F. Gherlinzoni

Histologic evaluation of necrosis in osteosarcoma induced by chemotherapy regional mapping of viable and nonviable tumor

The predominant sites of viable and nonviable tumor were determined in the primary lesions of 50 patients with osteosarcoma after initial treatment with preoperative chemotherapy. The degree of tumor destruction was classified as good, fair, and poor and a map of the sites revealing viable and nonviable tumor was constructed. The study revealed several preferential sites where viable tumor was likely to persist: soft tissues, cortex, subcortex, ligaments, and areas in contact with cartilage (growth plate and/or articular cartilage). Localized areas of hemorrhage and necrosis, designated “lacunae,” were noted within the tumor. They were frequently surrounded by bundles of viable tumor and appeared to correlate with open surgical biopsies. Factors responsible for this phenomenon and the persistence of viable tumor are discussed. The findings have important implications in the design of surgical treatment and in the use of needle biopsies to determine the effects of preoperative treatment. Cancer 56: 1515‐1521, 1985.

Primary chemotherapy and delayed surgery (neoadjuvant chemotherapy) for osteosarcoma of the extremities the istituto rizzoli experience in 127 patients treated preoperatively with intravenous methotrexate (high versus moderate doses) and intraarterial cisplatin

Between March 1983 and June 1986 127 patients with localized osteosarcoma of the extremity were treated with neoadjuvant chemotherapy. Preoperative chemotherapy consisted of two cycles of methotrexate (MTX) (high or moderate doses) followed by 6 days by cisplatin (CDP). Surgery was an amputation or a rotation plasty, or a limb salvage. Necrosis was good in 52% of cases, fair in 36%, and poor in 12%. Postoperative chemotherapy consisted of Adriamycin (doxorubicin [ADM]) and bleomycin (BCD) for poor responders; and ADM, MTX, and CDP for fair responders. Good responders were treated as fair responders or with only MTX and CDP. At a 47‐month follow‐up, 66 patients remained continuously disease free and 61 patients developed metastases. Six of these patients had also a local recurrence. According to the grade of necrosis, the cumulative disease‐free probability at 5 years was 67% for good responders, 42% for fair responders, and for poor responders 10% at 45 months. According to the doses of MTX, survival at 5 years was 58% for patients who received high doses and 42% for patients treated with moderate doses. No differences in the rate of survivors were observed between amputated patients and patients treated with limb salvage. The authors conclude that (1) a limb salvage procedure is possible in about 70% of cases and as safe as demolitive surgery, if adequate surgical margins are achieved; (2) good responders have a better prognosis than fair and poor responders if postoperative chemotherapy is sufficiently prolonged and also includes ADM; (3) a different postoperative chemotherapy for poor responders did not improve their prognosis; and (4) a multidrug regimen using high doses of MTX is probably more effective than moderate doses.

The role of positron emission tomography (PET) in the management of lymphoma patients

BACKGROUND Treatment of both Hodgkins disease (HD) and aggressive non-Hodgkins lymphoma (NHL) with abdominal presentation at the time of diagnosis is often followed by detection of residual masses by computed tomography (CT). However, CT is usually unable to discriminate between residual tumor and fibrosis/necrosis. We investigated the ability of fluorine-18 fluorodeoxyglucose positron emission tomography (PET) to differentiate between residual active tumor tissue and fibrosis. PATIENTS AND METHODS Forty-four patients with HD or aggressive NHL presenting abdominal involvement (41% with bulky mass) were studied with CT and PET at the end of chemotherapy +/- radiation therapy. RESULTS After treatment, seven patients had negative PET and CT, and none of them relapsed. The remaining 37 patients all had positive CT (abnormalities < or = 10%). All of the 13 who also had positive PET relapsed (100%). By contrast, there was only 1 (4%) relapse among the 24 patients who were positive at CT but negative at PET. The two-year actuarial relapse-free survival rate was 95% for those with negative PET compared with 0% for positive PET patients (P < 0.000000). CONCLUSIONS In lymphoma patients with abdominal masses who present CT positivity at restaging, PET should be considered the noninvasive imaging modality of choice for differentiating early recurrences or residual disease from fibrosis.

Ifosfamide in the adjuvant therapy of soft tissue sarcomas

Ifosfamide and anthracyclines are the only active agents in advanced soft tissue sarcomas. Doxorubicin was always used in sarcomas, whereas ifosfamide was reintroduced in the clinic after the discovery of mesna which prevents its typical dose-limiting toxicity: hemorrhagic cystitis. In the adjuvant setting, doxorubicin was used alone or in combination in the first-generation trials, whereas its parent compounds epirubicin and ifosfamide were employed in the second-generation adjuvant trials, which started in the early 90s. Other relevant aspects of the second-generation trials are the use of the hematopoietic growth factors and the increase of the dose intensity, the introduction of more restrictive selection criteria and the use of the two most active agents, ifosfamide and anthracyclines. Only the Italian cooperative trial has been concluded, and the results reported and updated. After a median follow-up of 89.6 months (range 56–119), the intention-to-treat analysis still reveals a difference in overall survival which, however, is not statistically significant. However, the 5-year overall survival estimate, which is a reasonable end point for the survival analysis of adjuvant treatment in soft tissue sarcomas, was 66.0 and 46.1% for the treatment and the control groups, respectively (p = 0.04).

A randomized trial for the treatment of high-grade soft-tissue sarcomas of the extremities: preliminary observations.

A new trial for evaluating the effectiveness of adjuvant chemotherapy in high-grade soft-tissue sarcomas of the extremities in adult patients is presented. All patients after local treatment were randomized into two arms, one without further therapy and the other to receive adjuvant chemotherapy (Adriamycin [Farmitalia-Carlo Erba, Milan, Italy], 450 mg/m2). The preliminary results of the study are reported at a median observation period of 27.6 months. Of the 59 patients who entered the study, 79.1% in the chemotherapy group are without sign of disease, whereas the corresponding figure in the nonadjuvant chemotherapy group is 54.3%. The difference between the two groups is statistically significant (P less than .005, log rank test). These preliminary observations encourage continuation of the study.

Anaplastic large-cell lymphoma: clinical and prognostic evaluation of 90 adult patients.

PURPOSE During the last few years, the application of CD30 monoclonal antibodies has led to the identification of a new lymphoma entity, termed anaplastic large cell lymphoma (ALCL). This tumor includes four distinct histologic subtypes, among which the Hodgkins-like/Hodgkins-related one (ALCL-HL) shares morphologic and phenotypic features with Hodgkins disease (HD). PATIENTS AND METHODS From September 1988 to October 1993, 90 ALCL patients were treated with third-generation chemotherapy regimens (either vincristine, cyclophosphamide, fluorouracil, cytarabine, doxorubicin, methotrexate with leucovorin, and prednisone [F-MACHOP] or methotrexate with leucovorin, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin [MACOP-B]) during the course of an Italian multicentric randomized trial on high-grade non-Hodgkins lymphomas (HG-NHL). In particular, 47 patients had ALCL of the common type (ALCL-CT) and 43 ALCL-HL. Null phenotype was the most common (39.8%), while T-cell, B-cell, and hybrid forms accounted for 35.5%, 22.2%, and 2.5%, respectively. RESULTS Complete remission (CR) was achieved in 66 of 90 (73.5%) patients (33 of 47 [70%] with ALCL-CT and 33 of 43 [77%] with ALCL-HL). The majority of the patients in CR (56.5%) were alive and well at a median follow-up time of 38 months; no significant differences were observed between the two histologic groups, with the rate of complete responders being 49% and 65% in ALCL-CT and ALCL-HL, respectively. The probability of relapse-free survival (RFS), projected at 63 months, was 67% for ALCL-CT and 82% for ALCL-HL. The risk of lower CR and RFS rates was associated with the presence of bulky disease, advanced stage, and B symptoms. CONCLUSION The data of the present study confirm that ALCL responds to third-generation chemotherapy regimens similarly to other aggressive malignant lymphomas in terms of both CR and RFS rates.

Immunohistochemical detection of the multidrug transport protein P170 in human normal tissues and malignant lymphomas

Two monoclonal antibodies, MRK16 and C219, both directed at the 170 kDa P‐glycoprotein multidrug resistance agent, were applied to frozen sections or cytospin preparations from normal human tissues and 60 non‐Hodgkins malignant lymphomas. Adrenal gland, kidney, liver and pancreas were always stained by the reagents, albeit with slightly different patterns. Brain capillaries as well as macrophages and some elements of the bone marrow, peripheral blood, ovarian stroma and colonic, gastric and jejunal mucosa were positive in all examined preparations. There were differences in the staining patterns with the two antibodies. Among the 60 non‐Hodgkins lymphomas, 25 contained a number of positive cells, which ranged from 2% to 100%. No correlation was seen between the expression of P1 70 and histological type, stage, clinical symptoms or growth fraction. A close relationship was shown between the presence of P1 70 positive elements and the clinical course of the disease (P<0.001).

Isolated Central Nervous System Relapse in Aggressive Non-Hodgkin's Lymphoma: the Bologna Experience

Isolated central nervous system (CNS) relapse was evaluated in terms of incidence, risk factors, and outcome in a consecutive cohort of 175 patients with aggressive non-Hodgkins lymphoma in which no case of lymphoblastic or Burkitts lymphoma was encountered. All these patients had obtained a complete remission with first-line treatment and none had received prophylactic CNS treatment at diagnosis. Nine patients (5.2%) developed isolated CNS relapse after a median of 8 months from diagnosis. CNS involvement was documented by cerebrospinal fluid (CSF) cytology in 4 patients and on the basis of radiologic and clinical features in 5 others. Factors significantly associated with a greater likelihood of CNS relapse were advanced stage, B symptoms, bone marrow involvement, and high LDH levels in univariate analysis with only advanced stage being of significance in multivariate analysis. All relapsed CNS lymphoma patients died within a median time of 4 months from the disease recurrence, confirming the poor prognosis after CNS relapse and stressing the need to develop new treatment strategies for patients at high risk of CNS recurrence.

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

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

Localized Ewing's sarcoma of bone: ten years' experience at the Istituto Ortopedico Rizzoli in 124 cases treated with multimodal therapy.

The results obtained in the treatment by multimodal therapy (surgery, radiation therapy and chemotherapy) of 124 cases of Ewings sarcoma are presented. At a medium follow-up of 65 months 48% of the patients are disease-free. One patient died of leukemia and two patients developed an irradiation-induced sarcoma. Analysing the data, three factors seem to be correlated to prognosis: location of the initial lesion outside the pelvis and sacrum, a four-drug chemotherapy protocol and the use of surgery in the treatment of the initial lesion seem to give better results.