Prognostic factors for survival of non-Hodgkin's lymphoma patients treated with high-dose chemotherapy and autologous bone marrow transplantation

Prognostic factors to identify patients with high-risk non-Hodgkin's lymphoma (NHL) have recently been developed. We retrospectively investigated the relation between prognostic factors and treatment outcome after autologous bone marrow transplantation (ABMT). From 1984 to 1994, 80 consecutive patients with NHL responding slowly to or relapsing after front-line therapy were treated with high-dose chemotherapy and ABMT. Prognostic factors at the time of diagnosis and of ABMT were related to clinical outcome after ABMT. The cumulative 5-year overall survival (OS) was 51%, progression-free survival (PFS) 41%, and relapse-free survival (RFS) 53%. Absence of B symptoms and intermediate-grade malignancy at first presentation of disease were independently related to prolonged OS (P = 0.02 and P < 0.01, respectively) and prolonged PFS (P = 0.005 and P = 0.01, respectively). At the time of ABMT, first PR or CR, normal LDH levels and tumour stage I + II were associated with prolonged OS (P = 0.0005, P = 0.03 and P = 0.004, respectively). A Coiffier index of 0 or 1, first PR or CR and no extranodal disease involvement were related to prolonged PFS (P = 0.0002, P = 0.005 and P = 0.07, respectively). Treatment-related deaths occurred in 10% of patients. Assessment of disease status, LDH level, tumour stage, extranodal disease involvement and Coiffier index at the time of ABMT is respectively efficient in predicting treatment outcome after ABMT.     

BEAM chemotherapy followed by autologous stem cell support in lymphoma patients: analysis of efficacy, toxicity and prognostic factors

In the present paper, we evaluate tolerability, outcome and prognostic factors in patients with poor prognosis non-Hodgkin's lymphoma (NHL) and Hodgkin's disease (HD) when uniformly treated with BCNU, etoposide, cytarabine and melphalan (BEAM) and autologous stem cell transplant (ASCT). On hundred and forty-eight patients with NHL (n = 112) or HD (n = 36) received BEAM followed by infusion of bone marrow (n = 55), peripheral blood stem cells (n = 79) or both (n = 14). Twenty-eight patients had low-grade lymphoma (LGL), 68 intermediate- and 16 high-grade lymphoma (IGL). Within the NHL group, 21 patients were in 2nd or subsequent complete remission (CR) at transplant, 34 had sensitive disease and 11 resistant disease; 46 patients were transplanted in 1st CR due to the presence of > or = 2 adverse prognostic features at diagnosis or to a slow CR. Of the HD patients at transplant 17 had active disease, 16 were in > or = 2 CR and three in 1st CR. The overall percentage of toxic deaths was 5.4%, while in the group of patients transplanted with PBSC it was only 1.3%. NHL patients: 78% were in CR following ASCT, including 25 out of 45 patients (56%) who were transplanted with active disease. Only two of the 11 patients transplanted with resistant disease achieved CR. Incidence of overall survival (OS) and disease-free survival (DFS) at 3 years was 65 and 75%, respectively. As far as histology was concerned, OS was significantly better for patients with LGL in comparison with IGL (88 vs 56%) (P = 0.002). DFS was significantly higher for patients transplanted in first CR or first partial remission (PR) than it was for those transplanted in a later CR or PR (86 vs 53%) (P = 0.02). Multivariate analysis for OS showed that histology, bulky disease, poor performance status at transplant and achievement of CR were independent prognostic factors. In addition, a high number of infused MNC was associated with poor DFS. HD patients: 30 (83%) were in CR after transplantation, with 25 maintaining CR at the end of the study. Only one of the four patients transplanted with resistant disease reached CR. Incidence of OS and DFS at 3 years was 78 and 81%. DFS was similar for patients transplanted with early or late relapse (95 and 93%). With multivariate analysis, the only independent variable for OS was CR after transplant. In conclusion, the present results demonstrate the efficacy and low toxicity of the BEAM regimen in high-risk lymphoma patients with sensitive disease. Other strategies should be investigated for patients with refractory lymphoma.     

Preliminary report of the Asian-Oceanian Clinical Oncology Association randomized trial comparing cisplatin and epirubicin followed by radiotherapy versus radiotherapy alone in the treatment of patients with locoregionally advanced nasopharyngeal carcinoma. Asian-Oceanian Clinical Oncology Association Nasopharynx Cancer Study Group

BACKGROUND: The aim of this trial was to compare the outcome achieved with neoadjuvant chemotherapy followed by radiotherapy to that achieved with radiotherapy alone for patients with locoregionally advanced undifferentiated or poorly differentiated nasopharyngeal carcinoma (NPC) meeting one of the following criteria: Ho's T3 disease, Ho's N2-N3 disease, or lymph node size > or =3 cm. METHODS: Between September 1989 and August 1993, 334 patients were enrolled in the study, with equal numbers of patients randomized to the neoadjuvant chemotherapy arm (CT arm) and the radiotherapy arm (RT arm). Neoadjuvant chemotherapy consisting of 2-3 cycles of cisplatin (60 mg/m2 on Day 1) and epirubicin (110 mg/m2 on Day 1) followed by radiotherapy was given to the CT arm. For radiotherapy, a dose of 66-74 gray (Gy) (median, 71 Gy) was delivered to the primary tumor and 60-76 Gy (median, 66 Gy) to the neck. Two hundred eighty-six eligible patients completed the treatment and were evaluable for treatment response (134 in the CT arm, 152 in the RT arm). All patients were included in the survival analysis based on the intention to treat. The median follow-up was 30 months for the whole cohort and 41 months for the surviving patients. RESULTS: Analysis of the 334 patients based on the intention to treat showed no significant difference in relapse free survival (RFS) or overall survival (OS) between the 2 treatment arms (3-year RFS rate: 48% in the CT arm vs. 42% in the RT arm, P = 0.45; 3-year OS rate: 78% vs. 71%, P = 0.57). In an efficacy analysis based on only the 286 evaluable patients, a trend of improved RFS favoring the CT arm was observed (3-year RFS rate: 58% vs. 46%, P = 0.053), with again no significant difference in OS (3-year OS rate: 80% vs. 72%, P = 0.21). In the subgroup of 49 patients with bulky neck lymph nodes >6 cm, improved RFS (3-year RFS rate: 63% vs. 28%, P = 0.026) and OS (3-year OS rate: 73% vs. 37%, P = 0.057) were observed, favoring the CT arm. CONCLUSIONS: This multicenter randomized study did not demonstrate any benefit with the addition of cisplatin-epirubicin neoadjuvant chemotherapy for patients with locoregionally advanced nasopharyngeal carcinoma; therefore routine administration of neoadjuvant chemotherapy to this target group cannot be recommended. Although the overall incidence of recurrence was reduced with the addition of chemotherapy in the efficacy analysis, the overall survival was not affected. A more effective chemotherapy regimen, the selection of an appropriate target group, and the use of an alternative strategy for combining chemoradiotherapy should be explored in future trials.     

The MACOP-B and VACOP-B combination chemotherapy for young patients with intermediate-grade non-Hodgkin's lymphoma

Since the early 1970s, three generations of combination chemotherapy for intermediate-grade non-Hodgkin's lymphomas (NHL) have been developed. One of the third-generation regimens is MACOP-B (methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin). The VACOP-B regimen is a modification of MACOP-B in which methotrexate is omitted and etoposide is added. This study assesses treatment outcome using the MACOP-B and VACOP-B combination chemotherapy in a population of young patients with intermediate-grade NHL treated in a single tertiary hematological center. The files of 45 patients aged 18-55 who were diagnosed as having intermediate-grade NHL (working formulation types F-H) and treated between January 1986 and March 1994 were reviewed. Treatment response, overall survival, disease-free survival and treatment toxicity were determined. The predictive value of the age-adjusted international prognostic index was also assessed. Median follow-up was 80 months in the MACOP-B group and 29 months in the VACOP-B group. The complete response rate was 71% (95% confidence interval CI: 58-84), 4-year overall survival was 74 +/- 7% and 4-year disease-free survival was 79 +/- 8%. No toxicity-related deaths were observed. The main adverse effects were WHO grade 3 or 4 neutropenia (51%), anemia (24%) and mucositis (20%). Only the CR rate was correlated with the Age-Adjusted International Prognostic Index. Mean relative dose intensity was high (95.7%, 95%) CI: 91.7-99.7) and had no correlation with treatment outcome. The MACOP-B and VACOP-B combination chemotherapy regimens were found to be effective and minimally toxic for young patients up to 55 years old with intermediate-grade NHL.     

Characterization of anticapsular monoclonal antibodies that regulate activation of the complement system by the Cryptococcus neoformans capsule

PURPOSE: To evaluate the effectiveness of adding interferon (IFN) alfa-2b to chemotherapy in the induction treatment of low-grade non-Hodgkin's lymphoma (NHL), and to assess the role of maintenance IFN. PATIENTS AND METHODS: A multicenter, two-phase controlled trial with double randomization was conducted in 155 patients with low-grade NHL. In the first randomization, 78 patients received cyclophosphamide, vincristine, and prednisone (CVP) and IFN, 3 MU/m2 three times a week for 3 months, and 77 patients received CVP alone. Responding patients were randomized to receive IFN for 1 year versus observation. RESULTS: Of 144 assessable patients, 73 received CVP + IFN and 71 received CVP. Responses were similar: CVP + IFN 79% versus CVP 76% (P = .62). The number of patients who did not complete the treatment was higher in the CVP + IFN group than in the CVP group (18% v 4%; P = .009), although the received dose-intensity of chemotherapy was comparable. Duration of response and progression-free survival (PFS) were significantly higher in the CVP + IFN group than in the CVP group (P = .0004). However, we observed no differences in overall survival (OS) (P = .30), with a median follow-up for the surviving patients of 3 years. Grade 3/4 granulocytopenia was the most frequent toxicity and was similar in both groups (33% v32%). Eighty-three (74%) of the 112 responding patients were randomized to maintenance IFN or observation. The duration of response was similar between 42 patients that received IFN compared with 41 control patients (P = .83), independently of treatment previously administered. CONCLUSION: Adding IFN alfa-2b to induction CVP in low-grade NHL did not induce a higher response rate, but it significantly increased the duration of the responses. We found significant differences in PFS that favored the patients who received CVP + IFN, but not in OS. To date, no additional benefit has been seen from the administration of IFN for maintenance.     

A phase II multicenter trial of high-dose sequential chemotherapy and peripheral blood stem cell transplantation as initial therapy for patients with high-risk non-Hodgkin's lymphoma

The purpose of this study was to evaluate the safety and feasibility of front-line high-dose sequential (HDS) chemotherapy with peripheral blood stem cell (PBSC) transplantation in patients with newly diagnosed high-risk non-Hodgkin's lymphoma (NHL). Thirty-two patients with high-risk NHL (defined by the age-adjusted international index) underwent HDS chemotherapy followed by PBSC transplantation and consolidative radiotherapy. Twenty-eight patients (88%) had intermediate/high grade NHL and four patients (12%) had small noncleaved or lymphoblastic lymphoma. Twenty-four patients were classified as high-intermediate-risk (two risk factors) and eight patients were classified as high-risk (three risk factors). The five phases of HDS (see Fig. 1) consisted of Phase I (adriamycin, vincristine, and prednisone); Phase II (cyclophosphamide, filgrastim [G-CSF], and PBSC harvest); Phase III (methotrexate, leucovorin, vincristine; Phase IV (etoposide, filgrastim [G-CSF]); and Phase V (mitoxantrone, melphalan, autologous peripheral blood stem cell infusion, and filgrastim [G-CSF]). Radiation therapy was given to sites of previous bulk disease, 2400 cGy, (D + 30-100)]. Toxicity, engraftment, hospital utilization, overall survival, and relapse-free survival were evaluated. The high-dose sequential chemotherapeutic regimen was well tolerated. Treatment-related mortality was 6.25% with two deaths occurring secondary to sepsis and one death was caused by progressive disease. The major toxicity in Phase I-IV was grade 3 nausea/vomiting. The major toxicity in Phase V was grade 3 or 4 nausea/vomiting and mucositis. The median follow-up is 18.8 months (range 4-44 months). The overall survival (OS) and relapse-free survival (RFS) at 18 months for all patients were 78% (95% CI 37-90%) and 67% (95% CI 46-88%), respectively. The OS at 18 months for all patients, excluding the four patients with either small noncleaved or lymphoblastic lymphoma, was 82% (95% CI 65-98%) vs. 30% (95% CI 0-86%) (p = 0.0059). One patient in this latter group remains alive at 6 months follow-up. The RFS for all patients, excluding the four patients with either small noncleaved or lymphoblastic lymphoma, was 78% (95% CI 58-97%) vs. 0% (95% CI 0-0%) (p = 0.0004). High-dose sequential chemotherapy with initial PBSC transplantation is well tolerated and appears effective in high-risk NHL. Superior results were noted in patients with intermediate grade versus those with small noncleaved or lymphoblastic NHL.     

Prognostic significance of Bcl-2 protein expression and Bcl-2 gene rearrangement in diffuse aggressive non-Hodgkin's lymphoma

The prognostic significance of Bcl-2 protein expression and bcl-2 gene rearrangement in diffuse large cell lymphomas (DLCL) is controversial. Bcl-2 protein expression prevents apoptosis and may have an important role in clinical drug resistance. The presence of a bcl-2 gene rearrangement in de novo DLCL suggests a possible follicle center cell origin and perhaps a distinct clinical behavior more akin to low-grade non-Hodgkin's lymphoma (NHL). The purpose of this study was to determine the impact of Bcl-2 protein expression and bcl-2 gene rearrangement (mbr and mcr) on survival of a cohort of patients with DLCL who were uniformly evaluated and treated with effective chemotherapy. Patients included the original MACOP-B cohort (n = 121) and the initial 18 patients treated with the VACOP-B regimen (total = 139). All patients had advanced-stage disease, were 16 to 70 years old, and corresponded to Working Formulation categories F, G, or H. No patients had prior treatment, discordant lymphoma, or human immunodeficiency virus seropositivity. Paraffin sections from diagnostic biopsies were analyzed for bcl-2 gene rearrangement including mbr and mcr breakpoints by polymerase chain reaction and Bcl-2 protein expression by immunohistochemistry. With a median follow-up of 81 months, overall (OS), disease-free (DFS), and relapse-free survival (RFS) were measured to determine the prognostic significance of these parameters. Analyzable DNA was present in 118 of 139 (85%) cases, with 14 demonstrating a bcl-2 rearrangement (11 mbr, 3 mcr). All 14 of these bcl-2 gene rearrangement-positive cases were found in the 102 patients with a B-cell immunophenotype, but the presence of this rearrangement had no significant influence on survival. Bcl-2 protein expression was interpretable in 116 of 139 (83%) cases, with immunopositivity detected in 54 of 116 (47%). Using a cut-off of greater than 10% Bcl-2 immunopositive tumor cells for analysis, positive Bcl-2 protein expression was seen in 28 of 116 (24%) patients and the presence of this expression correlated with decreased 8-year OS (34% v 60%, P < .01), DFS (32% v 66%, P < .001), and RFS (25% v 59%, P < .001). Bcl-2 protein expression remained significant in multivariate analysis that included the clinical international prognostic index factors and immunophenotype (P < .02). In conclusion, although bcl-2 gene rearrangement status could not be shown to have an impact on outcome, Bcl-2 protein expression is a strong significant predictor of OS, DFS, and RFS in DLCLs.     

Surgery in the management of small cell lung cancer

OBJECTIVE: We analyzed our experience in the period January 1975-December 1995 aiming to confirm the role of surgery in the multimodality treatment of small cell lung cancer (SCLC). METHODS: 127 patients (5.28% of the overall lung resections for carcinoma) underwent surgery for SCLC. The median age was 60 years (range 34-73). In 87 patients (68.5%) a pre-operative tissue diagnosis was effected and those patients underwent a complete staging procedure. Fifteen patients received up to six complete courses of neoadjuvant and adjuvant chemotherapy. The surgical procedures included: 50 pneumonectomies, 71 lobectomies and six wedge resections. Two patients experienced a local recurrence and a completion pneumonectomy was performed. RESULTS: The median follow-up is 66 months (range 6-214). The 5-year actuarial survival rate is 22.6% (median 18 months). Twenty-three patients are still alive, 21 of them being disease-free. Considering the most conspicuous group of patients (n = 92) treated by surgery and adjuvant chemotherapy, the survival data were 47.2, 14.8 and 14.4% for Stage I, II and III, respectively (P = 0.001). NO patients had a significantly better survival than N1 and N2 patients (P = 0.035). CONCLUSIONS: Surgery and adjuvant chemotherapy might represent an effective form of treatment of limited SCLC without lymph-node involvement. The role of surgery is yet to be verified as regards N1 and N2 status, where even neoadjuvant chemotherapy has not achieved the hoped-for results (no patient reaching a 2-year survival).     

Soft tissue sarcomas: preoperative versus postoperative radiotherapy

External beam radiation may be given either before or after excision of a primary soft tissue sarcoma. This study was undertaken to determine whether or not the timing of radiotherapy was associated with any difference in either local control, survival, or incidence of complications. The files of 112 patients with a primary, nonmetastatic, extremity soft tissue sarcoma, treated with limb salvage surgery and irradiation were evaluated. Data regarding tumor stage, grade, site, surgical margin, dosage and timing of radiotherapy, treatment complications, disease relapse, and relapse-free survival (RFS) were analyzed. Kaplan-Meier lifetable analysis was used to determine survival estimates. There was no significant difference in the 5-year RFS between patients receiving radiotherapy (RT) preoperatively versus postoperatively; 56 +/- 15% and 67 +/- 12% (P = 0.12, Mantel-Cox), respectively. There was no significant difference in the overall survival between patients receiving RT preoperatively versus postoperatively; 75 +/- 15% and 79 +/- 11% (P = 0.94), respectively. Actuarial local control at 5 years for preoperative versus postoperative RT patients was not statistically different; 83 +/- 12% versus 91 +/- 8% (P = 0.41), respectively. Wound complications were more frequent in preoperative RT patients (31%) compared to postoperative RT patients (8%) (P = 0.0014, chi-square). Preoperative irradiation was not associated with any benefit in terms of relapse-free survival, overall survival or actuarial local control in this series. A higher incidence of major wound complications was found among patients treated with preoperative irradiation. We recommend that patients with a resectable extremity soft tissue sarcoma be treated with postoperative irradiation, reserving preoperative irradiation for those situations in which either the tumor is initially thought to be unresectable or the original tumor boundaries are obscured.     

Autologous stem cell transplantation (ASCT) for poor prognostic Hodgkin's disease (HD): comparative results with two CBV regimens and importance of disease status at transplant

Clinical outcome of 47 consecutive patients with advanced HD who underwent ASCT in our Department was analyzed retrospectively. Median age was 28 years (28 males and 19 females). At transplant, 15 (32%) patients were in CR (five in first CR after two chemotherapy regimens and 10 in second CR), eight (17%) in PR (seven without a prior CR), 22 (51%) had relapsing disease (19 with sensitive relapse) and two had primary refractory disease. The CVB regimen with two different schedules was used: 22 (47%) patients received standard CBV (CY 6 g/m2, BCNU 300 mg/m2 and etoposide 600 mg/m2) and 25 (53%) received an increased CBV dose (CY 7.2 g/m2, BCNU 440 mg/m2 and etoposide 2 g/m2). Antitumor response for 28 evaluable patients was similar for both CBV regimens: 87 and 75% (P=0.39). At 7.2 years, actuarial overall survival (OS), progression-free survival (PFS) and event-free survival (EFS) for the whole series were 51.7+/-8%, 34+/-9% and 28+/-8%, with a median follow-up for the surviving patients of 3 years (0.7-7.6). No differences in these survival functions according to the CBV regimen used were observed (P=0.57). A history of a prior CR (P=0.003), duration of first CR >1 year (P=0.04), absence of bulky nodal disease at transplant (P=0.054), absence of extranodal disease at transplant (P=0.01), and a CR status at transplant (P=0.0006) were associated with a better PFS on univariant analysis. On multivariate analysis, only CR status at transplant remained significant (P=0.05). When patients in second CR at transplant and those in first sensitive relapse were analyzed separately, no differences in clinical characteristics or in treatment received pretransplant were observed; however, PFS was significantly different (P=0.01). In conclusion, CR status at transplant is useful in identifying 'good risk' patients and is necessary to obtain the greatest benefit from ASCT independent of the CBV regimen used.     

Treatment of localized non-Hodgkin's lymphomas of the head and neck

BACKGROUND: Localized non-Hodgkin's lymphomas of the head and neck are generally treated with radiotherapy with or without chemotherapy, although the results of treatment of localized non-Hodgkin's lymphomas with of treatment of localized non-Hodgkin's lymphomas with chemotherapy alone appear to be favorable. It is unclear if and when combined modality therapy should be used. METHODS: The authors reviewed the records of 53 patients with Stage I or II non-Hodgkin's lymphoma of the head and neck, who were treated with radiotherapy alone (13 patients), chemotherapy according to the cyclophosphamide, doxorubicin, vincristine, prednisone- (CHOP) regimen (27 patients), or a combination of both treatments (13 patients). RESULTS: A complete remission was achieved in 43 (81%) patients. The 5-year survival for all patients was 78%. A significant difference (P = 0.03) in 5-year relapse-free survival was observed between Stages I and II disease, of 92 and 60%, respectively. Extensive tumor was a significantly poor prognostic factor (P = 0.04) with a 5-year relapse-free survival of 52 versus 84% for patients with nonextensive lymphoma. Eight relapses occurred; in five patients, a local relapse was the first presentation. Although salvage radiotherapy was successful in these five patients, a distant relapse developed in three. No relapses were observed in previously irradiated areas. CONCLUSIONS: Our results suggest that radiotherapy alone is the appropriate treatment for nonextensive Stage I intermediate grade non-Hodgkin's lymphoma of the head and neck. For extensive Stage I or II non-Hodgkin's lymphomas, chemotherapy is preferable. The value of combined modality therapy remains unclear.     

DNA unwinding in the CYC1 and DED1 yeast promoters

The superiority of intensive versus standard chemotherapy for aggressive (I: intermediate; H: high grade) NHL is still debated; increased antitumor activity may be counterbalanced by increased toxicity. We have designed a first-line five-drug regimen (vincristine, idarubicin, cyclophosphamide, etoposide and deflazacort), with the aim of potentiating the CHOP protocol without losing tolerability and ease of administration. Seventy-one patients (33% aged > or = 65) entered the study. CR was obtained in 66.7% of patients (I: 74%; H: 56%), PR in 19.7%: overall response rate was 86.4%. Six patients were resistant, two died during treatment. With a median follow up of two years, relapse has occurred in 14 patients (8 I, 6 H). At 3 years, overall survival was projected to be 62.5% (I 73.5%; H 31.4%), disease free survival 66% (I 71%, H 56.3%). No organ toxicity occurred. Myelosuppression was moderate, with a nadir on the 14th day. Febrile episodes occurred in 16% of courses, dose delay in 19% of courses; dose reduction in 3% of patients. No patient required hospitalization. G-CSF was only occasionally used. This regimen has shown a potent antitumor effect with an excellent tolerance, even in elderly patients.     

Effect of radiologic stage III substage on nonsurgical therapy of non-small cell lung cancer

BACKGROUND: Patients with Stage III non-small cell lung cancer (NSCLC) whose cases are staged or treated surgically have different prognoses, depending on the substage (IIIa, IIIb). It is not known whether the prognostic differences apply to clinically staged nonsurgical cases. The authors wanted to determine whether radiologic Stage III substages, determined by computerized axial tomography (CT) scans, are prognostically important in these patients with NSCLC: In addition, they wanted to determine whether the observed superior survival of selected patients with Stage III NSCLC receiving chemotherapy in addition to radiation therapy (chemo-RT) (Cancer and Leukemia Group B protocol 8433: N Engl J Med 1990; 323:940-5) was influenced by an imbalance in the radiologic Stage III substage. METHODS: Review of pretreatment chest radiographs and CT scans with determination of TNM status and stage was done by the consensus of three readers, who were unaware of which treatment each patient had received (radiation therapy alone [RT] or chemo-RT). RESULTS: Patient characteristics in the two treatment arms were similar. Fifty-five percent of patients receiving RT had Stage IIIa and 33% Stage IIIb disease; in the chemo-RT treatment arm, 73% had Stage IIIa and 25% Stage IIIb disease (P = 0.11). Seven patients (12%) who received RT and one in the chemo-RT treatment arm (2%) had Stage I-II disease on CT scan. Patients with Stage IIIa disease had superior survival to those with Stage IIIb disease (median, 16.5 versus 10.5 months, respectively; P = 0.0045). Within each substage, survival was superior in the chemo-RT (versus RT) treatment arm (Stage IIIa, 17.2 versus 10.7 months, respectively; P = 0.16; Stage IIIb, 12.0 versus 6.9 months, respectively; P = 0.089). CONCLUSIONS: The survival advantage for selected patients with Stage III NSCLC treated with chemo-RT in this study did not result from a more favorable pretreatment radiologic Stage III substage. An advantage for induction chemotherapy was seen in patients with Stage IIIa and IIIb disease. Future studies in this population should prospectively assess and consider stratification for Stage III substage.     

A radioreceptor assay for mass measurement of inositol (1,4,5)-trisphosphate using saponin-permeabilized outdated human platelets

PURPOSE: To evaluate the therapeutic efficacy of moderate-dose total abdominopelvic irradiation (TAI) in a retrospective series of pretreated non-Hodgkin's lymphomas (NHL). METHODS AND MATERIALS: From 1977 to 1994, 45 patients received TAI after failure of chemotherapy (CT). According to the Working Formulation, 10 patients were diagnosed with class A (group I), 19 with class B, C, or D (follicular) (group II), and 16 with class E or more severe (group III) NHL. Irradiation consisted of two daily fractions of 0.80 Gy each for a total dose of 20 Gy. RESULTS: Mean follow-up after TAI was 102 months (range 8-156). For the entire group, the complete response (CR) rate was 66%, the partial response (PR) rate 29%, 10-year overall survival (OS) 35%, 10-year disease-free survival (DFS) 29%, and median survival 32 months. When results between subgroups were compared, CR was 70% in group I, 84% in group II, and 44% in group III; and survival was statistically higher in group II than in groups I and III: 10-year OS 52% vs. 10% (p < 0.01) and 31% (p < 0.05), respectively, 10-year DFS 37% vs. 10% (p < 0.03) and 19% (p < 0.05), respectively. Grade III or IV complications were gastrointestinal in 27% of patients and hematologic in 25%. CONCLUSION: Large-field irradiation in moderate doses could provide an alternative to bone marrow transplantation in refractory NHL, especially in cases showing a follicular growth pattern.     

Clinical significance of cyclin D1 expression in patients with node-positive breast carcinoma treated with adjuvant therapy

BACKGROUND: Experimental and clinical studies suggest that cyclin D1 is involved in transformation and tumour progression. However, there is little and contradictory data on the clinical significance of cyclin D1 in human invasive breast carcinoma. PATIENTS AND METHODS: We investigated whether the determination of cyclin D1 has prognostic value in a series of 180 patients with node-positive breast carcinoma and treated with adjuvant therapy with a median follow-up exceeding 6 years. We assessed cyclin D1 expression using the CDS-6 monoclonal antibody and a highly sensitive immunohistochemical technique. RESULTS: We found that most of the evaluable tumours (117 of 167; 70.1%) presented nuclear cyclin D1 staining and that its expression was significantly associated with both the hormone receptors (P = 0.009 and P = 0.005 for ER and PgR, respectively). Furthermore, 29 (17%) of 167 tumours had a weak (15 cases) or strong (9 cases) cytoplasmic cyclin D1 staining. In a subgroup of cases we also studied the amplification of the cyclin D1 gene and a moderate agreement between cyclin D1 nuclear overexpression assessed immunohistochemically and the gene amplification was found. In univariate analysis, cyclin D1 nuclear positivity was significantly associated with improved 6-year relapse-free survival (RFS) (P = 0.004), but not with overall survival (OS) (P = 0.12). The results of the Cox multivariate analysis (final model) indicate that cyclin D1 expression (P = 0.0049) as well as the number of involved nodes (P < 0.001) and tumour size (P = 0.036) are significant prognostic indicators for RFS. Only the number of involved nodes retained significance (P < 0.001) for OS in our series. The joint assessment of the variables considered in the final model of the multivariate analyses had a moderate prognostic capability as determined using the Harrell c statistic (c = 0.66 and 0.64 for RFS and OS, respectively). CONCLUSIONS: The patients with node-positive breast cancer who have a higher likelihood of gaining benefit from adjuvant therapy are those with tumours with cyclin D1 nuclear expression, small size and less than 3 metastatic nodes. Further studies are needed to verify the prognostic value of cyclin D1 in relation to different adjuvant treatments and to deepen the biological pathways that regulate its activation/ suppression in human breast carcinoma.     

A new technique for the distal locking of solid AO unreamed tibial nails

Forty patients with aggressive (intermediate-grade and high-grade) non-Hodgkin's lymphoma (NHL) were treated primarily with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy regimen, and then evaluated for prognostic features. Age, tumor stage, performance status, number of extranodal disease sites and serum concentrations of lactate dehydrogenase (LDH) were considered prognostic features. All the patients treated with the CHOP regimen were grouped into four risk categories, including low (L), low-intermediate (LI), high-intermediate (HI) and high (H) according to the International Prognostic Index. Twenty-one of 23 patients (91.3%) in the L plus LI risk groups and 5 of 17 patients (29.4%) in the H plus HI risk groups had complete response and the difference between these percentages was statistically significant (P<0.001). The overall survival rate (2 yr) of 23 patients in the L+LI risk group was 52.1% and of 17 patients in H+HI risk group was 11.7% and this difference was statistically significant (P<0.05). Our results indicated that the CHOP regimen is not effective in the HI+H risk groups of patients with aggressive NHL. New experimental approaches are needed for these patients.     

Low transplant mortality in allogeneic bone marrow transplantation for acute myeloid leukemia: a randomized study of low-dose cyclosporin versus low-dose cyclosporin and low-dose methotrexate

Sixty patients undergoing allogeneic bone marrow transplant for acute myeloid leukemia (AML) in first remission (CR1; n = 49) or more advanced phase (n = 11) were entered in a prospective trial of graft-versus-host disease (GvHD) prophylaxis: low-dose cyclosporin A (IdCSA; 1 mg/kg/d from day -1 to +20 day; n = 28) or IdCSA plus low-dose methotrexate (IdMTX; 10 mg/m2 for day +1, 8 mg/m2 for days +3, +6, and +11; n = 32). Primary end points were acute GvHD (aGvHD) and transplant-related mortality (TRM); secondary end points were relapse and survival. The conditioning regimen consisted of cyclophosphamide (120 mg/kg) and fractionated total body irradiation (3.3 Gy/d for 3 consecutive days). The actuarial risk of developing aGvHD grade II-III was 61% for IdCSA alone and 34% for IdCSA + IdMTX (P = .02). The actuarial risk of TRM at 1 year was 11% versus 13%, respectively, and older patients (>/= 29 years) had higher TRM than younger patients (22% v 5%, P = .01). The age effect was significant in the IdCSA group (P = .04) but not in the IdCSA + IdMTX group (P = .1). The median follow-up is 4.4 years, with an overall actuarial survival of 78% for CR1 patients and 36% for patients with advanced disease. For patients in CR1 the outcome of the two regimens was as follows: survival 77% versus 80% (P = .6), relapse 20% versus 9% (P = .1), and TRM 13% versus 17% (P = .6). This study suggests that TRM can be reduced in AML patients undergoing allogeneic marrow transplants with a mild conditioning regimen and low-dose immunosuppression, and this translates in a 78% 5-year survival for CR1 patients. Beyond CR1 the major obstacle remains leukemia relapse, which is not prevented by low-dose in vivo immunosuppression.     

Non-Hodgkin's lymphoma of the thyroid: a retrospective review of all patients diagnosed in Nottinghamshire from 1973 to 1992

The pathological and clinical features were reviewed of all primary non-Hodgkin's lymphomas (NHL) of the thyroid gland diagnosed between 1973 and 1992 in the population (1.1 million) served by the Nottingham and North Nottinghamshire Health Authorities. Of the 43 patients with histologically proven NHL, three had low grade mucosa associated lymphoid tissue (MALT) lymphomas (Stage IEA, 2; Stage IIEA, 1), 35 had intermediate or high grade lymphomas, Stage IEA or IIEA (intermediate MALT, 2; high grade MALT, 14; B-cell diffuse centroblastic, 17; anaplastic large cell (Ki-1) of null cell type, 1; high grade unclassifiable, 1), and one had unclassifiable NHL Stage IIEA. One patient had Stage IIIEA disease (high grade MALT) and three had stage IVA disease (high grade MALT, 2; B-cell diffuse centroblastic, 1). The median age was 68 years (range 45-86) with a female: male ratio of 6:1. For the 35 patients with intermediate or high grade thyroid NHL (Stages IEA and IIEA) the 5- and 10-year cause specific survival was 60%. The 21 patients treated between 1985 and 1992 initially with chemotherapy (except stage IEA (< 5 cm diameter) had a 5-year cause specific survival of 69% (95% CI 48-90) compared with 46% (95% CI 19-73) for the 14 patients treated between 1973 and 1984 with initial radiotherapy (Chi 2 = 1.62). The survival of those patients with intermediate or high grade MALT lymphomas was not significantly greater than of those patients with B-cell diffuse centroblastic NHL.     

Tumor microvessel density, p53 expression, tumor size, and peritumoral lymphatic vessel invasion are relevant prognostic markers in node-negative breast carcinoma

PURPOSE: To determine the absolute and relative value of microvessel density (MVD), p53 and c-erbB-2 protein expression, peritumoral lymphatic vessel invasion (PLVI), and conventional prognosticators in predicting relapse-free (RFS) and overall survival (OS) rates in patients with node-negative breast carcinoma (NNBC). PATIENTS AND METHODS: We monitored 254 consecutive patients with NNBC for a median of 62 months. Intratumoral MVD was measured after microvessels were immunostained using anti-CD31 antibody. p53 and c-erbB-2 protein and hormone receptors were also determined immunocytochemically. Results were analyzed by both univariate and multivariate statistical analysis. RESULTS: Univariate analysis showed that MVD was significantly predictive of both RFS (odds ratio [OR], 8.30; P = .0001) and OS (OR, 4.50; P = .012) when tested as a continuous or dichotomous variable. Likewise, tumor size (OR, 3.16; P = .0012), PLVI (OR, 4.36; P = .0009), estrogen receptor (ER) status (OR, 2.35; P = .016), progesterone receptor (PR) status (OR, 2.00; P = .017), and expression of p53 protein (OR, 2.82; P = .004) were significantly associated with RFS. Tumor size (OR, 3.80; P = .0038) and expression of p53 protein (OR, 2.58; P = .024) were significantly associated with OS by univariate analysis. Multivariate analysis showed that MVD (P = .0004), p53 protein expression (P = .0063), tumor size (P = .0144), and PLVI (P = .0033) were all significant and independent prognostic factors for RFS. However, only tumor size (P = .004) and MVD (P = .047) were independent predictors for OS. c-erbB2 expression was not associated with outcome by either univariate or multivariate analysis. CONCLUSION: MVD, p53 expression, PLVI, and tumor size are independent prognostic indicators of recurrence, which are useful in selection of high-risk NNBC patients who may be eligible to receive adjuvant therapies.     

The National Cancer Data Base report on non-Hodgkin's lymphoma

BACKGROUND: The National Cancer Data Base (NCDB) has reported on many malignancies occurring in men and women in the U. S. from >1400 contributing hospitals. The current report on non-Hodgkin's lymphoma (NHL) is a companion to an upcoming Patient Care Evaluation study of this relatively common and serious cancer. METHODS: This report is comprised of all NHL cases submitted to the NCDB divided into two diagnostic-year groups: 1985-1988 and 1990-1993. Variables routinely collected by hospital cancer registries have been analyzed to report on patterns of diagnosis and treatment. RESULTS: High grade NHL cases were more likely to be Stage IV (40.8%) than were low or intermediate grade cases (34.8% and 32.5%, respectively). Patients with NHL arising from lymph node sites tended to present with more advanced disease (55.8% with Stages III and IV disease), whereas patients with NHL arising from extranodal sites and non-lymph node nodal sites presented at an earlier stage (64.7% and 74.0%, respectively, with Stage I or Stage II disease). Approximately 67% of all patients underwent chemotherapy, whereas only 25% underwent surgery or radiation. By histology, 5-year survival was 68.8% for low grade disease, 51.9% for intermediate grade disease, and 45.8% for high grade disease; by stage, survival rates ranged from 73.5% for Stage I to 42.9% for Stage IV disease. CONCLUSIONS: To the authors' knowledge, the 91,306 cases in this study represent the largest contemporary sample of NHL patients. The material reported here may serve as a reference with which to compare local patterns with national data. The Working Formulation's ability to stratify patients' survival rates confirms its utility for NHL. Stage according to the American Joint Committee on Cancer also was accurate in predicting survival.