Radiation-induced gadd45 expression correlates with clinical response to radiotherapy of cervical carcinoma.

BACKGROUND: Recent work has identified a category of genes devoted to the control of genomic stability and prevention of cellular evolution. They encode components of cell cycle checkpoint, i.e., regulatory pathways committed to ordered cell cycle transition and fidelity of replicated DNA under adverse environmental conditions, such as those following exposure to genotoxic agents. Gadd45 belongs to the class II family of DNA damage-inducible (DDI) gene, and its role in DNA repair has been proved in many experimental models. The aim of our study was to correlate gadd45 radio-induction with the responsiveness to radiotherapy of cervical carcinomas, a type of cancer most commonly treated with radiotherapy alone. METHODS: By means of a competitive polymerase chain reaction strategy, we compared in 14 patients the gene expression levels before and during external beam radiotherapy, when a dose ranging from 18 to 25 Gy was delivered to the target. RESULTS: We found a correlation between the lack of gadd45 induction and a good clinical response to radiotherapy, in terms of both local control and disease-free survival. CONCLUSION: Our results support the measure of the induction of gadd45, and possibly of other genes required for regulated G1-S checkpoint, as a method useful for prognostic evaluation of cervical carcinoma patients.

Radiotherapy in vertebral tumors. Indications and limits: a report on 28 cases of Ewing's sarcoma of the spine.

After brief notes on techniques used to radiate the spine, its indications and the limits of doses required by its adjacency to the spinal cord, our experience in the treatment of 28 patients with a diagnosis of Ewing's sarcoma localized in the spine, not metastatic at onset, that came to our observation between 1980 and 1994 is reported. All of the patients were treated by chemotherapy. As for local treatment radiotherapy was performed in all of the cases, in 50% of cases it was associated with surgery (6 laminectomies, 6 excisions, and 2 vertebrectomies). Five-year survival rate was 43.5%. The prognosis of this group of patients was intermediate among forms localized in the limbs and those localized in the pelvis. There is a greater frequency of cerebral (20%) and skeletal metastases (55%) as compared to the disease that occurred in other sites where secondary pulmonary localizations generally prevailed. Local control was similar for disease occurring in other sites despite the need to deliver doses that were lower than those typically used for this pathology in regions above the cauda.

Non conventional fractionation in radiotherapy of the musculo-skeletal sarcomas.

In 1989 we started an accelerated hyperfractionated schedule of radiotherapy (two 1.6 Gy daily fractions) in standard risk localized Ewing's sarcoma of bone, with the aim at reducing late effects in young patients and at improving disease control through a better integration of treatment modalities. From 1991, the same schedule was used in preoperative radiotherapy of adult soft tissue sarcomas of the extremities: the main purpose was to reduce the time to surgery and to evaluate surgical complications in comparison with a previous experience of hypofractionated radiotherapy (one 3 Gy daily fraction). From 1991 to 1997, 76 patients with Ewing's sarcoma and 24 patients with soft tissue sarcoma were treated at our Institution. Results and complication rates are analyzed in comparison with historical data. In Ewing's sarcoma, a correct evaluation of improvement in local control was difficult because of changing treatment policy (bulky disease was not included in the present series). Late effects, as evaluated in patients with a minimum follow-up of 3 years, occurred with similar incidence, but at higher total dose levels in patients treated with accelerated hyperfractionation. In patients with soft tissue sarcomas, incidence of surgical complications is reduced as compared to historical experience. Major problems of wound healing were seen in association with intraoperative brachitherapy boost.

The effect of cytokines, including IL4, IL7, stem cell factor, insulin-like growth factor on childhood acute lymphoblastic leukemia.

We have investigated the effects of some interleukins, such as interleukin (IL) 4, IL7, stem cell factor (SCF) and insulin-like growth factor (IGF-1), known to be involved in human lymphopoiesis, on proliferation, clonal growth and differentiation of cells from two acute lymphoblastic leukemia (ALL) derived pre-B cell lines, that is, Nalm 1, Nalm 6 and purified blasts from 37 childhood ALL. IL4 did not display any promoting activity, an inhibitory effect being observed in two patients. IL7 showed an heterogeneous responsiveness, not related to immunophenotype or cytogenetic features, proliferation and clonal growth being observed in a minority of ALL. In other patients no or even inhibitory effects on proliferation were observed. In one case this inhibition of DNA synthesis was accompanied by maturation of the cells, as demonstrated by the induced expression of surface immunoglobulins (slg); other IL7 treated samples failed to express slg, but showed a decreased expression of terminal deoxynucleotidyl transferase and cALL antigen, suggesting that the cells have a potential of limited maturation by IL7. SCF, known to synergize with IL7 in the most primitive stages of normal B cell development, did not enhance the IL7 response in B cell precursor ALL. Finally IGF-1 failed to induce a proliferative response and clonal growth in BCP ALL either alone or in combination with IL7.

Evaluation of minimal residual disease in high risk childhood acute lymphoblastic leukemia using an immunological approach during complete remission. AIEOP Cooperative Group for Immunology of Acute Leukemias.

BACKGROUND: Sensitive methods for detecting residual disease may complement conventional morphology while monitoring the response to treatment in leukemia patients. METHODS: We studied minimal residual disease (MRD) by selecting via a colony assay a peripheral blood (PB) cell population enriched in putative malignant cells and detecting occult leukemic cells by double immunologic analysis performed on colonyforming cells (CFC). Using this combined technique we assayed the PB of high risk children with acute lymphoblastic leukemia (ALL) in order to demonstrate possible differences in "the residual tumor cell burden" among leukemia patients and to correlate these with a 3-year clinical follow-up. RESULTS: In all 22 patients positive results were obtained for up to 18 months following induction chemotherapy at times of apparent hematologic remission. Common ALL (cALL) patients exhibited a mean of 9.6% cAlla+ cells (range: 2% to 30%), whereas cALL antigen (cALLA) and cALLA/Tdt or CD1a/Tdt combination were never found in the colonies derived from healthy individuals. Six out of 22 cALL patients expressed a mean of 16.5% cALLA+/Tdt+ CFC (range: 2% to 35%). Five T-ALL children presented a mean of 24% CD1a/Tdt+ cells (range: 8% to 44%). Extensive follow-up indicates a correlation between the percentage of CFC Tdt+/lymphoid marker+ cells (more than 10%) and subsequent clinical relapse. In one patient relapse occurred after 16 months with a dramatic increase in the number of leukemic cells. In contrast, the decline in malignant cells, observed in two cases, predicted a favourable course. Five patients tested before autologous bone marrow transplantation (ABMT) presented high number of positive cells and relapsed at various times. CONCLUSIONS: We conclude that this approach to the study of MRD could be valuable in monitoring the efficacy of chemotherapy, as well in evaluating the quality of purged marrow.

Surgery and radiation therapy in the treatment of soft tissue sarcomas of extremities.

Between January 1979 and December 1987, 99 patients (pts.) with a diagnosis of localized soft tissue sarcoma of the extremities received preoperative radiation therapy (Preop. RT, 50 pts.) or postoperative irradiation (Postop. RT, 49 pts.). In the preop. RT group, doses ranged from 42 Gy/17 fractions to 51 Gy/17 fractions; pts. treated with RT after surgery, received a dose comprised between 46 Gy/23 fractions to 66 Gy/33 fractions. The surgical procedure consisted of making a wide resection of the mass with preservation of the affected limb, in each patient. The main cause of failure was dissemination of the disease (33.3%). The incidence of local failures was low (7.1%). Recurrences were related to the size of the disease (5 cm: 0/12; 5-10 cm: 2/45 2.3%; 10 cm: 5/42, 11.9%), as were also distant metastases. The incidence of distant failures was higher in the group treated with preop. RT (44.0% vs. 22.4%), probably because a higher percentage of patients in this group had large volume diseases. Late sequelae were evaluable in 59 pts. with a follow up longer than 24 months. The incidence of complications was low (10.1%, 6/59); it was higher in the preoperative than in the postoperative group (15.4% vs. 6.1%); this observation is probably related to the different modalities of fractionation.

Co-expression of myeloid antigens in childhood acute lymphoblastic leukaemia: relationship with the stage of differentiation and clinical significance.

Co-expression of myeloid antigens on the leukaemic blast cells was evaluated in 532 children with a diagnosis of acute lymphoblastic leukaemia (ALL). Using a panel of monoclonal antibodies belonging to CD11b, CD13, CD14, CD15 and CD33 an overall incidence of 4.3% was found, with values ranging between 1.8% for CD14 and 6.1% for CD15. When the data were further dissected, a significantly higher incidence of co-expression was noted in null-ALL (15/70 cases = 21.4%), compared to cases expressing a more mature immunophenotype, i.e. common-ALL (7/394 cases = 1.7%) and T-ALL (1/68 cases = 1.4%) (P less than 0.001). In null-ALL, 9/15 patients were infants, five of whom with the t(4;11); two further children also had a t(4;11). The clinical outcome of the 23 cases which co-expressed myeloid antigens was unfavourable. Only two of the 15 null-ALL, two of the seven common-ALL and the unique case with T-ALL are in fact in persistent first remission between 19 and 93 months from diagnosis. Though the overall incidence of childhood ALL expressing myeloid antigens is low, the evidence that this co-expression may be related to an unfavourable clinical course and that it more frequently occurs in null-ALL, particularly in the first year of life, suggests that the routine assessment of myeloid antigens may allow to identify a subgroup of childhood ALL with a poor clinical outcome.

[Radiosurgical combination for the treatment of soft tissue sarcoma of the extremities]. / L'associazione radiochirurgica nel trattamento dei sarcomi delle parti molli delle estremità.

From January 1979 to December 1987, 99 patients with a diagnosis of localized soft-tissue sarcoma of the extremities received preoperative radiation therapy (50 patients) or postoperative irradiation (49 cases). In the preoperative RT group, doses ranged from 42 Gy/14 fractions to 51 Gy/17 fractions; the patients treated with postoperative radiation therapy received 46 Gy/23 fractions. The surgical procedure was in each patient complete resection of the mass with preservation of the affected limb. The main cause of failure were distant metastases (33.3%). The incidence of local recurrences was low (7.1%). Recurrences were related to tumor size [less than 5 cm: 0/12; 5-10 cm: 2/45 (2.3%; greater than 10 cm: 5/42 (11.9%)]. The incidence of distant metastases was higher in the group treated with preoperative radiation therapy (44% versus 22.4%), probably because a higher percentage of patients in this group had large tumors. Late complications were analyzed in 59 patients with a follow-up longer than 24 months. Severe complications rate was low (6/59 cases, 10.1%), and higher in the preoperative than in the postoperative RT group (15.4% versus 6.1%), which is probably related to the different fractionations administered.

Combined therapy of localized Ewing's sarcoma of bone: analysis of results in 100 patients.

From 1979 to 1986, 182 patients with biopsy proven diagnosis of Ewing's sarcoma of bone were observed. One hundred of the 182 patients (72 males, 28 females, median age 15.8 years) with localized disease and no previous treatment were treated with chemotherapy (VCR, ADM, CTX, D-ACT) for 15-18 months. Local treatment was radiotherapy (42 patients), surgery (31 patients), or a combination of both (27 pts). Radiation doses ranged from 45 to 64 Gy given with conventional fractionation. Median follow-up was 51.2 months (24-106). Overall and disease-free survival were, respectively, 58.7 and 42.6%. Resected patients tended to have a better local control (Surgery 93.6%, Surgery + Radiation therapy 92.6%, Radiation therapy 69.1%). Disease-free survival was significantly related to the volume of the primary tumor (bulky: 33.2%, not-bulky: 57.7%), to site (extremities 54.6%, central sites 16.6%, other sites 40.9%), and to local treatment (Radiation therapy 30.3%, Surgery + Radiation therapy 47.9%, Surgery 59.1%). These results are, however, biased because resected patients tended to have smaller tumors in favorable sites.

[Neuroblastoma metastatic to the skull. Radiologic aspects and therapeutic problems]. / Neuroblastoma metastatico al cranio. Aspetti radiologici e problemi terapeutici.

Clinical-radiological findings, treatment and prognosis of cranial involvement in 19 cases of neuroblastoma stage IV have been considered. The most frequent clinical features were periorbital ecchymosis and intracranial hypertension. The radiographic aspects, graduated according to the type of the lesion, showed a close correlation with clinical findings and sometimes preceded them. Computerized tomography, carried out in 12 cases, was more reliable than plain films in identifying the site and extent of cranial lesions and the presence of cerebral extensions, as occurred in 2 patients. The presence of cranial involvement at diagnosis was an unfavorable prognostic sign. The 19 children were treated in various ways so that firm conclusions cannot be drawn, but cranial radiotherapy in combination with chemotherapy appeared to be more efficacious than chemotherapy alone.

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 Ewing's 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.

[Radiotherapy by the Bollini technic in pseudoparalytic myasthenia gravis]. / La radioterapia secondo la tecnica di Bollini nella miastenia grave pseudoparalitica.

The Authors report the results on 20 patients affected by myasthenia gravis treated by radiotherapy following the method of Bollini (1945). This treatment obtained good results in 90% of the cases. There were no deaths during therapy nor "radiation disease". The advantages of this technique of radiotherapy in comparison to other methods of radiotherapy and to surgical and steroid therapy are presented and briefly discussed.

[Sialography and scintigraphy in salivary pathology (author's transl)]. / La scialografia e la scintigrafia nello studio delle ghiandole salivari

58 cases of salivary glands pathology were investigated by means of sialography and scintigraphy in order to compare these methods. The usefulness of this association is discussed and a number of significant cases are presented.