A novel zinc finger gene is fused to EWS in small round cell tumor.

Ewing sarcoma family of tumors share recurrent translocations that fuse EWS from 22q12 to five different members of transcription factors namely FLI-1, ERG, ETV1, E1AF and FEV. Different classes of DNA binding proteins, ATF1, WT1 and CHOP are fused to EWS generating distinct tumor phenotypes: clear cell sarcoma, desmoplastic small round cell tumor, and myxoid liposarcoma, respectively. We have cloned a novel gene located at 22q12 fused to EWS by a submicroscopic inversion of 22q in a small round cell sarcoma showing a translocation (t(1;22)(p36.1;q12). The gene, designated ZSG (Zinc finger Sarcoma Gene), is a putative Cys2-His2 zinc finger protein which contains a POZ transcriptional repressor-like domain at the N-terminus. The rearrangement involves intron 8 of EWS and exon 1 of ZSG creating a chimeric sequence containing the transactivation domain of EWS fused to zinc finger domain of ZSG. This product lacks the transcriptional repressor domain at the N-terminus of ZSG. A rearrangement of the second ZSG allele was also found in tumor cells. This is the first example of an intra-chromosomal rearrangement of chromosome 22, undetectable by cytogenetics, activating EWS in soft tissue sarcoma.

The contribution of salvage surgery to the management of childhood osteosarcoma.

Between January 1970 and December 1988, 174 consecutive patients under the age of 20 years with curatively resected primary osteosarcoma were treated at our institute; 72 in the years of 1970 to 1981 and 102 in the years 1982 to 1988. In the latter period, adjuvant chemotherapy was replaced by neoadjuvant programs, and new criteria were adopted for the management of lung metastases, consisting in early bilateral surgical staging and lung resection through median sternotomy for all patients with purely intrathoracic relapse. Follow-up was updated in December 1989. During the last period, the overall 5-year survival improved significantly from 35% to 58% (P less than .001). The disease-free survival rose from 38% to 45% at 5 years, with median values of 15 months versus 33 months, while the frequency of isolated lung metastases dropped from 58% to the actuarial 48%. The proportion of patients who underwent complete resections of their pulmonary metastases rose from 17% (seven of 42) to 55% (27 of 49), without operative mortality. Due to such a high proportion of patients eligible for salvage surgery, the overall survival from detection of lung metastases improved from 0% to 28% at 5 years (P less than .001). Contralateral occult metastases were resected in three of 15 subjects with monolateral clinical lesions, and five patients underwent subsequent lung resections. These data indicate that systematic bilateral pulmonary resection plays an important role in improving the final cure rate of childhood osteosarcoma, beyond the benefit resulting from neoadjuvant chemotherapy.

Adjuvant chemotherapy for adult soft tissue sarcomas of the extremities and girdles: results of the Italian randomized cooperative trial.

PURPOSE: Adjuvant chemotherapy for soft tissue sarcoma is controversial because previous trials reported conflicting results. The present study was designed with restricted selection criteria and high dose-intensities of the two most active chemotherapeutic agents. PATIENTS AND METHODS: Patients between 18 and 65 years of age with grade 3 to 4 spindle-cell sarcomas (primary diameter > or = 5 cm or any size recurrent tumor) in extremities or girdles were eligible. Stratification was by primary versus recurrent tumors and by tumor diameter greater than or equal to 10 cm versus less than 10 cm. One hundred four patients were randomized, 51 to the control group and 53 to the treatment group (five cycles of 4'-epidoxorubicin 60 mg/m(2) days 1 and 2 and ifosfamide 1.8 g/m(2) days 1 through 5, with hydration, mesna, and granulocyte colony-stimulating factor). RESULTS: After a median follow-up of 59 months, 60 patients had relapsed and 48 died (28 and 20 in the treatment arm and 32 and 28 in the control arm, respectively). The median disease-free survival (DFS) was 48 months in the treatment group and 16 months in the control group (P =.04); and the median overall survival (OS) was 75 months for treated and 46 months for untreated patients (P =.03). For OS, the absolute benefit deriving from chemotherapy was 13% at 2 years and increased to 19% at 4 years (P =.04). CONCLUSION: Intensified adjuvant chemotherapy had a positive impact on the DFS and OS of patients with high-risk extremity soft tissue sarcomas at a median follow-up of 59 months. Therefore, our data favor an intensified treatment in similar cases. Although cure is still difficult to achieve, a significant delay in death is worthwhile, also considering the short duration of treatment and the absence of toxic deaths.

Surgery in soft tissue sarcomas.

The surgical treatment of soft tissue sarcomas improved in the last decade, with better regional control and an increased number of limb sparing operations, but procedures and criteria of indication are not unified. Moreover, a great discrepancy exists in the incidence rate of local recurrence reported in literature, and also major centres denounce a high rate of local failures. The major predictive parameters of adequate regional control are the size and location of primary lesion, the pathological grading, previous treatments and the quality of surgical margins. Results in terms of regional control of 417 cases treated at our institute in the period 1974-1984 are analysed and discussed. Local failure occurred in 113 cases (27% crude, 31% actuarial risk at 5 years) and has been analysed according to factors which had impact on local failures: pathological grading (low grade 24% local recurrence vs. high grade 35% recurrence, P = 0.05), site (extremity and girdle 26% vs. trunk and head and neck 47%, P = 0.001), previous surgical treatment (32% for lesions recurrent at entry vs. 43% for virgin tumours, P = 0.05), quality of margins (adequate surgery 24% vs. marginal surgery 47%, P < 0.001); intralesional operations are excluded from this series. Histopathology is stratified in four categories that can actually influence the treatment schedule: low grade, spindle cell type high grade, small blue cell, miscellaneous sarcomas of different or unclear histogenesis. The size is detailed in different definitions of small or large, in a site-size relationship which may be useful in surgical practice, with no prognostic purposes. Finally, the adequacy of a surgical treatment is evaluated and discussed by the quality of surgical margins, defined according to the concept of compartment. A surgical indication rationale is, therefore, proposed taking into account the above-mentioned parameters and conclusive points of discussion.

A randomised phase II study on neo-adjuvant chemotherapy for 'high-risk' adult soft-tissue sarcoma.

The aim of this study was to examine the strategy, feasibility and outcome of neo-adjuvant chemotherapy, with doxorubicin and ifosfamide, in adult patients with 'high-risk' soft-tissue sarcomas. Patients with 'high-risk' soft-tissue sarcomas, defined as tumours > or =8 cm of any grade, or grade II/III tumours <8 cm, or grade II/III locally recurrent tumours, or grade II/III tumours with inadequate surgery performed in the previous 6 weeks and therefore requiring further surgery, were randomised between either surgery alone or three cycles of 3-weekly doxorubicin 50 mg/m(2) intravenous (i.v.) bolus and ifosfamide 5 g/m(2) (24 h infusion) before surgery. The type of surgery had to be planned at randomisation. Tumours were to be amenable to surgery by amputation, compartmental resection, wide or marginal excision. If chemotherapy was given, surgery had to be performed within 21 days after the last chemotherapy. Patients received postoperative radiotherapy in cases of marginal surgery, microscopically incomplete resection and no further possibility for surgery, and in cases of surgery because of local recurrence. 150 patients were entered into the study and 134 were eligible, 67 in each arm. The most frequent side-effects of chemotherapy were alopecia, nausea and vomiting (95%), and leucocytopenia (32%). One patient died of neutropenic fever after the first cycle of chemotherapy. Chemotherapy did not interfere with planned surgery and did not affect postoperative wound healing. Limb-salvage was achieved in 88%, amputation was necessary in 12% (all according to the plan at randomisation). The trial was closed after completion of phase II, since accrual was too slow to justify expanding the study into the scheduled phase III study. At a median follow-up of 7.3 years, the 5 year disease-free survival is estimated at 52% for the no chemotherapy and 56% for the chemotherapy arm (standard error: 7%) (P=0.3548). The 5 year overall survival for both arms is 64 and 65%, respectively (standard error 7%) (P=0.2204). Neo-adjuvant-chemotherapy with doxorubicin and ifosfamide at these doses and with this schedule was feasible and did not compromise subsequent treatment, surgery with or without radiotherapy. Although not powered to draw definitive conclusions on benefit, but with an at least 7 year median follow-up, the results render it less likely that major survival benefits will be achieved with this type of chemotherapy.

Relevance of cytogenetic and fluorescent in situ hybridization analyses in the clinical assessment of soft tissue sarcoma.

Soft tissue sarcomas are a heterogeneous group of malignant tumors displaying a wide range of clinical presentations, morphological features, and biological behaviors. These characteristics and the recent development of differentiated treatment regimens for the different types of soft tissue sarcomas call for refined histological classification using additional ancillary approaches such as cytogenetic and molecular genetic analyses. We coupled classical cytogenetics and fluorescent in situ hybridization (FISH) on both metaphases and interphase nuclei to show the feasibility of this approach to characterize tumor type-specific chromosome rearrangements in soft tissue sarcomas of different histotype. In 35 cases analyzed, we detected the presence of specific chromosome rearrangements such as t(X;18) in synovial sarcoma (SS), t(12;16) in myxoid liposarcoma (MLS), t(11;22) in peripheral primitive neuroectodermal tumors (pPNET), t(2;13) in alveolar rhabdomyosarcoma (ARMS) and ring chromosomes in dermatofibrosarcoma protuberans (DFSP). In several cases, the presence of these cytogenetic rearrangements was of help for a differential diagnosis. The FISH analysis using painting probes not only confirmed the cytogenetic results but also allowed the identification of tumor-specific chromosome changes in those cases presenting low mitotic index or with poor quality chromosomes. Moreover, in the absence of analysable metaphases, FISH was successfully performed on interphase nuclei. Taken together, these results indicate both the diagnostic and clinical relevance of a molecular cytogenetic analysis in the study of soft tissue sarcomas.

Low grade fibromyxoid sarcoma. a further low-grade soft tissue malignancy characterized by a ring chromosome.

Supernumerary rings in the context of a simple karyotype characterize several low-grade malignant tumors of soft tissue and bone. Low-grade fibromyxoid sarcoma is an uncommon low-grade sarcoma, the cytogenetics of which has not yet been reported. Here we describe the first molecular-cytogenetic characterization of a pulmonary metastasis of low-grade fibromyxoid sarcoma. The histology of the primary and recurrent tumors was consistent with the diagnosis of low-grade fibromyxoid sarcoma of the usual type, whereas the pulmonary metastasis was of the "giant rosettes" variant. Cytogenetic analysis revealed a ring chromosome. Because gain of material of chromosomes 7 and 16 was detected by CGH, the ring chromosome is assumed to be composed of material from these respective chromosomes.

Preoperative doxorubicin plus ifosfamide in primary soft-tissue sarcomas of the extremities.

A total of 51 patients with large, primary, high-grade soft-tissue sarcomas of the extremities were treated at our institute with two preoperative and three postoperative cycles of doxorubicin plus ifosfamide/mesna. Preoperative doxorubicin was given intra-arterially for lesions of the lower extremities. Of 47 evaluable patients, 22 (47%) showed clinical responses and 21 (45%), pathologic responses. Clinical and pathologic responses, however, were not necessarily coincident in the same patient. Conservative limb-sparing surgery was performed in 41 cases (87%), and in 4 cases amputation was avoided as a result of the local improvement induced by chemotherapy. Local recurrence occurred in 12 cases (25%), 3 of which required further amputation. Although the follow-up period was only 28 months, the 4-year actuarial survival was 91% and the 4-year metastasis-free value was 69%. An evident difference existed between patients who showed a documented clinical response to chemotherapy and those who did not, the 4-year metastasis-free value being 85% and 59% (P = 0.1), respectively. Adjuvant preoperative chemotherapy may allow for limb-salvage surgical procedures in selected cases.

Perspectives on anthracyclines plus ifosfamide in advanced soft tissue sarcomas.

Doxorubicin and ifosfamide are currently the two main drugs for the treatment of soft tissue sarcomas in adults. Given in combination at full doses, with or without dacarbazine, these agents have induced higher response rates than were obtained with single-agent therapy. Because they involve considerable myelotoxicity, however, full-dose regimens should be reserved for patients with good performance status and without potential septic foci. Obviously, higher response rates do not automatically translate into improved survival. In soft tissue sarcomas, full-dose polychemotherapy will most probably provide a survival benefit only in selected patients in whom surgery can be performed in combination with chemotherapy. Prospective trials in such patients, although difficult to carry out, would be highly desirable. The information they would provide might help the clinician tailor treatment in a more rational way and improve chances of cure or long-term survival in at least some patient subgroups.

TNF-alpha and doxorubicin in hyperthermic perfusion for limb sarcomas.

Eighteen patients, subdivided into groups of three, were perfused for 90 min with escalating doses of TNF-alpha (0.5-3.3 mg) and standard doses of doxorubicin (bolus 0.7-1.4 mg/kg) at a tumor temperature of at least 41 degrees C, with the aim to ascertain the maximum tolerable dose (MTD) and the activity of TNF-alpha combined with doxorubicin in hyperthermic antiblastic perfusion (HAP) for patients with limb sarcomas, candidates for amputation. Tumor response was assessed both pathologically and radiologically. Severe systemic toxicity (WHO) was observed in only 2 patients. Locoregional toxicity (Wieberdink's) was grade I in 3 patients, grade II or III in 10 and grade IV in 5. A strict correlation between the TNF dosage and the grade of limb reaction was found, grade IV being retrieved only with TNF dose >1 mg and/or muscular temperature >41.5 degrees C. Tumor necrosis was evaluated in 16 patients: in 11 (68.8%) it scored more than 75% while in 5 it was 25 to 75%. Four cases (25%) had 100% tumor histological necrosis. Limb sparing surgery was feasible in 13 (81%). Our findings suggest that this is a well-tolerated and highly active regimen in HAP.

Unusual types of chondrosarcoma: chondrosarcoma arising in soft tissue and in non-skeletal cartilage.

Five cases of unusual chondrosarcomas of the soft tissue and of the skeletal cartilage are reported. A retrospective clinical study has been evaluated on ways to improve our knowledge of these rare neoplasms.

Chondrosarcoma--55 unreported cases: epidemiology, surgical treatment and prognostic factors.

Fifty-five cases of chondrosarcoma, seen at the Istituto Nazionale Tumori of Milan, were reviewed to collect epidemiological data in order to verify therapeutic effects and the validity of possible prognostic factors. Epidemiological data according to sex and age distribution and skeletal location were in accordance with the literature (male:female ratio, 1.8; mean age, 37 years, 62% of lesions located in the pelvic or scapular girdle). Of 52 cases operated on with the intent of radicality, 5 were intralesional operations, 20 marginal and 27 radical. The local recurrence rate was dependent upon the degree of surgical radicality (60%, 35% and 11% respectively for intralesional, marginal and radical surgery). Age, site, type of first symptom and pathological grading were significant as prognostic factors. The type of the first symptom was directly correlated to the site of the tumour. Sex, tumour size and degree of surgical radicality were not relevant.

NIDDM as unfavorable factor to the postinfarctual ventricular function in the elderly: echocardiography study.

BACKGROUND: Aging and diabetes mellitus have been recognized as strong predictors of heart failure in patients with acute myocardial infarction. The aim of this study was to assess, by echocardiography, the influence of aging and non-insulin-dependent diabetes mellitus on the changes of left ventricular parietal kinesis in patients with acute myocardial infarction over the 6 months after hospitalization. METHODS: The study population consisted of 82 patients (42 male, 40 female) aged 70 years, consecutively admitted to coronary care unit with acute myocardial infarction from January 1991 to May 1993. They were divided into two groups: group 1 comprised 36 patients with non-insulin-dependent diabetes mellitus, aged 78.8 +/- 6.02 years, 17 men and 19 women; group 2 comprised 46 patients without diabetes aged 78.7 +/- 6.9 years, 25 men and 21 women. Echocardiography was performed at admission to the unit (T0), at discharge (T1), and after 6 months of follow-up (T2). The echocardiographic wall motion score index was calculated by considering the number of akinetic and dyskinetic left ventricular wall segments. Fatal and non-fatal incidents of heart failure were also considered and a multivariate analysis was applied to identify the clinical and instrumental parameters that were independent predictors of wall motion score index changes and heart failure events. RESULTS: At T1 the two groups were comparable in localization of acute myocardial infarction, previous myocardial infarction, creatinine kinase serum peak, ECG score and wall motion score index. A statistically significant reduction in akinesia (P < 0.001) was observed in group 2 at T1 and T2, but was not seen in group 1. At T2 the difference in wall motion score index between the groups became significant (P < 0.05). The occurrence of heart failure was significantly higher in group 1 than in group 2 either during hospitalization (P < 0.03) or during follow-up (P < 0.004). The multivariate analysis identified non-insulin-dependent diabetes mellitus as an independent predictor of lacking recovery in LV kinesis (P < 0.01) and of heart failure development (P < 0.001). CONCLUSION: In elderly patients with non-insulin-dependent diabetes mellitus lack of recovery in wall motion score index after acute myocardial infarction seems to be an important factor, with a higher heart failure prevalence adversely affecting the in-hospital and long-term outcome. Non-insulin-dependent diabetes mellitus appears to be an important factor related to this unfavorable outcome.

Median sternotomy and multiple lung resections for metastatic sarcomas.

In the attempt to apply salvage surgery to the majority of patients with pulmonary tumour relapse, we have adopted a new treatment plan consisting of early bilateral lung exploration and resection through median sternotomy in all cases of sarcoma with resectable lung metastases, including synchronous or previously resected ones. The present paper summarizes the early results achieved with this technique in 56 consecutive patients treated between 1985 and 1988. Perioperative mortality was zero, and morbidity negligible. Occult contralateral metastases were resected in about one third of subjects with monolateral clinical lesions. Overall actuarial survival from first pulmonary resection is 51% at 2 years and 35% at 3 years. A slightly more favourable trend is evident for solitary lesions but the difference is not statistically significant. No difference in survival is observed in relation to the initial disease-free interval or to the histological type. The majority of relapses occurred within 6 months of sternotomy (23/35) and were confined to the lungs (21/35). Ten of these 21 patients with pulmonary relapse have undergone further resection and 5 of them are alive, with a median survival of 28 months. Present results are encouraging as far as resectability and early recurrence rate are concerned. Median sternotomy appears a most valuable therapeutic approach to pulmonary metastases from sarcomas, being safe and effective in local control of disease, and compatible with further surgical management of pulmonary recurrences.

A posterior approach for the excision of sacral chordoma.

We report eight cases of sacrococcygeal chordoma treated by high sacral resection through S2 by a posterior approach, with the intention of achieving radical removal. The technique we describe is easier than the combined abdominosacral approach, and there have been no serious intra-operative or postoperative complications. The major technical problems were the margins of excision in the sacrum itself (one recurred) and in the perirectal soft tissues (four recurred), and the preservation of sacral nerve roots. When both S2 roots were preserved, sphincter problems were mild and reversible. One patient died from recurrence 32 months after operation and one was lost to follow-up at eight months. Six patients are alive with a median survival of three years; three of them are free of disease after 22, 36 and 80 months respectively. These results indicate the possibility of surgical cure of this malignant tumour.

[The action of chemotherapy on cicatrization processes]. / L'azione della chemioterapia sui processi di cicatrizzazione

The increasing use of chemotherapy in association with surgery has prompted the suggestion that cancer chemotherapeutic drugs may interfer with the healing process. To test this hypothesis 30 Wistar rats were subjected to laparotomy and colonic resection and treated with 5-Fluorouracil or Mitomycin C. The bursting strength of the abdominal scars and the colonic anastomotic bursting pressure revealed some interference in the rats treated with 5-Fluorouracil (Student's t test P less than 0.05) but none in the case of Mitomycin C. This preliminary study deserves to be followed up.

Unexpected breast cancer detection after outpatient biopsy for benign lesion.

At the Istituto Nazionale Tumori of Milan, in its Outpatient Department, 1302 breast surgical biopsies were carried out in 1978. Fibroadenomas occurred in 44.2% and benign dysplasias in 39.3%. Sixty-two cancers (4.8%) and 23 atypical hyperplasias (1.8%) were unexpected findings, with an increasing incidence in women over 50. Seventy-nine duct resections were performed for significant nipple discharge and revealed 5 unexpected carcinomas and 28 papillomas or papillomatosis. In our opinion and experience, this procedure of performing breast biopsy in the presence of a solid lump in women over 30 without hospitalization improves early detection of cancer, lowers costs, cuts down admission waiting lists and increases the number of women who better accept a surgical diagnosis and treatment.

A case of pancreatoduodenectomy as resolutive treatment for a solitary metastasis of breast cancer.

A 49-year-old woman was hospitalized for obstructive jaundice 4 years after extended mastectomy for lobular infiltrating carcinoma. After routine investigations that detected a malignant lesion of the pancreas head, the patient underwent pancreatoduodenectomy. The surgical specimen revealed unexpected breast carcinoma metastatic to the pancreas and duodenum wall. The woman is alive and free of disease at 10 years from the mastectomy and 6 years from the pancreatoduodenectomy. This experience confirms the validity of a surgical radical treatment for metastatic lesions in selected cases.

[Neurinoma of the abdominal vagus and replapsing peptic ulcer (author's transl)]. / Neurinoma del vago addominale ed ulcera peptica recidivante

A singular association of neurinoma of the abdominal vagus with relapsing peptic ulcer is reported. The singularity lies in the exceptional finding of a neurinoma of the left abdominal vagus -- not previously recorded in the literature -- and in the concomitant severe relapsing peptic ulcer, for which the nerve lesion may have been partly responsible.

Sacral chordoma and rehabilitative treatment of urinary disorders.

Sacral chordoma is one of the rarest tumors of the central nervous system (less than 1% of the entire group). Mictional disorders are among the most frequent symptoms and are caused by the extrinsic compression brought to bear on the cauda equina and by surgical demolition of the sacrum. Seven patients who had undergone sacral resection for chordoma, starting from S2, were followed for at least one year. It was observed that mictional disorders were often early symptoms signalling the presence of chordoma. Several patients were affected by a complete bladder denervation (infrasacral lesion) after surgery. Early rehabilitative treatment given after surgery for one year restored normal bladder functions in all the patients whose bladder denervation seemed to be not total (negative Lapides' test). Even when a complete infrasacral lesion of the bladder has been ascertained, early rehabilitative treatment may well prevent serious renal damage.