The Natural History of pT1 Colorectal Cancer

Colorectal carcinoma invading the submucosa but not the muscular layer (pT1, early invasive cancer) represents the earliest form of clinically relevant colorectal cancer in most patients. Neoplastic invasion of the submucosa, in fact, opens the way to metastasis via the lymphatic and blood vessels, and the choice between surveillance and major surgery will turn on its metastatic potential. The following histological features predict the risk of metastasis and the different clinical outcomes: grade of differentiation of carcinoma, lymphovascular invasion, state of the resection margin. Microstaging of invasive cancer, namely the width and the depth of submucosal invasion, together with tumor budding at the advancing edge allow the metastatic risk to be further stratified in minimal, low, and high. Different, although morphologically undistinguishable, tumorigenic pathways are supposed to lead to the malignant transformation of colonic mucosa and subsequently to drive the progression from early to advanced cancer: new biomarkers are needed to identify progressive and non-progressive pT1 neoplasia

Evaluation of 7q31 region improves the accuracy of EGFR FISH assay in non small cell lung cancer

<p>Abstract</p> <p>Background</p> <p>Increase of <it>EGFR </it>gene copy number consequent to gene amplification and/or polysomy of chromosome 7 has been significantly associated with better clinical outcome in Non Small Cell Lung Cancer (NSCLC) patients treated with Tyrosin-Kinase Inhibitors (TKIs).</p> <p>The primary method to detect <it>EGFR </it>copy number is FISH (Fluorescence in Situ Hybridization), that in lung cancer requires a precise standardization due to the presence of intratumor heterogeneity and high frequency of chromosome 7 polysomy.</p> <p>Recommendations and interpretative guidelines to discriminate NSCLC patients into FISH positive (gene amplification and high chromosome 7 polysomy) and FISH negative have been proposed by the University of Colorado Cancer Center (UCCC). However, in a subset of cases the distinction between <it>EGFR </it>amplification and chromosome 7 polysomy can be controversial because of a complex pattern of multiple <it>EGFR </it>and centromere signals.</p> <p>Methods</p> <p>In order to distinguish more accurately these two genetic events, 20 NSCLC FISH positive patients, showing a controversial pattern of <it>EGFR </it>and centromere specific signals, were further evaluated for the status of 7q31 distal region.</p> <p>Results</p> <p>A discrepancy between FISH results obtained with UCCC scoring system and 7q31 control was evidenced in 2 patients (10%).</p> <p>Conclusion</p> <p>Our data strengthen the usefulness of 7q31 region evaluation to discriminate EGFR amplification from chromosome 7 polysomy in controversial <it>EGFR </it>FISH positive cases. Since it has been reported a possible different contribution of amplification and polysomy to TKIs susceptibility in NSCLC, the clear distinction between these two genetic events may be important to identify a subset of patients more responsive to the therapy.</p

Substance Related Exogenous Psychosis: a post-modern syndrome

© 2020 Cambridge University Press. This paper has been accepted for publication and will appear in a revised form, subsequent to peer-review and/or editorial input by Cambridge University Press. This manuscript is made available under the terms of the Creative Commons Non-Commercial No-Derivatives License (CC-BY-NC-ND). For further information please see: https://creativecommons.org/licenses/by-nc-nd/4.0/.The past two decades have been marked by dramatic social changes, widely characterized by the term “postmodern”. These major transformations have had profound and complex implications for psychiatry, influencing mental health risk factors, dynamics in clinical encounters, styles of help-seeking behavior and clinical outcomes. Underlying themes of postmodern thought that are particularly relevant to psychiatry include: individualization and social roles; the nature of self-identity and intimacy; future orientation (Whitley r. 2008).Peer reviewe

Gambling disorder and bilateral transcranial direct current stimulation: A case report

Introduction Gambling disorder (GD) is a major public health concern with currently no validated and efficacious treatments approved. In this single case study, we report the short- and long-term effect of bilateral transcranial direct current stimulation (tDCS) of dorsolateral prefrontal cortex (DLPFC) on craving and impulse control in a subject with GD. Methods The patient is a 26-year-old Caucasian male with an 8-year history of GD as well as alcohol and cocaine misuse. Treatment consisted of twice-a-day stimulation for 10 days. According to the literature, both the left (to control craving) and the right (to control emotional impulses) DLPFC were stimulated. Patients subsequently received tDCS once a week for 3 months and then once every 2 weeks for another 3 months. Results After 10 days of treatment, the subject reported improved psychiatric symptoms (depression, anxiety, and impulsivity), as well as reduced gambling craving symptom severity. After 3 and 6 months of treatment, the clinical picture further improved. Discussion This is the first report of tDCS effectiveness in a single case study of GD. Therapeutic effects, both on the addictive behavior and on psychiatric comorbid symptomatology, were lasting and continued over 6 months of tDCS maintenance treatment. Future case–control studies are required to test the efficacy of this tool in patients with GD

YKL-40/c-Met Expression in Rectal Cancer Biopsies Predicts Tumor Regression following Neoadjuvant Chemoradiotherapy: A Multi-Institutional Study

BACKGROUND:Neoadjuvant chemo-radiotherapy (CRT) followed by surgical resection is the standard treatment for locally advanced rectal cancer, although complete tumor pathological regression is achieved in only up to 30% of cases. A clinicopathological and molecular predictive stratification of patients with advanced rectal cancer is still lacking. Here, c-Met and YKL-40 have been studied as putative predictors of CRT response in rectal cancer, due to their reported involvement in chemoradioresistance in various solid tumors. MATERIAL AND METHODS:A multicentric study was designed to assess the role of c-Met and YKL-40 expression in predicting chemoradioresistance and to correlate clinical and pathological features with CRT response. Immunohistochemistry and fluorescent in situ hybridization for c-Met were performed on 81 rectal cancer biopsies from patients with locally advanced rectal adenocarcinoma. All patients underwent standard (50.4 gy in 28 fractions + concurrent capecitabine 825 mg/m2) neoadjuvant CRT or the XELOXART protocol. CRT response was documented on surgical resection specimens and recorded as tumor regression grade (TRG) according to the Mandard criteria. RESULTS:A significant correlation between c-Met and YKL-40 expression was observed (R = 0.43). The expressions of c-Met and YKL-40 were both significantly associated with a lack of complete response (86% and 87% of c-Met and YKL-40 positive cases, p< 0.01 and p = 0.006, respectively). Thirty of the 32 biopsies co-expressing both markers had partial or absent tumor response (TRG 2-5), strengthening their positive predictive value (94%). The exclusive predictive role of YKL-40 and c-Met was confirmed using a multivariate analysis (p = 0.004 and p = 0.007 for YKL-40 and c-Met, respectively). TRG was the sole morphological parameter associated with poor outcome. CONCLUSION:c-Met and YKL-40 expression is a reliable predictor of partial/absent response to neoadjuvant CRT in rectal cancer. Targeted therapy protocols could take advantage of prior evaluations of c-MET and YKL-40 expression levels to increase therapeutic efficacy

Telocytes are the physiological counterpart of inflammatory fibroid polyps and PDGFRA-mutant GISTs

PDGFRA mutations in the gastrointestinal (GI) tract can cause GI stromal tumour (GIST) and inflammatory fibroid polyp (IFP). Hitherto no cell type has been identified as a physiological counterpart of the latter, while interstitial Cajal cells (ICC) are considered the precursor of the former. However, ICC hyperplasia (ICCH), which strongly supports the ICC role in GIST pathogenesis, has been identified in germline KIT-mutant settings but not in PDGFRA-mutant ones, challenging the precursor role of ICC for PDGFRA-driven GISTs. Telocytes are a recently described interstitial cell type, CD34+/PDGFRA+. Formerly considered fibroblasts, they are found in many organs, including the GI tract where they are thought to be involved in neurotransmission. Alongside IFPs and gastric GISTs, GI wall \u201cfibrosis\u201d has been reported in germline PDGFRA-mutants. Taking the opportunity offered by its presence in a germline PDGFRA-mutant individual, we demonstrate that this lesion is sustained by hyperplastic telocytes, constituting the PDGFRA-mutant counterpart of germline KIT mutation-associated ICCH. Moreover, our findings support a pathogenetic relationship between telocyte hyperplasia and both IFPs and PDGFRA-mutant GISTs. We propose the term \u201ctelocytoma\u201d for defining IFP, as it conveys both the pathogenetic (neoplastic) and histotypic (\u201ctelocytary\u201d) essence of this tumour, unlike IFP, which rather evokes an inflammatory-hyperplastic lesion

Quality assurance in pathology in colorectal cancer screening and diagnosis—European recommendations

In Europe, colorectal cancer is the most common newly diagnosed cancer and the second most common cause of cancer deaths, accounting for approximately 436,000 incident cases and 212,000 deaths in 2008. The potential of high-quality screening to improve control of the disease has been recognized by the Council of the European Union who issued a recommendation on cancer screening in 2003. Multidisciplinary, evidence-based European Guidelines for quality assurance in colorectal cancer screening and diagnosis have recently been developed by experts in a pan-European project coordinated by the International Agency for Research on Cancer. The full guideline document consists of ten chapters and an extensive evidence base. The content of the chapter dealing with pathology in colorectal cancer screening and diagnosis is presented here in order to promote international discussion and collaboration leading to improvements in colorectal cancer screening and diagnosis by making the principles and standards recommended in the new EU Guidelines known to a wider scientific community

Targeting EGFR/HER2 pathways enhances the antiproliferative effect of gemcitabine in biliary tract and gallbladder carcinomas

<p>Abstract</p> <p>Background</p> <p>Advanced biliary tract carcinomas (BTCs) have poor prognosis and limited therapeutic options. Therefore, it is crucial to combine standard therapies with molecular targeting. In this study EGFR, HER2, and their molecular transducers were analysed in terms of mutations, amplifications and over-expression in a BTC case series. Furthermore, we tested the efficacy of drugs targeting these molecules, as single agents or in combination with gemcitabine, the standard therapeutic agent against BTC.</p> <p>Methods</p> <p>Immunohistochemistry, FISH and mutational analysis were performed on 49 BTC samples of intrahepatic (ICCs), extrahepatic (ECCs), and gallbladder (GBCs) origin. The effect on cell proliferation of different EGFR/HER2 pathway inhibitors as single agents or in combination with gemcitabine was investigated on BTC cell lines. Western blot analyses were performed to investigate molecular mechanisms of targeted drugs.</p> <p>Results</p> <p>EGFR is expressed in 100% of ICCs, 52.6% of ECCs, and in 38.5% of GBCs. P-MAPK and p-Akt are highly expressed in ICCs (>58% of samples), and to a lower extent in ECCs and GBCs (<46%), indicating EGFR pathway activation. HER2 is overexpressed in 10% of GBCs (with genomic amplification), and 26.3% of ECCs (half of which has genomic amplification). EGFR or its signal transducers are mutated in 26.5% of cases: 4 samples bear mutations of PI3K (8.2%), 3 cases (6.1%) in K-RAS, 4 (8.2%) in B-RAF, and 2 cases (4.1%) in PTEN, but no loss of PTEN expression is detected. EGI-1 cell line is highly sensitive to gemcitabine, TFK1 and TGBC1-TKB cell lines are responsive and HuH28 cell line is resistant. In EGI-1 cells, combination with gefitinib further increases the antiproliferative effect of gemcitabine. In TFK1 and TGBC1-TKB cells, the efficacy of gemcitabine is increased with addiction of sorafenib and everolimus. In TGBC1-TKB cells, lapatinib also has a synergic effect with gemcitabine. HuH28 becomes responsive if treated in combination with erlotinib. Moreover, HuH28 cells are sensitive to lapatinib as a single agent. Molecular mechanisms were confirmed by western blot analysis.</p> <p>Conclusion</p> <p>These data demonstrate that EGFR and HER2 pathways are suitable therapeutic targets for BTCs. The combination of gemcitabine with drugs targeting these pathways gives encouraging results and further clinical studies could be warranted.</p

Annex to Quirke et al. Quality assurance in pathology in colorectal cancer screening and diagnosis: annotations of colorectal lesions

Multidisciplinary, evidence-based European Guidelines for quality assurance in colorectal cancer screening and diagnosis have recently been developed by experts in a pan-European project coordinated by the International Agency for Research on Cancer. The full guideline document includes a chapter on pathology with pan-European recommendations which take into account the diversity and heterogeneity of health care systems across the EU. The present paper is based on the annex to the pathology chapter which attempts to describe in greater depth some of the issues raised in the chapter in greater depth, particularly details of special interest to pathologists. It is presented here to make the relevant discussion known to a wider scientific audience