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Biomedical subjects

Franco Cavalli

Publications and source records attributed to Franco Cavalli.

At least 19 recordsLinked to original sources

Thrombotic thrombocytopenic purpura associated with renal failure after autologous transplantation for multiple myeloma successfully treated with rituximab.

Thrombotic thrombocytopenic purpura (TTP) is a haematological syndrome characterised by a dramatic onset requiring an urgent treatment with plasma exchange (PE). However, the prognosis is still dismal for PE related complications, a rate of failure and remarkable frequencies of relapse. TTP post transplantation is largely described as an outstanding, unusual complication of allogenic transplantation, but it is rarely mentioned after autologous transplantation. We describe a 62-year-old Caucasian patient who presented with TTP, accompanied by renal failure, after an autologous transplantation for multiple myeloma. PE together with hemodialysis was rapidly initiated but without any benefit. Since empirical administration of Rituximab, anti CD20 monoclonal antibody,was reported to be effective, we administered four courses of Rituximab inducing a complete remission of TTP and subsequently of the renal failure. This response to Rituximab in TTP post transplantation is suggestive of a possible implication of B-lymphocytes in the pathogenesis of TTP and it paves the way for an investigational approach in this settings.

Antibodies, Monoclonal↗

Metastatic colorectal cancer.

Metastatic colorectal cancer remains a public-health issue on a global scale. With development of a new generation of cytotoxic agents, survival has improved for patients with metastatic disease. How to maximize the benefit of chemotherapy with acceptable toxicity remains incompletely answered. Hepatic resection can provide a significant hope for long term survival, and a subset of patients might benefit from perioperative approaches. More recently, specific molecular processes have been targeted for therapeutic interventions, and encouraging results have been achieved using inhibitors of the Epidermal Growth Factor Receptor and the Vascular Endothelial Growth Factor.

Aged↗

Update on the molecular biology of mantle cell lymphoma.

Mantle cell lymphoma (MCL) accounts for 5-10% of non-Hodgkin's lymphomas and it bears the worst prognosis among B cell lymphomas. Even more than in the other lymphomas, new insights in MCL biology are needed. In this review we will discuss the most recent published data. Immunoglobulin sequencing data suggest that the MCL cell of origin is a mature B cell which might have undergone an extra-follicular T-cell independent antigen maturation. The main aberrations that affect cell cycle and DNA repair pathways in MCL are summarized, also discussing the need of the t(11;14)(q13;q32) to make diagnosis of MCL. After the gene expression studies of the last years, now the research focus has moved towards the new opportunities provided by arrayCGH technique for gene discovery and for identification of therapeutic targets. Examples of genes identified because deleted or amplified at DNA level and that might be relevant for MCL pathogenesis are presented.

Cell Cycle↗

Report of an international workshop to standardize baseline evaluation and response criteria for primary CNS lymphoma.

Standardized guidelines for the baseline evaluation and response assessment of primary CNS lymphoma (PCNSL) are critical to ensure comparability among clinical trials for newly diagnosed patients. The relative rarity of this tumor precludes rapid completion of large-scale phase III trials and, therefore, our reliance on the results of well-designed phase II trials is critical. To formulate this recommendation, an international group of experts representing hematologic oncology, medical oncology, neuro-oncology, neurology, radiation oncology, neurosurgery, and ophthalmology met to review current standards of reporting and to formulate a consensus opinion regarding minimum baseline evaluation and common standards for assessing response to therapy. The response guidelines were based on the results of neuroimaging, corticosteroid use, ophthalmologic examination, and CSF cytology. A critical issue that requires additional study is the optimal method to assess the neurocognitive impact of therapy and address the quality of life of PCNSL survivors. We hope that these guidelines will improve communication among investigators and comparability among clinical trials in a way that will allow us to develop better therapies for patients.

Central Nervous System Neoplasms↗

Primary pulmonary lymphoma: current status.

Primary pulmonary lymphoma (PPL) is a rare disease with a favorable prognosis compared with lung cancer. Although a number of histologic variables of B- and T-cell lymphoma were reported as PPL, marginal zone lymphoma of the mucosa-associated lymphoid tissue type is by far the most frequent diagnosis. This review summarizes the present knowledge of histopathology, molecular biology, diagnosis, prognosis, and treatment of this heterogeneous entity.

Diagnosis, Differential↗

Triplex DNA-mediated downregulation of Ets2 expression results in growth inhibition and apoptosis in human prostate cancer cells.

Ets2 is a member of the Ets family of transcription factors that in humans comprise 25 distinct members. Various Ets-domain transcription factors have been implicated in cancer development. Ets2 is expressed in prostate and breast cancer cells and is thought to have a role in promoting growth and survival in these cell types. However, a definitive role and the mechanisms whereby Ets2 acts in cancer cells are still unclear. Structural and functional similarities as well as overlapping DNA binding specificities complicate the identification of the specific roles of the various Ets factors. In this study, we used a triplex-forming oligonucleotide (TFO) to selectively inhibit Ets2 transcription in prostate cancer cells. We had previously shown that the Ets2-targeting TFO, which was directed to a unique purine-rich sequence critical for Ets2 promoter activity, acted with a high degree of sequence-specificity and target selectivity. TFO-mediated downregulation of Ets2 in prostate cancer cells induced important phenotypic changes, including inhibition of anchorage-dependent and anchorage -independent growth, cell cycle alterations and induction of apoptotic cell death. Expression of Ets2 under the control of a heterologous promoter abolished the anti-proliferative effects of the TFO in both short- and long-term assays, suggesting that these effects were a direct result of downregulation of Ets2 transcription and confirming target selectivity of the TFO. Furthermore, normal human fibroblasts, which expressed low levels of Ets2, were not affected by the Ets2-targeting TFO. Downregulation of Ets2 in prostate cancer cells was associated with reduced levels of the anti-apoptotic protein bcl-x(L) and growth regulatory factors cyclin D1 and c-myc. These data revealed a specific role of this transcription factor in promoting growth and survival of prostate cancer cells. Furthermore, the activity and selectivity of the Ets2-targeting TFO suggest that it might represent a valid approach to prostate cancer therapy.

Apoptosis↗

Immunoglobulin heavy chain genes somatic hypermutations and chromosome 11q22-23 deletion in classic mantle cell lymphoma: a study of the Swiss Group for Clinical Cancer Research.

Mantle cell lymphoma (MCL) shares immunophenotypic and karyotypic features with chronic lymphocytic leukaemia. The latter comprises two distinct entities with prognosis dependent upon immunoglobulin heavy chain (IgH) gene mutational status and the presence of 11q deletion. We evaluated the relevance of IgH gene mutational status, IgV gene family usage and presence of 11q deletion in a series of 42 histologically reviewed classical MCL cases to determine the prognostic impact. VH3 was the most common VH family, with VH3-21 being the most frequent individual VH gene. Approximately 30% of the cases had a IgH somatic mutation rate higher than 2%, but was only higher than 4% in <10% of cases. Half of the cases had deletion of chromosome 11q21-telomere (11q21->ter), with two minimal deleted regions, at 11q22.2 and 11q23.2. There was no association between 11q loss and IgH gene somatic mutation rate; the use of VH3-21 gene could be associated with a better prognosis.

Aged↗

Mantle cell lymphoma.

PURPOSE OF REVIEW: Mantle cell lymphoma is the B-cell lymphoma with the worst prognosis. Until now, no standard treatment has resulted in cure. Improvements in understanding of the disease are needed to advance therapeutic efforts. RECENT FINDINGS: Pathology and immunohistochemistry can identify the subset of patients with the worse prognosis. New data suggest that at least a subset of mantle cell lymphoma cases have undergone some form of antigene selection, and particular types of Ig gene rearrangement seem to give a better prognosis. The cell cycle, the ATM, gene and the nuclear factor kappaB pathways are the main targets of the genetic abnormalities occurring in mantle cell lymphoma: new genomic and expression data have been recently published. Unfortunately, this progress has not yet brought any major improvements in therapeutic approaches, which still remain highly unsatisfactory. Autologous and allogenic bone marrow transplantations appear to be the only current treatments that might improve the outcome of patients with PMCL. New additional treatment modalities are currently under investigation. SUMMARY: This review summarizes all the most recent data published on the biology and treatment of mantle cell lymphoma.

Chromosome Deletion↗

Intravascular lymphoma: clinical presentation, natural history, management and prognostic factors in a series of 38 cases, with special emphasis on the 'cutaneous variant'.

Despite its recognition as a distinct, extremely rare entity, no large studies of intravascular lymphoma (IVL) have been reported. The clinico-pathological characteristics of 38 human immunodeficiency virus-negative patients with IVL diagnosed in Western countries were reviewed to better delineate clinical presentation, clinical variants, natural history and optimal therapy. The IVL is an aggressive and usually disseminated disease (Ann Arbor stage IV in 68% of cases) that predominantly affects elderly patients (median age 70 years, range: 34-90; male:female ratio 0.9), resulting in poor Eastern Cooperative Oncology Group Performance Status (ECOG-PS >1 in 61%), B symptoms (55%), anaemia (63%) and high serum lactate dehydrogenase level (86%). The brain and skin are the most common sites of disease. In contrast to previous reports, hepatosplenic involvement (26%) and bone marrow infiltration (32%) were found to be common features in IVL, while nodal disease was confirmed as rare (11% of cases). Patients with disease limited to the skin ('cutaneous variant'; 26% of cases) were invariably females with a normal platelet count, and exhibited a significantly better outcome than the remaining patients, which deserves further investigation. Overall survival was usually poor; however, the early use of intensive therapies could improve outcome in young patients with unfavourable features. ECOG-PS >1, 'cutaneous variant', stage I and chemotherapy use were independently associated with improved survival.

Adult↗

Are antibiotics the treatment of choice for gastric lymphoma?

There is compelling evidence supporting the link between Helicobacter pylori infection and gastric mucosa-associated lymphoid tissue (MALT) lymphoma, and it seems undeniable that eradication of H. pylori with antibiotics can be effectively used as the sole initial treatment of localized (ie, confined to the gastric wall) gastric MALT lymphoma. This treatment is the best studied therapeutic approach, with more than 20 reported studies confirming that histologic regression of the lymphoma can be achieved in most cases. However, antibiotic treatments seem to suppress but not eradicate the neoplastic clone, and MALT lymphoma relapses have been seen years after treatment. Molecular follow-up studies revealed the persistence of the malignant clone in more than 50% of the cases in histologic remission after antibiotic therapy. The clinical significance of this finding is still unclear. Transient and self-limiting histologic and molecular relapses can also occur. Therefore, a careful long-term follow-up is mandatory for all of the patients who received antibiotic treatment.

Anti-Bacterial Agents↗

A phase 2 clinical study of SU5416 in patients with refractory acute myeloid leukemia.

Neoangiogenesis has been shown to play an important role in the pathogenesis of acute myeloid leukemia (AML). Autocrine and paracrine secretion of angiogenic and hematopoietic growth factors such as vascular endothelial growth factor (VEGF) and stem cell factor (SCF) in the bone marrow microenvironment may promote proliferation and survival of leukemic blasts. This concept represented the rationale for the initiation of a multicenter phase 2 trial of SU5416, a small molecule inhibitor of phosphorylation of VEGF receptors 1 and 2, c-kit, the SCF receptor, and fms-like tyrosine kinase-3 (FLT3) in patients with advanced AML. Entered into the study were 43 patients with refractory AML or elderly patients not judged medically fit for intensive induction chemotherapy; 42 patients received at least one dose of study drug. Treatment was generally well tolerated, with nausea, headache, and bone pain the most frequent treatment-related side effects. One patient had a morphologic remission (French-American-British [FAB] criteria of complete response without normalization of blood neutrophil and platelet counts) lasting for 2 months. There were 7 patients who achieved a partial response (reduction of blasts by at least 50% in bone marrow and peripheral blood) lasting 1 to 5 months. Patients with AML blasts expressing high levels of VEGF mRNA by quantitative polymerase chain reaction (PCR) had a significantly higher response rate and reduction of bone marrow microvessel density than patients with low VEGF expression consistent with the antiangiogenic effects of SU5416.

Adult↗

Clinical activity of rituximab in extranodal marginal zone B-cell lymphoma of MALT type.

The clinical activity of rituximab has been evaluated in a phase 2 study in both untreated and relapsed mucosa-associated lymphoid tissue (MALT) lymphomas. Treatment consisted of 4 standard (375 mg/m2) weekly doses. Thirty-five patients were enrolled, and 34 completed the treatment program. The primary lymphoma location was stomach in 15 patients, and extragastric in 20. Eleven patients had previously been treated with chemotherapy. At study entry 12 patients had Ann Arbor stage IE, 3 had stage IIE, and 20 had stage IV disease. The overall response rate was 73% (95% confidence interval, 56%-87%), with 15 complete responses and 10 partial responses, and the response rate was significantly higher in the chemotherapy-naive patients, who had an 87% response rate compared with 45% of the previously treated patients (P =.03). The median response duration was 10.5 months. At a median follow-up of 15 months, 9 patients (26%) relapsed. The median time to treatment failure was 14.2 months in the whole series, but it was significantly longer (22 versus 12 months) in the chemotherapy-naive patients compared with those who had prior chemotherapy (P =.001). Most adverse events were of mild to moderate severity with no grade 4 toxicity. This study indicates that rituximab is safe with significant activity in MALT lymphomas.

Adult↗

Summary statement on primary central nervous system lymphomas from the Eighth International Conference on Malignant Lymphoma, Lugano, Switzerland, June 12 to 15, 2002.

Under the sponsorship of the International Extranodal Lymphoma Study Group, a Multidisciplinary Workshop on primary CNS lymphoma (PCNSL) with over 50 participants from Europe, North America, Israel, and Australia was held as part of the Eighth International Conference on Malignant Lymphoma in Lugano, Switzerland (June 12 to 15, 2002). The main purposes of the Workshop were to exchange the latest scientific information, to analyze methodologic issues in the design of clinical trials, to reach a consensus on treatment recommendations and prognostic factors, to discuss clinical and molecular targets for future studies, and to establish an international collaborative group to conduct laboratory and clinical investigations in PCNSL. This article summarizes the contents of the Workshop, analyzes the current knowledge on the most relevant biologic and clinical issues in PCNSL, and focuses on fundamental challenges to be addressed in future studies.

Animals↗

Prognostic scoring system for primary CNS lymphomas: the International Extranodal Lymphoma Study Group experience.

PURPOSE: To identify survival predictors and to design a prognostic score useful for distinguishing risk groups in immunocompetent patients with primary CNS lymphomas (PCNSL). PATIENTS AND METHODS: The prognostic role of patient-, lymphoma-, and treatment-related variables was analyzed in a multicenter series of 378 PCNSL patients treated at 23 cancer centers from five different countries. RESULTS: Age more than 60 years, performance status (PS) more than 1, elevated lactate dehydrogenase (LDH) serum level, high CSF protein concentration, and involvement of deep regions of the brain (periventricular regions, basal ganglia, brainstem, and/or cerebellum) were significantly and independently associated with a worse survival. These five variables were used to design a prognostic score. Each variable was assigned a value of either 0, if favorable, or 1, if unfavorable. The values were then added together to arrive at a final score, which was tested in 105 assessable patients for which complete data of all five variables were available. The 2-year overall survival (OS) +/- SD was 80% +/- 8%, 48% +/- 7%, and 15% +/- 7% (P =.00001) for patients with zero to one, two to three, and four to five unfavorable features, respectively. The prognostic role of this score was confirmed by limiting analysis to assessable patients treated with high-dose methotrexate-based chemotherapy (2-year OS +/- SD: 85% +/- 8%, 57% +/- 8%, and 24% +/- 11%; P =.0004). CONCLUSION: Age, PS, LDH serum level, CSF protein concentration, and involvement of deep structures of the brain were independent predictors of survival. A prognostic score including these five parameters seems advisable in distinguishing different risk groups in PCNSL patients. The proposed score and its relevance in therapeutic decision deserve to be validated in further studies.

Adolescent↗

Primary mediastinal B-cell lymphoma: high frequency of BCL-6 mutations and consistent expression of the transcription factors OCT-2, BOB.1, and PU.1 in the absence of immunoglobulins.

Although primary mediastinal (thymic) large B-cell lymphoma has been primarily studied, its precise phenotype, molecular characteristics, and histogenesis are still a matter of debate. The International Extranodal Lymphoma Study Group collected 137 such cases for extensive pathological review. Histologically, the lymphomatous growth was predominantly diffuse with fibrosis that induced compartmentalized cell aggregation. It consisted of large cells with varying degrees of nuclear polymorphism and clear to basophilic cytoplasm. On immunohistochemistry, the following phenotype was observed: CD45(+), CD20(+), CD79a(+), PAX5/BSAP(+), BOB.1(+), Oct-2(+), PU.1(+), Bcl-2(+), CD30(+), HLA-DR(+), MAL protein(+/-), Bcl-6(+/-), MUM1/IRF4(+/-), CD10(-/+), CD21(-), CD15(-), CD138(-), CD68(-), and CD3(-). Immunoglobulins were negative both at immunohistochemistry and in situ hybridization. Molecular analysis, performed in 45 cases, showed novel findings. More than half of the cases displayed BCL-6 gene mutations, which usually occurred along with functioning somatic IgV(H) gene mutations and Bcl-6 and/or MUM1/IRF4 expression. The present study supports the concept that a sizable fraction of cases of this lymphoma are from activated germinal center or postgerminal center cells. However, it differs from other aggressive B-cell lymphomas in that it shows defective immunoglobulin production despite the expression of OCT-2, BOB.1, and PU.1 transcription factors and the lack of IgV(H) gene crippling mutations.

Antigens, CD↗

Chlorambucil in combination with induction and maintenance rituximab is feasible and active in indolent non-Hodgkin's lymphoma.

We investigated the toxicity and efficacy of the chimaeric anti-CD20 antibody rituximab in combination with standard-dose chlorambucil in newly diagnosed and relapsed/refractory indolent B-cell lymphoma patients. A total of 29 patients (15 newly diagnosed and 14 relapsed/refractory) with low-grade or follicular B-cell non-Hodgkin's lymphoma (NHL) were included in this phase II study. Therapy consisted of chlorambucil 6 mg/m2/d for 6 consecutive weeks in combination with a standard 4-weekly rituximab administration schedule in the induction phase. Patients responding to the induction therapy received four additional cycles with chlorambucil (6 mg/m2/d for 2 weeks/month) plus rituximab (once a month). Twenty-six patients (89%) completed the treatment; only one patient discontinued treatment because of haematological toxicity. At the end of the study, the dose of chlorambucil had to be reduced in seven patients (27%) and six patients (23%) required a delay in further treatment, as a result of toxicity during consolidation therapy. Only one patient was withdrawn from the study because of progressive disease; the 27 patients evaluable for response at the end of consolidation achieved a clinical response (63% complete response and 26% partial response). A significant CD4+ and CD56+ depletion was observed after induction and during consolidation therapy; two herpes zoster virus infections and one perianal abscess represented major infectious morbidities registered during the study. Based on our preliminary data, the combination of chlorambucil with rituximab seemed to be well tolerated and active. Its definitive role in the treatment of low-grade NHL should be further evaluated in randomized trials.

Adult↗