18-fluorine fluorodeoxyglucose positron emission tomography with computerized tomography versus computerized tomography alone for the management of solitary lung nodules with diameters inferior to 1.5 cm.

OBJECTIVE: Aim of the study was to establish a noninvasive method for the preoperative characterisation of a pulmonary nodule when biopsy of the small mass is impossible. METHODS: From 1 January 2006 to 31 December 2008, we observed 124 asymptomatic patients with a noncalcified single lung nodule highlighted by computerised tomography (CT) of the thorax. Patients were divided into 2 groups: Group A consisted of 57 patients with lesion diameters between 0.5 cm and 0.99 cm; Group B consisted of 67 patients with lesion diameters between 1.0 cm and 1.5 cm. Fibreoptic bronchoscopy was negative for endobronchial neoformation in all patients. The topographic distribution of the lesions advised against CT-guided transthoracic needle biopsy or video-assisted thoracoscopy. All patients had preoperative 18-fluorine fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) associated with CT of the thorax, which was compared with CT for evaluation of the mass. RESULTS: Postoperative histological diagnosis revealed 54 primary lung cancers, 47 lung metastases and 23 benign lesions. In Group A the sensitivity of 18F-FDG PET/CT and CT was 95 % and 73 % and the specificity was 72 % and 64 %, respectively ( P = 0.000001 for 18F-FDG PET/CT; P = 0.000177 for CT). In Group B the sensitivity of 18F-FDG PET/CT and CT was 95 % and 97 %, and the specificity was 80 % and 87 %, respectively ( P = 0.000001). CONCLUSIONS: Our study shows that 18F-FDG PET/CT improves the identification and characterisation of potentially malignant pulmonary nodules with a diameter < 1 cm. This technique could be a valid alternative to a surgical approach, currently the main method to investigate indeterminate lung nodules.

Schedule-dependent activity of 5-fluorouracil and irinotecan combination in the treatment of human colorectal cancer: in vitro evidence and a phase I dose-escalating clinical trial.

Several schedules of 5-fluorouracil (FU) and irinotecan (IRI) have been shown to improve overall survival in advanced colorectal cancer (CRC). Preclinical evidence suggests that the sequential administration of IRI and FU produces synergistic activity, although their clinical use has not been fully optimised. We investigated the interaction between short-term exposure to SN-38, the active metabolite of IRI, and prolonged exposure to FU in human CRC HT-29 cells and observed that the synergism of action between the two agents can be increased by extending the time of cell exposure to FU and reducing the interval between administration of the two agents. Based on these findings, we performed a phase I trial in 25 advanced CRC patients using a modified IRI/FU regimen as first-line therapy and evaluated three dose levels of IRI (150-300 mg/m(2)) and two of continuous infusion of FU (800-1000 mg/m(2)) in a 3-weekly schedule. The most severe grade III-IV toxicities were neutropoenia in four cycles and diarrhoea in three. One patient achieved complete response (4%), 12 a partial response (48%), the overall response rate was 52% (+/-20, 95% CI); seven of 25 patients had stable disease (28%), the overall disease control was 80% (+/-16, 95% CI). This modified IRI/FU schedule is feasible and exhibits potentially interesting clinical activity.

S100A13, a new marker of angiogenesis in human astrocytic gliomas.

S100 proteins are Ca(2+)-binding polypeptides involved in the tumourigenesis of several human neoplasms. S100A13 is a key regulator of the stress-dependent release of FGF1, the prototype of the FGF protein family involved in angiogenesis. Indeed, S100A13 is a copper binding protein able to enhance the export of FGF1 in response to stress in vitro and to induce the formation of a multiprotein aggregate responsible for FGF1 release. We investigated the expression of S100A13 in human astrocytic gliomas in relation to tumour grading and vascularization. A series of 26 astrocytic gliomas was studied to evaluate microvessel density and to assess FGF1, S100A13 and VEGF-A expression. FGF1 was equally expressed in the vast majority of tumours, whereas S100A13 and VEGF-A were significantly up-regulated in high-grade vascularized gliomas. Moreover, both S100A13 and VEGF-A expression significantly correlated with microvessel density and tumour grading. These data suggest that the up-regulation of S100A13 and VEGF-A expression correlates with the activation of angiogenesis in high-grade human astrocytic gliomas.

Leukaemic transformation in a case of thrombocythaemia. Case report and review of the literature.

The authors describe a case of thrombocythaemia, with subsequent leukaemic transformation. Cytochemical and immunocytochemical investigations indicated a trilineage involvement of the myeloid series, compatible with a leukaemic transformation at the level of the colony-forming unit granulocytes, erythrocytes, macrophages, megakaryocytes. No cytogenetic abnormalities were observed. The criteria which have been proposed to differentiate essential thrombocythaemia from pre-fibrotic thrombocythaemia, as an early phase of idiopathic myelofibrosis, are discussed. The differentiation is not only of academic interest but has relevant practical implications, since survival in the two conditions is significantly different. The possible significance of an accompanying monoclonal gammopathy is discussed.

[Extranodal localizations of lymphoma. Clinico-epidemiologic study of 353 cases]. / Le localizzazioni extranodali del linfoma. Studio clinico-epidemiologico di 353 casi.

The Authors have carried out a retrospective study on 353 cases of lymphoma, of which 252 of non-Hodgkin lymphoma (NHL) and 101 cases of Hodgkin's disease (HD), during a 17 year period, i.e. from 1982 to 1999, with the purpose of evaluating the frequency of primitive and secondary extra-nodal localizations and assess their influence on the percentage of survival. A highly significant statistical difference was observed comparing patients with nodal LNH and those with a primitive extra-nodal localization of the disease. In HD extra-nodal localizations were observed at the time of diagnosis in 13% of the cases studied, in which however in the great majority of patients presentation was associated with generalized disease and was therefore the consequence of local spread from near-by lymphoid sites. However, primitive localizations were surely observed and carefully documented. In our patients they were detected in the intestine, in the skin and in the mammary gland. In 253 patients with NHL, 123 sites of extranodal localizations were found (50%) and were observed in the skeletal system, in the skin and in the orbital cavity. The Authors underline the need to improve our knowledge on the structures and mechanisms of spread of the mucosal associated lymphoid tissue in order to better understand the clinical aspects and the necessary therapeutic approach in cases of extranodal and especially MALT lymphomas.

[Blood coagulation changes and neoplastic pathology]. / Alterazioni emocagulative e patologia neoplastica.

Cancer patients show an increased susceptibility to develop thromboembolic diseases, suggesting that disorders of coagulation are very common in this pathology. Tumor cells possess the capacity to interact with the hemostatic system, activating the coagulation cascade and stimulating the prothrombotic properties of other blood cell components; the same events while inducing a hypercoagulable state, also contribute to the processes of tumor growth, neoangiogenesis and metastatic formation. Multiple risk factors associated with malignant disease contribute to the hypercoagulability state: stasis induced by prolonged bed rest, vascular invasion by the tumor and iatrogenic complications including the use of central vein catheters and chemotherapy. Several tests have been developed to assess the hypercoagulable state, however their clinical significance still needs to be defined, especially in terms of their predictive value for thrombosis. Clinical manifestations vary from localized deep venous thrombosis (DVT) or pulmonary embolism, more generally associated with solid tumors, to disseminated intravascular coagulation, frequent in hematologic malignancies and metastatic cancer. Diagnosis of idiopathic DVT, in the absence of other risk factors, could indicate the presence of occult cancer, but the usefulness of an extensive work-up to detect malignancy in terms of cost to benefit ratio still has to be demonstrated. Patients with cancer and thromboembolism must be treated with anticoagulant therapy; a large number of studies have shown that either low molecular weight heparins or standard unfractionated heparin for the treatment of acute deep vein thrombosis in hospitalized patients are equally safe and effective; however, the first treatment has been reported to be associated with a lower mortality. After an episode of thrombosis the patients should be protected by a long term course of oral anticoagulation, remaining high the risk of recurrence for as long as the cancer is active.

[Biological and clinical characteristics of granular lymphocyte proliferation. Review of the literature and personal experience]. / Caratteristiche biologiche e cliniche delle proliferazioni di linfociti granulari. Revisione della letteratura ed esperienze personali.

The Authors, on the basis of reports from the literature and their personal experience, describe the morphological, immunophenotypic, genotypic and functional features of Large Granular Lymphocytes (LGL). An increased number of the these particular types of lymphocytes may be observed in different pathological conditions and may be interpreted as a reactive process to a possible underlying antigenic stimulation. However, a significant and prolonged increase in LGL's may also identify the existence of a true definite Lymphoproliferative disorder (LGL-PD). It is now well known that phenotypically LGL-PD may be present in two different variants: a CD3+ form, which is more frequent, and a CD3-variant. The former usually is characterized by T-cell receptor monoclonal rearrangement, while CD3- NK cells are frequently polyclonal. However also this latter variant may express clonality and in this case the clinical course is particularly aggressive. Although LGL-PD is a distinct clinical disorder, the Authors underline the extreme variability of the clinical course and the need therefore to adopt a policy of "wait and see" before taking into consideration the choice of different therapeutic options, which are often disappointing and provide remission of only brief duration.

Therapeutic management of hematological malignancies in elderly patients. Biological and clinical considerations. Part IV: Multiple myeloma and Waldenström's macroglobulinemia.

Following recent data on multiple myeloma (MM) in the literature, a possible model of myeloma development, involving different cytokine signals, is advanced, and the prognostic significance of two principle staging systems is evaluated. Different therapeutic approaches to MM have been employed, consisting of either treatment with only melphalan and prednisone, or combination chemotherapy, especially in patients with a poor prognosis. However, for the initial therapy, melphalan plus prednisone in doses that compensate for individual variation in drug absorption still appears the best choice in the vast majority of MM patients. The main clinical and hematological features which distinguish Waldenström's macroglobulinemia from MM are described, as are the criteria which should be used in choosing the most appropriate treatment based, when necessary, on chemotherapy with standard alkylating agents, as well as on the new nucleoside analogues, and repeated courses of plasmapheresis.

Incidence of malignant lymphoproliferative diseases by stage and histological variants in central Italy: a population based study 1982-1994.

A population-based epidemiological study that concerns the estimate of incidence rates of Hodgkin's Disease (HD) and Non Hodgkin's Lymphoma (NHL) in a Central Italy area was performed. All the new cases of HD and NHL diagnosed from 1982 till 1994 in the target population were collected by multiple information sources. The temporal trend of incidence rates and their relation with age, gender and histological variant were analyzed. In the considered period 95 cases of HD and 297 cases of NHL were collected. Constant age-adjusted incidence rates of HD were observed, while an increasing trend of NHL incidence rates was observed especially for cases at presentation in stage III and IV and for histotypes G, H and I. The investigations carried out on patients with HD have shown that this condition prevails in women in the younger age groups, while in men presentation occurs more frequently at an advanced age. Moreover the authors have confirmed previous reports of a distinctly increased incidence of nodular sclerosis in contrast to the other three histological variants which do not show a juvenile peak but a gradual increase in incidence with advancing age. The epidemiological features of NHL's observed correspond to the standard incidence rates obtained in Europe and throughout the world. NHL's appear to be a pathological entity typical of elderly patients: however high-grade NHL's, in contrast to low-grade NHL's, was present with increased frequency also in childhood and in patients under the age of 30.

Cutaneous involvement in leukaemic patients. A review of the literature and personal experience.

The authors, on the basis of a review of the literature and on their personal experience, derived from the observation of 169 cases of acute and chronic leukaemias, describe the different aspects of the cutaneous lesions present during the course of these neoplastic conditions. The cutaneous lesions, subdivided according to the type of leukaemia, show an extremely variable pattern and it is therefore difficult to differentiate on the basis of the sole macroscopic appearances, specific leukaemic nodules or infiltrates from dermatoses due to bacterial, viral and fungal infections on which an haemorrhagic component may be superimposed. Similarly, if a clearly established diagnosis of leukaemia has not been confirmed, it is difficult to distinguish leukaemic infiltrates from cutaneous lesions caused by a malignant lymphoma, metastatic carcinoma, an eosinophilic granuloma, or from benign lymphohistiocytic infiltrates, secondary to cutaneous infections. It is important also to bear in mind the development of skin eruptions, often with an haemorrhagic component, due to acquired sensitivity to numerous agents, cytostatic drugs, antibiotics, blood products and others, used in therapy. The authors therefore underline the importance of an early recognition of an infectious lesion, often complicated by a previous haemorrhagic event or secondary to microbial invasion of a catheter tip or of a venipuncture site, and consequently, the authors emphasize the need to distinguish these non-specific skin alterations, amenable to appropriate treatment from those lesions due to the development of a skin tumour or to a leukaemic infiltrate, which is nearly always indicative of a leukaemia recurrence or extension of the leukaemic process.

Therapeutic management of hematological malignancies in elderly patients. Biological and clinical considerations. Part 1. Myelodysplasias and the acute leukemias.

The different therapeutic options that may be employed in the treatment of elderly patients with acute leukemias and myelodysplastic states are considered following an analysis of certain biological features, that have been investigated by cytochemical, cytogenetic and cytokinetic techniques, immunophenotyping, and studies on G-6-PD isoenzymes. These studies imply that in the elderly the pattern of hematological malignancies and the lack of response to conventional treatment derive from intrinsic biological differences between these pathological states in older and younger patients. Treatment in elderly patients has ranged from palliative treatment to intensive chemotherapy, often with disappointing results in both cases. Palliative treatment does not induce remissions, and median survival is short. On the other hand, elderly patients do not tolerate well both induction and post-remission therapy due to the degree of toxicity and the effects of drug-induced pancytopenia. In this scenario, in vitro drug-sensitivity testing and karyotyping assume increasing importance, because they may predict which patients are likely to benefit from intensive therapy. In both acute leukemias and myelodysplasias, treatment ideally should be designed case by case, according to the hematological, clinical and biological features.

Association between chronic lymphocytic leukaemia and secondary tumours: unusual occurrence of a neuroendocrine (Merkell cell) carcinoma.

The authors describe a case of cutaneous neuroendocrine (Merkell cell) carcinoma in a patient previously treated for Chronic Lymphocytic Leukaemia (CLL). The authors discuss some of the mechanisms concerning the increased frequency of a second tumour in patients with CLL and focus attention on the high incidence in CLL of secondary tumours, especially skin tumours, of which Merkell cell carcinoma is a rare example. The authors consider the possible therapeutic approaches, reported in the literature, for the treatment of this particular skin carcinoma, which on account of its aggressiveness and the preexistence of a leukaemic process requires a particularly careful therapeutic approach.

Therapeutic management of hematological malignancies in elderly patients. Biological and clinical considerations. Part II: Non-Hodgkin lymphomas and Hodgkin's disease.

Increased knowledge of the nature and biology of lymphoid cells has provided more rational classification schemes, and has improved therapeutic strategies. However, non-Hodgkin lymphomas (NHL) as well as Hodgkin's disease (HD) show a less favorable outcome in elderly compared to young patients. The poorer outcome in elderly patients with NHL is largely due to chemotherapy-related issues, although other age-related factors may contribute to determine a poor prognosis, such as the presence of more aggressive pathological subtypes and an increase in extranodal vs nodal presentations. Similarly, HD patients older than 50 years have higher rates of advanced disease, B symptoms, and histological types associated with poor prognosis at presentation. The poor prognosis in lymphoid malignancies also appears to be attributable to inadequate treatment. However, the inability to administer full therapy may be real, due to the high percentages of deaths caused by severe infections and intercurrent disease (cardiac, renal, lung) related to diminished organ function. The availability of growth factors may help to reduce the incidence of severe neutropenia and other related septic conditions.

Therapeutic management of hematological malignancies in elderly patients. Biological and clinical considerations. Part III: The chronic leukemias and myelofibrosis.

The different therapeutic options available for the treatment of chronic leukemias and myelofibrosis are discussed. In reference to chronic myeloid leukemia (CML), the choice of the most appropriate treatment must take into account not only the clinical condition but also the age of the patient. While subjects under 50 might benefit from the options offered by alpha-interferon, bone marrow and peripheral stem cell transplant, in older age groups treatment of the chronic phase must still rely on standard treatment. Chronic lymphocytic leukemia (CLL) and its variants is a disease of mostly middle and late life, with a variable clinical course. Patients show wide differences in morbidity and mortality. Many features have been shown to influence the prognosis, and the most important ones are incorporated into the staging systems currently in use. The results obtained from the study of large trials support the concept that treatment of patients with stable stage A CLL should be postponed until progression of disease. Treatment relies principally on alkylating agents, corticosteroids and radiation therapy; the new nucleoside analogues, such as fludarabine and 2-chlorodeoxyadenosine, have recently acquired established value in improving overall survival. With regard to myelofibrosis, the histological and biological features that influence the natural course of the disease are described, as well as the choice of the most appropriate treatment, which ranges from the use of alkylating agents and androgens, to splenectomy and splenic irradiation.

Secondary leukaemias. Clinical and cytobiological aspects.

Patients treated with radiation and cytotoxic agents for a variety of neoplastic conditions develop with increased frequency a secondary leukaemia, usually a form of acute myeloblastic leukaemia. The authors illustrate and discuss the various morphological and cytobiological which characterize the "preleukaemic phase", and which comprise myelodysplastic alterations, cytochemical abnormalities, concerning the presence of glycogen and free iron in the red cell series, as well as a number of changes in enzymatic activities in the myeloid series, cytokinetic changes, indicative of accumulation of cells in G0 and G1, cytogenetic non-random abnormalities, involving specific chromosomes, and finally in vitro cultures which show a reduction in colony formation. The authors underline the differences between primary and secondary preleukaemic myelodysplastic states, consisting in the presence in the latter of frequent hypocellularity, fibrosis and almost invariability a clear involvement of multiple cell lines.

Selective involvement of monocytes by acquired myeloperoxidase deficiency in a case of chronic myelomonocytic leukemia.

The authors describe a case of chronic myelomonocytic leukemia in which a myeloperoxidase (MPO) deficiency of circulating monocytes was first detected by automated differential cell counting, and subsequently confirmed by cytochemical and immunocytochemical investigations. MPO activity in neutrophil granulocytes from the same case was found to be normal. MPO deficiency in monocytes appeared to be associated with impaired phagocytic capacity and, based on the results of immunophenotypic and ultrastructural studies, was most likely attributable to a partial maturation arrest of monocytes. The present case suggests that MPO deficiency in myelodysplastic syndromes may have its origin in a number of different pathogenetic mechanisms.