VACOP-B versus VACOP-B plus autologous bone marrow transplantation for advanced diffuse non-Hodgkin's lymphoma: results of a prospective randomized trial by the non-Hodgkin's Lymphoma Cooperative Study Group.

PURPOSE: The aim of this multicenter randomized study was to compare conventional therapy with conventional plus high-dose therapy (HDT) and autologous bone marrow transplantation (ABMT) as front-line treatment for poor-prognosis non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Between October 1991 and June 1995, 124 patients, aged 15 to 60 years, with diffuse intermediate- to high-grade NHL (Working Formulation criteria), stages II bulky (> or = 10 cm), III, or IV were enrolled. Sixty-one patients were randomized to receive etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (VACOP-B) for 12 weeks and cisplatin, cytarabine, and dexamethasone (DHAP) as a salvage regimen (arm A), and 63 to receive VACOP-B for 12 weeks plus HDT and ABMT (Arm B). RESULTS: There was no significant difference in terms of complete remissions (CRS) in the two groups: 75% in arm A, and 73% in arm B. The median follow-up observation time was 42 months. The 6-year survival probability was 65% in both arms. There was no difference in disease-free survival (DFS) or progression-free survival (PFS) between the two groups. DFS was 60% and 80% (P = .1) and PFS was 48% and 60% (P = .4) for arms A and B, respectively. Procedure feasibility was the major problem. In arm B, 29% of enrolled patients did not undergo HDT and ABMT. A statistical improvement in terms of DFS (P = .008) and a favorable trend in terms of PFS (P = .08) for intermediate-/high- plus high-risk group patients assigned to HDT and ABMT was observed. CONCLUSION: In this study, conventional chemotherapy followed by HDT and ABMT as front-line therapy seems no more successful than conventional treatment in terms of overall results. However, our results suggest that controlled studies of HDT plus ABMT should be proposed for higher risk patients.

Mobilization/transplantation of peripheral blood progenitor cells for aggressive non-Hodgkin's lymphoma with marrow involvement.

Thirty-five aggressive non-Hodgkin's lymphomas (NHL) with marrow involvement received high-dose cyclophosphamide (7 g/m2) and G-CSF in order to collect peripheral blood progenitor cells (PBPC). Fourteen patients were in partial remission, 16 patients were in relapse ('sensitive', 12; 'resistant', 4) and five patients were refractory to conventional treatment. A good yield of PBPC was obtained in 30 patients, while a low number of CD34+ cells and of CFU-GM was seen in two cases. Two patients entered progression and one patient died. Thirty patients underwent PBPC autografting. Twenty-nine out of 35 (83%) patients entered complete remission (CR). Two patients died in CR of infection following marrow aplasia 3 and 6 months after autografting. At 3 years the probability of survival and disease-free survival (DFS) are 62 and 51%, respectively.

Autologous unpurged bone marrow transplantation for acute non-lymphoblastic leukaemia in first complete remission.

Twenty-five patients with acute non-lymphoblastic leukemia (ANLL) in first complete remission underwent autologous bone marrow transplantation (ABMT) between March 1984 and March 1988. The high-dose therapy employed included cyclophosphamide followed by total body irradiation (10 Gy), administered as a single dose. The median time from complete remission to ABMT was 5 months (range 2-9 months). Thirteen (52%) patients remain in complete remission 10-51 months (median 25 months) after ABMT and 14-60 months (median 32 months) after achieving complete remission. Causes of death were recurrent leukemia (five patients), parenchymal toxicities (acute respiratory distress syndrome, veno-occlusive disease) (three patients), cerebral haemorrhage (one patient), cerebral aspergillosis (one patient) and viral hepatitis (one patient). Six patients relapsed at a median of 5 months after ABMT (range 4-10 months). In conclusion, this study has resulted in survival data comparable to those of other institutions and the best reported outcomes of conventional chemotherapy.

Autologous bone marrow transplantation as adjuvant treatment for high-risk Hodgkin's disease in first complete remission after MOPP/ABVD protocol.

Fifteen patients with very poor prognosis Hodgkin's disease in remission after MOPP/ABVD regimen, were treated with high-dose chemotherapy (HDC) and autologous marrow transplantation (ABMT) immediately after achieving complete remission (CR). Thirteen patients (86.6%) remain alive in unmaintained CR at a median time of 36 months (range 10-64 months) post-transplant. In the other two patients reasons for failure included relapse of Hodgkin's disease (one patient) and death due to interstitial pneumonitis secondary to carmustine therapy. These patients were compared with a historical control group consisting of 24 patients with the same poor prognostic factors, who achieved CR with MOPP/ABVD and did not receive other treatment. Eight out of 24 patients (33%) remain alive and well in unmaintained CR at a median time of 42 months (range 19-83 months). The administration of MOPP/ABVD combined with HDC and ABMT was not associated with an increased incidence of major toxicity. The results achieved support the early sequential treatment of a highly effective drug combination followed by HDC/ABMT that can substantially improve the likelihood of cure in these advanced stage very poor prognosis Hodgkin's disease patients.

Mobilization of cytogenetically 'normal' blood progenitors cells by intensive conventional chemotherapy for chronic myeloid and acute lymphoblastic leukemia.

Various lines of evidence suggest that substantial numbers of very primitive normal hematopoietic cells persist in the marrow of most patients with CML, despite the presence of an expanded Philadelphia-Chromosome (Ph) positive population, and that normal clones might, in certain circumstances, have a proliferative advantage over leukemic populations. We have recently demonstrated in 5/8 CML patients with blastic phase (BP) that the blood progenitor cells/(BPC) harvested during early recovery from marrow aplasia were Ph-negative on cytogenetic analysis, suggesting that leukapheresis may provide a useful source of 'normal' progenitors for subsequent reinfusions. We report here an update on 40 patients with Ph + CML and 9 patients with ALL in first or subsequent relapses with associated cytogenetic translocations including t(8;14) t(4;8) t(4;11) and t(9;22). All these patients received intensive conventional chemotherapy and during early recovery from marrow aplasia, when the WBC reached 0.5-2.0 x 10(9)/L, BPC were collected by 4-8 leukapheresis and tested for the persistence of the marker translocations and, when possible, for the presence of the hybrid bcr/abl transcripts by polymerase chain reaction (PCR). In seven out of 10 patients with chronic phase CML, BPC were Ph-negative and in 5 PCR negative. In both accelerated phase patients, BPC were Ph-negative but PCR-positive and in eight out of 28 blastic CML patients, BPC were Ph-negative and in two cases also PCR-negative. Six out of 9 ALL patients, lost the cytogenic translocations. After complete recovery, 16 patients were subsequently given high-dose therapy followed by reinfusion of 'normal' BPC.(ABSTRACT TRUNCATED AT 250 WORDS)

A New Combination of Idarubicin, Etoposide and Cytarabine in Untreated Acute Non-Lymphoblastic Leukemia.

Sixty-seven unselected adult patients with untreated acute non lymphotblastic leukemia (ANLL) ranging in age from 15 to 80 years received a new induction regimen consisting of Idarubicin, Etoposide and Cytarabine. Patients who entered complete remission (CR) were then allocated to 4 courses of post remission intensification. After this, patients under 50 years of age with a compatible donor were given allogeneic bone marrow transplantation (BMT) or autologous BMT (ABMT) in those without an HLA-compatible donor; the remainder, older than 50, did not receive further therapy. Fifty-six of 67 patients (83.5%) achieved CR (02.5% in young and 70.3% in old patients) and 40 (71 %) after the first course. Seven patients (of whom, 6 were > 50 years) died in aplasia during the induction phase and four additional patients (all elderly) died during post-remission intensification without recurrent disease. Subsequently, the younger patients received transplants (BMT: 4 pts; ABMT: 10 pts). Twelve: of the 52 (23%) who survived post remission intensification (BMT: 1; ABMT: 4; others: 7) are disease free survivors 9-67 months (median, 32 months) after achieving CR. In conclusion, this intensive chemotherapy regimen is highly effective both in young and odder patients but the post-remission intensification may be too aggressive for elderly patients.

Autologous Unpurged Bone Marrow Transplantation for Acute Non Lymphoblastic Leukemia in First Remission.

Forty consecutive adult patients under the age of 50 with acute non-lymphoblastic leukemia (ANLL) in first complete remission, underwent autologous bone marrow transplantation (ABMT) between March 1984 and April 1990. The conditioning regimen employed included cyclophosphamide and total body irradiation, followed by the administration of unpurged ABMT. The median time from diagnosis to transplant was 7 months (3-15 months), and the median time from complete remission to ABMT was 4 months (range 3-9 months). Twenty-two (51%) patients remain in complete remission 6-81 months (median 24 months) after ABMT. The causes of death were, recurrent leukemia (11 patients), parenchymal toxicities such as acute respiratory distress syndrome and veno-occlusive disease (3 patients), hemorrhage (2 patients) and infection (2 patients). Eleven patients relapsed after 3-12 months (median 5 months). This study has produced survival data comparable to those of other institutions employing TBI for either allo or autotransplants.

Twelve years experience with high-dose therapy and autologous stem cell transplantation for high-risk Hodgkin's disease patients in first remission after MOPP/ABVD chemotherapy.

High-dose therapy followed by autografting can cure patients with aggressive Hodgkin's disease (HD) refractory or with early relapse to first-line combination chemotherapy. On the other hand, the eradication of the disease is rarely achieved in heavily pretreated patients. It has been suggested that patients with HD with very high risk characteristics at diagnosis, often relapse despite appropriate therapy with 7-8 drugs combination. Thus it seems to us that such patients are potential candidates for early autografting during first remission. Twelve years ago, we initiated a pilot study to investigate whether patients with very high risk characteristics, would benefit from early autografting. The application of early autografting was compared with our historical group of patients in complete remission after receiving MOPP/ABVD, who had the same negative prognostic characteristics, refused autografting and who did not receive other treatment after achieving complete remission. Among the 22 consecutive patients entered into the pilot study and autografted, 18 are alive and 17 (77%) remain alive in unmaintained remission at a median of 86 months. One patient (4%) died of interstitial pneumonitis in the transplantation group. Only 8/24 (33%) patients, who did not receive an autograft, are currently alive and disease free at a median of 89 months. In conclusion, the early application of autografting appears to improve the outcome in patients with very high risk HD who achieved remission with MOPP/ABVD.

Mobilization/transplantation of peripheral blood progenitor cells for aggressive non-Hodgkin's lymphoma with marrow involvement.

Thirty-five aggressive non-Hodgkin's lymphomas (NHL) with marrow involvement received high-dose cyclophosphamide (7 g/m2) and G-CSF in order to collect peripheral blood progenitor cells (PBPC). Fourteen patients were in partial remission, 16 patients were in relapse ("sensitive", 12; "resistant", 4) and 5 patients were in refractory to conventional treatment. A good yield of PBPC was obtained in 30 patients, while a low number of CD34+ cells and of CFU-GM was seen in two cases. Two patients entered progression and one patient died. Thirty patients underwent PBPC autografting. Twenty-nine out of 35 (83%) patients entered complete remission (CR). Two patients died in CR of infection following marrow aplasia 3 and 6 months after autografting. At 3 years the probability of survival and disease-free survival (DFS) are of 62% and 51% respectively.

High-dose cyclophosphamide followed by autografting can improve the outcome of relapsed or resistant non-Hodgkin's lymphomas with involved or hypoplastic bone marrow.

We report our experience of high-dose cyclophosphamide (HDCY) followed by high-dose therapy (HDT) and peripheral blood progenitor cell (PBPC) autografting in patients with diffuse, intermediate and high-grade non-Hodgkin's lymphomas who have failed conventional treatment. From 1991 to 1996, 54 consecutive patients pre-treated with a median of two chemotherapy lines entered the study. Eighteen patients (33%) were still responders to conventional chemotherapy (sensitive relapse), and 20 patients (37%) were in partial response (PR) after chemotherapy (CT). Sixteen patients (30%) were resistant to conventional CT either at presentation (non responder) or in relapse (resistant relapse). Thirty-nine patients had bone marrow involved by disease and fifteen had an hypoplastic marrow following conventional treatment. Patients received HDCY (7gr/m2) and G-CSF or GM-CSF in order to collect PBPC. Median collected CD34+ cells was 12.3 x 10(6)/Kg (range 0.7-197). After HDT (BEAM or Melphalan + TBI) 50 patients underwent PBPC autografting. According to intention to treat, 44 (81%) of 54 patients achieved complete remission (CR) (50% after HDCY and 31% after HDT). Procedure related death occurred in 6 patients (11%), one after HDCY and 5 after autografting. Twenty-nine (66%) of 44 patients are still in CR, 7 to 63 months (median 27 months) after the procedure. Three-year probability of survival, disease-free survival and progression-free survival are 63%, 64% and 52% respectively. In conclusion, HDCY is an effective procedure not only in mobilizing PBPC, but also in reducing tumour burden. HDT with PBPC support may further improve the outcome in this category of high-risk non-Hodgkin's lymphomas.

Amifostine (WR-2721), a cytoprotective agent during high-dose cyclophosphamide treatment of non-Hodgkin's lymphomas: a phase II study.

Clinical trials indicate that amifostine may confer protection on various normal tissues without attenuating anti-tumor response. When administered prior to chemotherapy or radiotherapy, it may provide a broad spectrum of cytoprotection including against alkylating drugs. The mechanism of protection resides in the metabolism at normal tissue site by membrane-bound alkaline phosphatase. Toxicity of this drug is moderate with hypotension, nausea and vomiting, and hypocalcemia being observed. We report a phase II study using amifostine as a protective drug against high-dose cyclophosphamide (HDCY) (7 g/m2), used to mobilize peripheral blood progenitor cells (PBPC) and to reduce tumor burden. We enrolled 29 patients, 22 (75. 9%) affected by aggressive and 7 (24.1%) by indolent non-Hodgkin's lymphoma (NHL), who were submitted to 58 infusions of amifostine and compared them with a historical group (33 patients) affected by aggressive NHL and treated with VACOP-B followed by HDCY. The most important results in favor of amifostine were the reduction of intensity of cardiac, pulmonary and hepatic toxicity, and a significant reduction of frequency and severity of mucositis (P = 0. 04). None of the 29 patients died in the protected group, while in the historical group 2/33 patients died because of cardiac or pulmonary toxicity and 2 patients stopped therapy due to toxicity. Amifostine did not prevent the aplastic phase following HDCY. PBPC collection and hematological recovery were adequate in both groups. The number of CFU-GM (colony-forming units-granulocyte/macrophage) colonies and mononuclear cells in the apheresis products was significantly higher in the amifostine group (P = 0.02 and 0.01, respectively). Side effects were mild and easily controlled. We conclude that amifostine protection should be useful in HDCY to protect normal tissues, with acceptable side effects.

[Neoplastic residues in the trocar tract in oncologic laparoscopic surgery]. / Recidive neoplastiche in sede di trocar nella chirurgia oncologica laparoscopica.

AIM: The laparoscopic approach to malignant diseases runs up against both old and new problems: respect for the principles of radicality, operating times, the postoperative course and surgical complications, long-term oncological results in terms of survival and recurrence of the disease. One of the problems which has received most attention regards the onset of a metastasis on a trocar scar or a mini-laparotomy recurrence. Trocar site tumor recurrences have been described in the literature following laparoscopic surgery in almost all abdominal malignant pathologies (colorectal, gynaecological, pancreatic, etc.) and even after thoracoscopy. The real frequency is currently of the order of 1% (0-2%) in colic surgery and of 14% (10-17%) after cholecystectomy for occult gallbladder carcinoma. METHODS: A retrospective survey was carried out of our laparoscopic experience; between 1994 and 2002 213 colic resections were carried out for cancer; we also observed 18 occult carcinomas of the gallbladder in 2386 laparoscopic cholecystectomies for lithiasis. RESULTS: Respectively 2 cases (11%) of trocar site neoplastic recurrences in gallbladder carcinoma and 2 cases (0.9%) from colon carcinoma were observed. CONCLUSIONS: The real extent of the problem would appear to be on a much lesser scale at the moment than was initially thought, especially as regards colic surgery. The multifactorial aetiology of the problem explains the importance of their prevention, on the basis above all of rigorous respect for the rules and protocols of laparoscopic technique.

Upfront high-dose sequential therapy (HDS) versus VACOP-B with or without HDS in aggressive non-Hodgkin's lymphoma: long-term results by the NHLCSG.

BACKGROUND: There is not univocal concordance for using high-dose sequential therapy (HDS) as first-line treatment for aggressive non-Hodgkin's lymphoma (NHL). We designed this study to evaluate the usefulness of HDS followed by high-dose therapy (HDT) with autologous stem cell transplantation as front-line treatment in different subsets of aggressive NHL. PATIENTS AND METHODS: Among 223 patients aged 15-60 years with aggressive, advanced stage NHL, 106 patients were randomized to VACOP-B (etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, bleomycin) for 12 weeks (plus HDS/HDT in case of persistent disease) (arm A), and 117 patients to VACOP-B for 8 weeks plus upfront HDS/HDT (arm B). RESULTS: According to the intention-to-treat analysis, the complete response rate was 75% for arm A and 72.6% for arm B. With a median follow-up of 62 months there was no difference in 7-year probability of survival (60% and 57.8%; P = 0.5), disease-free survival (DFS) (62% and 71%; P = 0.2) and progression-free survival (PFS) (44.9% and 40.9%; P = 0.7) between the two arms. Subgroup analyses confirmed that the best results in terms of survival, DFS and PFS were achieved by patients with large B-cell NHL without bone marrow (BM) involvement, independently of the treatment arm. Results were poorer in other categories of patients and poorest in patients with BM involvement. CONCLUSIONS: Aggressive NHL patients do not benefit from upfront HDS/HDT.

[Multiple granular cell tumor: case report and review of the literature]. / Tumore a cellule granulose multiplo. Descrizione di un caso e revisione della letteratura.

We describe a case of multiple granular cell tumour (GCT) in 41 years old man. It manifested as subcutaneous synchronous multiple lesions. GCT is, usually, a benign lesion that is histologically diagnosed after biopsy or surgical excision. It raises doubts about his benignity in relation to multiple and distant localizations as in the present case.