18 F-FET PET/CT in Calcifying Pseudoneoplasm of the Neuraxis : First Case.

ABSTRACT: A 66-year-old man has been treated in a psychiatric department for 4-5 years for a depressive syndrome, which is associated with poor motor initiative, confusional state, and dysosmia. Dynamic 18 F-FET PET/CT showed only faint uptake of radiotracer just above the background on the left frontal calcific lesion. The time-activity curve of the neoplasms showed a descending pattern. After a left fronto-orbitary minicraniotomy surgery, histology examination concluded for a rare calcifying pseudoneoplasm of the neuraxis (CAPNON). To our knowledge, no data are available on the metabolic behavior of CAPNON in 18 F-FET PET/CT. This case highlighted that a faint uptake and descending pattern on dynamic 18 F-FET PET/CT may be helpful in suspected CAPNON before surgery.

Discordance of Biomarker Expression Profile between Primary Breast Cancer and Synchronous Axillary Lymph Node Metastasis in Preoperative Core Needle Biopsy.

Background: Breast cancer (BC) is a heterogeneous disease made up of clones with different metastatic potential. Intratumoral heterogeneity may cause metastases to show divergent biomarker expression, potentially affecting chemotherapy response. Methods: We investigated the immunohistochemical (IHC) and FISH profile of estrogen receptors (ER), progesterone (PR) receptors, Ki67, and HER2 in a series of BC-matched primary tumors (PTs) and axillary lymph node (ALN) metastases in pre-operative core needle biopsies (CNBs). Phenotypical findings were correlated to morphological features and their clinical implications. Results: Divergent expression between PTs and ALNs was found in 10% of the tumors, often involving multiple biomarkers (12/31, 39%). Most (52%) displayed significant differences in ER and PR staining. HER2 divergences were observed in almost three-quarters of the cases (23/31, 74%), with five (16%) switching from negativity to overexpression/amplification in ALNs. Roughly 90% of disparities reflected significant morphological differences between PTs and ALN metastases. Less than half of the discrepancies (12/31, 39%) modified pre/post-operative treatment options. Conclusions: We observed relevant discrepancies in biomarker expression between PTs and metastatic ALNs in a noteworthy proportion (10%) of preoperative BC CNBs, which were often able to influence therapies. Hence, our data suggest routine preoperative assessment of biomarkers in both PTs and ALNs in cases showing significant morphological differences.

Advancing the PD-L1 CPS test in metastatic TNBC: Insights from pathologists and findings from a nationwide survey.

Pembrolizumab has received approval as a first-line treatment for unresectable/metastatic triple-negative breast cancer (mTNBC) with a PD-L1 combined positive score (CPS) of ≥ 10. However, assessing CPS in mTNBC poses challenges. Firstly, it represents a novel analysis for breast pathologists. Secondly, the heterogeneity of PD-L1 expression in mTNBC further complicates the assessment. Lastly, the lack of standardized assays and staining platforms adds to the complexity. In KEYNOTE trials, PD-L1 expression was evaluated using the IHC 22C3 pharmDx kit as a companion diagnostic test. However, both the 22C3 pharmDx and VENTANA PD-L1 (SP263) assays are validated for CPS assessment. Consequently, assay-platform choice, staining conditions, and scoring methods can significantly impact the testing outcomes. This consensus paper aims to discuss the intricacies of PD-L1 CPS testing in mTNBC and provide practical recommendations for pathologists. Additionally, we present findings from a nationwide Italian survey elucidating the state-of-the-art in PD-L1 CPS testing in mTNBC.

Coexpression of ΔNp63/p40 and TTF1 Within Most of the Same Individual Cells Identifies Life-Threatening NSCLC Featuring Squamous and Glandular Biphenotypic Differentiation: Clinicopathologic Correlations.

Introduction: Double occurrence of TTF1 and ΔNp63/p40 (henceforth, p40) within the same individual cells is exceedingly rare in lung cancer. Little is known on their biological and clinical implications. Methods: Two index cases immunoreactive for both p40 and TTF1 and nine tumors selected from The Cancer Genome Atlas (TCGA) according to the mRNA levels of the two relevant genes entered the study. Results: The two index cases were peripherally located, poorly differentiated, and behaviorally unfavorable carcinomas, which shared widespread p40 and TTF1 decoration within the same individual tumor cells. They also retained SMARCA2 and SMARCA4 expression, while variably stained for p53, cytokeratin 5, and programmed death-ligand 1. A subset of basal cells p40+/TTF1+ could be found in normal distal airways. Biphenotypic glandular and squamous differentiation was unveiled by electron microscopy, along with EGFR, RAD51B, CCND3, or NF1 mutations and IGF1R, MYC, CCND1, or CDK2 copy number variations on next-generation sequencing analysis. The nine tumors from TCGA (0.88% of 1018 tumors) shared the same poor prognosis, clinical presentation, and challenging histology and had activated pathways of enhanced angiogenesis and epithelial-mesenchymal transition. Mutation and copy number variation profiles did not differ from the other TCGA tumors. Conclusions: Double p40+/TTF1+ lung carcinomas are aggressive and likely underrecognized non-small cell carcinomas, whose origin could reside in double-positive distal airway stem-like basal cells through either de novo-basal-like or differentiating cell mechanisms according to a model of epithelial renewal.

Author Correction: Establishment of patient derived xenografts as functional testing of lung cancer aggressiveness.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Establishment of patient derived xenografts as functional testing of lung cancer aggressiveness.

Despite many years of research efforts, lung cancer still remains the leading cause of cancer deaths worldwide. Objective of this study was to set up a platform of non-small cell lung cancer patient derived xenografts (PDXs) faithfully representing primary tumour characteristics and offering a unique tool for studying effectiveness of therapies at a preclinical level. We established 38 PDXs with a successful take rate of 39.2%. All models closely mirrored parental tumour characteristics although a selective pressure for solid patterns, vimentin expression and EMT was observed in several models. An increased grafting rate for tumours derived from patients with worse outcome (p = 0.006), higher stage (p = 0.038) and higher CD133+/CXCR4+/EpCAM- stem cell content (p = 0.019) was observed whereas a trend towards an association with SUVmax higher than 8 (p = 0.084) was detected. Kaplan Meier analyses showed a significantly worse (p = 0.0008) overall survival at 5 years in patients with grafted vs not grafted PDXs also after adjusting for tumour stage. Moreover, for 63.2% models, grafting was reached before clinical recurrence occurred. Our findings strengthen the relevance of PDXs as useful preclinical models closely reflecting parental patients tumours and highlight PDXs establishment as a functional testing of lung cancer aggressiveness and personalized therapies.

Solitary fibrous tumor of the breast: report of a case with emphasis on diagnostic role of STAT6 immunostaining.

We herein report the clinical, radiological, and pathological findings of a rare case of a solitary fibrous tumor (SFT) occurring in the breast parenchyma of a 62-year-old female. The tumor was incidentally detected at a mammographic screening, and, ultrasonographically, presented as a single, well-circumscribed nodule. On needle core biopsy, the diagnosis of SFT was suggested based on a proliferation of CD34-positive spindly cells set in a fibrous stroma containing medium-sized blood vessels with hyalinization of their walls and branching configuration. The diagnosis was confirmed in the excised specimen, which exhibited a tumor with an immunohistochemical profile consistent with SFT, including diffuse expression of CD34, CD99 and bcl2. As STAT6 nuclear immunoexpression is the result of the inv12(q13q13)-derived NAB2-STAT6 fusion, which characterizes SFT, we analyzed immunohistochemically our case with a commercially available anti-STAT6 antibody. We showed that mammary SFT exhibits a diffuse nuclear STAT6 immunoreactivty, suggesting its potential diagnostic role. The present case emphasizes that the diagnosis of SFT can be confidentially rendered on needle core biopsy. Although SFT is suspected on characteristic morphologic features, immunohistochemistry, revealing immunoreactivity for CD34, bcl-2, CD99 and STAT6, is crucial in the differential diagnosis of potential benign and malignant mimics.

Dose-Dense Temozolomide in Patients with MGMT-Silenced Chemorefractory Colorectal Cancer.

BACKGROUND: In a phase II study, we showed that temozolomide (TMZ) was tolerable and active in heavily pre-treated patients with advanced colorectal cancer (CRC) and MGMT methylation. A schedule of dose-dense TMZ may have enhanced activity due to the higher cumulative dose and induction of MGMT depletion, even in resistant tumors. METHODS: Thirty-two patients with chemorefractory MGMT-methylated CRC were treated with TMZ at a daily dose of 75 mg/m(2) for 21 consecutive days every 4 weeks, for up to six cycles or until the occurrence of progressive disease/unacceptable toxicity. The primary endpoint was treatment activity in terms of objective response rate (ORR). MGMT protein expression was tested by immunohistochemistry (IHC) on two pooled cohorts: patients from the previous study of standard-dose TMZ and those from the current investigation. RESULTS: From November 2013 to December 2014, 32 patients were treated at Fondazione IRCCS Istituto Nazionale dei Tumori. We observed only three episodes of grade 3 asthenia and no significant myelotoxicity. The ORR was 16 % (all partial responses occurring in RAS-BRAF-mutated tumors). Median progression-free survival (PFS) and overall survival (OS) were 2.3 and 6.7 months, respectively. Patients with MGMT-low expression by IHC had a significantly higher ORR (p < 0.0001) and PFS (p = 0.001) compared to those with MGMT-high expression, while no difference was observed in OS. CONCLUSIONS: Our data confirm the encouraging activity of TMZ in chemorefractory CRC patients selected for MGMT silencing, even in the RAS-BRAF-mutated population. The role of MGMT IHC as a biomarker for improving patient selection warrants further prospective confirmation.

Conversion to stem-cell state in response to microenvironmental cues is regulated by balance between epithelial and mesenchymal features in lung cancer cells.

Cancer cells within a tumor are functionally heterogeneous and specific subpopulations, defined as cancer initiating cells (CICs), are endowed with higher tumor forming potential. The CIC state, however, is not hierarchically stable and conversion of non-CICs to CICs under microenvironment signals might represent a determinant of tumor aggressiveness. How plasticity is regulated at the cellular level is however poorly understood. To identify determinants of plasticity in lung cancer we exposed eight different cell lines to TGFß1 to induce EMT and stimulate modulation of CD133(+) CICs. We show that response to TGFß1 treatment is heterogeneous with some cells readily switching to stem cell state (1.5-2 fold CICs increase) and others being unresponsive to stimulation. This response is unrelated to original CICs content or extent of EMT engagement but is tightly dependent on balance between epithelial and mesenchymal features as measured by the ratio of expression of CDH1 (E-cadherin) to SNAI2. Epigenetic modulation of this balance can restore sensitivity of unresponsive models to microenvironmental stimuli, including those elicited by cancer-associated fibroblasts both in vitro and in vivo. In particular, tumors with increased prevalence of cells with features of partial EMT (hybrid epithelial/mesenchymal phenotype) are endowed with the highest plasticity and specific patterns of expression of SNAI2 and CDH1 markers identify a subset of tumors with worse prognosis. In conclusion, here we describe a connection between a hybrid epithelial/mesenchymal phenotype and conversion to stem-cell state in response to external stimuli. These findings have implications for current endeavors to identify tumors with increased plasticity.

Wilms tumor 1 (WT1) protein: Diagnostic utility in pediatric tumors.

Despite Wilms tumor 1 (WT1) protein was originally considered as a specific immunomarker of Wilms tumor, with the increasing use of immunohistochemistry, there is evidence that other tumors may share WT1 protein expression. This review focuses on the immunohistochemical profile of WT1 protein in the most common malignant tumors of children and adolescents. The variable expression and distribution patterns (nuclear vs cytoplasmic) in the different tumors, dependent on the antibodies used (anti-C or N-terminus WT1 protein), will be emphasized by providing explicative illustrations. Potential diagnostic pitfalls from unexpected WT1 protein expression in some tumors will be discussed in order to avoid diagnostic errors, especially when dealing with small biopsies.

Gain of ALK gene copy number may predict lack of benefit from anti-EGFR treatment in patients with advanced colorectal cancer and RAS-RAF-PI3KCA wild-type status.

INTRODUCTION: Although cetuximab and panitumumab show an increased efficacy for patients with KRAS-NRAS-BRAF and PI3KCA wild-type metastatic colorectal cancer, primary resistance occurs in a relevant subset of molecularly enriched populations. PATIENTS AND METHODS: We evaluated the outcome of 68 patients with advanced colorectal cancer and RAS, BRAF and PI3KCA status according to ALK gene status (disomic vs. gain of ALK gene copy number--defined as mean of 3 to 5 fusion signals in ≥ 10% of cells). All consecutive patients received cetuximab and irinotecan or panitumumab alone for chemorefractory disease. RESULTS: No ALK translocations or amplifications were detected. ALK gene copy number gain was found in 25 (37%) tumors. Response rate was significantly higher in patients with disomic ALK as compared to those with gain of gene copy number (70% vs. 32%; p = 0.0048). Similarly, progression-free survival was significantly different when comparing the two groups (6.7 vs. 5.3 months; p = 0.045). A trend was observed also for overall survival (18.5 vs. 15.6 months; p = 0.885). CONCLUSION: Gain of ALK gene copy number might represent a negative prognostic factor in mCRC and may have a role in resistance to anti-EGFR therapy.

Does immunohistochemistry affect response to therapy and survival of inoperable non-small cell lung carcinoma patients? A survey of 145 stage III-IV consecutive cases.

Whether non-small cell lung carcinoma (NSCLC) unveiled by immunohistochemistry (IHC) has the same clinical outcome as those typed by morphology is still matter of debate. A total of 145 stage III-IV, consecutive inoperable NSCLC patients treated by chemotherapy (133 cases) or EGFR tyrosine kinase inhibitor (12 cases) and including 100 biopsies, 11 surgical specimens, and 34 cytological samples had originally accounted for 120 adenocarcinomas (ADs), 19 squamous cell carcinomas (SQCs), and 6 adenosquamous carcinomas (ADSQCs) by integrating morphology and thyroid transcription factor-1 (TTF1)/p40 IHC. Thirty-two NSCLC-not otherwise specified (NSCLC-NOS) cases were identified by morphology revision of the original diagnoses, which showed solid growth pattern (P < .001), 22 ADs, 5 SQCs, and 5 ADSQCs by IHC profiling (P < .001), and 10 gene-altered tumors (3 EGFR, 5 KRAS, and 2 ALK). While no significant relationships were observed between response to therapy and original, morphology or IHC diagnoses, driver mutations and tumor differentiation by TTF1 expression, AD run better progression-free survival (PFS) or overall survival (OS) than other tumor types by morphology (P = .010 and P = .047) and IHC (P = .033 and P = .046), respectively. Furthermore, patients with NSCLC-NOS confirmed as AD by IHC tended to have poorer OS (P = .179) and PFS (P = .193) similar to that of ADSQC and SQC (P = .702 and P = .540, respectively). A category of less differentiated AD with poorer prognosis on therapy could be identified by IHC, while there were no differences for SQC or ADSQC. The terminology of "NSCLC-NOS, favor by IHC" is appropriate to alert clinicians toward more aggressive tumors.

Rare pancreatic neoplasm: MDCT and MRI features of a typical solid pseudopapillary tumor.

Solid pseudopapillary tumor of the pancreas is a rare neoplasm, predominantly observed in young women and with greatest incidence in the second and third decade. It has clinically good behavior, although large at the time of diagnosis. We report the case of a thirty-year-old woman with a giant mass in the pancreas, incidentally discovered during an abdominal ultrasonography. The mass was later investigated by multidetector computed tomography and magnetic resonance imaging. The cystic-solid appearance of the encapsulated lesion suggested to radiologists the possibility of a solid pseudopapillary tumor. Imaging features of this pancreatic neoplasm and differential diagnosis from other cystic pancreatic tumors are discussed in our report, in order to help radiologists and clinicians achieve correct diagnosis and management.

Efficacy and tolerability of pregabalin versus topiramate in the prophylaxis of chronic daily headache with analgesic overuse: an open-label prospective study.

OBJECTIVES: Medication-overuse headache is one of the most disabling headaches. Antiepileptic drugs have been considered a promising strategy as prophylactic treatment in these patients, even if their use often has been limited by low tolerability or safety. The objective of this study was to evaluate the efficacy and safety of pregabalin compared with topiramate for the prophylaxis of chronic daily headache with medication overuse using an open-label prospective study. METHODS: After a 2-month baseline period (T0), 100 consecutive patients with medication overuse headache were assigned to receive 150 mg/d pregabalin or 100 mg/d topiramate. After a titration period of 4 weeks, a follow-up visit was scheduled every 2 months (T1 and T2) to evaluate headache frequency, the amount of rescue medication intake, and disability. RESULTS: Of the 46 pregabalin-treated patients, the mean monthly headache frequency significantly decreased from 21.8 ± 4.8 (T0) to 5.1 ± 3.8 (T2), and the monthly number of days with medication intake decreased from 15.1 ± 4.8 (T0) to 2.9 ± 1.9 (T2). Similarly, of the 42 topiramate-treated patients, the mean monthly headache frequency decreased from 21.8 ± 4.9 (T0) to 5.3 ± 3.5 (T2), and the mean monthly number of days with medication intake decreased from 15.1 ± 3.7 (T0) to 2.6 ± 1.5 (T2). A significant improvement of disability score was reported in both groups. CONCLUSIONS: Similar to topiramate, pregabalin seems to be an effective and well-tolerated preventive therapy in chronic headache and a new option in the management of withdrawal from abused drugs in patients with analgesic overuse, a difficult-to-treat population.

Biliary adenofibroma of the liver: report of a case and review of the literature.

We herein report the clinicopathologic features of a rare case of biliary adenofibroma (BAF) of the liver in a 79-year-old man. Grossly, tumour presented as a well-circumscribed, 5.5-cm mass with a solid and microcystic appearance. Histological examination was typical of biliary adenofibroma, showing a proliferation of variable-sized tubulocystic structures embedded in a moderately cellular fibrous stroma. Immunohistochemistry, revealing immunoreactivity of the epithelial component to cytokeratins 7 and 19, was consistent with a bile duct origin. Notably, the stromal cells had a myofibroblastic profile, showing a diffuse and strong expression of vimentin and α-smooth muscle actin. Differential diagnosis with Von Meyenburg complex, biliary adenoma, biliary cistadenoma, congenital biliary cystsy, and hepatic benign cystic mesothelioma is provided. The occasionally reported expression of p53 in biliary adenofibroma has suggested that this tumour could represent a premalignant lesion. The absence of both cytological atypia and p53 immunoreactivity in our case confirms that BAF is a benign tumour with an indolent clinical behaviour. However, a careful histological examination of BAF is mandatory because malignant transformation of the epithelial component has been documented in two cases.

CSF biomarkers, impairment of cerebral hemodynamics and degree of cognitive decline in Alzheimer's and mixed dementia.

The in vivo diagnosis of Alzheimer's disease (AD) may be facilitated by cerebro-spinal fluid (CSF) biomarkers in combination with imaging and clinical assessments. By determining the concentration of beta amyloid fragments, total tau (t-tau) and phospho-tau (p-tau), it is possible to detect the conversion of mild cognitive impairment (MCI) to AD or distinguish AD vs. pseudo-dementia. However, these markers are poorly sensitive to the progressive disease stages. And far from clear is their role in "mixed" forms of dementia, as far as hemodynamic deficits complicate the clinical history. We have studied cerebral hemodynamic impairment in AD patients, relative to control subjects. Mean flow velocity (MFV), pulsatility index (PI) and cerebrovascular reactivity (assayed as breath-holding index, BHI) were evaluated by bilateral transcranial Doppler (TCD) monitoring of middle cerebral arteries. MFV and BHI were significantly lower and PI was significantly higher in AD patients with respect to control subjects. The presence of white-matter changes (WMC) in the AD cases did not influence any of the hemodynamic variables. Noticeably, MMSE score was correlated to BHI reduction (P<0.005). Our results, consistent with the recent literature indicate that hemodynamic impairment is a critical marker of cognitive decline and supports once more the hypothesis of a significant pathigenic role of vascular damage in AD. Similar functional alterations might be early hallmarks in a variety of dementia subtypes, including "mixed" dementia, whose prevalence is undoubtedly increased. Assessment of hemodynamic reactivity could provide valuable correlations with individual patient's cognitive profile, which in turn would assist in the identification of critical steps in disease progression and the validation of effective therapies.

Cytotoxin-associated Gene-A-positive Helicobacter pylori strains infection increases the risk of recurrent atherosclerotic stroke.

BACKGROUND: CagA-positive Helicobacter pylori infection has been found to be associated with a first-ever atherosclerotic stroke. The aim of this study was to investigate whether these strains represent an independent risk factor for recurrent atherosclerotic stroke. MATERIALS AND METHODS: We performed a longitudinal study of patients with a first-ever large vessels stroke and resulted positive at H. pylori serology. Patients had clinical examination 1 month after the acute event, and were subsequently visited or contacted by telephone up to 3 years at 6-month intervals. Sera obtained at the time of enrollment were frozen and analyzed for the presence of anti-CagA antibodies at the end of the study. The primary outcome event was any fatal or nonfatal stroke after the index stroke. RESULTS: One hundred seventy H. pylori-positive patients were included (n = 68 CagA positive and n = 102 CagA negative). No significant difference regarding age and other stroke risk factors was detected. According to Kaplan-Meier survival analysis, CagA-positive patients showed a significantly higher risk for stroke recurrence than CagA-negative ones (45.6% vs 17.6%; p < .001). Difference in the rate of recurrent stroke between the two groups persisted after Cox regression analysis taking into account possible confounding factors (hazard ratio = 3.5; 95% CI = 1.9-6.4; p < .001). CONCLUSIONS: Infection with H. pylori CagA-positive strains increases the risk of recurrent atherosclerotic stroke. Seropositivity determination should be performed in order to identify high-risk patients requiring a strict clinical surveillance, and the possible beneficial effect of eradication therapy should be evaluated.

The role of chronic infection and inflammation in the pathogenesis of cardiovascular and cerebrovascular disease.

Molecular and cellular immune activities have a fundamental role in all stages of the atherosclerotic process and in the pathogenesis of cerebrovascular and cardiovascular diseases. Recent studies have demonstrated how chronic infections can support a local and systemic chronic inflammation, leading to the atherosclerotic process. The pathogenic link between infection and cardiovascular and cerebrovascular disease is not completely defined. Some therapeutic strategies, able to influence the persistence of the infections or to modify the inflammatory process, could be useful in primary and secondary vascular disease prevention and in modifying the acute event outcome.

The role of chronic infection and inflammation in the pathogenesis of cardiovascular and cerebrovascular disease.

Molecular and cellular immune activities have a fundamental role in all stages of the atherosclerotic process and in the pathogenesis of cerebrovascular and cardiovascular diseases. Recent studies have demonstrated how chronic infections can support a local and systemic chronic inflammation, leading to the atherosclerotic process. The pathogenic link between infection and cardiovascular and cerebrovascular disease is not completely defined. Some therapeutic strategies, able to influence the persistence of the infections or to modify the inflammatory process, could be useful in primary and secondary vascular disease prevention and in modifying the acute event outcome.

Coactivation of GABA(A) and GABA(B) receptor results in neuroprotection during in vitro ischemia.

BACKGROUND AND PURPOSE: The possible neuroprotective effect of endogenous gamma-aminobutyric acid (GABA) on the irreversible electrophysiological changes induced by in vitro ischemia on striatal neurons was investigated. In particular, the aim of the study was the characterization of the neuroprotective action of 2 antiepileptic drugs increasing GABAergic transmission such as tiagabine, a GABA transporter inhibitor, and vigabatrin, an irreversible inhibitor of GABA transaminase. METHODS: Extracellular field potential recordings were obtained from rat corticostriatal slice preparations. In vitro ischemia was delivered by switching to an artificial cerebrospinal fluid solution in which glucose was omitted and oxygen was replaced with N(2). RESULTS: An irreversible loss of the field potentials recorded from striatal neurons was observed after 10 minutes of ischemia in control solution. Conversely, tiagabine and vigabatrin partially prevented the ischemia-induced field potential loss. Surprisingly, both GABA(A) and GABA(B) receptor antagonists blocked these effects. Accordingly, neuroprotection could be obtained only when GABA(A) and GABA(B) receptor agonists were coapplied, but not when a single agonist was given in isolation. CONCLUSIONS: Antiepileptic drugs targeting GABAergic transmission can exert neuroprotective effects against ischemia by increasing endogenous GABA levels and via the activation of both GABA(A) and GABA(B) receptors.