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In oncology, there is a growing number of therapies given in combination. Recently, several dose-finding designs for Phase I dose-escalation trials for combinations were proposed. The majority of novel designs use a pre-specified parametric model restricting the search of the target combination to a surface of a particular form. In this work, we propose a novel model-free design for combination studies, which is based on the assumption of monotonicity within each agent only. Specifically, we parametrise the ratios between each neighbouring combination by independent Beta distributions. As a result, the design does not require the specification of any particular parametric model or knowledge about increasing orderings of toxicity. We compare the performance of the proposed design to the model-based continual reassessment method for partial ordering and to another model-free alternative, the product of independent beta design. In an extensive simulation study, we show that the proposed design leads to comparable or better proportions of correct selections of the target combination while leading to the same or fewer average number of toxic responses in a trial.

Quantitative methods have been proposed to assess and compare the benefit-risk balance of treatments. Among them, multicriteria decision analysis (MCDA) is a popular decision tool as it permits to summarise the benefits and the risks of a drug in a single utility score, accounting for the preferences of the decision-makers. However, the utility score is often derived using a linear model which might lead to counter-intuitive conclusions; for example, drugs with no benefit or extreme risk could be recommended. Moreover, it assumes that the relative importance of benefits against risks is constant for all levels of benefit or risk, which might not hold for all drugs. We propose Scale Loss Score (SLoS) as a new tool for the benefit-risk assessment, which offers the same advantages as the linear multicriteria decision analysis utility score but has, in addition, desirable properties permitting to avoid recommendations of non-effective or extremely unsafe treatments, and to tolerate larger increases in risk for a given increase in benefit when the amount of benefit is small than when it is high. We present an application to a real case study on telithromycin in Community Acquired Pneumonia and Acute Bacterial Sinusitis, and we investigated the patterns of behaviour of Scale Loss Score, as compared to the linear multicriteria decision analysis, in a comprehensive simulation study.

In this paper, a new discrete statistical model for ordered categorical data is proposed via fixed-point discretization of a beta latent variable. The resulting discretized beta distribution has a highly flexible shape and it can be either over-dispersed or under-dispersed with respect to the binomial distribution. It has only two parameters, which may therefore parsimoniously depend on covariates and on random effects, providing new tools for the analysis of structured, clustered or longitudinal ordinal data. Practical examples and advices are given and an application of the new model to subjective evaluations of a gastrointestinal disease is shown.

Background: Restless legs syndrome (RLS) is a neurological disorder characterized by the urge to move the legs associated with peculiar unpleasant sensations during periods of rest and inactivity that are relieved by movement. A few studies analyzed RLS in neurodegenerative diseases such as Alzheimer's Disease (AD). The aim of our study was to assess the prevalence and the clinical characteristics of RLS in a cohort of AD patients., Methods: Three hundred and thirty-nine subjects with a diagnosis of AD were recruited. Cognitive, functional, and neuropsychiatric measures were collected at baseline and six-monthly for a 2-years follow-up, Results: Fourteen subjects met the RLS criteria. RLS subjects were more frequently male (p:0,006) and younger than AD subject without RLS (p:0,029). MMSE, ADL and IADL were not significantly different. NPI total scores did not differ significantly, however, AD patients with RLS were found to be more apathetic (p:0,001) than AD subjects without RLS., Conclusion: RLS prevalence in our AD cohort was estimated to be about 4%. RLS appeared to be associated with neuropsychiatric symptoms such as apathy. RLS and apathy might share a common pathophysiological basis represented by a dysfunction of the central dopaminergic system.

Knowledge of markers in the human genome which show spatial patterns and display extreme correlation with different environmental determinants play an important role in understanding the factors which affect the biological evolution of our species. We used the genotype data of more than half a million single nucleotide polymorphisms (SNPs) from the data set Human Genome Diversity Panel (HGDP-CEPH -CEPH) and we calculated Spearman's correlation between absolute latitude and one of the two allele frequencies of each SNP. We selected SNPs with a correlation coefficient within the upper 1% tail of the distribution. We then used a criterion of proximity between significant variants to focus on DNA regions showing a continuous signal over a portion of the genome. Based on external information and genome annotations, we demonstrated that most regions with the strongest signals also have biological relevance. We believe this proximity requirement adds an edge to our novel method compared to the existing literature, highlighting several genes (for example DTNB, DOT1L, TPCN2, RELN, MSRA, NRG3) related to body size or shape, human height, hair color, and schizophrenia. Our approach can be applied generally to any measure of association between polymorphic frequencies and continuously varying environmental variables.

Background: At present 67Ga can be considered one of the most widely used viability radiotracers. There is general consensus in the literature that 67Ga has the highest clinical value in the management of lymphoma patients., Methods: We critically discuss the role of gallium scintigraphy in lymphoma patients on the basis of the experience of the Nuclear Medicine Division at the National Cancer Institute of Milan., Results and Conclusions: The sensitivity of gallium scan is very high (80-90%) in the staging and follow-up of Hodgkin's disease, and the method is also of great importance in the follow-up of lymphoma patients. We recommend scintigraphy to study the residual mediastinal mass after treatment. Our experiences during the follow-up of 189 lymphoma patients clearly showed the superior performance of gallium scan compared to MRI in the study of the mediastinal region after treatment. Sensitivity and specificity were both very high (90% and 96.9% vs 88.7% and 89.2%, respectively). Gallium scintigraphy can also be used to study the disease-free interval, post-treatment survival, early signs of recurrence and treatment response times. Comparison of the survival curves of 33 patients with diffuse large cell Non-Hodgkin's lymphoma examined at the National Cancer Institute showed a statistically significant difference (logrank test, P = 0.0125) between patients with positive and those with negative gallium scan after 4-6 cycles of chemotherapy.

We evaluated the frequency of serum antineuronal antibodies in a cohort of 39 neuroblastoma patients and related their presence to clinical features. Twelve patients displayed antineuronal antibodies at immunocytochemistry. Only one of these 12 patients suffered from a clinically overt paraneoplastic syndrome. No significant differences emerged between autoantibody-positive and autoantibody-negative patients in terms of progression-free and overall survival, although when only patients evolving to disease progression were considered, the time interval between diagnosis and progression was slightly longer in autoantibody-positive patients.

Aims and Background: Adequate clinical staging of non-Hodgkin's lymphoma patients is essential because only localized disease can be treated satisfactorily. Many imaging procedures are necessary to stage the disease accurately. The objective of this study was to evaluate the efficacy of an antilymphoma antibody in the Fab' fragment form, labelled with 99mTc, to detect malignant lesions., Methods: Radioimmunodetection (RAID) with 99mTc-labelled B-cell lymphoma monoclonal antibody IMMU-LL2-Fab' (LymphoSCAN; Immunomedics, Morris Plain, NJ, USA) was investigated in 10 patients (5 females and 5 males; age range, 20-72 years) with histologically proved non-Hodgkin's lymphoma. Of the 10 lymphomas, 7 were intermediate grade and 3 were low grade. Whole body images with multiple planar views were obtained at 30 min, 4-6 and 24 h after i.v. injection of 1 mg LL2-Fab' labelled with 740-925 MBq of 99mTc. SPET of the chest or abdomen was performed in all patients 5-8 h after the immunoreagent injection., Results: No adverse reactions were observed in any patient after Mab infusion, and no appreciable changes were seen in the blood counts, renal or liver function tests. A total of 18 of 21 (85.7%) lymphoma lesions were detected by RAID. All the tumor localizations were confirmed by clinical examination and with other imaging techniques, such as CT scan, MRI or gallium scan. In this series of patients no false-positive results were noted. As regards the biodistribution of the immunoreagent, no appreciable bone marrow activity was seen; splenic targeting was demonstrated in all patients; the tumor-to-non-tumor ratios ranged from 1.2 to 2.8 ad measured by the ROI technique; no difference in uptake was noted for different tumor grades. The images obtained 24 h after injection did not reveal new lesions, but areas of doubtful uptake were seen as positive focal areas in the delayed scan., Conclusions: LymphoSCAN seems to be useful for detection, staging and follow-up of non-Hodgkin's lymphoma patients.

From January 1968 to March 1975, 115 patients with malignant lymphomas, all aged under 15 years were admitted to the Istituto Nazionale Tumori of Milan : 57 had Hodgkin's disease (mean age 9.7 years) and 58 non-Hodgkin's lymphomas (mean age 7.7 yrs). In this group of consecutive unselected and untreated patients the incidence of lesions radiologically evident at disease presentation was comparatively evaluated in relation to histology, 36 cases underwent a subsequent diagnostic laparotomy with splenectomy.

The series comprises 57 consecutive patients with Ewing's sarcoma admitted to the National Cancer Institute of Milan from 1965 to 1976. In 75% the diseas was confined to one bone, while in 25% multiple bone and/or visceral lesions were present. Patients with clinically localized tumor treated before 1971 with local therapy, showed a median disease-free survival of 5 months. After 1971, radiotherapy and/or surgery to local tumor was combined with multiple drug chemotherapy (ADM, VCR, CTX) and the projected median disease-free survival increased to 24+ months. In previously untreated patients with advanced tumor adriamycin, used as single drug, achieved an overall response rate of 73%. This is comparable to that achieved by a new combination including ADM, VCR, CTX, CCNU (75%). This multiple drug regimen is, however, expected to prolong the duration of response.

Resection of pulmonary metastases has achieved a central role in the overall management of osteosarcoma, since a number of studies have demonstrated that salvage surgery is able to cure 20 to 40% of all relapsing patients. This paper presents the results of surgical management of 27 consecutive cases of pulmonary metastases from osteosarcoma, who underwent complete resection at the Istituto Nazionale Tumori of Milan between 1975 and 1986. In the present series, overall actuarial survival at 3 years from the first thoracotomy was 47%, with a median survival of 28 months and no operative mortality. Better results were observed in patients with single lesions (68% survival) or when the interval to lung metastases exceeded 12 months (60% survival). These data support the concept of pulmonary metastasectomy as effective salvage therapy for metastatic osteosarcomas whose distant spread is confined in the lungs.

From January 1969 to June 1978, 413 children under 15 years of age underwent lymphography at the Istituto Nazionale Tumori of Milan. Successful lymphatic cannulation was accomplished in 97.7% (769/787) of the sites where it was attempted. No major or permanent complications were encountered. In those children undergoing biopsy of opacified lymph nodes, the lymphographic-histologic correlation was 94.5% (104/110). This study has shown that lymphography in childhood can be as readily performed as in the adult and that its diagnostic accuracy is acceptable. As in adults, it is useful in treatment planning, evaluating results of therapy, and detecting a recurrent tumor.

To investigate possible undesirable effects due to the intravenous administration of a reagent of a xenogenic nature (monoclonal antibody 225-28S) in man, a toxicologic study was carried out on 85 patients with metastatic cutaneous melanoma. Two reagents were tested in this study: purified monoclonal antibody (MoAb) 225-28S and its F(ab')2 fragment. Purified MoAb was labelled with 131I and F(ab')2 fragment with 131I, or 123I, or 111In or 99Tc. The quantity of MoAb or F(ab')2 injected ranged from 14 to 750 micrograms, and the specific activity from 37.0 to 2116.4 MBq/mg. The total radioactivity injected varied from 25.9 to 891.7 MBq/mg. In addition to a careful clinical examination, the following tests were done to monitor possible adverse effects: blood glucose, azotemia, RBC, WBC, platelet count, serum creatinine, creatinine clearance, plasma electrolyte levels, serum proteins, albumin/globulin ratio, serum bilirubin, SGOT, SGPT, gamma GT, and CPK. These tests were done before the injection and on days 7 and 14. No patient experienced adverse general effects like fever, nausea, vomiting or allergic reactions. None of the aforementioned hematometric and biochemical tests showed significant variations compared with the initial values. It is concluded that a single injection of these reagents at the dosages tested is completely atoxic.

From 1962 to 1976, 15 children up to the age of 15 years with malignant neoplasms of the ovary were observed at the Istituto Nazionale Tumori of Milan. 13 patients had a germ cell tumor and 2 a stromal tumor. Natural history and treatment results are reported. Out of 7 patients with dysgerminoma, 3 at stage IA, 2 at stage III retroperitoneal and 1 with recurrent disease are alive and disease free 38+, 20+, 36+, 16+, 23+, 156+ months after the histologic diagnosis; the last case with stage III peritoneal disease died 2 months after the diagnosis. Four children had immature malignant teratoma: 2 patients are alive and disease free 19+ and 51+ months, 1 is alive with disease 20+ months and 1 died 16 months after histologic diagnosis. Two patients with extra-embryonal teratoma died 7 and 12 months after diagnosis. One patient, treated by surgery plus chemotherapy for granulosa cell tumor at stage III, is alive 43+ months later. The child with arrhenoblastoma at stage III treated by surgery plus radiochemotherapy died 6 months after diagnosis. Through a close scrutiny of the literature and by drawing on experience gained in the treatment of the same tumors in adults, a rational approach to the diagnosis and treatment of each childhood ovarian tumor histotype is worked out.

All the pertinent radiographs of 83 patients with histologically proven Ewing's sarcoma were reviewed. Forty-nine patients were in the pediatric age group, and 34 were adults. The mean age, the symptoms and time from symptoms to diagnosis were evaluated in the 2 groups. The site of primary involvement was in 54% the long bones, 35% the flat bones, 8% the small bones and 3% extraosseous. For the primary site we considered the diagnostic results of the standard radiographic investigations and in some cases the usefulness of angiography, xeroradiography and telethermography. At presentation we also evaluated the possible diffusion of the disease with standard radiographic surveys (chest and skeletal, including limbs) and with foot lymphography in selected cases. In this way, 57 patients (69%) were considered to have localized disease. In this group, we also considered the value of the periodic radiographic follow-up, which enabled us to disclose the appearance of metastases (chest 64%, bone 54%, lymph nodes 11%) in 28 cases (49%). Finally, we made a comparison of the different radiologic and epidemiologic findings between children and adults.