Brain gliomas and growth factors: immunohistochemical, immunofluorescence, flow cytometry and RT-PCR profile in pediatric age.

Gliomas represent over 50% of tumors occurring in children. Evidence suggests that glioma stem cells (GSCs), maintained by the transforming growth factor-beta (TGF-ß1) pathway, and vascularization substantially contribute to tumor aggressiveness. The identification of important angiogenic factors such as vascular endothelial growth factor (VEGF) may represent a crucial step in the therapeutic approach against tumor growth and metastatic diffusion. The aim of this study was to identify the expression of TGF-ß1, VEGF and VEGF-receptors in brain gliomas. Specimens of 16 gliomas and 4 controls from children aged 0.2-14 years were used in the study. Immunohistochemical analysis and gene expression study from specimens was performed. Flow cytometry analysis on GSCs was performed to ascertain the expression of VEGF and VEGF-R2 in the tumor stem cell compartment. Newly diagnosed gliomas mainly showed moderate to strong VEGF immunostaining and increased expression of pro-inflammatory molecules in glioma cells. The proportion of TGF-ß1 positive endothelial cells was markedly lower in normal brain vessels compared to tumor vessels. These findings demonstrate that the glioma mass is constituted by a phenotypically immature anoxic central area with a proliferating hypoxic layer; the peripheral area is characterized by cell types with a higher degree of differentiation expressing pro-angiogenic factors. Our data have proven that GSCs play a central role in promoting glioma neovascularization. These findings are useful to understand glioma vascularization, have relevant implications in the therapeutic options and may favor new insights into stem cells biology and suggest therapeutic opportunities for the anti-vascular treatment strategy.

Environmental nanoparticles are significantly over-expressed in acute myeloid leukemia.

The increase in the incidence of acute myeloid leukemia (AML) may suggest a possible environmental etiology. PM2.5 was declared by IARC a Class I carcinogen. No report has focused on particulate environmental pollution together with AML. The study investigated the presence and composition of particulate matter in blood with a Scanning Electron Microscope coupled with an Energy Dispersive Spectroscope, a sensor capable of identifying the composition of foreign bodies. 38 peripheral blood samples, 19 AML cases and 19 healthy controls, were analyzed. A significant overload of particulate matter-derived nanoparticles linked or aggregated to blood components was found in AML patients, while almost absent in matched healthy controls. Two-tailed Student's t-test, MANOVA and Principal Component Analysis indicated that the total numbers of aggregates and particles were statistically different between cases and controls (MANOVA, P<0.001 and P=0.009 respectively). The particles detected showed to contain highly-reactive, non-biocompatible and non-biodegradable metals; in particular, micro- and nano-sized particles grouped in organic/inorganic clusters, with statistically higher frequency of a subgroup of elements in AML samples. The demonstration, for the first time, of an overload of nanoparticles linked to blood components in AML patients could be the basis for a possible, novel pathogenetic mechanism for AML development.

Growth factors, their receptor expression and markers for proliferation of endothelial and neoplastic cells in human osteosarcoma.

Osteosarcoma is the most common primary malignant tumour of the bone. Although new therapies continue to be reported, osteosarcoma-related morbidity and mortality remain high. Modern medicine has greatly increased knowledge of the physiopathology of this neoplasm. Novel targets for drug development may be identified through an understanding of the normal molecular processes that are deeply modified in pathological conditions. The aim of the present study is to investigate, by immunohistochemistry, the localisation of different growth factors and of the proliferative marker Ki-67 in order to determine whether these factors are involved in the transformation of osteogenic cells and in the development of human osteosarcoma. We observed a general positivity for NGF - TrKA - NT3 - TrKC - VEGF in the cytoplasm of neoplastic cells and a strong expression for NT4 in the nuclear compartment. TGF-beta was strongly expressed in the extracellular matrix and vascular endothelium. BDNF and TrKB showed a strong immunolabeling in the extracellular matrix. Ki-67/MIB-1 was moderately expressed in the nucleus of neoplastic cells. We believe that these growth factors may be considered potential therapeutic targets in the treatment of osteosarcoma, although proof of this hypothesis requires further investigation.

Shortened and intensified MJMA: an effective salvage therapy for relapsed and refractory lymphomas and a strong mobilizer of PBSCs.

There is great interest in chemotherapies for relapsed or refractory lymphomas that are both directly effective against the lymphoma and able to mobilize PBSCs for rescue after high-dose chemotherapy (HDC). Twenty-eight patients with relapsed or refractory lymphomas were treated with a shortened, intensified MJMA regimen (mitoxantrone 10 mg/m(2) i.v. day 1, carboplatin 200 mg/m(2) i.v. days 1-2, methylprednisolone 500 mg/m(2) i.v. days 1-3, cytarabine 2000 mg/m(2) i.v. day 3) for six cycles every 21 days. A median of five cycles/patient was administered. Nineteen patients had complete responses, seven partial responses and two no responses. The only remarkable toxicity was hematological. In 18 patients who were candidates for HDC, a mean of 10.45 x 10(6) CD34/kg of patients' body weight was collected (range: 3.70-24.88 x 10(6)/kg). Eleven patients underwent transplantation, which converted two of four partial responses into complete responses. The median follow-up was 49 months. Survival parameters were not related to relapsed/refractory status or to the time from the last chemotherapy, but were related only weakly to the number of prior chemotherapies. Outpatient MJMA is a feasible and very effective salvage chemotherapy per se. The complete response rate is high and it is a powerful PBSC mobilizer.

Complete long-term response to radiotherapy of gastric early-stage marginal zone lymphoma resistant to both anti-Helicobacter pylori antibiotics and chemotherapy.

BACKGROUND: The optimal approach to patients with gastric lymphoma of extranodal mucosa-associated lymphoid tissue (MALT) that resist to anti-Helicobacter pylori (HP) eradication therapy is still to be defined. PATIENTS AND METHODS: From January 1997 to December 2004, we observed 24 patients affected with newly diagnosed early-stage and HP-positive gastric lymphoma of the MALT type. Five of them resisted to oral anti-HP antibiotic regimens and to subsequent one (two patients) or two (three patients) chemotherapy regimens. Age ranged between 51 and 77 years (median 70); three were females. Translocation (11;18) was ascertained in one subject. They were admitted to local radiation therapy with a total dose of 30 Gy. RESULTS: All such resistant patients achieved complete remission after radiotherapy. No relapses were observed after 21, 45, 48, 52, and 67 months of uninterrupted follow-up. Early toxicity was very low and consisted of mild nausea. Late toxicity or secondary malignancy was not recorded so far. CONCLUSIONS: Radiotherapy proved to be effective and safe for early-stage HP-positive gastric extranodal lymphoma of MALT type that is resistant to anti-HP eradication antibiotics and to following chemotherapy. Radiotherapy might be suggested as principal salvage therapy after resistance to HP eradication, instead of chemotherapy.

ABVD plus radiotherapy versus EVE plus radiotherapy in unfavorable stage IA and IIA Hodgkin's lymphoma: results from an Intergruppo Italiano Linfomi randomized study.

BACKGROUND: In 1997, the Intergruppo Italiano Linfomi started a randomized trial to evaluate, in unfavorable stage IA and IIA Hodgkin's lymphoma (HL) patients, the efficacy and toxicity of the low toxic epirubicin, vinblastine and etoposide (EVE) regimen followed by involved field radiotherapy in comparison to the gold standard doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) regimen followed by the same radiotherapy program. PATIENTS AND METHODS: Patients should be younger than 65 years with unfavorable stage IA and IIA HL (i.e. stage IA or IIA with bulky disease and/or subdiaphragmatic disease, erythrocyte sedimentation rate higher than 40, extranodal (E) involvement, hilar involvement and more than three involved lymph node areas). RESULTS: Ninety-two patients were allocated to the ABVD arm and 89 to the EVE arm. Complete remission (CR) rates at the end of treatment program [chemotherapy (CT) + RT] were 93% and 92% for ABVD and EVE arms, respectively (P = NS). The 5-year relapse-free survival (RFS) rate was 95% for ABVD and 78% for EVE (P < 0.05). As a consequence of the different relapse rate, the 5-year failure-free survival (FFS) rate was significantly better for ABVD (90%) than for EVE (73%) arm (P < 0.05). No differences in terms of overall survival (OS) were observed for the two study arms. CONCLUSIONS: In unfavorable stage IA and IIA HL patients, no differences were observed between ABVD and EVE arms in terms of CR rate and OS. EVE CT, however, was significantly worse than ABVD in terms of RFS and FFS and cannot be recommended as initial treatment for HL.

New insights into the role of age and carcinoembryonic antigen in the prognosis of colorectal cancer.

The aim of this study was to verify through relative survival (an estimate of cancer-specific survival) the true prognostic factors of colorectal cancer. The study involved 506 patients who underwent locally radical resection. All the clinical, histological and laboratory parameters were prognostically analysed for both overall and relative survival. This latter was calculated from the expected survival of the general population with identical age, sex and calendar years of observation. Univariate and multivariate analyses were applied to the proportional hazards model. Liver metastases, age, lymph node involvement and depth of bowel wall involvement were independent prognosticators of both overall and relative survival, whereas carcinoembryonic antigen (CEA) was predictive only of relative survival. Increasing age was unfavourably related to overall survival, but mildly protective with regard to relative survival. Three out of the five prognostic factors identified are the cornerstones of the current staging systems, and were confirmed as adequate by the analysis of relative survival. The results regarding age explain the conflicting findings so far obtained from studies considering overall survival only and advise against the adoption of absolute age limits in therapeutic protocols. Moreover, the prechemotherapy CEA level showed a high clinical value.

The role of dose size in a chemotherapy regimen (ProMECE-CytaBOM) for the first-line treatment of large B-cell lymphomas: a randomized trial by the Gruppo Italiano Studio Linfomi (GISL).

BACKGROUND: It is still unclear the actual contribute of dose intensity (DI), dose size (DS) and dose density (DD) in the conventional chemotherapy of large, B-cell non-Hodgkin lymphomas. METHODS: A prospective, randomized trial compared the cyclic schedule of ProMECE-CytaBOM chemotherapy (cyc-PC, 6 cycles) with a modified version of it, which administered the same drugs sequentially (seq-PC), with the same planned cumulative DI and an 83% DD, within the same time frame (113 days), but with three times higher DS of all the drugs except vincristine. RESULTS: Fifty-six patients received cyc-PC and 52 seq-PC. The actual mean cumulative DI was 0.79 +/- 0.15 with cyc-PC, 0.78 +/- 0.17 with seq-PC. Response was complete in 59% and 52%, partial in 20% and 21%, null in 5% and 6%, respectively. There were four toxic deaths (two per arm). Relapses occurred in 36% and 37%, respectively. Toxicity was similar in both arms. Overall, failure-free, progression-free and disease-free survival (median follow-up: 54 months) were statistically indifferent. CONCLUSIONS: The very similar DI actually delivered in both arm seems to be the main common determinant of the indifferent results recorded. Increasing DS--at least within the limits clinically attainable without stem cell rescue--does not improve results.

The role of high-dose therapy and autologous stem cell transplantation in patients with primary refractory Hodgkin's lymphoma: a report from the Gruppo Italiano per lo Studio dei Linfomi (GISL).

GISL recently conducted an exhaustive survey of 1078 patients with Hodgkin's Lymphoma (HL) enrolled between 1988 and 2002 in different prospective trials. Treatment failure was observed in 82 out of 1078 patients; of these 82 patients with refractory HL, complete information was available for 72, who form the evaluable population of the present study. After the initial therapy failure, 51 patients were treated with conventional salvage chemotherapy (CC) (n = 24) or high-dose chemotherapy (HDC) (n = 27); 4-year overall survival (OS) was 81% in the HDC group versus 38% in the CC group (P = 0.019). The remaining 21 patients had rapidly progressive disease and died. After a median follow-up of 2.8 years, the projected OS for all 72 patients is 58 and 49% at 3 and 5 years, respectively. Age <45 years, the absence of systemic symptoms and a PS <1 predicted a significantly longer OS. Interestingly, the majority of patients with two or three negative prognostic factors did not receive potentially curative therapy. In conclusion, HDC seems to be a reasonable option for selected patients with refractory HL, although the majority of them did not receive a transplant. Finally, patients with a high-risk score had little chance of receiving potentially curative treatment.

Radiological evidence of anatomical variation of the inferior vena cava: report of two cases.

The inferior vena cava (IVC) is a retroperitoneal key structure whose location and integrity must be checked in every scan. A number of studies are reported in the literature concerning congenital variations of the inferior vena cava. Anatomical variations of this main venous trunk are relatively infrequent clinical findings during surgery or diagnostic procedures in patients without symptoms such as an aberrant venous drainage or abdominal pain. Among the other imaging techniques, computerized tomography is a non-invasive, effective technique for diagnosing diseases of the retroperitoneal space and, particularly, for detecting anomalies of the main vessels, such as the aorta or IVC, in asymptomatic patients. We present two cases of IVC variation as an incidental finding in patients studied by means of CT scan for the gradation of kidney carcinoma and pancreatic cancer respectively. Two different configurations of the system of the IVC (agenesis of the IVC with hypertrophy of the azygos vein and a double IVC respectively) were found in our cases. The embryological development of the IVC system is discussed, bearing in mind that knowledge of the different variations is important in order to avoid major surgical complications.

Human articular chondrocytes immortalized by HPV-16 E6 and E7 genes: Maintenance of differentiated phenotype under defined culture conditions.

OBJECTIVE: To establish an immortalized normal human articular chondrocyte line which could be useful for a better understanding of cell molecular mechanisms relevant for the development of new therapeutic approaches in rheumatic diseases. DESIGN: Chondrocytes from human adult articular healthy cartilage were transfected in primary culture with a plasmid containing two human papilloma virus type 16 (HPV-16) early function genes: E6 and E7, using the highly efficient cationic liposome-mediated (lipofection) procedure. The transfection was verified by reverse transcriptase-polymerase chain reaction analysis of E7 mRNA and by immunofluorence localization of the E7 protein in the cell cytoplasm. The established chondrocyte cell line was examined in monolayer and in two culture conditions that were described to re-induce differentiated characteristics: culturing in a serum-free defined medium supplemented with an insulin-containing serum substitute and seeding on a hyaluronan-based non-woven structured biomaterial. The expression of markers characteristic of cartilage was shown in the mRNA by reverse transcriptase-polymerase chain reaction. Immunohistological staining and Western blotting analysis were performed to evaluate type II collagen synthesis. Proteoglycans deposition was detected by Alcian Blue staining. A Field Emission In Lens Scanning Microscopy was used to look at the morphology of the immortalized cells at very high magnification. RESULTS: Normal human articular chondrocytes were efficiently transfected leading to the establishment of an immortalized cell line as confirmed by HPV-16 E7 mRNA and protein detection. These cells were able to re-express type II collagen both at mRNA and protein levels under the two defined cultured conditions we used, still maintaining type I collagen expression. Collagen IX mRNA was present only in early primary culture while collagen type X and aggrecan transcripts were always detected. Alcian Blue staining showed a proteoglycan-rich matrix production. The ultrastructural analysis of the immortalized cells revealed that their morphology strictly resembled that of normal chondrocytes. CONCLUSIONS: The cell line that we obtained may be a useful tool for increasing our knowledge of the genetic and biochemical events involved in the processes of cartilage growth and differentiation. Moreover, it appears to be a suitable model for pharmacological and toxicological studies related to rheumatic diseases relevant to humans.

ABVD versus stanford V versus MEC in unfavourable Hodgkin's lymphoma: results of a randomised trial.

BACKGROUND: Between January 1996 and April 2000, 355 patients with advanced Hodgkin's disease (HD) (stage II bulky disease, III and IV) were enrolled in a prospective, multicentre, randomised trial aimed at comparing the efficacy of two new promising regimens: Stanford V and MEC hybrid. ABVD was chosen as the control arm. Radiotherapy was planned at the end of induction therapy on residual masses or on sites of previous bulky lesions. One hundred and seventeen, 123 and 115 patients were treated with Stanford V, MEC and ABVD, respectively. The records of 275 enrolled patients (89 Stanford V, 88 MEC, 98 ABVD) have been reviewed and are the subject of this report. RESULTS: After induction therapy a complete response (CR) was observed in 93, 89 and 74% of patients treated with MEC, ABVD and Stanford V, respectively, with a statistically significant difference (P = 0.013) between the arms. After a median follow-up of 24 months, 16 relapses have been recorded among 196 patients who achieved a CR. Relapse rates are 16, 6 and 4% for Stanford V, ABVD and MEC, respectively (P = 0.042). The 3-year survival was 93%, without any significant difference among the arms. However, a significant difference emerged in terms of failure free survival (FFS). Patients treated with Stanford V did the worst compared with those treated with ABVD or MEC (P = 0.001). Toxicity was comparable in the three treatment arms. CONCLUSION: For this randomised study, both ABVD and MEC gave superior results to Stanford V in terms of response and FFS; MEC seems to be the best regimen in terms of relapse-free survival, even if a significant difference has not yet been achieved. Notwithstanding the short follow-up, these results seem to be very impressive in defining the best standard treatment for HD for this subset of patients.

Chromatin fibers organization within the nucleus.

In order to evaluate at the ultrastructural level the three dimensional arrangement of the dispersed chromatin during the intephase, the immunogold detection of Bromodeoxyuridine (BrdU), of the DNA polymerase alpha and of the proliferating cell nuclear antigen (PCNA) was performed on human HL60 leukemia cells and nuclear matrices extracted from the same cellular model. The Field Emission In lens Scanning Electron Microscopy analysis of the ultrathin cryosectioned cells revealed the presence of a chromatin three dimensional network where the different constituents appeared repetitively assembled. Also the nuclear matrix showed a repetitive structure, on which the deprivation of the DNA corresponded to the selective loss of particular class sized fibers. The single or multiple combined immunolocalization of different structures involved in the DNA replication, where BrdU, DNA polymerase alpha and PCNA represent, respectively, the substratum, the polymerizing enzyme and a regulator of the reaction, allowed the understanding of its reciprocal spatial relationship on the dispersed interphasic chromatin and the role of the nuclear matrix in the replicative process.

Comparison of prognostic models in patients with advanced Hodgkin disease. Promising results from integration of the best three systems.

BACKGROUND: Several prognostic systems have been elaborated for patients with Hodgkin disease (HD) over the last 12 years, but early identification of a reasonably large group of both low and high risk, advanced stage patients remains unsatisfactory. METHODS: Seven well known models were applied to 516 patients with advanced HD, with 315 patients used for the study sample and 201 patients used for the test sample. Individual performances as well as joint performances were analyzed univariately and multivariately in relation to overall survival, recurrence free survival, and time to treatment failure by means of a proportional hazards model. RESULTS: None of the models identified a group containing > 10% of patients from the total population who had a failure risk of either < or = 10% or > or = 50%. The systems of the International Database on Hodgkin Disease, the Memorial Sloan-Kettering Cancer Center, and the International Prognostic Factor Project showed the best prognostic power; only these three, when analyzed together, predicted clinical outcome with a statistically significant fit to the clinical data. Integration of the three systems in a linear model dramatically improved their individual discriminatory capacity by identifying patients with 10% and 50% failure risks, respectively, in 23% and 24% of the study patient population and in 19% and 25% of the test population, respectively. CONCLUSIONS: As powerful and simple new prognostic factors are awaited that may improve our predictive ability, this integrated index is probably the best way to exploit the significance of those presently available. The program required for the calculations can be downloaded from the Internet at the web site http://www.unimo.it/gisl/default.htm.

Image-aided estimate of tumor burden in Hodgkin's disease: evidence of its primary prognostic importance.

PURPOSE: To explore a more direct method for evaluating tumor burden (TB) in Hodgkin's disease (HD) and to verify its prognostic importance. PATIENTS AND METHODS: The volume of TB at diagnosis was directly and retrospectively measured in 121 HD patients through images of the lesions recorded by computed tomographic (CT) scan of the thorax, abdomen, and pelvis for all deep sites of involvement and many superficial ones, and by ultrasonography (US) for the remaining superficial lesions. RESULTS: The TB, which was obtained from the sum of the volumes of all the lesions measured on CT scans and US and normalized to body-surface area (relative TB [rTB]), showed a median value of 102.6 cm(3)/m(2) (range, 2.2 to 582.8). At multivariate analysis for prognostic value, rTB was the parameter that statistically correlated best with time to treatment failure (P = 2.2 x 10(-6)), followed by erythrocyte sedimentation rate (ESR) (P =.0003), and serum fibrinogen (P =.0112). The prognostic discrimination allowed by rTB alone proved to be clearly superior to that obtained with the score of the International Prognostic Factor Project. The rTB was found to be correlated with many clinical staging parameters (bulky disease, number of involved lymph node regions, serum lactate dehydrogenase, ESR, hemoglobin, Karnofsky index), but its predictability from these variables was low (R(2) =.668). CONCLUSION: Relative TB is emerging as a strong prognostic factor in HD, more powerful than and largely independent of those hitherto known and used. Further studies are needed to confirm these results and exploit their clinical value, particularly the relationship among rTB, drug doses, and response.

Lomustine and melphalan cannot be replaced by cyclophosphamide and etoposide without reducing efficacy in MOPPEBVCAD chemotherapy for advanced Hodgkin's disease.

BACKGROUND AND OBJECTIVES: To evaluate the feasibility, toxicity and preliminary results of a potentially less toxic variant of the MOPPEBVCAD chemotherapy regimen for advanced Hodgkin's disease: MOPPEBVCyED, in which cyclophosphamide and etoposide replace lomustine and melphalan, respectively, with the remaining components being unaltered. DESIGN AND METHODS: The study was multicenter, prospective and randomized, and enrolled 67 patients with newly diagnosed stage IIB, III, IV Hodgkin's disease (62 were expected on the grounds of statistical considerations). Radiotherapy was restricted to sites of bulky involvement or to areas that responded incompletely to chemotherapy. Median follow-up was 48 months. RESULTS: Comparing MOPPEBVCAD vs. MOPPEBVCyED, the results were as follows: complete remissions 35/35 vs. 30/32 (plus one partial remission and one disease progression); relapses 5 vs. 8; deaths 2 (one of myelodysplasia) vs. 2; delivered mean dose intensity (DI): lomustine 0.79+/-0.67 vs. cyclophosphamide 0.82+/-0.32; melphalan 0.80+/-0.13 vs. etoposide 0.86+/-0.18; average DI of the 7 drugs common to both regimens 0.73+/-0.10 vs. 0.83+/-0.11; all 9 drugs 0.75+/-0.13 vs. 0.84+/-0.09 (p=0.002); projected 5-year failure-free survival 0.79 vs 0.62; second cancers, two myelodysplasias vs. one carcinoma of the kidney. Toxicities were not statistically different except for heavier thrombocytopenia being recorded with MOPPEBVCAD. INTERPRETATION AND CONCLUSIONS: The higher cumulative and single drug DI recorded with MOPPEBVCyED may reflect better short-term tolerability, but it does not lead to better disease control. Its late toxicity may be expected to be lower in the future but at present it does not seem to be a sufficient reason to substitute MOPPEBVCyED for MOPPEBVCAD.

An unusual case of hyperekplexia.

Hyperekplexia is a rare paroxysmal disorder characterized by exaggerated startle response, hypertonia during infancy and a transient increase in tone following startle attacks. We report an unusual case of hyperekplexia in a young man. In addition to common symptoms of the condition, we found generalized spasticity persisting beyond infancy, and facial and skeletal dysmorphism. Because of an unsteady gait with frequent falls and raised serum creatine kinase levels, a congenital myopathy had been suspected in the past and an abnormal muscle biopsy had been documented. We diagnosed hyperekplexia at the age of 21 years on clinical grounds and following the response to pharmacological treatment. A mutation in the alpha1 subunit of the glycine receptor confirmed the diagnosis. A repeated needle muscle biopsy demonstrated mild myopathic changes, which we considered to be secondary to increased muscle tone. This case highlights the diagnostic difficulties of hyperekplexia, particularly in sporadic cases with unusual presentation.

The role of surgery in the treatment of gastrointestinal lymphomas other than low-grade MALT lymphomas.

BACKGROUND AND OBJECTIVE: A bias in clinical investigations on gastrointestinal lymphomas is the lack of testing the intention to treat as to resection, emergency conditions at presentation and selection brought about by the evaluation of feasibility of surgery. DESIGN AND METHODS: A prospective study involved 154 patients with gastrointestinal nodular or high-grade MALT lymphomas, 111 with a gastric and 43 with an intestinal presentation. The decision to resect or treat conservatively was left to clinicians, on condition that it was previously defined for each patient. RESULTS: Failure-free survival was significantly higher in the 106 resected patients than in the 48 unresected ones but did not differ according to either primary intention to treat or emergency surgery/elective treatment. Survival was similar in patients operated on by choice and in those because of an emergency. Intentionally unresected patients had a significantly better survival than those not undergoing surgery despite the initial intention, for a number of clinical reasons. Patients with gastric lymphoma survived longer than those with intestinal disease and prognostic factors were analyzed separately in the two groups. The best predictors of prognosis were performance status and serum lactic dehydrogenase level in gastric lymphomas, resection alone in intestinal ones. INTERPRETATION AND CONCLUSIONS: The prognosis of gastric lymphomas depends on lymphoma-related factors and not on surgical treatment. The prognosis of intestinal ones is exclusively related to surgery. These data support the appropriateness of different clinical approaches to gastric and intestinal lymphomas.

A variant of ProMACE-CytaBOM chemotherapy for non-Hodgkin's lymphoma with threefold higher drug dose size but identical cumulative dose intensity. A pilot study of the Italian lymphoma study group (GISL).

BACKGROUND AND OBJECTIVE: The positive results of high-dose chemotherapy followed by rescue with bone marrow progenitor cell transplantation are generally ascribed to the high dose size (DS) of the drugs given. However, a concomitant marked increase in dose intensity (DI) is always involved. With the aim of comparing the role of DS and DI in non-Hodgkin's lymphomas, a variant of Fisher's ProMACE-CytaBOM regimen was designed in which the projected cumulative drug DIs remained the same as in the original schedule but the DSs were tripled. DESIGN AND METHODS: Dosages in mg/m(2), route and days of administration were the following: cyclophosphamide 1,950 i.v. on days 1, 64; methotrexate 360 i.v. days 15, 78; vincristine 1.4 iv days 15, 78, 43, 106; etoposide 360 i.v. days 29, 92; epirubicin 120 i.v. days 29, 92; bleomycin 15 i.v. days 43, 106; cytarabine 900 i.v. days 50, 113. Thirty-six outpatients with intermediate- and high-grade non-Hodgkin's lymphomas entered the pilot study; 29 were untreated and 7 had relapse disease. Clinical stage was I in 1 patient, II in 7, III in 5 and IV in 23; 10 had B symptoms; the IPI score was 0-2 in 29 cases and > or =3 in the remaining 7. RESULTS: Of the 29 previously untreated patients, 16 achieved complete remission, 8 partial remission, 4 developed progressive disease and 1 was withdrawn early from the study because of acute viral hepatitis; subsequently 4 relapsed and 3 died (2 of disease progression, 1 of causes unrelated to the disease). In the pre-treated group 3 patients obtained complete remission, 2 partial remission and in 1 patient the disease progressed; 3 of these pre-treated patients died (1 of progressive disease, 1 of a new relapse, 1 of myocardial infarction during therapy). With a 20-month median follow-up, the 30-month overall and relapse-free survival were 0.58 and 0.70, respectively. G-CSF was administered to all but 2 patients, with median delivery throughout the whole regimen of 8, 400 microg per patient. Actual cumulative DI was 0.82+/-0.11. Grade 3-4 hematologic toxicity consisted of anemia in 3 cases, of leukopenia in 8 and of thrombocytopenia in 2; the same grade of non-hematologic toxicity involved the liver in 2 cases, the heart in 1 (the above mentioned death), the digestive mucosa in 2 and the peripheral nerves in 1 patient. INTERPRETATION AND CONCLUSIONS: The iso-DI sequential variant of the ProMACE-CytaBOM regimen can be considered feasibile, relatively non-toxic, and can be given on an out-patient basis. Limited use of G-CSF is required (about 3 vials after each drug administration). Thus, a randomized trial with the original ProMACE-CytaBOM regimen can be designed.