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Pierluigi Porcu

Publications and source records attributed to Pierluigi Porcu.

At least 19 recordsLinked to original sources
PubMed2006

A phase 2 study of rituximab in combination with recombinant interleukin-2 for rituximab-refractory indolent non-Hodgkin's lymphoma.

PURPOSE: The incidence of non-Hodgkin's lymphoma (NHL), the fifth most common malignancy in the United States, has increased over 70% in the last 30 years. Fifty percent to 75% of patients with low-grade or follicular NHL respond to rituximab therapy. However, responses are generally of limited duration, and complete responses are rare. Preclinical work suggests that human recombinant interleukin-2 (rIL-2; aldesleukin, Proleukin) enhances rituximab efficacy. Antibody-dependent cellular cytotoxicity (ADCC) is an important mechanism of action of rituximab. rIL-2 induces expansion and activation of Fc receptor (FcR)-bearing cells, thereby enhancing ADCC. Therefore, a large, multicenter phase 2 trial to assess the effects of rIL-2 on rituximab therapy in patients with rituxumab-refractory low-grade NHL was conducted. EXPERIMENTAL DESIGN: The combination of rituximab and rIL-2 was studied in 57 patients with rituximab-refractory low-grade NHL (i.e., patients must have received a single-agent course of rituximab and showed no tumor response, or had a response lasting <6 months). I.V. rituximab was given at 375 mg/m(2) (weeks 1-4). S.C. rIL-2 was given thrice a week at 14 MIU (weeks 2-5) and at 10 MIU (weeks 6-9). RESULTS: Rituximab plus rIL-2 combination therapy was safe and generally well tolerated, but responses were low. Fifty-seven patients were enrolled with 54 evaluable for response; however, only five responses (one complete and four partial) were observed. Correlative data indicate that rIL-2 expanded FcR-bearing cells and enhanced ADCC. However, other factors, such as FcgammaR polymorphisms in patients refractory to single-agent rituxumab and heterogeneous tumor biology, may have influenced the lack of clinical efficacy seen with this combination therapy. CONCLUSIONS: rIL-2 expands FcR-bearing cellular subsets in vivo and enhances in vitro ADCC of rituxumab. However, these findings do not directly translate into meaningful clinical benefit for patients with rituxumab-refractory NHL.

Adult↗
PubMed2006

Fine-needle aspiration biopsy of non-Hodgkin lymphoma for use in expression microarray analysis.

BACKGROUND: The majority of patients with lymphoma undergo a single biopsy for diagnosis, and there are few opportunities to acquire posttreatment material. Fine-needle aspiration (FNA) biopsy is a minimally invasive procedure, and acquiring routine posttreatment material would require minimal effort and provide needed material for gene expression profiling. METHODS: Ex vivo FNA biopsies were performed using a standard clinical technique with 21-gauge, 22-gauge, 23-gauge, and 25-gauge needles for 8 lymph node specimens and were collected in either RNA stabilization reagent (RNAlater) or Trizol. Eight patients with known or suspected Non-Hodgkin lymphoma (NHL) underwent interoperative (in vivo) FNA biopsies based on the best technique derived from the ex vivo aspirates. RNA derived from the in vivo FNA biopsies and the matched, snap-frozen surgical lymph node biopsy remnant was used for gene expression analysis with proprietary U133A chips. RESULTS: The results confirmed the authors' experience, that RNA isolated from FNA biopsies of lymph nodes collected in Trizol is superior both quantitatively and qualitatively to RNA collected in RNAlater. Gene expression profiles of NHL derived from in vivo FNA biopsies and matched, frozen surgical specimens showed good overall correlation. CONCLUSIONS: High-throughput gene expression analysis in patients with NHL derived from material acquired by FNA biopsy is a feasible approach to developing a platform for real-time analysis of treatment responses in this group of patients.

Biopsy, Fine-Needle↗
PubMed2006

T-cell prolymphocytic leukemia: an aggressive T cell malignancy with frequent cutaneous tropism.

BACKGROUND: T-cell prolymphocytic leukemia (T-PLL), formerly categorized as T-cell chronic lymphocytic leukemia, is a rare and aggressive hematologic malignancy. Although the skin is characteristically involved, it is not a well-recognized entity in the dermatologic literature. METHODS: Six cases of cutaneous T-PLL are presented from a clinical, light microscopic, and phenotypic perspective. RESULTS: The patient population comprised 2 women and 4 men, with a mean age of 69.8 years. The disease was associated in all with skin involvement with facial preference; edema, purpura, and lesional symmetry were characteristic. The skin biopsies demonstrated a largely non-epidermotropic angiocentric lymphocytic infiltrate with accompanying hemorrhage. The cells showed irregular- to reniform-shaped nuclei with small nucleoli and eosinophilic rims of cytoplasm. Phenotypic studies revealed three prevailing profiles: CD4 dominant in 4, CD8 dominant in one, and co-expression of CD4 and CD8 in one. CD3 loss was seen in one case. All expressed T-cell leukemia 1 (TCL-1) and CD7; cutaneous lymphocyte antigen expression was discernible in a dot-like perinuclear array. All cases tested excluding one expressed TCL-1 and CD52. In two cases tested, T-cell receptor beta rearrangements were observed. Cytogenetic studies demonstrated a paracentromeric chromosome 14 inversion. Polysomy 8 and MYC amplification was seen in one case, manifesting an aggressive clinical course. Four patients died from their disease within 18 months of diagnosis. LIMITATIONS: Cytogenetic MYC amplification, FISH, and TCR beta studies were conducted on each of 2 cases, respectively, due to limitations of tissue block samples and/or peripheral blood. cMYC translocation studies were conducted on 3 of the 6 cases, again due to limitations imposed by the tissue samples on the cases. The last case was recently diagnosed and, therefore, long-term follow-up is not possible. CONCLUSION: T-PLL is a distinctive post-thymic T-cell malignancy with frequent cutaneous tropism. A diagnosis is possible in almost all cases based on characteristic clinical, light microscopic, phenotypic, and cytogenetic features. While a chromosome 14 inversion is highly characteristic, additional inherent cytogenetic differences, such as trisomy 8 with CMYC over-amplification, may account for some case to case variation in clinical course.

Aged↗
PubMed2006

Primary cutaneous CD30+ large cell B-cell lymphoma: a series of 10 cases.

BACKGROUND: White CD30 expression is described in extracutaneous diffuse large B-cell lymphomas, a primary cutaneous B-cell lymphoma (PCBCL) equivalent is not well defined. METHODS: Between June 1999 and July 2002 the authors encountered 10 patients with CD30+ PCBCLs of the large cell type. RESULTS: The patients comprised seven women and three men; five patients were over 80 years of age, all except one presenting with solitary plaques. With the exception of one death from myocardial infarction and one recurrence, all patients are well at a mean follow-up of 23.4 months. Skin biopsies showed a background of T-cell-rich reactive lymphoid hyperplasia in 7 of 10 patients, with variable granulomatous inflammation in 5 cases. The neoplastic large cells were immunoblastic in appearance. In four patients the infiltrate was dominated by large cells. In the remaining patients the reactive infiltrate defined the dominant cell population. The neoplastic cells expressed CD20, CD30, CD43, and BCL-2. In two cases associated with methotrexate therapy, Epstein-Barr virus expression was observed amid the neoplastic cell populace. CONCLUSIONS: CD30+ PCBCL is a distinctive form of B-cell lymphoma presenting in elderly patients and can be associated with a very good prognosis. In some patients the intensity of reactive inflammation obscures the diagnosis. In the authors' experience almost a third of the cases were associated with Epstein-Barr virus infection and methotrexate therapy, suggesting a distinctive association.

Adult↗
PubMed2006

Cutaneous marginal zone B-cell lymphoma in the setting of fluoxetine therapy: a hypothesis regarding pathogenesis based on in vitro suppression of T-cell-proliferative response.

INTRODUCTION: Drugs may be an important cause of atypical lymphocytic infiltration. Oftentimes, these infiltrates are in the context of pseudolymphomata. We report a patient who developed lymphocytoma cutis temporally associated with initiation of fluoxetine therapy that later went on to develop cutaneous marginal zone B-cell lymphoma. The response of peripheral blood lymphocytes to fluoxetine and other drugs was examined in an attempt to ascertain the potential role for drugs in the propagation of these infiltrates. MATERIALS AND METHODS: Routine light microscopic analysis and phenotypic studies were performed on tissue obtained from a skin biopsy. Lymphocyte mitogenic studies were carried out using increasing concentrations of fluoxetine, bupropion, and two anticonvulsants. RESULTS: An initial biopsy was consistent with lymphocytoma cutis. The patient stopped fluoxetine associated with lesional regression. The lesions recurred despite being off fluoxetine; a repeat biopsy was compatible with marginal zone lymphoma. Lymphocyte proliferation assays revealed a suppressive effect on T-lymphocyte proliferation at physiologic concentrations. Other tested drugs did not have a similar suppressive effect. CONCLUSIONS: Fluoxetine may be associated with pseudolymphomata and marginal zone lymphoma. The inhibitory effects on T-lymphocyte function and more specifically T-suppressor function may lead to excessive antigen-driven B-cell proliferation.

Anticonvulsants↗
PubMed2006

Primary CD20+CD10+CD8+ T-cell lymphoma of the skin with IgH and TCR beta gene rearrangement.

Most cutaneous T-cell lymphomas are derived from mature postthymic T cells of the CD4 subtype. When other less common profiles are encountered, a diagnostic challenge is posed. Accurate categorization is critical because of the specificity of therapeutic regimens, including biologics. A 65-year-old woman was seen in 2001 because of a thigh mass manifesting an unusual phenotype eventually categorized as a mature postthymic CD8+ T-cell lymphoma with CD10 and weak CD20 expression. Molecular studies revealed T-cell receptor and heavy chain immunoglobulin rearrangement. Her cutaneous disease progressed despite several cycles of chemotherapy and radiation therapy. However, a therapeutic trial with denileukin diftitox resulted in a striking response. The importance of this case lies in the novel phenotype and dual T- and B-cell rearrangements. Rather than representing an aberrant phenotype, this tumor may represent the malignant counterpart of a benign population of weakly CD20+ T cells of the CD8 subset.

Aged↗
PubMed2006

CD8+ lymphomatoid papulosis and its differential diagnosis.

We describe 5 cases (4 males, 14-43 years old; 1 female, 61 years old) of primary cutaneous T-cell lymphoproliferative lesions expressing a CD8/granzyme/CD30-positive phenotype. Four cases were compatible with lymphomatoid papulosis (LyP) based on the clinical course, which was recurrent asymptomatic papular nodular lesions over years responding to methotrexate; granulomatous inflammation and lack of other inflammatory cell elements were characteristic. In 1 case, an initial erroneous diagnosis was made of aggressive epidermotropic CD8+ T-cell lymphoma. The fifth case in this series was first interpreted as representing primary cutaneous anaplastic large cell lymphoma but was later recategorized as primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma owing to the extent of extracutaneous dissemination, including testicular involvement and disease progression despite chemotherapeutic intervention. Although all cases of LyP showed sharp cytoplasmic membrane staining with perinuclear Golgi accentuation with CD30, the recategorized case of aggressive epidermotropic CD8 cytotoxic T-cell lymphoma manifested only a weak cytoplasmic staining pattern. CD8 LyP defines a distinctive entity with characteristic light microscopic and phenotypic findings and has a predilection for young males. CD30 expression can occur in other forms of CD8 lymphoproliferative disease unrelated to primary cutaneous anaplastic large cell lymphoma or LyP.

Adolescent↗
PubMed2005

Durable hematologic complete response and suppression of HTLV-1 viral load following alemtuzumab in zidovudine/IFN-{alpha}-refractory adult T-cell leukemia.

Adult T-cell leukemia (ATL) is a highly chemoresistant and usually fatal T-cell malignancy due to the human T-cell lymphotropic virus-1 (HTLV-1). After chemotherapy failure, antiretrovirals and interferon-alpha (IFN-alpha) produce brief responses followed by progression and death. More effective agents and new approaches to detect and treat minimal residual disease are needed. ATL cells express CD52, the target of the antibody alemtuzumab, which is active in a preclinical model of ATL and is cytotoxic for p53-deficient cells. A patient with refractory chronic ATL in transformation achieved longer than a 1-year complete hematologic response following 12 weeks of outpatient subcutaneous alemtuzumab. Persistent suppression of HTLV-1 viral load, even at recovery of T cells, after alemtuzumab and efficient in vitro complement-mediated cytotoxicity of primary ATL cells with mutated TP53 were observed. The unprecedented response and the profound suppression of HTLV-1 viral load observed in this patient suggest that further clinical investigation of alemtuzumab in ATL is warranted.

Alemtuzumab↗
PubMed2005

Epstein-Barr virus- and human herpesvirus 8-associated primary cutaneous plasmablastic lymphoma in the setting of renal transplantation.

BACKGROUND: Plasmablastic lymphoma (PBL) is a recently recognized entity most often reported in the oral cavity, mainly in the setting of underlying human immunodeficiency viral infection whereby a role for Epstein-Barr virus (EBV) and more recently human herpesvirus 8 (HHV8) has been described. Although EBV has been implicated in a variety of lymphoproliferative lesions, until recently HHV8 has only been associated with primary effusion lymphoma, multicentric Castleman's disease, and Kaposi's sarcoma. We describe a case of PBL occurring in the setting of renal transplantation. METHODS: We encountered a case of PBL occurring in the setting of renal transplantation. We characterized the tumor by routine immunohistochemistry and evaluated for the presence of immunoglobulin light chain restriction and EBV RNA by in situ hybridization. We assessed for the presence of HHV8 RNA by reverse transcriptase in situ hybridization. RESULTS: The tumor showed a histomorphology compatible with a PBL. In addition, there was strong RNA expression in the neoplastic cells for EBER-1, EBER-2, and HHV8. CONCLUSION: This case suggests a possible role of both viruses in the pathogenesis of PBL in sites other than the oral cavity and expands the spectrum of post-transplantation lymphoproliferative disease to include PBL.

Adult↗
PubMed2005

The absence of CD20 messenger RNA in recurrent cutaneous B-cell lymphoma following rituximab therapy.

BACKGROUND: Rituximab has been used to treat relapsed low-grade or advanced non-Hodgkin's lymphoma since 1997, targeting the CD20 antigen expressed by B cells. Single-agent rituximab therapy is safe and well tolerated. Recurrences showing a loss of CD20 expression following rituximab therapy have been reported. METHODS: Four patients with CD20-positive cutaneous B-cell lymphoma received rituximab therapy with subsequent recurrences. The biopsies were assessed for cytoplasmic CD20 expression; CD20 messenger RNA was also assessed where tissue was available. RESULTS: Cutaneous relapses occurring within 1.5-3 months following the last dose of rituximab were CD20 negative. In three cases, subsequent relapses showed renewed expression of CD20. Those biopsies demonstrating a loss of surface and cytoplasmic CD20 by immunohistochemistry also showed no evidence of messenger RNA for CD20 using an in situ polymerase chain reaction-based methodology. CONCLUSIONS: Rituximab may be associated with the emergence of CD20-negative B-cell clones, potentially rendering a tumor insensitive to this drug. Conversely, following cessation of the drug, a re-expression of CD20 within the neoplastic cells may occur allowing therapeutic intervention with this monoclonal antibody. The loss of CD20 expression appears to be a direct effect of the drug on CD20 messenger RNA synthesis.

Adult↗
PubMed2005

Epstein--Barr virus-associated B-cell lymphoma in the setting of iatrogenic immune dysregulation presenting initially in the skin.

BACKGROUND: Epstein-Barr virus (EBV) has been implicated in B-cell lymphoma associated with iatrogenic immune dysregulation, primarily in the context of extracutaneous lymphoma. METHODS: We describe six patients, five transplant recipients receiving cyclosporine and one patient with rheumatoid arthritis receiving methotrexate, who developed cutaneous presentations of EBV-associated B-cell lymphoma. Human herpesvirus 8 (HHV8) and EBV thymidine kinase (vTK) expression were also explored. RESULTS: The cases comprised plasmablastic lymphoma (one case), plasmacytic marginal zone lymphoma (two cases), and diffuse large B-cell lymphoma (three cases). There was a monoclonal gammopathy in one and concurrent extracutaneous disease in two of the six patients. EBV-associated latent small nuclear RNA was detected in all cases with coexpression of HHV8 in one of the five cases and of vTK in three of the six cases. Three patients responded to a reduction in the immunosuppressive regimen and antiviral therapy. Recurrent disease developed in two, with one patient succumbing to multiorgan dissemination. CONCLUSIONS: EBV-associated cutaneous B-cell lymphoma is characterized by a long interval between the initiation of immunosuppression and the development of lymphoma. Although previous reports have reported an indolent clinical course, an aggressive clinical course may occur. HHV8 and lytic phase EBV antigens are detected in some cases, possibly suggesting a pathogenetic role.

Adult↗
PubMed2004

Combination immunotherapy of B-cell non-Hodgkin's lymphoma with rituximab and interleukin-2: a preclinical and phase I study.

PURPOSE: Cytokine-induced modulation of innate immunity is being explored to enhance the activity of monoclonal antibodies. Severe combined immunodeficient (SCID) mice engrafted with peripheral blood leukocytes (PBLs) from Epstein Barr virus-seropositive donors develop human B-cell non-Hodgkin's lymphomas [B-NHLs (hu-PBL-SCID mouse model)]. We used this hu-PBL-SCID mouse model to study the synergism between interleukin (IL)-2 and rituximab. We also conducted a phase I trial of IL-2 and rituximab in relapsed B-NHL to study whether expansion of natural killer (NK) cells and enhanced cellular cytotoxicity could be safely accomplished in vivo. EXPERIMENTAL DESIGN: Hu-PBL-SCID mice were treated with various schedules of rituximab and IL-2, with survival as the end point. Patients with relapsed B-NHL received rituximab (375 mg/m2 weekly x 4) followed by daily low-dose IL-2 (1 MIU/m2/day x 4 weeks) with pulses of intermediate-dose IL-2 (3-15 MIU/m2). Toxicity, NK cell numbers, and cellular cytotoxicity were measured. RESULTS: In the hu-PBL-SCID mouse, the combination of rituximab and IL-2 showed greater activity against B-NHL than either agent alone. Treatment was most effective when IL-2 was given before rituximab. Twelve patients with heavily pretreated B-NHL entered the phase I trial. Toxicity was manageable, and responses were observed. NK cell expansion and enhanced cellular cytotoxicity against a B-cell lymphoma target were observed but did not correlate with response. CONCLUSIONS: The combination of IL-2 and rituximab is synergistic against B-NHL in the hu-PBL-SCID model. In the phase I trial, a sequential combination of rituximab and IL-2 was well tolerated and achieved biological end points. Responses were observed.

Adult↗
PubMed2004

EBV kidney allograft infection: possible relationship with a peri-graft localization of PTLD.

Post-transplant lymphoproliferative disorder (PTLD) is a grave complication of transplantation and the result of uncontrolled proliferation of B lymphocytes infected with Epstein-Barr virus (EBV). Herein we assess whether EBV infects renal grafts and whether there is a relationship between EBV kidney infection and PTLD. Allograft biopsies from 23 patients with PTLD were studied for the presence of EBV DNA and RNA (EBER-1, -2) by in situ hybridization and for CD21 by immunohistochemistry. Results were compared to 43 transplants from people without PTLD. EBV DNA and RNA were detected in 11/43 patients without PTLD (26%), and in 15/23 (65%) patients with PTLD (p = 0.004). EBV DNA and RNA localized to proximal tubular cells and these cells showed up-regulation of the EBV receptor CD21. EBV-infected allografts were noted in 12/12 patients with PTLD located near the allograft and in 3/11 (27%) of patients with PTLD distant from the graft. Multiple biopsies in eight patients showed that graft EBV infection can precede the diagnosis of PTLD by as long as 42 months. It is concluded that EBV can infect kidney allografts, and there appears to be a relationship between this infection and the presence of PTLD near the graft.

Adult↗
PubMed2004

Cutaneous immunocytoma: a clinical, histologic, and phenotypic study of 11 cases.

Immunocytomas represent low grade B cell lymphomas related to marginal zone lymphoma but with a predominance of cells having plasmacytic features. Eleven patients presented with lesions compatible with primary cutaneous immunocytoma. The expression of CD2, CD3, CD5, CD20, CD21, CD23, CD43, CD56, CD79, and bcl-2 was analyzed immunohistochemically and of lambda and kappa light chains by an in situ hybridization assay. There were 6 men and 5 women ranging in age from 43 to 76 years. The most common clinical presentation was as extremity based clustered erythematous brown papules. Therapy with local irradiation or Rituximab resulted in lesional resolution. Underlying illnesses included Sjögren's syndrome, hepatitis C, ulcerative colitis, autoimmune thyroid disease, and rheumatoid arthritis. Four patients were taking medications previously associated with immune dysregulation. In two patients in whom a paraproteinemia was uncovered. The most common pattern light microscopically was perivascular small lymphocytic and plasmacellular infiltrates mimicking architecturally a reactive process. Phenotypic studies revealed a marginal zone (MZL) phenotype amid the small atypical lymphocytic infiltrate and highlighted a reactive background population of non-neoplastic T and B cells; light chain restriction was seen amid the plasma cells. In one case there was EBER staining of plasma cells while in another case in whom there was hepatitis C seropositivity staining of plasma cells for hepatitis C associated RNA transcripts was observed. Primary cutaneous immunocytoma appears to arise from a pre-existing state of reactive lymphoid hyperplasia. latrogenic and endogenous immune dysregulation including in the context of lymphotropic viral infections is implicated.

Adult↗
PubMed2003

Experimental treatment of Epstein-Barr virus-associated primary central nervous system lymphoma.

Primary central nervous system lymphoma (PCNSL) that arises in immune-deficient patients is an aggressive B-cell neoplasm that is universally associated with the EBV. Patients with EBV(+) PCNSL face a particularly poor prognosis with median survival times of 2-12 months despite aggressive management with radiation therapy. We have developed a preclinical model of EBV(+) PCNSL to explore strategies that specifically target EBV-infected B lymphoblasts in vivo. Stereotactic implantation of EBV-transformed human lymphoblastoid B-cell lines into the caudate nucleus of the nude rat resulted in lethal CNS tumor burden manifested by the onset of focal neurological symptoms within 21 days. Histological evaluation at autopsy revealed a multifocal, perivascular human EBV(+) lymphoblastic B-cell infiltrate that displayed a latency type III EBV gene expression profile similar to PCNSL that develops in some immune-deficient patients. Radiation (1600 cGy) of lymphoblastoid B-cell lines resulted in up-regulation of the EBV thymidine kinase (EBV-TK) transcript and sensitization of these cells to drug-induced apoptosis using nucleoside analogs. Enhanced expression of EBV-TK mRNA in EBV(+) PCNSL tumors by radiation therapy occurred in a dose-dependent fashion. In vivo trials using the nude rat PCNSL model demonstrated significantly improved mean survival time (MST) with single fraction whole-brain radiotherapy (WBRT) and antiviral therapy consisting of zidovudine (AZT) and ganciclovir (GCV; MST 41.3 +/- 3.3 days; P = 0.05), compared with either antiviral therapy (MST 32.1 +/- 1.1 days) or WBRT alone (MST 22 +/- 0.8 days). We found constitutive and abundant EBV-TK mRNA expression in a stereotactic core biopsy specimen from a solid organ transplant patient with EBV(+) PCNSL. Withdrawal of immunosuppression did not result in disease regression. This patient achieved a complete response after therapy with high-dose AZT and GCV in the absence of WBRT, and remains in remission on oral maintenance AZT/GCV therapy 3 years after diagnosis. These results suggest that antiviral therapies can be effectively explored in vivo using a preclinical animal model of human EBV(+) PCNSL with subsequent translation to patients with EBV(+) PCNSL.

Animals↗