Pathologic response was quantified using: (i) major pathologic response (MPR), (ii) complete pathologic response (pCR), and (iii) mean residual viable tumor cells (MRTC). Two groups were formed based on the presence or absence of driver mutations. Clinical and pathological correlations between the groups were studied. RESULTS: Forty-seven patients underwent tumor molecular profile testing, NA-ChRT, and completion surgery. Compared to the no-driver mutation group, the driver mutation group had lower MPR (23% vs 71%, p = 0.003), pCR (0% vs 26%, p = 0.02), and higher MRTC (43.4% vs 15.8%, p = 0.009). Univariate analysis showed an increased MPR rate for smokers, squamous cell histology, ChRT-surgery interval >65 days, and no-driver mutations. Multivariate analysis showed that only no-driver mutations (OR 0.39, p = 0.02) remained significant for MPR. PD-L1 status did not affect MPR. At 2 years, the driver mutation group had lower rates of local control (Hazard ration [HR] 0.67, p = 0.17) and disease-free survival (HR 0.5, p = 0.001). Overall survival was similar for both groups (HR = 1.04, p = 0.86). CONCLUSION: Following 60 Gray NA-ChRT, tumors with a driver mutation had lower MPR and pCR rates than tumors without a driver mutation. PD-L1 was not associated with tumor regression. ADVANCES IN KNOWLEDGE: Patients with resectable LA-NSCLC and an EGFR driver mutation treated with neoadjuvant-ChRT and completion surgery have reduced pathologic regression, lower local control rates, and shorter disease-free survival than patients without a driver mutation. Evaluation of molecular testing should be introduced in LA-NSCLC intended for prognostication and treatment decisions.

Driver mutation characteristics of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) in advanced non-small cell lung cancer.

OBJECTIVES: The identification and targeting of actionable genomic alterations (AGA) have revolutionized the treatment of cancer in general and mostly for non-small cell lung cancer (NSCLC). We investigated whether in NSCLC patients PIK3CA mutations are actionable. MATERIALS AND METHODS: Chart review was performed of advanced NSCLC patients. PIK3CA mutated patients were analyzed as two groups: Group A: without any non-PIK3CA established AGA; Group B: with coexisting AGA. Group A was compared to a cohort of non-PIK3CA patients (group C), using t-test and chi-square. To evaluate the impact of PIK3CA mutation on outcome, we compared Group A survival to age/sex/histology matched cohort of non-PIK3CA mutated patients (group D) by Kaplan-Meier method. A patient with a PIK3CA mutation was treated with a PI3Ka-isoform selective inhibitor BYL719 (Alpelisib). RESULTS: Of a cohort of 1377 patients, 57 are PIK3CA mutated (4.1%). Group A: n-22, group B: n-35. Group A median age is 76 years, 16 (72.7%) men, 10 (45.5%) squamous, 4 (18.2%) never smokers. Two never-smoker female adenocarcinoma patients had solitary PIK3CA mutation. One of them was treated with a PI3Ka-isoform selective inhibitor BYL719 (Alpelisib), with rapid clinical and partial radiological improvement. Group B, compared with Group A, included younger patients (p = 0.030), more females (p = 0.028) and more adenocarcinoma cases (p < 0.001). Compared to group C, group A patients were older (p = 0.030) and had more squamous histology (p = 0.011). CONCLUSION: In a small minority of NSCLC patients with PIK3CA mutation there are no additional AGA. PIK3CA mutations may be actionable in these cases.

Direct identification of ALK and ROS1 fusions in non-small cell lung cancer from hematoxylin and eosin-stained slides using deep learning algorithms.

Anaplastic lymphoma kinase (ALK) and ROS oncogene 1 (ROS1) gene fusions are well-established key players in non-small cell lung cancer (NSCLC). Although their frequency is relatively low, their detection is important for patient care and guides therapeutic decisions. The accepted methods used for their detection are immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) assay, as well as DNA and RNA-based sequencing methodologies. These assays are expensive, time-consuming, and require technical expertise and specialized equipment as well as biological specimens that are not always available. Here we present an alternative detection method using a computer vision deep learning approach. An advanced convolutional neural network (CNN) was used to generate classifier models to detect ALK and ROS1-fusions directly from scanned hematoxylin and eosin (H&E) whole slide images prepared from NSCLC tumors of patients. A two-step training approach was applied, with an initial unsupervised training step performed on a pan-cancer sample cohort followed by a semi-supervised fine-tuning step, which supported the development of a classifier with performances equal to those accepted for diagnostic tests. Validation of the ALK/ROS1 classifier on a cohort of 72 lung cancer cases who underwent ALK and ROS1-fusion testing at the pathology department at Sheba Medical Center displayed sensitivities of 100% for both genes (six ALK-positive and two ROS1-positive cases) and specificities of 100% and 98.6% respectively for ALK and ROS1, with only one false-positive result for ROS1-alteration. These results demonstrate the potential advantages that machine learning solutions may have in the molecular pathology domain, by allowing fast, standardized, accurate, and robust biomarker detection overcoming many limitations encountered when using current techniques. The integration of such novel solutions into the routine pathology workflow can support and improve the current clinical pipeline.

Upfront rational therapy in BRAF V600E mutated pediatric ameloblastoma promotes ad integrum mandibular regeneration.

Ameloblastoma is a neoplasm arising in the craniofacial skeleton. Proliferating odontogenic epithelial cells comprise this benign, yet locally invasive tumor, often causing severe disfiguration. High recurrence rate entails ablative surgical resection, which is the current standard of care, resulting in subsequent critical size osteocutaneous defects. The high incidence of BRAF mutations in ameloblastoma, most notably the BRAF V600E mutation, enabled the use of BRAF inhibiting agent in a neoadjuvant setting. In this investigator-initiated, open-label study, three consecutive pediatric patients, with confirmed BRAF V600E ameloblastoma deemed marginally resectable, were treated with BRAF inhibiting agents, prior to undergoing surgery. The use of upfront BRAF inhibitor treatment resulted in substantial tumor regression, allowing for non-mutilating complete surgical removal, ad integrum bone regeneration and organ preservation. All patients showed a marked radiologic and clinical response to medical treatment, enabling successful conservative surgery. Microscopically, all patients showed evidence of minimal residual tumor with extensive tumor necrosis, fibrosis and generation of new bone. At a median follow-up of 31 months, all patients remained free of disease. Face preservation therapy was achieved in pediatric patients presenting with BRAF V600E mutated ameloblastoma. Our study demonstrates the translational potential of targeted therapy as a neoadjuvant agent. Patient-specific organ preservation therapy should be considered as the new standard of care in ameloblastoma, mainly for children and adolescents.

Multicenter Evaluation of the Idylla NRAS-BRAF Mutation Test in Metastatic Colorectal Cancer.

Treatment of colorectal cancer (CRC) with monoclonal antibodies against epidermal growth factor receptor requires the assessment of the mutational status of exons 2, 3, and 4 of the NRAS and KRAS oncogenes. Moreover, the mutational status of exon 15 of the BRAF oncogene is a marker of poor prognosis in CRC. The Idylla NRAS-BRAF Mutation Test is a reliable, simple (<2 minutes hands-on time), and quick (<2 hours turnaround time) sample-to-result solution, enabling the detection of clinically relevant mutations in NRAS (18 mutations) and BRAF (5 mutations). A multicenter study was conducted in 14 centers using the Idylla NRAS-BRAF Mutation Test to assess the NRAS and BRAF mutational status of 418 formalin-fixed, paraffin-embedded tissue samples from CRC patients. Results were compared with those obtained earlier by routine reference methods, including next-generation sequencing, pyrosequencing, mass spectrometry-based assays, PCR-based assays, and Sanger sequencing. In case of discordance, additional tests were performed by digital droplet PCR. Overall, after testing confirmation and excluding invalids/errors by design, concordances between the Idylla NRAS-BRAF Mutation Test and the reference test results were found in almost perfect agreement. In conclusion, the Idylla NRAS-BRAF Mutation Test enables the routine detection of all NRAS and BRAF mutations deemed clinically relevant according to the latest clinical guidelines, without necessitating molecular expertise or infrastructure.

[Correlation between the presence of Kras mutation and the presence of the proteins epiregulin and amphiregulin in colon cancer tissue].

INTRODUCTION: Progress has been made in the treatment of metastatic colorectal cancer with the development of biologic agents such as Cetuximab and Panitumumab. These monoclonal antibodies are directed against EGFR and influence cell division, attachment, angiogenesis, migration and apoptosis. Correlation has been found between the presence of mutations in the K-ras gene and resistance to treatment with Cetuximab.New guidelines require K-ras mutation analysis before anti-EGFR treatment is provided. The proteins Amphiregulin and Epiregulin belong to the Epidermal growth factors family (EGF, that act through the EGFR. Over-expression of these proteins has been seen in a variety of malignancies and non-malignant pathologies. These proteins can be detected in samples from colorectal malignancies and inflammatory bowel disease by immunohistochemical staining. Jacobs et at showed that mRNA expression of these proteins n colorectal malignancy predicts outcomes in wild type K-ras metastatic patients treated with Cetuximab. AIM: The purpose of our study is to examine whether there is a correlation between the presence of colorectal cancer K-ras mutations and the level of expression of EpireguLin and Amphiregulin in the malignant tissue. MATERIAL AND METHODS: In a retrospective study we examined 30 tissue samples of colon cancer patients for the presence of K-ras mutation and immunohistochemicaL staining for Epiregulin and AmphireguLin. RESULTS: A total of 14 (46.66%] samples showed mutation in the K-ras gene; 15 of 30 samples [50%] were positive for AmphireguLin. As for Epiregulin, 10 (33.3%) samples had strong staining, 10 (33.3%) samples had Light staining and the rest, 10 (33.3%) didn't have any staining. In conclusion, we did not find a correlation between the presence of a K-ras mutation and the presence of Epiregulin and Amphiregulin in colon cancer tissue.

Targeting autophagy potentiates tyrosine kinase inhibitor-induced cell death in Philadelphia chromosome-positive cells, including primary CML stem cells.

Imatinib mesylate (IM), a potent inhibitor of the BCR/ABL tyrosine kinase, has become standard first-line therapy for patients with chronic myeloid leukemia (CML), but the frequency of resistance increases in advancing stages of disease. Elimination of BCR/ABL-dependent intracellular signals triggers apoptosis, but it is unclear whether this activates additional cell survival and/or death pathways. We have shown here that IM induces autophagy in CML blast crisis cell lines, CML primary cells, and p210BCR/ABL-expressing myeloid precursor cells. IM-induced autophagy did not involve c-Abl or Bcl-2 activity but was associated with ER stress and was suppressed by depletion of intracellular Ca2+, suggesting it is mechanistically nonoverlapping with IM-induced apoptosis. We further demonstrated that suppression of autophagy using either pharmacological inhibitors or RNA interference of essential autophagy genes enhanced cell death induced by IM in cell lines and primary CML cells. Critically, the combination of a tyrosine kinase inhibitor (TKI), i.e., IM, nilotinib, or dasatinib, with inhibitors of autophagy resulted in near complete elimination of phenotypically and functionally defined CML stem cells. Together, these findings suggest that autophagy inhibitors may enhance the therapeutic effects of TKIs in the treatment of CML.

Cardiotoxicity of the cancer therapeutic agent imatinib mesylate.

Imatinib mesylate (Gleevec) is a small-molecule inhibitor of the fusion protein Bcr-Abl, the causal agent in chronic myelogenous leukemia. Here we report ten individuals who developed severe congestive heart failure while on imatinib and we show that imatinib-treated mice develop left ventricular contractile dysfunction. Transmission electron micrographs from humans and mice treated with imatinib show mitochondrial abnormalities and accumulation of membrane whorls in both vacuoles and the sarco- (endo-) plasmic reticulum, findings suggestive of a toxic myopathy. With imatinib treatment, cardiomyocytes in culture show activation of the endoplasmic reticulum (ER) stress response, collapse of the mitochondrial membrane potential, release of cytochrome c into the cytosol, reduction in cellular ATP content and cell death. Retroviral gene transfer of an imatinib-resistant mutant of c-Abl, alleviation of ER stress or inhibition of Jun amino-terminal kinases, which are activated as a consequence of ER stress, largely rescues cardiomyocytes from imatinib-induced death. Thus, cardiotoxicity is an unanticipated side effect of inhibition of c-Abl by imatinib.

Autoinhibition of Bcr-Abl through its SH3 domain.

Bcr-Abl is a dysregulated tyrosine kinase whose mechanism of activation is unclear. Here, we demonstrate that, like c-Abl, Bcr-Abl is negatively regulated through its SH3 domain. Kinase activity, transformation, and leukemogenesis by Bcr-Abl are greatly impaired by mutations of the Bcr coiled-coil domain that disrupt oligomerization, but restored by an SH3 point mutation that blocks ligand binding or a complementary mutation at the intramolecular SH3 binding site defined in c-Abl. Phosphorylation of tyrosines in the activation loop of the catalytic domain and the linker between the SH2 and catalytic domains (SH2-CD linker) is dependent on oligomerization and required for leukemogenesis. These results suggest that Bcr-Abl has a monomeric, unphosphorylated state with the SH3 domain engaged intramolecularly to Pro1124 in the SH2-CD linker, the form that is sensitive to the inhibitor imatinib (STI-571). The sole function of the coiled-coil domain is to disrupt the autoinhibited conformation through oligomerization and intermolecular autophosphorylation.