Marco Ungari

Delayed-onset peripheral blood cytopenia after rituximab: Frequency and risk factor assessment in a consecutive series of 77 treatments

The occurrence of unexplained peripheral blood cytopenia, particularly neutropenia, has been recently reported after rituximab. Its prevalence may be underestimated since it may occur late after treatment. This study analysed all cases of unexplained delayed-onset peripheral blood cytopenia of WHO grade II – IV occurring in an unselected series of patients treated with rituximab in order to evaluate its prevalence and clinical significance. Seventy-seven courses of rituximab (corresponding to 317 rituximab infusions) given to 72 consecutive patients affected by non-Hodgkins Lymphoma and treated at a single Center with rituximab, alone (nine cases), associated with chemotherapy (50) or with chemotherapy and autologous stem cell transplantation (18) were evaluated. Twenty-three cases of cytopenia (29.8%) were observed. Neutropenia developed in 21 cases (27.3%), thrombocytopenia in eight (10.4%), anemia in four (5.2%). Multiple cytopenias were observed in nine cases. Neutropenia developed after a median of 10 weeks, anemia of 5 weeks and thrombocytopenia of 4 weeks after the last rituximab dose. Severe infections occurred in four of 21 neutropenic patients (19%), compared to two of 56 controls (3.6%) (p = 0.043). Cytopenia eventually resolved in nine of 18 evaluable cases after a median of 10 weeks (range 1 – 23). Age, sex, histology, bone marrow infiltration, hypogammaglobulinemia, previous chemotherapy, autologous stem cell transplant, rituximab schedule and timing, rituximab doses were analysed as predictors for cytopenia; by multivariate analysis only a previous treatment with chemotherapy and more than four rituximab doses were significantly associated with a higher risk of post-rituximab delayed cytopenia. Delayed-onset cytopenia, particularly neutropenia, is a clinically significant complication of rituximab treatment, which merits further investigation.

Sinonasal mucosal melanoma: Molecular profile and therapeutic implications from a series of 32 cases

Primary sinonasal mucosal melanomas are aggressive tumors with a poor clinical control by current treatments, raising the urgent need of novel strategies.

SDF-1 Inhibition Targets the Bone Marrow Niche for Cancer Therapy

Bone marrow (BM) metastasis remains one of the main causes of death associated with solid tumors as well as multiple myeloma (MM). Targeting the BM niche to prevent or modulate metastasis has not been successful to date. Here, we show that stromal cell-derived factor-1 (SDF-1/CXCL12) is highly expressed in active MM, as well as in BM sites of tumor metastasis and report on the discovery of the high-affinity anti-SDF-1 PEGylated mirror-image l-oligonucleotide (olaptesed-pegol). In vivo confocal imaging showed that SDF-1 levels are increased within MM cell-colonized BM areas. Using in vivo murine and xenograft mouse models, we document that in vivo SDF-1 neutralization within BM niches leads to a microenvironment that is less receptive for MM cells and reduces MM cell homing and growth, thereby inhibiting MM disease progression. Targeting of SDF-1 represents a valid strategy for preventing or disrupting colonization of the BM by MM cells.

Lymph node pathology in primary combined immunodeficiency diseases

ConclusionsThis study has provided information on the spectrum of changes which can occur in different PID. Using a pattern-based approach for the analysis of the lymph node parenchyma, it is obvious that there are no morphological features specifically associated with a single disease. This indicates that the lymph node biopsy is per se insufficient to identify any specific form of PID. There are, however, a few exceptions: with the advantage of immunohistochemistry we found severe abnormalities of FDC in X-linked hyper-IgM, which can be used for diagnostic purposes. Other morphological phenotypical features of lymph nodes, when correlated with clinical and hematological data, can be relevant for the correct attribution to a specific disease: a lymph node with preserved cellularity is never found in T−B− SCID, unless associated with engraftment of maternal/donor lymphocytes. On the other hand, lymph node changes that have been considered characteristic of OS, can also be observed in other conditions, and may sometimes derive from associated skin diseases. This indicates that the distinction between these PID might not be absolute, not only in terms of morphology, but also in terms of cell defects and pathogenesis.The heterogeneity of lymph node histology observed within the same disease can be explained by the complex of interactions regulating the ontogeny and development of lymphoid organs. In addition, it may reflect the phenomenon of identical genetic anomalies that give different phenotypes [72]. In certain conditions, such as the WAS, this morphological variability can be correlated with clinical variations of the disease, and can be helpful in the study of the biological mechanisms associated with gene mutations and protein expression defects.Knowledge of the spectrum of changes which can be found in lymph nodes in different forms of PID may be helpful not only in better defining the clinical diagnosis, but also in the evaluation of biopsy/autopsy material from patients who died without a precise diagnosis being made, and in genetic counselling. With the help of advanced techniques, such as in situ hybridization for mRNA encoding specific immune-related gene products, the study of lymph node biopsy samples will provide greater insight into the processes regulating the immune response, in normal and pathological conditions.

Lymphoid abnormalities in CD40 ligand transgenic mice suggest the need for tight regulation in gene therapy approaches to hyper immunoglobulin M (IgM) syndrome

Mutations in the CD40 ligand (CD40L) are responsible for human hyper immunoglobulin M (IgM) syndrome. The absence of the interaction between CD40L, expressed by T lymphocytes, and the CD40 receptor present on the surface of B cells is responsible for the inability of B cells to carry out the isotype switch from IgM to the other Ig classes. This leads to a fatal immunodeficiency for which no cure exists. For these reasons, the CD40L gene is a good candidate for gene therapy studies. To investigate the possible effects of the expression of this tightly regulated gene in vivo, we produced transgenic mice in which CD40L expression was deregulated. Widespread ectopic expression appears to be lethal. Overexpression in mature T cells is compatible with life, but in one-third of the cases, mice developed atypical lymphoid proliferations which, occasionally, progressed into frank lymphomas. Even though gene therapy is one of the most promising approaches to cure human hyper IgM syndrome, these results suggest that when we modify very tightly regulated genes such as cytokines or other growth factors, particular care has to be taken to avoid excessive stimulation of the target cells.

Sinonasal mucosal melanoma: A 12-year experience of 58 cases

Sinonasal mucosal melanoma is a rare malignancy with poor prognosis.

Transformation of a MGUS to Overt Multiple Myeloma: The Possible Role of a Pituitary Macroadenoma Secreting High Levels of Insulin-like Growth Factor 1 (IGF-1)

We present a female patient with monoclonal gammopathy of undetermined significance who has remained stable for five years but evolved to overt myeloma in strict temporal relationship with the diagnosis of GH-secreting pituitary macroadenoma. IGF-I serum levels correlated with serum and urine M component. Since the in vitro role of IGF-I on proliferation and survival of normal and neoplastic plasma cells has been recently emphasized, the pathogenetic link between acromegaly and transformation of gammopathy to overt myeloma in this case is discussed.

Plasmablastic lymphoma among human immunodeficiency virus-positive patients: results of a single center's experience.

Plasmablastic lymphoma (PBL) is a recently introduced entity, with a particularly aggressive clinical behavior among human immunodefi ciency virus-positive (HIV-pos) patients [1], and with a predilection for the mucosa of the oral cavity [2,3]. Occasionally, PBL has also been reported among HIV-negative patients, with a similar unfavorable prognosis [4]. Markers of plasmacytic diff erentiation (CD38/CD138) and CD20 negativity are usually observed, together with a phenotypic pattern indicating a post-germinal center origin [5]. An etiological role of Epstein – Barr virus (EBV) has been suggested [6]. c-myc translocation has been observed in 49% of PBL, and may be associated with a worse prognosis [7]. Due to the rarity of this disease, data concerning its clinical characteristics and prognosis are limited to case reports and small series [8,9]. Recently, Castillo et al . [10] and Schommers et al . [11] reported the results of multicentric retrospective studies on HIV-pos patients aff ected by PBL, confi rming the aggressive behavior and a poor prognosis of PBL. In order to verify this clinical behavior among our patients, we evaluated clinical characteristics, response to treatment and outcome of all consecutive HIV-pos patients with PBL admitted to and treated at our institution. Data concerning patients aff ected by PBL were extracted from the institutional database, where all consecutive HIV-pos patients with a diagnosis of lymphoma have been prospectively registered since 1985. Diagnosis of PBL required plasmablastic morphology, CD20 negativity and the expression of at least one plasmacytic marker (CD138 and/or MUM1/IRF4). EBV expression and c-myc rearrangement were also evaluated. Detailed information on age, gender, immunological status, histopathological features, clinical characteristics of lymphoma, type of treatment, toxicity and outcome were retrieved from the clinical charts of all patients included in the study. Progression-free survival (PFS) was defi ned as the time between diagnosis and progression or death, whichever happened fi rst, or last follow-up visit. Overall survival (OS) was defi ned as the time between diagnosis and death or last follow-up visit [12]. OS and PFS were evaluated according to the Kaplan – Meier method, and diff erences among subgroups were assessed by the log-rank test. Between January 1985 and August 2013, 221 cases of HIV-pos aggressive non-Hodgkin lymphoma (NHL) were recorded in the database (98 in the pre-highly active antiretroviral therapy [HAART] and 123 in the HAART era) and 18 patients were found with a reported diagnosis of PBL. After histological revision, 17 patients with newly diagnosed PBL were retrieved. Four patients were diagnosed before 1997, when HAART was not available (pre-HAART era) and 13 after 1997 (HAART era). However, three patients were HAARTnaive at lymphoma diagnosis. A trend for a higher frequency of PBL was found in the HAART period (13/123, 10.6%) as compared to the pre-HAART period (4/98, 4.1%) ( p 0.08, Fisher ’ s exact test). Characteristics of the patients were as follows: median age 36 years (range 25 – 54); male/female ratio 14/3; median time from HIV diagnosis to lymphoma 29 months (0 – 299); median CD4 count at PBL diagnosis 241/ m L (13 – 727); six patients (35%) with less than 200/ m L CD4; advanced disease (stage III – IV) and B symptoms in 14 (87.5%) and fi ve (31.3%) out of 16 evaluable patients, respectively; and oral cavity involvement in seven cases, more frequently in the preHAART (75%) than in the HAART era (30.8%). Extranodal involvement other than the oral cavity was observed in 88% of patients (gastrointestinal tract four cases; bone marrow, liver and bone two cases each; breast, testis and lung one case each). EBV encoded small RNA (EBER) positivity was observed in all 13 evaluable cases (100%). c-myc translocation analysis was performed in eight patients and c-myc rearrangement was observed in fi ve (62.5%), at baseline. Two patients, in the HAART era, did not receive any treatment because of early death and refusal, respectively. All the remaining 15 patients were treated with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) or CHOP-like regimens. Involved fi eld irradiation L eu k L ym ph om a D ow nl oa de d fr om in fo rm ah ea lth ca re .c om b y N yu M ed ic al C en te r on 0 7/ 21 /1 5

Dermoscopic, histological and immunohistochemical evaluation of cancerous features in acquired melanocytic nevi that have been repeatedly exposed to UVA or UVB

Abstract:  Previous studies have reported that repeated solar and artificial UVB (280–320 nm) and UVA (320–400 nm) exposures can modify acquired melanocytic nevi (AMN). We therefore investigated the clinical, dermoscopic, histological and immunohistochemical changes in AMN exposed to UVB and UVA radiation. Twenty healthy volunteers with at least three AMN on the trunk were enrolled in the present study and randomized into two groups to receive equally effective doses of narrow‐band (NB)‐UVB or UVA1. Three exposures per week were delivered for a total of 4 weeks. During exposures, one AMN was left unprotected, a second one was shielded with an opaque adhesive tape and the third nevus was covered with a commercial sunscreen. After the irradiation cycle, the AMN were surgically removed and underwent histological and immunohistochemical assessment of melanocyte/melanogenesis‐related proteins (MART‐1, tyrosinase, HMB‐45), cell cycle activation markers (Ki‐67, topoisomerase IIalpha, p53, Cdk2) and transcription factors (microphthalmia‐associated transcription factor, STAT3). Nevi that were exposed to NB‐UVB or UVA1 also showed statistically significant increase in size and changes in their dermoscopic features, including overall darkening, increased pigment network expression, formation of branched streaks, and increased number and size of brown globules and dots. AMN that had been covered with opaque tape or sunscreen did not show changes in size or dermoscopic features following UVA1 or NB‐UVB exposure. Histological and immunohistochemical analysis did not show any significant change in exposed AMN in comparison with AMN shielded with an opaque adhesive tape or covered with the sunscreen.

Merkel cell carcinoma arising in immunosuppressed patients treated with high-dose ultraviolet A1 (320–400 nm) phototherapy: a report of two cases

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine tumour of the skin. Though immunodeficiency is the most relevant risk factor, ultraviolet (UV) radiation is also involved, but as of yet we do not know the action spectrum, pattern or dose which would produce a dangerous exposure. A retrospective study of two immunosuppressed patients who developed MCC during, or soon after a treatment cycle with high dose UVA1 exposures was conducted, in order to understand wether repeated exposures to suberythemogenic UVA1 radiation may have a cancerogenic activity provoking MCC in immunosuppressed patients.