Neuroendocrine neoplasms represent a heterogeneous group of rare tumors, more frequently arising from gastroenteropancreatic tract and lungs. At the time of diagnosis, 20% of cases are metastatic, and 10% of cases are considered as cancer of unknown primary origin. Several immunohistochemical markers are routinely used to confirm the neuroendocrine differentiation, first among all Synaptophysin and Chromogranin-A; on the other hand, different immunohistochemical markers are used to establish primary anatomical site, as TTF1, CDX2, Islet-1 and Calcitonin, but no marker is available in order to distinguish among different sites of the digestive tract. DOG1 (discovered on GIST-1) is a gene normally expressed in interstitial cells of Cajal and, in routine practice, DOG1 immunostaining is used in diagnosis of GIST (gastrointestinal stromal tumor). DOG1 expression has been described in several neoplasms other than GIST, both in mesenchymal and epithelial neoplasms. In the present study, DOG1 immunostaining has been performed in a large cohort of neuroendocrine neoplasms, including neuroendocrine tumors and neuroendocrine carcinomas, in order to evaluate frequency, intensity and pattern of expression in different anatomical site and in different tumor grade. DOG1 expression was detected in a large percentage of neuroendocrine tumors, with statistically significant association between DOG1 expression and gastrointestinal tract neuroendocrine tumors. As a consequence, DOG1 could be included in marker panel for the identification of primary site in neuroendocrine metastases of unknown primary origin; moreover, these results recommend careful evaluation of DOG1 expression in gastrointestinal neoplasms, in particular in differential diagnosis between epithelioid GIST and neuroendocrine tumors.

Central nervous system (CNS) metastases rarely occur in colorectal cancer (CRC) patients (1-4%). ERBB2 amplification is detected in 5% of RAS WT metastatic CRC and has been recognized as a therapeutic target for trastuzumab in combination with lapatinib or pertuzumab. We recently reported a high rate of CNS recurrences (19%) among 32 HER2-positive mCRC treated with trastuzumab and lapatinib. Here we describe the prevalence, timing of onset, and management of CNS recurrences in the largest cohort of CRC treated with anti-HER2 therapies. Consecutive patients with HER2-positive mCRC by immunohistochemistry and in-situ hybridization, treated with both anti-HER2 regimens within the multi-center HERACLES clinical program and per institutional protocols at Niguarda Cancer Center were included in the analysis. Between August 2012 and April 2020, 92 patients have been treated with an anti-HER2 regimen: 42 received trastuzumab and lapatinib, 31 pertuzumab and T-DM1 and 19 other treatments in clinical trials. Progression in CNS was clinically evident in 10/92 (11%), with 2 pre-existing and stable after SRS, 5 documented under and 3 after anti-HER2 treatment (table). In 1 patient who underwent neurosurgery to remove metastasis, maintenance of HER2-positivity in the cerebellum was demonstrated.Table: 507PPatientAnti-HER2 TreatmentORR to anti-HER2 treatmentBrain PFS* (months)Brain metastases treatmentOS (months)1T+LSD59.8Surgery77.92T+LPR51.0None51.33T+LSD32.9-36.54T+LPR57.8None62.65T+LPD33.9SRS36.86T+LSD13.7SRS21.47T+LPD26.3SRS29.08P+T-DPD38.7SRS45.79P+T-D--> OSD; PD18.6None19.810O--> T+LPR; PD84.9Surgery85.4+*=from diagnosis of stage IV ORR=Objective Response Rate; PFS=Progression Free Survival; OS=Overall Survival; PD=Progressive Disease; PR=Partial Response; SD=Stable Disease; T=trastuzumab; L=lapatinib; P=pertuzumab; T-D=T-DM1; O=other anti-Her2 in clinical trial; SRS=Stereotactic radiosurgery; +=ongoing. Open table in a new tab *=from diagnosis of stage IV ORR=Objective Response Rate; PFS=Progression Free Survival; OS=Overall Survival; PD=Progressive Disease; PR=Partial Response; SD=Stable Disease; T=trastuzumab; L=lapatinib; P=pertuzumab; T-D=T-DM1; O=other anti-Her2 in clinical trial; SRS=Stereotactic radiosurgery; +=ongoing. Present data indicate a high prevalence of CNS recurrences in HER2-positive mCRC, suggesting that the CNS may represent a sanctuary of relapse and that brain imaging for staging and tumor assessment is warranted.

Background HER2 amplification (HER2+) is a therapeutic target for 2% (unselected)-6% (RAS wild-type) metastatic colorectal cancer (mCRC). In the HERACLES-A Trial of trastuzumab and lapatinib (Lancet Oncology, 2016), HER2+ KRAS wild-type mCRC patients achieved an overall objective response rate (CR+PR = ORR) of 30%. Based on this result and on preclinical trials, we activated HERACLES-B, evaluating a targeted chemotherapy precision approach by combining pertuzumab with T-DM1. Methods HERACLES-B is an open-label phase II trial in RAS/BRAF wild-type HER2+ mCRCs (as defined in Valtorta et al, 2015). ORR and Progression-Free Survival (PFS) are the primary and secondary end-points, respectively. With a Fleming/Hern design (H0=ORR 10%; α = 0.05; power=0.85), 7 OR/30 were required to demonstrate an ORR ≥30% (H1). Main inclusion criteria were: PS 0-1, progression after 5FU, oxaliplatin, irinotecan, and anti-EGFR containing regimens. Pertuzumab was dosed at 840 mg iv load, followed by 420 mg iv q3 weeks and T-DM1 at 3.6 mg/Kg q3 weeks. NGS-based molecular analyses of tumor tissue/plasma were performed. Results From 8/2016 to 3/2018, 30 patients were enrolled, treated and evaluable for efficacy. Patients received a median of 3 prior regimens. Data lock and centralized radiological revision were completed by 30/7/2019. ORR was 10% [95% CI: 0-28] and stable disease (SD) 70% [95% CI: 50-85]. Median PFS was 4.8 mos. [95% CI: 3.6-5.8]. Higher HER2 IHC score (3+ vs 2+) was associated with objective response/SD ≥4 mos. [p = 0.03]. Drug-related G3 adverse events were observed only in 2 patients (thrombocytopenia); G ≤ 2 events in 84% of cycles (N = 296), mainly nausea and fatigue. Conclusions Although HERACLES-B did not reach its primary endpoint, disease control was achieved in 80% of patients with a median PFS of 4.8 mos. that is superimposable to the 4.2 mos. achieved in the positive HERACLES-A trial. While the ORR could have been weakened by the lower trastuzumab dose delivered with T-DM1, the retained favorable PFS might be due the combined ‘broad-brush’ effect of emtansine and the synergy with pertuzumab. Preliminary molecular results will be presented. Clinical trial identification EudraCT: 2012-002128-33. Legal entity responsible for the study Fondazione del Piemonte per l’Oncologia IRCC di Candiolo. Funding Fondazione Piemontese per l’Oncologia - FPO funded by Associazione Italiana per la Ricerca sul Cancro (AIRC). Roche provided pertuzumab and T-DM1 for free. Disclosure A. Sartore-Bianchi: Advisory / Consultancy: Amgen; Advisory / Consultancy: Bayer; Advisory / Consultancy: Sanofi. A. Amatu: Advisory / Consultancy: Roche; Advisory / Consultancy: Bayer; Advisory / Consultancy: Amgen. A. Ardizzoni: Advisory / Consultancy: Roche. L. Trusolino: Research grant / Funding (self): Symphogen; Research grant / Funding (self): Merus; Research grant / Funding (self): Servier; Research grant / Funding (self): Pfizer; Speaker Bureau / Expert testimony: Eli Lilly; Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: Merck KGaA. S. Siena: Advisory / Consultancy: Amgen; Advisory / Consultancy: Bayer; Advisory / Consultancy: BMS; Advisory / Consultancy: CheckMab; Advisory / Consultancy: Celgene; Advisory / Consultancy: Clovis; Advisory / Consultancy: Daiichi Sankyo; Advisory / Consultancy: Incyte; Advisory / Consultancy: Merck; Advisory / Consultancy: Novartis; Advisory / Consultancy: Roche-Genentec; Advisory / Consultancy: Seattle Genetics. All other authors have declared no conflicts of interest.

Brain metastases are the most common brain tumors in adulthood. They arise from lung, breast, kidney, gastrointestinal cancer, melanoma and other primary cancers. A recent study (Sperduto, JCO 2012) has provided algorythms for prediction of the expected survival in patients with different histologies of the primary tumor, refining previously available risk stratification classes. Increase in survival in patients with brain metastases may be linked to earlier detection, availability of new treatments for primary tumor and adoption of stereotactic surgery/surgery in fit patients. The data obtained by Sperduto need to be validated in other populations of brain metastases patients. We assessed survival in a cohort of 156 patients with brain metastases (all undergoing neurosurgery) followed in 2 Hospitals (Lecco and Varese) in Lombardia over 12 years (2000 to 2012). 75 cases were from lung cancer, 36 breast, 21 melanoma and 12 colorectal and 12 from other sites. Mean time to metastatic brain disease was 4.6 months for lung, 35.4 for colorectal, 52.2 for breast, 61.2 for melanoma and 78.5 for kidney cancer, respectively. Mean survival after diagnosis of metastatic brain disease was 6.9 months for melanoma, 7.2 for colorectal, 14.5 for lung, 26.6 for kidney and 26.9 months for breast-derived metastases. Our data confirm that time to onset of metastatic brain disease is dependent on the type of primary tumor and - in agreement with those reported in Sperduto's graded prognostic assessment database - show the presence of a non-negligible percentage of patients with prolonged survival after diagnosis and treatment of brain metastatic disease.

Chlamydia pneumoniae, a pathogen responsible for respiratory tract infections, has been associated with atherosclerosis which, along with hypertension, hyperlipidemia, cardiovascular and/or cerebrovascular ischemia and stroke, is a risk factor for chronic neurological disorders. Several studies have demonstrated the ability of C. pneumoniae to disseminate from lungs to arteries through peripheral blood mononuclear cells. Once inside the vascular tissue, C. pneumoniae infection may disseminate via peripheral monocytes to the brain over the intact blood-brain barrier, and contribute to the development of chronic neurological disorders. The aim of our study was to evaluate whether past C. pneumoniae vascular infection may promote the dissemination of this microorganism to the brain, therefore we investigated the presence of C. pneumoniae in post-mortem brain tissue specimens of patients with past chlamydial vascular infection. Seventy six post-mortem brain tissue specimens from 19 patients with past chlamydial vascular infection were investigated for the presence of C. pneumoniae by immunohistochemistry, polymerase chain reaction, in situ polymerase chain reaction and in situ reverse transcription polymerase chain reaction. As control, 28 brain tissue specimens were taken from 7 age and sex matched subjects without chlamydial infection. C. pneumoniae was detected in 16 (84.2%) out of 19 patients with chlamydial vascular infection whereas it was not detected in control subjects (p= 0.0002). In conclusion, the main result of our study is the evidence that a chlamydial vascular infection can disseminate to the brain. It will be important for current and future researches to perform large-scale prospective studies on cardiovascular patients with chlamydial vascular infection in order to evaluate the long-term pathological alterations of the brain.

We report two novel cases of severe arterial thrombotic episodes occurring in two women with severe hypofibrinogenemia, not linked to the administration of replacement therapy. The first patient had sudden acute occlusion of the anterior branch of left renal artery with infarction of the antero-lateral region of the upper part of the left kidney during treatment with combined oestrogen-progestogen started 16 years before for recurrent haemoperitoneum caused by bleeding at ovulation. The second patient showed recurrent arterial thrombosis of lower limbs over 2 years, which eventually led to amputation of affected limbs. Thrombotic events in patients with inherited severe hypofibrinogenemia are rather frequent, may be severe and not associated with the use of replacement therapy.

A 40-year-old woman was admitted to the hospital for an acute outbreak of multiple pustular lesions with an underlying erythematous base affecting cheeks and chin. These lesions were referred to as "aching". The patient had been taking amoxicillin-clavulanic acid (3 g a day) over the past three days for oral prophylaxis for dental treatment. Given the possible allergic reaction to the drug administered and the extension of the pustular lesions over all face and neck during the following four days, we replaced the amoxicillin-clavulanic acid with another antibiotic with wide range (ciprofloxacin). Resolution of the pustular lesions occurred within ten days and was accompanied by light scarring and pigmentation. On the basis of the close relationship between the administration of amoxicillin-clavulanic acid and the development of the disease, in combination with a rapid, acute resolution as soon as this treatment was interrupted, and all the histologic findings, we consider this to be an unusual type of acute generalized pustular eruption (AGEP) recently defined as acute localized pustular eruption (ALEP) due to amoxicillin-clavulanic acid.

Journal of the European Academy of Dermatology and VenereologyVolume 23, Issue 2 p. 212-213 Penile chancre: an unusual presentation of cat-scratch disease A Vassilopoulou, Corresponding Author A Vassilopoulou Dermatology Unit and *Correspondence: A Vassilopoulou. E-mail: [email protected]Search for more papers by this authorP Betto, P Betto Dermatology Unit andSearch for more papers by this authorL Germi, L Germi Dermatology Unit andSearch for more papers by this authorE Bonoldi, E Bonoldi Pathologic Anatomy Service, San Bortolo Hospital, Vicenza, ItalySearch for more papers by this authorC Veller Fornasa, C Veller Fornasa Dermatology Unit andSearch for more papers by this author A Vassilopoulou, Corresponding Author A Vassilopoulou Dermatology Unit and *Correspondence: A Vassilopoulou. E-mail: [email protected]Search for more papers by this authorP Betto, P Betto Dermatology Unit andSearch for more papers by this authorL Germi, L Germi Dermatology Unit andSearch for more papers by this authorE Bonoldi, E Bonoldi Pathologic Anatomy Service, San Bortolo Hospital, Vicenza, ItalySearch for more papers by this authorC Veller Fornasa, C Veller Fornasa Dermatology Unit andSearch for more papers by this author First published: 20 January 2009 https://doi.org/10.1111/j.1468-3083.2008.02788.xCitations: 1 DOI: 10.1111/j.1468-3083.2008.02788.x Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. References 1 Rodriguez-Barrados MC, Hamill RJ, Houston ED et al . Genomic fingerprinting of Bartonella species by repetitive element PCR for distinguishing species and isolates. J Clin Microbiol 1995; 33: 1089–1093. 2 Lindroos H, Vinnere O, Mira A, Repsilber D, Näslund K, Andersson SG. Genome rearrangements, deletions and amplifications in the natural population of Bartonella henselae. J Bacteriol 2006; 188: 7426–7439. 3 Wear DJ, Margileth AM, Hadfield TL, Fischer GW, Schlagel CJ, King FM. Cat scratch disease: a bacterial infection. Science 1983; 221: 1403–1405. 4 Maurin M, Raoult D. Bartonella (Rochalimaea) quintana infections. Clin Microbiol Rev 1996; 9: 273–292. 5 Anderson B, Neuman M. Bartonella spp. as emerging human pathogens. Clin Microbiol Rev 1997; 10: 203–219. 6 Reguery RL, Childs JE, Koehler JE. Infections associated with Bartonella species in persons infected with human immunodeficiency virus. Clin Infect Dis 1995; 21 (Suppl. 1): S94–98. 7 Fouch B, Coventry S. A case of fatal disseminated Bartonella henselae infection (cat-scratch disease) with encephalitis. Arch Pathol Lab Med 2007; 131: 1591–1594. 8 Ferres GM, Abarca VK, Prado DP, Montecino PL, Navarrete CM. [Prevalence of Bartonella henselae antibodies in Chilean children, adolescents and veterinary workers.] Rev Med Chil 2006; 134: 863–867 (in Spanish). Citing Literature Volume23, Issue2February 2009Pages 212-213 ReferencesRelatedInformation

Journal of the European Academy of Dermatology and VenereologyVolume 22, Issue 6 p. 762-763 Tamoxifen and purpuric vasculitis: a case report P Betto, P Betto Dermatology Unit,Search for more papers by this authorE Gennari, E Gennari Dermatology Unit,Search for more papers by this authorL Germi, L Germi Dermatology Unit,Search for more papers by this authorE Bonoldi, E Bonoldi Pathologic Anatomy Service,Search for more papers by this authorG Scalco, G Scalco Surgery Unit, San Bortolo Hospital, Vicenza,Search for more papers by this authorA Tosti, A Tosti Dermatology Department, University of Bologna, BolognaSearch for more papers by this author P Betto, P Betto Dermatology Unit,Search for more papers by this authorE Gennari, E Gennari Dermatology Unit,Search for more papers by this authorL Germi, L Germi Dermatology Unit,Search for more papers by this authorE Bonoldi, E Bonoldi Pathologic Anatomy Service,Search for more papers by this authorG Scalco, G Scalco Surgery Unit, San Bortolo Hospital, Vicenza,Search for more papers by this authorA Tosti, A Tosti Dermatology Department, University of Bologna, BolognaSearch for more papers by this author First published: 21 November 2007 https://doi.org/10.1111/j.1468-3083.2007.02479.xCitations: 9 * Corresponding author, Unità Operativa Dermatologia, Ospedale San Bortolo, Via Rodolfi, 36100 Vicenza, tel. +444 753606; fax +444 753167; E-mail: [email protected] DOI: 10.1111/j.1468-3083.2007.02479.x Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. References 1 Gradishar WJ. Tamoxifen – what next? Oncologist 2004; 9: 378–384. 2 Crowell EB Jr, Higa GM. The chemo-hormonal therapy of metastatic melanoma: possible benefit of tamoxifen. W V Med J 1993; 89: 233–235. 3 Farge D, Chanu B, Debourdeau P et al . Tamoxifen and cardiovascular risk. Ann Med Interne (Paris) 1994; 145: 488–493. 4 Cobelli S, Dambrosio M, Farina G, Rovej R, Tomirotti M, Scanni A. Long-term toxicity in adjuvant treatment with tamoxifen. J Chemother 1997; 9: 300–303. 5 Weitz IC, Israel VK, Liebman HA. Tamoxifen-associated venous thrombosis and activated protein C resistance due to factor V Leiden. Cancer 1997; 79: 2024–2027. 6 Fisher B, Dignam J, Bryant J et al . Five versus more than five years of tamoxifen therapy for breast cancer patients with negative lymph nodes and estrogen receptor-positive tumors. J Nat Cancer Inst 1996; 88: 1529–1542. 7 Robinson E, Kimmick GG, Muss HB. Tamoxifen in postmenopausal women a safety perspective. Drugs Aging 1996; 8: 329–337. 8 Wickerham DL, Fisher B, Wolmark N et al . Association of tamoxifen uterine sarcoma. J Clin Oncol 2002; 20: 2758–2760. 9 Bruinsma W. A guide to drug eruptions. Oosthuizen, the Netherlands: the File of Medicines 1987; 93: 201–203. 10 Drago F, Arditi M, Rebora A. Tamoxifen and purpuric vasculitis. Ann Intern Med 1990; 112: 965–966. Citing Literature Volume22, Issue6June 2008Pages 762-763 ReferencesRelatedInformation

In this article, we describe the morphologic and immunophenotypic features of 75 cases of pediatric anaplastic large cell lymphoma (ALCL). According to the World Health Organization classification, 49 cases were common subtype ALCL, and respectively, 3, 6, and 17 cases were small cell, lymphohistiocytic, or mixed histologic variants. Anaplastic lymphoma kinase positivity was detected in 90.7% of the tumors and, using a panel of 9 T-cell surface markers, 88% could be assigned to the T-cell lineage. A molecular analysis for the T-cell receptor gamma (TCR- gamma) and the heavy chain of the immunoglobulin H rearrangements was performed on 6/9 ALCLs with a null immunophenotype, and a TCR clonal pattern was detected in 5/6 cases. In addition, 94.1% were immunoreactive for 1 or more cytotoxic proteins (Tia1, granzyme B, or perforin), and 15% expressed CD56. Clusterin, CD83, and Pax5, respectively, expressed in 91.3%, 1.7%, and 0% of the ALCLs, were useful biomarkers for the differential diagnosis with Hodgkin's lymphomas.

area del triveneto.La neuroborreliosi di Lyme (LN) è molto rara e la sintomatologia può a volte essere confusa con la malattia di Parkinson (PD) o altre patologie neurodegenerative.Metodi.Da un paziente (anni 57 M) con diagnosi clinica di PD deceduto per polmonite sono stati effettuati prelievi autoptici da corteccia cerebrale, cervelletto, ponte, nervo ottico, poligono di Willis, arteria coronaria, aorta toracica e addominale e arteria renale.I prelievi sono stati divisi in 2 parti, per l'estrazione e amplificazione del DNA (nested-PCR) e per PCR in situ.È stata ricercata una sequenza conservata del gene codificante per la flagellina di BB.Come controllo è stato utilizzato un ceppo di BB ATCC.Gli amplificati sono stati sequenziati per conferma.

BACKGROUND:Diffuse large B-cell lymphoma (DLBCL) has been correlated to hepatitis C virus (HCV) infection in few series, but characteristics and outcome of these patients remain undefined.PATIENTS AND METHODS:We analyzed 156 previously untreated consecutive HCV-positive patients with DLBCL observed between 1994 and 2004 in three major institutions from northern Italy.RESULTS:Median age at presentation was 63 years and 8% of patients had DLBCL transformed from low-grade lymphomas. Spleen was the most frequently involved extranodal site, followed by liver and stomach. Treatment was delivered with cure-intent in 132 patients, while the remaining 24 patients received monochemotherapy or radiotherapy alone due to old age or seriously impaired hepatic function. Only five patients (4%) had to discontinue chemotherapy due to severe liver function impairment. The addition of rituximab did not seem to affect patients' tolerance to treatment. Five-year overall survival of the entire cohort was 72%, while 5-year progression-free survival (PFS) of the 132 patients treated with cure-intent was 51%. Hepatitis B virus co-infection, advanced Ann Arbor stage and nodal origin of the tumor resulted the strongest adverse prognostic factors.CONCLUSIONS:Patients with HCV-positive DLBCL share distinctive clinical features. Future studies should prospectively evaluate the association between HCV and aggressive lymphomas.

The effect of antiretroviral therapy on the natural history of human papillomavirus (HPV)-associated genital lesions was evaluated in 201 human immunodeficiency virus (HIV)-infected women who were followed-up for 1-6 years. Gynecologic examinations were performed every 6-12 months. HPV sequences in cervico-vaginal cells, analyzed by polymerase chain reaction and typed by restriction fragment-length polymorphism analysis, were repeatedly detected in 126 women; 29 had transient HPV infection. Genital lesions were found in 137 patients; prevalence was comparable in women who were receiving different antiretroviral regimens. Regression of low-grade lesions was more prevalent among patients receiving highly active antiretroviral therapy than among those receiving other regimens; high-grade lesions regressed in the majority of cases, regardless of antiretroviral therapy. HPV infection persisted in nearly 80% of the cases. In conclusion, our data show that antiretroviral therapy does not prevent the development of HPV-associated lesions and does not eliminate HPV infection; therefore, early and strict gynecologic follow-up of HIV-infected women is warranted.