10 Tables displaying the clinical features of patient cohorts analyzed in this study, as well as correlation analyses among the clinical features and slan+ cell content.

Abstract Terminal tissue differentiation and function of slan+ monocytes in cancer is largely unexplored. Our recent studies demonstrated that slan+ monocytes differentiate into a distinct subset of dendritic cells (DC) in human tonsils and that slan+ cells colonize metastatic carcinoma-draining lymph nodes. Herein, we report by retrospective analysis of multi-institutional cohorts that slan+ cells infiltrate various types of non-Hodgkin lymphomas (NHL), particularly the diffuse large B-cell lymphoma (DLBCL) group, including the most aggressive, nodal and extranodal, forms. Nodal slan+ cells displayed features of either immature DC or macrophages, in the latter case ingesting tumor cells and apoptotic bodies. We also found in patients with DLBCL that peripheral blood slan+ monocytes, but not CD14+ monocytes, increased in number and displayed highly efficient rituximab-mediated antibody-dependent cellular cytotoxicity, almost equivalent to that exerted by NK cells. Notably, slan+ monocytes cultured in conditioned medium from nodal DLBCL (DCM) acquired a macrophage-like phenotype, retained CD16 expression, and became very efficient in rituximab-mediated antibody-dependent cellular phagocytosis (ADCP). Macrophages derived from DCM-treated CD14+ monocytes performed very efficient rituximab-mediated ADCP, however, using different FcγRs from those used by slan+ macrophages. Our observations shed new light on the complexity of the immune microenvironment of DLBCL and demonstrate plasticity of slan+ monocytes homing to cancer tissues. Altogether, data identify slan+ monocytes and macrophages as prominent effectors of antibody-mediated tumor cell targeting in patients with DLBCL. Significance: slan+ monocytes differentiate into macrophages that function as prominent effectors of antibody-mediated tumor cell targeting in lymphoma. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/13/3544/F1.large.jpg. Cancer Res; 78(13); 3544–59. ©2018 AACR.

Abstract Terminal tissue differentiation and function of slan+ monocytes in cancer is largely unexplored. Our recent studies demonstrated that slan+ monocytes differentiate into a distinct subset of dendritic cells (DC) in human tonsils and that slan+ cells colonize metastatic carcinoma-draining lymph nodes. Herein, we report by retrospective analysis of multi-institutional cohorts that slan+ cells infiltrate various types of non-Hodgkin lymphomas (NHL), particularly the diffuse large B-cell lymphoma (DLBCL) group, including the most aggressive, nodal and extranodal, forms. Nodal slan+ cells displayed features of either immature DC or macrophages, in the latter case ingesting tumor cells and apoptotic bodies. We also found in patients with DLBCL that peripheral blood slan+ monocytes, but not CD14+ monocytes, increased in number and displayed highly efficient rituximab-mediated antibody-dependent cellular cytotoxicity, almost equivalent to that exerted by NK cells. Notably, slan+ monocytes cultured in conditioned medium from nodal DLBCL (DCM) acquired a macrophage-like phenotype, retained CD16 expression, and became very efficient in rituximab-mediated antibody-dependent cellular phagocytosis (ADCP). Macrophages derived from DCM-treated CD14+ monocytes performed very efficient rituximab-mediated ADCP, however, using different FcγRs from those used by slan+ macrophages. Our observations shed new light on the complexity of the immune microenvironment of DLBCL and demonstrate plasticity of slan+ monocytes homing to cancer tissues. Altogether, data identify slan+ monocytes and macrophages as prominent effectors of antibody-mediated tumor cell targeting in patients with DLBCL. Significance: slan+ monocytes differentiate into macrophages that function as prominent effectors of antibody-mediated tumor cell targeting in lymphoma. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/13/3544/F1.large.jpg. Cancer Res; 78(13); 3544–59. ©2018 AACR.

The file contains 8 supplementary Figures displaying results in support of the data described in the results section.

A 58-year-old male with B-cell chronic lymphocytic leukemia presented with fever, chest pain, and acute-onset neurological deficits suggestive of multiple strokes (A). Brain autopsy revealed softening areas in the brain parenchyma (B, C) corresponding to extensive necrosis (D) caused by neuroinvasion by Aspergillus hyphae (E, F) necrosis (D) caused by neuroinvasion by Aspergillus hyphae (E, F).

Patients with indolent conjunctival lymphomas exhibit good prognosis, with exceptional cases of dissemination, and are suitable candidates for intralesional therapies. We report the first prospective phase 2 trial using intralesional rituximab supplemented with autologous serum in adults with relapsed/refractory indolent CD20+ lymphoma of the conjunctiva (NCT01514344). Patients received 4 weekly intralesional injections of rituximab, followed by 6 monthly injections; 500 μL of autologous serum was added to rituximab in patients with lymphoma unresponsive to weekly doses. Safety, activity, and antitumor effect of autologous serum were investigated. Twenty patients with mucosa-associated lymphoid tissue (MALT)-type lymphoma were enrolled. Tolerability was excellent, with only 3 mild local reactions. After weekly injections, 11 patients achieved tumor regression, 8 had stable disease, and 1 experienced progressive disease; 9 patients received autologous serum, with response improvement in 4 cases (3 complete responses, 1 partial response). At the end of treatment, 12 patients achieved a complete remission, and 1 achieved a partial response, with an overall response rate of 65% (95% confidence interval, 45-85). At a median follow-up of 42 months (range, 10-78), 12 patients remain relapse free, with 5-year progression-free survival and time-to-next-treatment rates of 59% ± 11% and 69% ± 11%, respectively. Three patients with local relapse were retreated with intralesional rituximab and serum; 2 achieved a complete response that lasted 25+ and 38+ months. Thus, intralesional rituximab is a safe and active therapy in patients with relapsed conjunctival MALT lymphoma. The addition of autologous serum improves response in some cases. Retreatment of local relapses can result in a second durable remission.

Abstract Terminal tissue differentiation and function of slan+ monocytes in cancer is largely unexplored. Our recent studies demonstrated that slan+ monocytes differentiate into a distinct subset of dendritic cells (DC) in human tonsils and that slan+ cells colonize metastatic carcinoma-draining lymph nodes. Herein, we report by retrospective analysis of multi-institutional cohorts that slan+ cells infiltrate various types of non-Hodgkin lymphomas (NHL), particularly the diffuse large B-cell lymphoma (DLBCL) group, including the most aggressive, nodal and extranodal, forms. Nodal slan+ cells displayed features of either immature DC or macrophages, in the latter case ingesting tumor cells and apoptotic bodies. We also found in patients with DLBCL that peripheral blood slan+ monocytes, but not CD14+ monocytes, increased in number and displayed highly efficient rituximab-mediated antibody-dependent cellular cytotoxicity, almost equivalent to that exerted by NK cells. Notably, slan+ monocytes cultured in conditioned medium from nodal DLBCL (DCM) acquired a macrophage-like phenotype, retained CD16 expression, and became very efficient in rituximab-mediated antibody-dependent cellular phagocytosis (ADCP). Macrophages derived from DCM-treated CD14+ monocytes performed very efficient rituximab-mediated ADCP, however, using different FcγRs from those used by slan+ macrophages. Our observations shed new light on the complexity of the immune microenvironment of DLBCL and demonstrate plasticity of slan+ monocytes homing to cancer tissues. Altogether, data identify slan+ monocytes and macrophages as prominent effectors of antibody-mediated tumor cell targeting in patients with DLBCL. Significance: slan+ monocytes differentiate into macrophages that function as prominent effectors of antibody-mediated tumor cell targeting in lymphoma. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/13/3544/F1.large.jpg. Cancer Res; 78(13); 3544–59. ©2018 AACR.

Human granulocytic myeloid-derived suppressor cells (G-MDSCs) have been described as low-density immunosuppressive CD66b(+)CD33(dim)HLA-DR- granulocytes that co-purify with mononuclear cells after density gradient centrifugation of blood from cancer patients. The role of G-MDSCs in Hodgkin (HL) and non-Hodgkin lymphoma (NHL) remains unclear.The percentage and immunophenotype of CD66b(+)CD33(dim)HLA-DR- cells were analyzed in PBMCs from HL and B-cell NHL patients (n = 124) and healthy donors (n = 48). The immunosuppressive functions of these cells were tested in vitro. Correlations between CD66b(+)CD33(dim)HLA-DR- cells and patient clinicopathological features and outcome, were evaluated.CD66b(+)CD33(dim)HLA-DR-cells were increased in PBMCs from HL and B-cell NHL patients as compared to healthy donors: 2.18 (0.02-70.92) vs 0.42 (0.04-2.97), p < 0.0001. Their percentage remained significantly higher even considering HL (n = 31), indolent (n = 31) and aggressive (n = 62) B-cell NHL patients separately: 1.54 (0.28-26.34), 2.15 (0.02-20.08), and 2.96 (0.25-70.92), respectively, p < 0.0001. CD66b(+)CD33(dim)HLA-DR-cells in patient PBMCs were mostly composed of mature CD11b(+)CD16(+) low-density neutrophils in an activated status, as revealed by their higher CD11b and CD66b expression as compared to conventionally isolated (normal-density) autologous or healthy donor neutrophils. The in vitro depletion of CD66b(+) cells from patient PBMCs restored the proliferation of autologous T cells. Higher frequencies of CD66b(+)CD33(dim)HLA-DR-G-MDSCs correlated significantly with unfavorable prognostic index scores and a shorter freedom from disease progression.PBMCs from HL and B-cell NHL patients contain a population of CD66b(+)CD33(dim) HLA-DR-G-MDSCs, mostly composed of activated low-density neutrophils with immunosuppressive properties. These findings disclose a previously unknown G-MDSC-mediated mechanism of immune-escape in lymphomas, therefore anticipating possible targets for therapeutic interventions.

Case Report A 50-year-old, previously healthy woman was referred to the emergency unit of our institution for sudden motor aphasia resolving spontaneously in 15 minutes. Magnetic resonance imaging (MRI) of the brain showed infiltrative contrast-enhancing tissue in the left temporal-insular lobe and thalamus, with surrounding edema and a mild axial median shift (Figs 1A and 1B). The tissue also infiltrated the corpus callosum with initial diffusion to the white matter of the right hemisphere. No dura mater or skull involvement was documented. MRI spectroscopy confirmed the presence of infiltrating lymphomalike tissue. Electroencephalography showed nonspecific wave slowing in the left frontotemporal region.

A general consensus on the role of testicular biopsy in non-obstructive azoospermia (NOA) is needed. This paper reviews and updates technical aspects and clinical performance of the percutaneous testicular biopsy techniques, in particular large-needle aspiration biopsy (LNAB), and proposes a flow chart for the management of NOA. The English literature and original data were reviewed or analyzed. Large-needle biopsy (LNB) includes large-needle cutting biopsy (LNCB) and large-needle aspiration biopsy (LNAB). LNCB usually requires scrotal incision for the insertion of relatively large needles. Fine-needle aspiration biopsy (FNAB) does not require surgical equipment or expertise, employs the smallest needles (23- to 20-gauge), and permits sperm cytologic detection. LNAB also does not require surgical equipment or expertise, employs needles of size from 20- to 18-gauge, is safe, and can be used for testicular histology and sperm recovery. An operative flow chart is proposed for the management of NOA in which FNAB, LNAB and open surgical biopsy are used for the optimal management of NOA.

The optimal treatment of advanced sporadic Burkitt lymphoma in adults is still a matter of debate. The salutary results of pediatric therapies did open the road for improving the adult outcome. Between May 1988 and March 2009, 71 consecutive patients—46 adults, 25 children—affected by Burkitt lymphoma/leukemia were treated with the same intensive pediatric protocol alternating vincristine, adriamycine and fractionated ciclophosphamide (phase A) with high dose methotrexate and high dose cytarabine (phase B) in four Italian institutions. Eighty‐nine per cent of patients were in Stage III–IV or had L3 leukemia. Complete remissions were 67/71 (94.4%), 24/25 (96%) in children, and 43/46 (93.5%) in adults. Toxic deaths were 3/71 (4.2%), all in adults. There were nine relapses (one in children, eight in adults), all but one observed early. After a median observation of 94 months (range 23–275), the Event–Free Survival rate is 92% in children and 71.7% in adults ( P = 0.067). The 23 more recent adults received also rituximab, without differences in outcome as compared to patients who did not. Our experience confirms that such an intensive pediatric‐derived chemotherapy is feasible and improves the long‐term outcome of adults with advanced Burkitt lymphoma. Am. J. Hematol., 2012. © 2011 Wiley Periodicals, Inc.

Hematological OncologyVolume 29, Issue 3 p. 151-153 Letter to the Editor A preliminary experience with the HyperCHiDAM Verona intensive chemotherapy regimen in heavily pretreated refractory Hodgkin's lymphoma Giuseppe Todeschini, Giuseppe Todeschini Department of Medicine, Section of Hematology, University of Verona, ItalySearch for more papers by this authorMassimiliano Bonifacio, Massimiliano Bonifacio Department of Medicine, Section of Hematology, University of Verona, ItalySearch for more papers by this authorCristina Tecchio, Cristina Tecchio Department of Medicine, Section of Hematology, University of Verona, ItalySearch for more papers by this authorDaniela Dalceggio, Daniela Dalceggio Department of Medicine, Section of Hematology, University of Verona, ItalySearch for more papers by this authorFabio Benedetti, Fabio Benedetti Department of Medicine, Section of Hematology, University of Verona, ItalySearch for more papers by this authorAttilio Gabbas, Attilio Gabbas Department of Hematology, Ospedale ‘San Francesco’, Nuoro, ItalySearch for more papers by this authorGiovanni Pizzolo, Giovanni Pizzolo Department of Medicine, Section of Hematology, University of Verona, ItalySearch for more papers by this author Giuseppe Todeschini, Giuseppe Todeschini Department of Medicine, Section of Hematology, University of Verona, ItalySearch for more papers by this authorMassimiliano Bonifacio, Massimiliano Bonifacio Department of Medicine, Section of Hematology, University of Verona, ItalySearch for more papers by this authorCristina Tecchio, Cristina Tecchio Department of Medicine, Section of Hematology, University of Verona, ItalySearch for more papers by this authorDaniela Dalceggio, Daniela Dalceggio Department of Medicine, Section of Hematology, University of Verona, ItalySearch for more papers by this authorFabio Benedetti, Fabio Benedetti Department of Medicine, Section of Hematology, University of Verona, ItalySearch for more papers by this authorAttilio Gabbas, Attilio Gabbas Department of Hematology, Ospedale ‘San Francesco’, Nuoro, ItalySearch for more papers by this authorGiovanni Pizzolo, Giovanni Pizzolo Department of Medicine, Section of Hematology, University of Verona, ItalySearch for more papers by this author First published: 27 September 2010 https://doi.org/10.1002/hon.966Read 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 onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume29, Issue3September 2011Pages 151-153 RelatedInformation

Bauditz, J. & Lochs, H. (2007) Angiogenesis and vascular malformations: antiangiogenic drugs for treatment of gastrointestinal bleeding. World Journal of Gastroenterology, 13, 5979–5984. Begbie, M.E., Wallace, G.M.F. & Shovlin, C.L. (2003) Hereditary haemorrhagic telangiectasia (Osler–Weber–Rendu syndrome): a view from the 21st century. Postgraduate Medical Journal, 79, 18–24. Dimopoulos, M., Spencer, A., Attal, M., Miles Prince, H., Harousseau, J.L., Dmoszynska, A., San Miguel, J., Hellmann, A., Facon, T., Foa, R., Corso, A., Masliak, Z., Olesnyckyj, M., Yu, Z., Patin, J., Zeldis, J.B. & Knight, R.D. (2007) Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. New England Journal of Medicine, 357, 2123–2132. Dredge, K., Marriott, J.B., Macdonald, C.D., Man, H.-W., Chen, R., Muller, G.W., Stirling, D. & Dalgleish, A.G. (2002) Novel thalidomide analogues display anti-angiogenic activity independently of immunomodulatory effects. British Journal of Cancer, 8710, 1166–1172. Dredge, K., Horsfall, R., Robinson, S.P., Zhang, L.H., Lu, L., Tang, Y., Shirley, M.A., Muller, G., Schafer, P., Stirling, D., Dalgleish, A.G. & Bartlett, J.B. (2005) Orally administered lenalidomide (CC-5013) is anti-angiogenic in vivo and inhibits endothelial cell migration and Akt phosphorylation in vitro. Microvascular Research, 69, 56–63. Galustian, C. & Dalgleish, A. (2009) Lenalidomide: a novel anticancer drug with multiple modalities. Expert Opinion on Pharmacotherapy., 10, 125–133. Heidt, J., Langers, A.M., van der Meer, F.J. & Brouwer, R.E. (2006) Thalidomide as treatment for digestive tract angiodysplasias. Netherlands Journal of Medicine, 64, 425–428.

Background. Peripheral T cell Lymphoma (PTCL) represent a major therapeutic challenge. In the previous Verona experience (Todeschini G et al. Cancer 2005;104:555–560), the novel intensive regimen HyperCHiDAM Verona897 (high-dose IV MTX 2 g/sqm 400 sqm bolus, 1600 sqm CI day 1 with IV leucovorin rescue; hyperfractionated IV CTX 300 mg/sqm Q12h, dd 2–4; high-dose IV AraC 2g/sqm Q12h, dd 2-4; plus G-CSF) achieved salutary results in refractory/relapsed aggressive lymphomas, in particular in PTCL. Supportive measures included hydratation 3000 ml/sqm/day, antimicrobial prophylaxis comprising oral ciprofloxacin, itraconazole, trimethoprim/sulfamethoxazole. CMV antigenemia (pp65) was monitored 2 times a week. Patients. Following these results, 7 centers belonging to the Italian co-operative group GITIL (Gruppo Italiano Terapie Innovative Linfomi) treated with 2 cycles of HyperCHiDAM Verona897, 33 patients affected by PTCL (17 upfront, 16 refractory/relapsed) followed in the majority of cases by stem cell transplant. Patients: M/F 21/12, median age 49 (19–63) years; histology: PTCL-NOS 15, ALCL ALK-negative 9, EALTC 4, AIL 3, T-NK nasal 1, Angiocentric 1; stage IV 19/33 (57.5%), bone-marrow positive 10/33 (30.3%), extranodal involvement 24/33 (72.7%), high LDH 18/33 (54.5%). Seven patients needing urgent treatment were treated before HyperCHiDAM with 1 cycle of Campath-CHOP (4 patients) or CHOP + L-ASE (3 patients).Results. Upfront patients: after 2 cycles of HyperCHiDAM, CR were 82.3% (14/17), early toxic deaths 0 (1 late toxic death occurred after SCT, due to CMV pneumonia), relapses 3/14. With a median follow-up of 21 months (3–90+), 11/17 (64.7%) patients are disease-free, 10 in first CR, 1 after rescue with stem cell transplant. Three of the CCR patients received HyperCHiDAM alone. Refractory/relapsed patients: CR were 5/16 (31.2%), CCR 4/16 (25%), with a median follow-up of 24 months (5–64+). The progression-free survival was significantly superior in upfront patients (p=0.036). Overall, toxic deaths were 3/33 (9%), 1/17 (5.8%) in upfront and 2/16 (12.5%) in refractory/relapsed patients. One patient had major cerebellar toxicity.Conclusions. The intensive regimen HyperCHiDAM Verona897 is effective in inducing CR in aggressive PTCL, in particular as upfront therapy. The intensiveness of this treatment requires a careful supportive therapy. Following these results, HyperCHiDAM has been included in a national trial for treatment of PTCL, after 2 cycles of Campath-CHOP and before stem cell transplant (allogeneic or autologous depending on the availability of an HLA-matched sibling). The co-operative study is recruiting.

Two hundred thirteen testicular specimens of men with nonobstructive azoospermia were obtained by large-needle percutaneous aspiration biopsy. The mean values of the number of seminiferous tubules per histologic section, dimension, weight, and the fraction of biopsies with spermatogenetic cells (53, 0.2 x 0.3 x 0.62 cm, 385 mg, and 63%, respectively) were similar to those obtained by open or other surgical biopsy techniques that were used for assisted fertilization in the same type of patients.

Fatality rates and prognostic factors for mortality due to Enterococcus spp. bacteraemia have not yet been fully defined in the setting of neutropenic patients affected with haematological malignancies. We have performed a retrospective, multi-centre cohort study on 98 episodes of Enterococcus bacteraemia occurring in patients hospitalised from January 1984 to December 2001 at the oncohaematology units in two tertiary-care hospitals (Verona Hospital and Vicenza Hospital, in north-east Italy). E. faecalis was isolated in 52 cases (53%), E. faecium in 39 (39.8%), E. avium in four, E. durans in one, and untyped Enterococcus spp. in two other cases; vancomycin resistance was detected in 15 (15.3%) isolates. A global mortality rate of 41.8% (41/98 cases) was revealed; Enterococcus spp. bacteraemia was associated with a fatal outcome in 29/98 cases (29.5%). The following variables were independently associated with an increased risk of death by multivariate analysis of survival: age ≥50years (OR 3.74; 95% CI 1.35–10.32), pneumonia (OR 4.70; 95% CI 1.67–13.20), and shock (OR 13.7; 95% CI 1.23–152.43), while the initial phase of haematological disease (responsive to chemotherapy) appeared to be protective (OR 0.23; 95% CI 0.008–0.64, P level 0.005); however, pneumonia alone (OR 7.2, 95% CI 2.52–20.88) was independently associated with fatal outcome by multivariate analysis for death related to enterococcal bacteraemia. In our experience, the poor outcome proper to enterococcal bacteraemia appears to be directly related to underlying disease, patient's age, presence of pneumonia and shock; in contrast, severe neutropaenia, antibiotic resistance, and species of Enterococcus do not appear to affect the fatality rate significantly.

Fever of unknown origin may represent a substantial diagnostic challenge. Metabolic total body imaging may be of help in detecting inflammatory foci when clinical evaluation cannot identify the source of prominent local symptoms. In particular, F-18 FDG PET may offer superior sensibility in detecting the considerable local increase of metabolism of activated granulocytes and macrophages in focal inflammation. On the other hand, systemic pathology with diffuse macrophage activation may determine peculiar PET patterns, contributing to draw the clinician's attention to diffuse rather than focal illness. A case of PET/CT total body imaging in visceral Mediterranean leishmaniasis, showing a diffuse increase of reticuloendothelial metabolic activity, is presented here.