Edoardo Pescarmona

Neutropenic Enterocolitis in Patients With Acute Leukemia: Prognostic Significance of Bowel Wall Thickening Detected by Ultrasonography

PURPOSE Neutropenic enterocolitis (NE) is a severe complication of intensive chemotherapy and is barely identifiable by clinical signs alone. Ultrasonography (US) supports the diagnosis of NE by showing pathologic thickening of the bowel wall. The aim of this study was to evaluate the prognostic value of the degree of mural thickening evaluated by US in patients with clinically suspected NE. PATIENTS AND METHODS Neutropenic patients with fever, diarrhea, and abdominal pain after intensive chemotherapy for hematologic malignancies were studied with abdominal US. We evaluated the degree of bowel wall thickening detected by US and its correlation with the duration of the clinical syndrome as well as NE-related mortality. RESULTS Eighty-eight (6%) of 1,450 consecutive patients treated for leukemia had clinical signs of NE. In 44 (50%) of 88 patients, US revealed pathologic wall thickening (mean +/- SD, 10.2 +/- 2.9 mm; range, 6 to 18). The mean duration of symptoms was significantly longer in this group (7.9 days) than among patients without mural thickening (3.8 days, P <.0001), and the NE-related mortality rate was higher (29.5% v 0%, P <.001). Patients with bowel wall thickness of more than 10 mm had a significantly higher mortality rate (60%) than did those with bowel wall thickness < or = 10 mm (4.2%, P <.001). CONCLUSION Symptomatic patients with sonographically detected bowel wall thickening have a poor prognosis compared with patients without this finding. In addition, mural thickness of more than 10 mm is associated with poorer outcome among patients with NE.

Early Autologous Stem-Cell Transplantation Versus Conventional Chemotherapy as Front-Line Therapy in High-Risk, Aggressive Non-Hodgkin’s Lymphoma: An Italian Multicenter Randomized Trial

PURPOSE To evaluate the role of early intensification with high-dose therapy (HDT) and autologous stem-cell transplantation (ASCT) as front-line chemotherapy for patients with high-risk, histologically aggressive non-Hodgkins lymphoma (NHL). PATIENTS AND METHODS We planned a multicenter, randomized trial to compare a conventional chemotherapy regimen of methotrexate with leucovorin rescue, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOP-B; arm A) with an abbreviated regimen of MACOP-B (8 weeks) followed by HDT and ASCT (arm B) for intermediate-high-risk/high-risk patients (according to the age-adjusted International Prognostic Index). From September 1994 to April 1998, 150 patients with aggressive lymphoma were enrolled onto the trial. Seventy-five patients were randomly assigned to arm A and 75 patients were randomly assigned to arm B. In both arms, involved-field radiation therapy (36 Gy) was delivered to the site of bulky disease. RESULTS The rate of complete response was 68% in arm A and 76% in arm B (P = not significant [NS]). Three toxic deaths (4%) occurred in arm B and one (1%) occurred in arm A (P = NS). In arm B, 30 patients (40%) did not undergo HDT and ASCT. According to the intention-to-treat analysis at a median follow-up of 24 months, 5-year overall survival probability in arms A and B was 65% and 64% (P =.95), 5-year progression-free survival was 49% and 61% (P =.21), and 5-year relapse-free survival was 65% and 77% (P =.22), respectively. CONCLUSION Abbreviated chemotherapy followed by intensification with HDT-ASCT is not superior to conventional chemotherapy in patients with high-risk, aggressive NHL. Additional randomized trials will clarify whether HDT-ASCT as front-line therapy after a complete course of conventional chemotherapy improves survival in this group of patients.

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.

Analysis of prognostic factors and clinicopathological staging of thymoma

The prognostic value of four clinical variables (age and sex of patients, association with myasthenia gravis, and clinical stage) and histological type was analyzed in 83 consecutive patients with thymoma, histologically classified as cortical, medullary, and mixed. Age, sex, and association with myasthenia gravis did not prove to represent significant prognostic factors; clinical stage and histological type, on the contrary, had a highly significant prognostic value (p less than 0.001). A model of clinicopathological staging, based on both clinical stage and histological type, in which three major prognostic groups are considered is proposed. The degree of significance of this model is higher (p less than 0.0001) than that of clinical stage and histological type considered individually; its validity is further supported by the results of multivariate analysis according to the Cox regression model (p = 0.0001). We think it represents a prognostically valuable approach to the problem of management of thymoma.

Multimodality Treatment of Thymoma: A Prospective Study

BACKGROUND Thymomas are a heterogeneous group of tumors. Treatment of invasive lesions is not well standardized. The aim of this study is to propose a clinicopathologically based protocol for multimodality therapy. METHODS Between 1965 and 1988, we operated on 83 patients with thymoma who did not receive standardized adjuvant therapy. In 1989, on the basis of the retrospective analysis of the data, we started a multimodality therapy protocol and used it for 65 patients. Twelve patients had medullary thymoma (11 stage I and 1 stage II), 13 had mixed type (6 stage I and 7 stage II), and 40 had cortical thymoma (4 stage I, 11 stage II, 12 stage III, and 13 stage IV). We considered three groups. Group I (n = 18 patients), benign thymoma, included stage I and II medullary and stage I mixed thymomas; radical resection with no adjuvant therapy was performed. Group II (n = 22), invasive thymoma, included stage I and II cortical and stage II mixed thymomas; postoperative chemotherapy plus radiotherapy was always administered. Group III (n = 25), malignant thymoma, comprised stage III and IV cortical thymomas and stage III mixed thymomas; resectable stage III lesions were removed, and highly invasive stage III and stage IV lesions underwent biopsy, neoadjuvant chemotherapy, and surgical resection; postoperative chemotherapy and radiotherapy was administered to all patients. RESULTS The 8-year survival rate for patients in stages I, II, III, and IV was 95%, 100%, 92%, and 68%, respectively. Patients with medullary thymoma had a 92% 8-year survival rate; those with mixed type, 100%; and those with cortical thymoma, 85%. Group I had an 8-year survival rate of 94%; group II, 100%; and group III, 76%. Survival was compared with that of patients operated on before 1989: differences were not significant for group I; survival improved in group II (100% versus 81%; p = not significant); and group III showed significant improvement (76% versus 43%; p < 0.049). CONCLUSIONS Multimodality treatment with neoadjuvant chemotherapy and adjuvant chemotherapy plus radiotherapy may improve the results of radical resection and the survival of patients with invasive and malignant thymoma.

miR-204 targets Bcl-2 expression and enhances responsiveness of gastric cancer

Micro RNAs (miRs) are small non-coding RNAs aberrantly expressed in human tumors. Here, we aim to identify miRs whose deregulated expression leads to the activation of oncogenic pathways in human gastric cancers (GCs). Thirty nine out of 123 tumoral and matched uninvolved peritumoral gastric specimens from three independent European subsets of patients were analyzed for the expression of 851 human miRs using Agilent Platform. The remaining 84 samples were used to validate miRs differentially expressed between tumoral and matched peritumoral specimens by qPCR. miR-204 falls into a group of eight miRs differentially expressed between tumoral and peritumoral samples. Downregulation of miR-204 has prognostic value and correlates with increased staining of Bcl-2 protein in tumoral specimens. Ectopic expression of miR-204 inhibited colony forming ability, migration and tumor engraftment of GC cells. miR-204 targeted Bcl-2 messenger RNA and increased responsiveness of GC cells to 5-fluorouracil and oxaliplatin treatment. Ectopic expression of Bcl-2 protein counteracted miR-204 pro-apoptotic activity in response to 5-fluorouracil. Altogether, these findings suggest that modulation of aberrant expression of miR-204, which in turn releases oncogenic Bcl-2 protein activity might hold promise for preventive and therapeutic strategies of GC.

Melphalan treatment in patients with myelofibrosis with myeloid metaplasia

Summary. Between January 1985 and December 1992, 104 consecutive patients with symptomatic myelofibrosis with myeloid metaplasia (MMM) [splenic enlargement > 5 cm and/or transfusional requirement or Hb < 10 g/dl and/or white blood cell (WBC) count > 20 × 109/l and/or platelets > 1·0 × 109/l] received low‐dose Melphalan (2·5 mg/3 times/week) to evaluate the efficacy and toxicity of this approach. Among 99 evaluable patients, 66 (66·7%) achieved a response after a median time of 6·7 months: 26 (26·3%) had a normalization of all clinical and haematological parameters (complete response, CR) and 40 (40·4%) showed an improvement > 50% (partial response, PR). Thirty‐three patients (33·3%) were resistant. Reversible haematological toxicity was the most common complication. Median durations of CR and PR were 28·4 and 26 months respectively: median survival of CR + PR patients was 71·2 months (95%CI: 33·8–108·7) versus 36·5 months (95%CI: 24·5–48·5) for the non‐responders (log‐rank test, P = 0·002). In the multivariate analysis, the following variables were significantly associated with a shorter survival: anaemia [hazard risk (HR) = 2·7], WBC count > 20 × 109/l (HR = 2·4) and not achieving any type of response, either partial or complete (HR = 3·9). In conclusion, Melphalan could be a promising first‐line option for MMM patients with clinical or haematological symptoms requiring treatment.

Epstein-Barr Virus Infection Is Predictive of CNS Involvement in Systemic AIDS-Related Non-Hodgkin’s Lymphomas

PURPOSE This study aimed at correlating Epstein-Barr virus (EBV) infection of systemic AIDS-related non-Hodgkin lymphomas (AIDS-NHL) with the development of a CNS localization of the tumor. PATIENTS AND METHODS Demographic, epidemiologic, clinical, histologic, and virologic features were collected for all systemic AIDS-NHL patients included in the study (n = 50). Pathologic specimens were classified according to the working formulation for NHL and the Revised European-American Lymphoma classification. EBV infection in tumor tissue samples was studied by EBV small encoded RNA in situ hybridization; EBV-DNA detection in CSF was carried out by nested polymerase chain reaction using Epstein-Barr nuclear antigen-1-specific primers. In addition, selected EBV-positive lymphomas were subjected to a detailed characterization of EBV molecular heterogeneity. RESULTS Eleven patients had a CNS involvement at some point during their clinical history (four at diagnosis and seven at relapse). Thirty patients (11 with CNS involvement and 19 without) harbored EBV infection of the tumor. Sensitivity, specificity, and positive and negative predictive values of EBV-DNA detection in CSF for CNS involvement by lymphoma were 90%, 100%, 100%, and 97.6%, respectively. Factors significantly predictive of CNS involvement were EBV infection of the tumor (P=.003), an extranodal disease at diagnosis other than CNS (P=.006), and a non-CNS relapse (P=.01). In four cases of CNS involvement, EBV-DNA in CSF preceded any other sign of disease by a mean of 35 days. CONCLUSION These results show that EBV infection of the tumor clone significantly increases the risk of CNS involvement by systemic AIDS-NHL, without regard of specific molecular features. The detection of EBV-DNA in the CSF of AIDS-NHL patients may select cases with higher risk of CNS involvement and, therefore, may prove useful in the therapeutic stratification of these tumors.

Comparative merits of thoracoscopy, mediastinoscopy, and mediastinotomy for mediastinal biopsy

Between April 1992 and April 1993, we performed fifty-four mediastinal biopsies in 51 patients with a mediastinal mass. Nine of these had lung cancer with mediastinal lymphadenopathy, and the remaining 42 had various primary mediastinal lesions. We have performed twenty video-assisted thoracic surgical procedure, twenty-six mediastinoscopies, and eight anterior mediastinotomies. In 3 patients the diagnosis was not obtained by mediastinoscopy, and video-assisted thoracoscopy was performed. We conclude that mediastinoscopy is indicated for the majority of lesions involving the peritracheal space. Restaging of lymphoma and highly infiltrative lesions are better managed by video-assisted thoracic surgery. Anterior mediastinotomy is indicated when feasible under local anesthesia for tumors infiltrating the anterior chest wall. In all other cases video-assisted thoracic surgery is preferable because it allows removal of large tissue biopsy specimens and even resection with wide surgical exposure and low operative trauma.

Mediastinal large B‐cell lymphoma: clinical and immunohistological findings in 18 patients treated with different third‐generation regimens

We report on the immunophenotype, clinical findings and response to aggressive chemotherapy of 18 patients with mediastinal large B‐cell lymphoma (MLCL). Cases were collected from a series of 286 high‐grade non‐Hodgkins lymphomas (HG‐NHL) which, in the period September 1988 to August 1991, were enrolled in a prospective multicentre trial designed to compare the MACOP‐B and F‐MACHOP regimens. Immunostaining on frozen sections revealed a previously unrecognized phenotype, i.e. co‐expression of B‐cell (CD19, CD20, CD22, Ig‐associated dimer) and activation‐associated antigens (CD30 and CDw70) in about 60% of MLCL cases; in contrast, the activation‐associated antigens CD25 and Ki‐27 (unclustered) were consistently negative. This peculiar phenotype may reflect a derivation of the tumour from a subset of thymic activated B cells. Clinically, the patients (median age 31 years; F/M ratio 2.6) presented with bulky mediastinal mass (72%) associated with mediastinal syndrome in >50% cases; disease was stage IIA in most cases. All 18 patients received aggressive chemotherapy (F‐MACHOP 11; MACOP‐B 7). Complete response (CR) was achieved in 57.1% of cases treated with MACOP‐B. In contrast, the response of the 11 MLCL treated with F‐MACHOP was poor (CR 18.2%) as compared to that of the 135 HG‐NHL treated with the same regimen during the trial (CR 69.6%). This difference was still statistically significant after adjusting for negative prognostic factors (mediastinal mass > 10 cm plus increased LDH) and suggests that F‐MACHOP might not be the most appropriate regimen for this kind of lymphoma.