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COVID-19 is a global health threat with a huge number of confirmed cases and deaths all over the world. Human-to-human transmission via respiratory droplets and contact with aerosol-infected surfaces are the major routes of virus spread. Because SARS-CoV-2 can remain in the air and on surfaces from several hours to several days, disinfection of frequently touched surfaces and critical rooms, in addition to observing individual hygiene tips, is required to reduce the virus spreading. Here we report on an investigation into the use of gaseous ozone as a potentially effective sanitizing method against the new coronavirus.

Objective: Sensory deficits are important risk factors for delirium but have been investigated in single-center studies and single clinical settings. This multicenter study aims to evaluate the association between hearing and visual impairment or bi-sensory impairment (visual and hearing impairment) and delirium. Design: Cross-sectional study nested in the 2017 "Delirium Day" project. Setting and participants: Patients 65 years and older admitted to acute hospital medical wards, emergency departments, rehabilitation wards, nursing homes, and hospices in Italy. Methods: Delirium was assessed with the 4AT (a short tool for delirium assessment) and sensory deficits with a clinical evaluation. We assessed the association between delirium, hearing and visual impairment in multivariable logistic regression models, adjusting for: Model 1, we included predisposing factors for delirium (ie, dementia, weight loss and autonomy in the activities of daily living); Model 2, we added to Model 1 variables, which could be considered precipitating factors for delirium (ie, psychoactive drugs and urinary catheters). Results: A total of 3038 patients were included; delirium prevalence was 25%. Patients with delirium had a higher prevalence of hearing impairment (30.5% vs 18%; P < .001), visual impairment (24.2% vs 15.7%; P < .01) and bi-sensory impairment (16.2% vs 7.5%) compared with those without delirium. In the multivariable logistic regression analysis, the presence of bi-sensory impairment was associated with delirium in Model 1 [odds ratio (OR) 1.5, confidence interval (CI) 1.2-2.1; P = .00] and in Model 2 (OR 1.4; CI 1.1-1.9; P = .02), whereas the presence of visual and hearing impairment alone was not associated with delirium either in Model 1 (OR 0.8; CI 0.6-1.2, P = .36; OR 1.1; CI 0.8-1.4; P = .42) or in Model 2 (OR 0.8, CI 0.6-1.2, P = .27; OR 1.1, CI 0.8-1.4, P = .63). Conclusions and implications: Our findings support the importance of routine screening and specific interventions by a multidisciplinary team to implement optimal management of sensory impairments and hence prevention and the management of the patients with delirium.

ObjectiveTo assess the prevalence and isotypes of anti-nodal/paranodal antibodies to nodal/paranodal proteins in a large chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) cohort, compare clinical features in seronegative vs seropositive patients, and gather evidence of their isotype-specific pathogenic role.MethodsAntibodies to neurofascin-155 (Nfasc155), neurofascin-140/186 (Nfasc140/186), contactin-1 (CNTN1), and contactin-associated protein 1 (Caspr1) were detected with ELISA and/or cell-based assay. Antibody pathogenicity was tested by immunohistochemistry on skin biopsy, intraneural injection, and cell aggregation assay.ResultsOf 342 patients with CIDP, 19 (5.5%) had antibodies against Nfasc155 (n = 9), Nfasc140/186 and Nfasc155 (n = 1), CNTN1 (n = 3), and Caspr1 (n = 6). Antibodies were absent from healthy and disease controls, including neuropathies of different causes, and were mostly detected in patients with European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) definite CIDP (n = 18). Predominant antibody isotypes were immunoglobulin G (IgG)4 (n = 13), IgG3 (n = 2), IgG1 (n = 2), or undetectable (n = 2). IgG4 antibody-associated phenotypes included onset before 30 years, severe neuropathy, subacute onset, tremor, sensory ataxia, and poor response to intravenous immunoglobulin (IVIG). Immunosuppressive treatments, including rituximab, cyclophosphamide, and methotrexate, proved effective if started early in IVIG-resistant IgG4-seropositive cases. Five patients with an IgG1, IgG3, or undetectable isotype showed clinical features indistinguishable from seronegative patients, including good response to IVIG. IgG4 autoantibodies were associated with morphological changes at paranodes in patients' skin biopsies. We also provided preliminary evidence from a single patient about the pathogenicity of anti-Caspr1 IgG4, showing their ability to penetrate paranodal regions and disrupt the integrity of the Nfasc155/CNTN1/Caspr1 complex.ConclusionsOur findings confirm previous data on the tight clinico-serological correlation between antibodies to nodal/paranodal proteins and CIDP. Despite the low prevalence, testing for their presence and isotype could ultimately be part of the diagnostic workup in suspected inflammatory demyelinating neuropathy to improve diagnostic accuracy and guide treatment.Classification of evidenceThis study provides Class III evidence that antibodies to nodal/paranodal proteins identify patients with CIDP (sensitivity 6%, specificity 100%).

Purpose The outcome of lung transplantion (LuTx) suffers from a high rejection rate, and there are still huge gaps of knowledge about immune-mediated rejection mechanisms. Acute rejection (AR) can lead to chronic lung allograft dysfunction (CLAD), the main cause of poor survival and low quality of life. The standardized morphologic evaluation of rejection is based on histopathologic diagnostic criteria at a given time-point, but it has a limited prognostic value towards clinical outcome and the likelihood to develop CLAD. We analyzed immune-check point proteins in lung tissues of patients who received a LuTx and who were or were not undergoing rejection in the attempt to define novel immunological markers that could predict rejection. Methods We conducted an observational retrospective study on eight consecutive explanted grafts for chronic rejection and on transbronchial cryobiopsies (TCB) obtained from 24 consecutive patients during the first year LuTx follow-up. A broad spectrum of immunohistochemical analysis was carried out (PD1/CD279, PDL1/CD274, CTLA4/CD152, CD4, CD8, hFoxp3, TIGIT, TOX, B-Cell-Specific Activator Protein). Of those TCB-patients we recorded at least 1 year follow up of survival, infections and rejections (acute and chronic) rate. Results Exhausted (PD1+/TOX+) as well as Treg (PD1+/FOXP3+) lymphocytes were significantly reduced in restrictive allograft syndrome (RAS)-compared to bronchiolitis-obliterans-syndrome (BOS)-rejected lungs. PD1-expressing T-lymphocytes in TCBs correlated (sensitivity 0.69; specificity 1) with the presence of AR and were highly suggestive of CLAD development (sensitivity 0.86; specificity 0.82; overall 10 times higher risk of developing CLAD) at one-year follow-up. Conclusion Results herein for the first time show the importance of immunological checkpoints in the setting of LuTx rejection and indicate that the evaluation of the expression of such proteins could offer a distinct prognostic advantage in monitoring the onset of AR in patients who underwent LuTx. Longitudinal analyses in ampler cohorts will be needed to confirm these data.

Boron neutron capture therapy (BNCT) is a binary radiotherapy based on thermal-neutron irradiation of cells enriched with (10)B, which produces α particles and (7)Li ions of short range and high biological effectiveness. The selective uptake of boron by tumor cells is a crucial issue for BNCT, and studies of boron uptake and washout associated with cell survival studies can be of great help in developing clinical applications. In this work, boron uptake and washout were characterized both in vitro for the DHDK12TRb (DHD) rat colon carcinoma cell line and in vivo using rats bearing liver metastases from DHD cells. Despite a remarkable uptake, a large boron release was observed after removal of the boron-enriched medium from in vitro cell cultures. However, analysis of boron washout after rat liver perfusion in vivo did not show a significant boron release, suggesting that organ perfusion does not limit the therapeutic effectiveness of the treatment. The survival of boron-loaded cells exposed to thermal neutrons was also assessed; the results indicated that the removal of extracellular boron does not limit treatment effectiveness if adequate amounts of boron are delivered and if the cells are kept at low temperature. Cell survival was also investigated theoretically using a mechanistic model/Monte Carlo code originally developed for radiation-induced chromosome aberrations and extended here to cell death; good agreement between simulation outcomes and experimental data was obtained.

Background:Whether arrhythmia risks will increase if drugs with electrocardiographic (ECG) QT-prolonging properties are combined is generally supposed but not well studied. Based on available evidence, the Arizona Center for Education and Research on Therapeutics (AZCERT) classification defines the risk of QT prolongation for exposure to single drugs. We aimed to investigate how combining AZCERT drug categories impacts QT duration and how relative drug exposure affects the extent of pharmacodynamic drug–drug interactions.Methods:In a cohort of 2558 psychiatric inpatients and outpatients, we modeled whether AZCERT class and number of coprescribed QT-prolonging drugs correlates with observed rate-corrected QT duration (QTc) while also considering age, sex, inpatient status, and other QTc-prolonging risk factors. We concurrently considered administered drug doses and pharmacokinetic interactions modulating drug clearance to calculate individual weights of relative exposure with AZCERT drugs. Because QTc duration is concentration-dependent, we estimated individual drug exposure with these drugs and included this information as weights in weighted regression analyses.Results:Drugs attributing a ‘known’ risk for clinical consequences were associated with the largest QTc prolongations. However, the presence of at least two versus one QTc-prolonging drug yielded nonsignificant prolongations [exposure-weighted parameter estimates with 95% confidence intervals for ‘known’ risk drugs + 0.93 ms (–8.88;10.75)]. Estimates for the ‘conditional’ risk class increased upon refinement with relative drug exposure and co-administration of a ‘known’ risk drug as a further risk factor.Conclusions:These observations indicate that indiscriminate combinations of QTc-prolonging drugs do not necessarily result in additive QTc prolongation and suggest that QT prolongation caused by drug combinations strongly depends on the nature of the combination partners and individual drug exposure. Concurrently, it stresses the value of the AZCERT classification also for the risk prediction of combination therapies with QT-prolonging drugs.

Background: To investigate, retrospectively, the role of tumour histotype and antiangiogenic drugs for venous thromboembolism (VTE) development in advanced cancer patients treated in phase I studies. Methods: Patients enrolled and treated in phase I studies conducted by SENDO (Southern Europe New Drugs Organisation) were considered. Results: Data of 1415 patients were included in the analysis: 526 (37.2%) patients were males, median age was 57.3 years (range: 13–85). Fifty-six (3.96%) patients developed a VTE. At multivariate analysis gynaecologic (hazard ratio (HR): 2.8, 95% confidence interval (CI): 1.29–6.23, P=0.009) and gastrointestinal tumours (HR: 3.23, 95% CI: 1.18–8.87, P=0.023) as well as combination regimens of cytotoxic and antiangiogenic agents (HR: 2.6, 95% CI: 1.11–6.30, P=0.028), white blood cell >11 000 μl−1 (HR: 2.59, 95% CI: 1.10–6.09, P=0.028) and haemoglobin

Almost eight years ago, in December 2001, we performed for the first time in the world thermal neutron irradiation on an isolated liver of a patient. The organ was affected by diffuse metastases of a colon carcinoma and had been previously loaded with a 10 B compound. In July 2003, the same procedure was applied again on a patient for the treatment of unresectable and incurable hepatic metastases of a carcinoma of the rectum. Both patients are dead at present. Now we can analyze in depth the clinical history of these patients and evaluate the effectiveness of this therapy. From this exciting experience we learned much, and we also found out about complications till then unknown, which need to be studied and addressed experimentally. Unfortunately we can base our conclusions just on the experience we had with these two patients. We could have been much more detailed and firm in our statements if the number of clinical cases was larger. The BNCT Pavia project has been suspended, but it is more than likely to resume in a short time. Good findings were many. The procedure is feasible; the original concept of complete immersion of the diseased liver in a homogeneous neutron field proved effective and winning. The tumor masses resulted completely necrotic and unknown metastases too appeared radically treated; healthy hepatic tissue was preserved from both morphological and functional points of view; no symptoms of cirrhosis appeared even four years after treatment. For the long term surviving patient, quality of life was excellent. Other findings require to be tackled in depth. The “post-irradiation syndrome” we observed in both patients, with identical symptoms and biochemical derangements, creates a dramatic—even though totally reversible—clinical condition, that is the probable cause of death for our second patient, suffering from cardiomyopathy, 33 days after treatment. For the first patient, recurrences were a late yet fatal complication, for which even a further surgical revision was ineffective. We offer some hypotheses about their origin and possible prevention.

The purpose of the study was to assess frequency and predictors of disability measures in ALS. One hundred and fourteen newly diagnosed patients resident in eight administrative districts of Lombardy, Italy (population 4,947,554), included in a population-based registry, were followed for 2570 person-months (mean 22.5 months). The cumulative time-dependent risk of wheelchair, percutaneous endoscopic gastrostomy, and assisted ventilation was estimated according to the Kaplan-Meier method. Predictors of disability (age, sex, disease duration at diagnosis, type of onset, El-Escorial diagnosis) were assessed with the Cox proportional hazard function. During follow-up, 29 patients (25.4%) became wheelchair bound, 51 (44.7%) received gastrostomy, and 47 (41.2%) received assisted ventilation. The median time to loss of ambulation was 46.7 months (95% CI 36.5-56.8). The median time to gastrostomy and assisted ventilation was 31.1 months (95% CI 26.8-35.4) and 34.6 months (95% CI 29.6-39.6), respectively. Spinal onset ALS was the only predictor of loss of ambulation. Predictors of gastrostomy were older age, definite ALS, and shorter disease duration. Shorter disease duration was the only predictor of assisted ventilation. In conclusion, patients with ALS differ in terms of measures and predictors of disability. These factors are sources of bias and confounding in randomized clinical trials.

Given the encouraging results from our previous work on the clinical application of BNCT on non-resectable, chemotherapy resistant liver metastases, we explore the possibility to extend our technique to lung metastases. A fundamental requirement for BNCT is achieving higher 10B concentrations in the metastases compared to those in healthy tissue. For this reason we developed a rat model with lung metastases in order to study the temporal distribution of 10B concentration in tissues and tumoral cells. Rats with induced lung metastases from colon adenocarcinoma were sacrificed two hours after intraperitoneal Boronphenylalanine infusion. The lungs were harvested, frozen in liquid nitrogen and subsequently histological sections underwent neutron autoradiography in the nuclear reactor Triga Mark II, University of Pavia. Our findings demonstrate higher Boron uptake in tumoral nodules compared to healthy lung parenchyma 2 hours after Boronphenylalanine infusion.

After a long series of studies on the effects of neutron irradiation of 10 B loaded neoplastic cells both in culture and in animal experiments, we started the clinical application of BNCT on humans affected by liver metastases of a radically resected colon adenocarcinoma. The procedure we adopted includes a first surgical phase, with hepatectomy; a radiotherapeutic phase, in which the isolated liver, washed and chilled, is extracorporeally irradiated with thermal neutrons; and then a second surgical phase for the reconnection of the liver to the patient. Until now two patients have been subjected to the BNCT treatment. The first one survived 44 months with a good quality of life, and died because of diffuse recurrences of his intestinal tumour. The second patient had the same early perioperative course, but after 33 days a worsening of a dilatative cardiomyopaty, from which he was suffering, determined a cardiac failure and eventually death. This clinical experience, although limited, has shown that extracorporeal neutron irradiation of the liver is a feasible procedure, able to ensure the complete destruction of liver metastases and a possible long lasting survival. In our patients neutron irradiation caused massive cellular necrosis highly specific to tumour cells, whereas normal cells were mostly spared. Nevertheless, the impact of such a traumatic operation on the patient's organism must be taken into account. Finally, we have to be aware that the fight against tumour rarely leads to a complete victory. We now have an innovative weapon which is both powerful and partly unsettled: it must be refined and above all used.

Background: Vinorelbine prolongs survival and improves quality of life in elderly patients with advanced non-smallcell lung cancer (NSCLC). Some studies have also suggested that gemcitabine is well tolerated and effective in such patients. We compared the effectiveness and toxicity of the combination of vinorelbine plus gemcitabine with those of each drug given alone in an open-label, randomized phase III trial in elderly patients with advanced NSCLC. Methods: Patients aged 70 years and older, enrolled between December 1997 and November 2000, were randomly assigned to receive intravenous vinorelbine (30 mg/m 2 of body surface area), gemcitabine (1200 mg/m 2 ), or vinorelbine (25 mg/m 2 ) plus gemcitabine (1000 mg/m 2 ). All treatments were delivered on days 1 and 8 every 3 weeks for a maximum of six cycles. The primary endpoint was survival. Survival curves were drawn using the Kaplan–Meier method and analyzed by the Mantel–Haenszel test. Secondary endpoints were quality of life and toxicity. Results: Of 698 patients available for intention-to-treat analysis, 233 were assigned to receive vinorelbine, 233 to gemcitabine, and 232 to vinorelbine plus gemcitabine. Compared with each single drug, the combination treatment did not improve survival. The hazard ratio of death for patients receiving the combination treatment was 1.17 (95% confidence interval [CI] = 0.95 to 1.44) that of patients receiving vinorelbine and 1.06 (95% CI = 0.86 to 1.29) that of patients receiving gemcitabine. Although quality of life was similar across the three treatment arms, the combination treatment was more toxic than the two drugs given singly. Conclusion: The combination of vinorelbine plus gemcitabine is not more effective than single-agent vinorelbine or gemcitabine in the treatment of elderly patients with advanced NSCLC. [J Natl Cancer Inst 2003;95: 362–72]

Objective : To evaluate the reliability and sensitivity of the high-voltage electrical stimulation for studying proximal conduction of peripheral motor axons in normal subjects, S 1 radiculopathies and acquired demyelinating neuropathies. Methods : Twelve patients with compressive S 1 radiculopathy, 22 patients with acquired demyelinating neuropathy and 29 healthy volunteers were examined. The conduction of peripheral motor axons between lumbosacral roots and the sciatic nerve at the gluteal fold was investigated by high-voltage electrical stimulation delivered percutaneously. Results : The main electrophysiological finding in S 1 radiculopathy was an abnormal side to side difference in the amplitude of the compound motor action potential by proximal stimulation. Overall, the frequency of abnormalities detected by using high-voltage electrical stimulation was similar to that found with conventional EMG studies, and the two methods showed electrophysiological alterations in the same patients. In all patients with acquired demyelinating neuropathy, the proximal motor nerve conduction velocity from lumbosacral roots to the sciatic nerve at the gluteal fold was reduced; proximal stimulation of the motor axons revealed electrophysiological abnormalities more often than when using other electrophysiological techniques (F wave and H reflex). Conclusions : High-voltage electrical stimulation of peripheral motor axons shows high sensitivity in detecting proximal neuropathies; it can also define the site and relevance of proximal lesions in the peripheral nervous system better than other conventional techniques.

Osteosarcoma is the most common non-hematologic primary cancer type that develops in bone. Current osteosarcoma treatments combine multiagent chemotherapy with extensive surgical resection, which in some cases makes necessary the amputation of the entire limb. Nevertheless its infiltrative growth leads to a high incidence of local and distant recurrences that reduce the percentage of cured patients to less than 60%. These poor data required to set up a new therapeutic approach aimed to restrict the surgical removal meanwhile performing a radical treatment. Boron neutron capture therapy (BNCT), a particular radiotherapy based on the nuclear capture and fission reactions by atoms of (10)B, when irradiated with thermal neutrons, could be a valid alternative or integrative option in case of osteosarcoma management, thanks to its peculiarity in selectively destroying neoplastic cells without damaging normal tissues. Aim of the present work is to investigate the feasibility of employing BNCT to treat the limb osteosarcoma. Boronophenylalanine (BPA) is used to carry (10)B inside the neoplastic cells. As a first step the endocellular BPA uptake is tested in vitro on the UMR-106 osteosarcoma cell line. The results show an adequate accumulation capability. For the in vivo experiments, an animal tumor model is developed in Sprague-Dawley rats by means of an intrafemoral injection of UMR-106 cells at the condyle site. The absolute amounts of boron loading and the tumor to normal tissue (10)B ratio are evaluated 2 h after the i.v. administration of BPA. The boron uptake by the neoplastic tissue is almost twice the normal one. However, higher values of boron concentration in tumor are requested before upholding BNCT as a valid therapeutic option in the treatment of osteosarcoma.

Aim To explore the feasibility and activity of a combined regimen of high-dose epirubicin and cisplatin as an alternative to current treatments for non-small cell lung cancer (NSCLC). Method Forty-four patients with stage IIIb or IV NSCLC, median Karnofsky index 90, were enrolled. Epirubicin (60 mg/m2) was administered on days 1 and 2 and cisplatin (100 mg/m2) on day 1. Treatment was repeated every 21 days for a maximum of six cycles. A hematopoietic growth factor (G-CSF) was used only for patients reaching codified nadir count values. Results A total of 130 cycles were administered with a mean of 2.9 cycles per patient. Of 41 assessable patients one showed a complete response and 15 had partial responses (overall response rate, 39%). Grade 3 or 4 leukopenia and grade 3 hemoglobin toxicity were seen in 40% and 14%, respectively, of the administered cycles. The most common nonhematologic toxic events were nausea and vomiting, mucositis, anorexia, and asthenia. Conclusions This epirubicin-cisplatin regimen seemed effective and was generally well tolerated, and therefore suitable for use in an outpatient setting.

To determine whether granulocyte-colony stimulating factor and erythropoietin are effective in the therapy of neutropenia and anaemia related to human immunodeficiency virus (HIV) infection and to anti-retroviral agents, we recruited 11 HIV-infected children (mean age 4 years 10 months). All the children were given granulocyte-colony stimulating factor at a dosage of 5 μ-g/kg twice or three times a week while erythropoietin was administered additionally to three patients at a dosage of 50 U/kg twice a week. Both agents were administered subcutaneously for at least 4 months. Leukocyte and neutrophil counts significantly increased during the treatment (after 1 month, P = 0.003 and P = 0.009, respectively). Erythropoietin prevented blood transfusions and increased haemoglobin levels in the three children treated. No side-effects were recorded during the administration of either agent. Granulocyte-colony stimulating factor and erythropoietin appear to be safe and useful agents in the management of HIV-infected children.

Background: Cisplatin-based chemotherapy is generally considered the most active treatment for advanced non-small-cell lung cancer. The combination of cisplatin and etoposide had for some time been the standard treatment at our center. Of the other active regimens, cisplatin in combination with mitomycin-C, vindesine or ifosfamide (MVP or MIC) showed the highest response rates. We decided to perform a comparative trial of the three «best» regimens in order to define a possible standard regimen in advanced NSCLC. Materials and methods: From May 1989 to April 1992, 393 consecutive, previously untreated NSCLC patients, stages IIIB and IV, were randomized to receive either cisplatin (120 mg/sqm day 1)+etoposide (100 mg/sqm days 1-3) every 3 weeks (PE) or cisplatin (120 mg/sqm every 4 weeks) + mitomycin-C (8 mg/sqm days 1-29-71) + vindesine (3 mg/sqm days 1-8-15-22) (MVP) or cisplatin (120 mg/sqm day 1) + mitomycin-C (6 mg/sqm day 1) + ifosfamide (3 mg/ sqm day 2) every 3 weeks (MIC). Of these, 382 were evaluable for survival and 360 for response. Results: Response rates were statistically higher for both MIC (40%) and MVP (36%) than for the PE arm (23%). Survival estimates analyzed by the log-rank test showed a significant benefit (p < 0.04) for patients treated with three-drug regimens (MVP; MIC) as compared to those in the PE arm. The main toxicity was myelosuppression; thrombocytopenia WHO grade 3-4 was worse in the MIC arm; nephrotoxicity grade 3-4 was also more frequent in the MIC arm. Conclusions: A three-drug cisplatin-based regimen (MVP; MIC) should be considered as reference treatment in NSCLC

Background To investigate the incidence, risk factors and clinical implications of venous thromboembolism (VTE) in advanced cancer patients treated in phase I studies. Patients and methods Patients enrolled and treated in phase I studies conducted by SENDO (Southern Europe New Drugs Organization) Foundation between 2000 and 2010 in 15 experimental centers were considered for the study. Clinical data, including adverse events, were prospectively collected during the studies and retrospectively pooled for VTE analysis. Results Data of 1415 patients were considered for analysis. Five hundred and twenty-six (37.2%) patients were males, and median age was 57.3 years (range: 13–85). Eighty-five percent of patients had metastatic disease, while the remaining had locally advanced irresectable disease. For 706 (49.9%) of the patients, the study treatment was with cytotoxic agent(s) only, for 314 with target therapy(ies) only, while the remaining patients received a target therapy in combination with a cytotoxic drug. Fifty-six (3.96%) patients who developed a VTE, almost all (89.3%) during the course of treatment, the remaining during the follow-up. At univariate analysis, the Khorana score, the combination of an antiangiogenic agent with a cytotoxic drug, and the time from first cancer diagnosis to study entry (as continuous variable) were associated with a statistically significant increase of VTE occurrence. The multivariate analysis confirmed only a statistically significant association for the Khorana score. The hazard ratio of VTE occurrence was 7.88 [95% confidence interval (CI) 2.86–21.70) and 2.74 (95% CI 1.27–5.92) times higher for the highest (≥3) and intermediate (1–2) scores as compared with score = 0. Conclusions VTE is a relatively common complication among patients treated in the context of phase I studies. The Khorana score predicts VTE development and can be used to identify patients at high of VTE.

Cell death is a crucial endpoint in radiation-induced biological damage: on one side, cell death is a reference endpoint to characterise the action of radiation in biological targets; on the other side, any cancer therapy aims to kill tumour cells. Starting from Lea's target theory, many models have been proposed to interpret radiation-induced cell killing; after briefly discussing some of these models, in this paper, a mechanistic approach based on an experimentally observed link between chromosome aberrations and cell death was presented. More specifically, a model and a Monte Carlo code originally developed for chromosome aberrations were extended to simulate radiation-induced cell death applying an experimentally observed one-to-one relationship between the average number of 'lethal aberrations' (dicentrics, rings and deletions) per cell and -ln S, S being the fraction of surviving cells. Although such observation was related to X rays, in the present work, the approach was also applied to protons and alpha particles. A good agreement between simulation outcomes and literature data provided a model validation for different radiation types. The same approach was then successfully applied to simulate the survival of cells enriched with boron and irradiated with thermal neutrons at the Triga Mark II reactor in Pavia, to mimic a typical treatment for boron neutron capture therapy.

Lung carcinoma is the leading cause of cancer mortality in the Western countries. Despite the introduction over the last few years of new therapeutic agents, survival from lung cancer has shown no discernible improvement in the last 20 years. For these reasons any efforts to find and validate new effective therapeutic procedures for lung cancer are very timely. The selective boron uptake in the tumour with respect to healthy tissues makes Boron Neutron Capture Therapy a potentially advantageous option in the treatment of tumours that affect whole vital organs, and that are surgically inoperable. To study the possibility of applying BNCT to the treatment of diffuse pulmonary tumours, an animal model for boron uptake measurements in lung metastases was developed. Both healthy and tumour-bearing rats were infused with Boronophenylalanine (BPA) and sacrificed at different time intervals after drug administration. The lungs were extracted, and prepared for boron analysis by neutron autoradiography and α-spectroscopy. The boron concentrations in tumour and normal lung were plotted as a function of the time elapsed after BPA administration. The concentration in tumour is almost constant within the error bars for all the time intervals of the experiment (1–8 h), while the curve in normal lung decreases after 4 h from BPA infusion. At 4 h, the ratio of boron concentration in tumour to boron concentration in healthy lung is higher than 3, and it stays above this level up to 8 h. Also the images of boron distribution in the samples, obtained by neutron autoradiography, show a selective absorption in the metastases.

Boron neutron capture therapy (BNCT) is an anticancer therapy based on the incorporation of (10)B in tumors, followed by neutron irradiation. Recently, the synthesis and delivery of new boronated compounds have been recognized as some of the main challenges in BNCT application. Here, we report on the use of liposomes as carriers for BNCT active compounds. Two carborane derivatives, i.e., o-closocarboranyl beta-lactoside (LCOB) and 1-methyl-o-closocarboranyl-2-hexylthioporphyrazine (H(2)PzCOB), were loaded into liposomes bearing different surface charges. The efficacy of these formulations was tested on model cell cultures, that is, DHD/K12/TRb rat colon carcinoma and B16-F10 murine melanoma. These induce liver and lung metastases, respectively, and are used to study the uptake of standard BNCT drugs, including borophenylalanine (BPA). Boron concentration in treated cells was measured by alpha spectrometry at the TRIGA mark II reactor (University of Pavia). Results showed high performance of the proposed formulations. In particular, the use of cationic liposomes increased the cellular concentration of (10)B by at least 30 times more than that achieved by BPA.

In order for boron neutron capture therapy (BNCT) to be eligible for application in lung tumour disease, three fundamental criteria must be fulfilled: there must be selective uptake of boron in the tumour cells with respect to surrounding healthy tissue, biological effectiveness of the radiation therapy and minimal damage or collateral effects of the irradiation on the surrounding tissues. In this study, we evaluated the biological effectiveness of BNCT by in vitro irradiation of rat colon-carcinoma cells previously incubated in boron-enriched medium. One part of these cells was re-cultured in vitro while the other was inoculated via the inferior vena cava to induce pulmonary metastases in a rat model. We observed a post-irradiation in vitro cell viability of 0.05% after 8 days of cell culture. At 4 months follow-up, all animal subjects in the treatment group that received irradiated boron-containing cells were alive. No animal survived beyond 1 month in the control group that received non-treated cells (p

Background: the EU Directive states the requirement of staff working in trials to be qualified by education, training and experience [14]. This includes the research nurse; however, in the transition from ward nurse to research nurse, new and highly developed skills and knowledge are required in order to work effectively. Methods: an educational programme was developed, which included a review of current knowledge and baseline practice, development of competencies related to the role of research nurse, haemato-oncology and clinical trial education to support this advanced practice for nurses in clinical trials. Results: overall, the feedback on the course by the nurses was very positive, and the nurses were able to undertake the role of research nurse within specified clinical trials.

The paper reports on the efficacy and side effects of high-dose vitamin A, administered as adjuvant treatment for resected stage I lung cancer in a randomized clinical trial. After a median follow-up

The ability to selectively hit the tumour cells is an essential characteristic of an anti-tumour therapy. In boron neutron capture therapy (BNCT) this characteristic is based on the selective uptake of 10 B in the tumour cells with respect to normal tissues. An important step in the BNCT planning is the measurement of the boron concentration in the tissue samples, both tumour and healthy. When the tumour is spread through the healthy tissue, as in the case of metastases, the knowledge of the different kinds of tissues in the sample being analysed is crucial. If the percentage of tumour and normal tissues cannot be evaluated, the obtained concentration is a mean value depending on the composition of the different samples being measured. In this case an imaging method that could give information both on the morphology and on the spatial distribution of boron concentration in the sample would be a fundamental support. In this paper, the results of the boron uptake analysis in the tumour and in the healthy samples taken from human livers after boron phenylalanine (BPA) infusion are shown; boron imaging was performed using neutron autoradiography.

PURPOSE: To evaluate whether two commonly used newer platinum-based regimens offer any advantage over vinorelbine-cisplatin (reference regimen) in response rate for patients with advanced non–small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Chemotherapy-naive patients were randomized to receive gemcitabine 1,250 mg/m2 days 1 and 8 plus cisplatin 75 mg/m2 day 2 every 21 days (GC arm), or paclitaxel 225 mg/m2 (3-hour infusion) then carboplatin (area under the concentration-time curve of 6 mg/mL·min), both on day 1 every 21 days (PCb arm), or vinorelbine 25 mg/m2/wk for 12 weeks then every other week plus cisplatin 100 mg/m2 day 1 every 28 days (VC arm). RESULTS: Six hundred twelve patients were randomized to treatment (205 GC, 204 PCb, and 203 VC). Overall response rates for the GC (30%) and PCb (32%) arms were not significantly different from that of the VC arm (30%). There were no differences in overall survival, time to disease progression, or time to treatment failure. Median survival for the GC, PCb, and VC groups was 9.8, 9.9, and 9.5 months, respectively. Neutropenia was significantly higher on the VC arm (GC 17% or PCb 35% v VC 43% of cycles, P < .001), as was thrombocytopenia on the GC arm (GC 16% v VC 0.1% of cycles, P < .001). Alopecia and peripheral neurotoxicity were most common on the PCb arm, as was nausea/vomiting on the VC arm (P < .05). CONCLUSION: Efficacy end points were not significantly different between experimental and reference arms, although toxicities showed differences. These findings suggest that chemotherapy in NSCLC has reached a therapeutic plateau.

The rate of seroconversion for antibody to Chlamydia pneumoniae was analysed in blood samples of 26 vertically HIV-1 infected children and 14 seroreverter children (HIV-negative children born to HIV-positive mothers) during a 3-year study period. Seroconversion for Chlamydia pneumoniae was found in 13 of 26 HIV-1 infected children and in 1 of 14 in the seroreverter group (P=0.013). A lower mean CD4+ cell count and p24 antigen positivity at enrolment were significantly associated with seroconversion for Chlamydia pneumoniae. Signs and symptoms of acute respiratory infection were recorded in the 30 to 40 days preceding collection of the blood samples showing seroconversion for Chlamydia pneumoniae in 8 of 13 HIV-1 infected children and in the single seroreverter. This study confirms the potential role of Chlamydia pneumoniae in the pathogenesis of respiratory tract infections in HIV-1 infected subjects.

PURPOSE The nucleoside analog, gemcitabine, has shown activity as a single agent in the treatment of metastatic non-small-cell lung cancer (NSCLC). Its combination with cisplatin in preclinical models suggested synergy between the two drugs. The aim of the study was to evaluate the clinical efficacy and toxicity of the cisplatin-gemcitabine combination in advanced NSCLC. PATIENTS AND METHODS Forty-eight consecutive previously untreated NSCLC patients entered the trial from January to June 1994. The median age was 60 years (range, 37 to 70) and performance status (PS) was 0 or 1; 22 patients had unresectable stage III disease (21 stage IIIB and one stage IIIA) and 26 had stage IV disease. Gemcitabine 1 g/m2 was administered weekly (days 1, 8, and 15) followed by a 1-week rest and cisplatin 100 mg/m2 on day 2 of each 28-day cycle. Survival and response were determined in accordance with the intention-to-treat principle in all enrolled patients. RESULTS Of 48 assessable patients, one (stage IV) had a complete response (CR) and 25 achieved a partial response (PR). The overall response rate was 54% (95% confidence interval [CI], 40% to 68%). Thrombocytopenia was the main side effect, with 52% of patients experiencing grade III to IV toxicity, which was usually short-lived and responsible for the omission of gemcitabine administration on day 15 in 50% of chemotherapy courses. The median survival time was 61.5 weeks (95% CI, 40 to 71). CONCLUSION The combination of gemcitabine and cisplatin induced a high response rate in both stage IIIB and IV NSCLC, with modest side effects. The regimen deserves further careful evaluation in a phase III prospective randomized trial.

To evaluate the efficacy of a three-drug regimen vs. a two-drug CDDP based combination in the treatment of NSCLC, we conducted a three-arm randomized parallel trial comparing (a) CDDP (120 mg/m 2 day 1) + etoposide (100 mg/m 2 days 1–3) every 3 weeks (PE —arm A); (b) CDDP (120 mg/m 2 every 4 weeks) + mitomycin (8 mg/m 2 days 1, 29, 71) + vindesine (3 mg/m 2 days 1, 8, 15, 22 every 2 weeks) (MVP —arm B); and (c) CDDP (120 mg/m 2 day 1) + mitomycin (6 mg/m 2 day 1) + ifosfamide (3 g/m 2 day 2) every 3 weeks (MIC —arm C). From May 1989 to April 1992, 393 consecutive previously untreated patients with NSCLC Stage IIIB and IV entered the trial; 373 were evaluable for survival and 360 for response. The response rate was significantly better for both the three-drug regimens compared with PE (Table 3). Logistic regression model showed a significantly better response in patients with a good P.S. and in Stage IIIB. Main toxicity consisted of myelosuppression: neutropenia Grade III —IV was recorded in 14% (arm A), 15% (arm B) and 21% (arm C). Thrombocytopenia Grade III —IV was worst in arm C: 10% vs. 5% (arm A) and 3% (arm B). Nephrotoxicity Grade III —IV was more common in arm C: 3.5%. Toxic deaths were 11 (3%: three in arm A, five in arm B, three in arm C). From our data, the three-drug containing regimens, MVP and MIC, appear more active than the two-drug combination PE in treatment of advanced NSCLC.

PURPOSE Vitamin A and retinoids are strong inhibitors of epithelial cancer promotion and progression in experimental carcinogenesis. This study examined whether they may prevent the occurrence of upper aerodigestive cancer in subjects heavily exposed to tobacco smoking, such as patients already cured of an early-stage lung cancer. PATIENTS AND METHODS The adjuvant effect of high-dose vitamin A was tested on 307 patients with stage I non-small-cell lung cancer. After curative surgery, patients were randomly assigned to either a group prescribed retinol palmitate administration (orally 300,000 IU daily for 12 months) or a control group prescribed no treatment. RESULTS After a median follow-up of 46 months, the number of patients with either recurrence or new primary tumors was 56 (37%) in the treated arm and 75 (48%) in the control arm. Eighteen patients in the treated group developed a second primary tumor, and 29 patients in the control group developed 33 second primary tumors. A statistically significant difference in favor of treatment was observed concerning time to new primary tumors in the field of prevention (P = .045, log-rank test). The treatment difference in terms of disease-free interval was close to statistical significance (P = .054, log-rank test) and just significant when adjusted for primary tumor classification (P = .038, Cox regression model). CONCLUSION Daily oral administration of high-dose vitamin A is effective in reducing the number of new primary tumors related to tobacco consumption and may improve the disease-free interval in patients curatively resected for stage I lung cancer. The impact of such a treatment on survival needs to be further explored.

The following paper reports the evaluation of 53 consecutive patients with advanced ovarian epithelial carcinoma (FIGO stage III-IV), treated between October 1984 and December 1987 with immediate or delayed cytoreduction surgery and chemotherapy. Combination chemotherapy consisted of cisplatinum 45 mg/m2 i.v. for 2 consecutive days and cyclophosphamide 900 mg/m2 i.v. on the second day, administered every 28 days for a maximum of 8 courses. Objective responses were observed in 35 of 50 evaluable patients (70%), 17 (34%) of whom were pathological complete remissions (pCR). For patients with minimal residual disease before chemotherapy a higher pCR rate was achieved (10/20 vs. 7/30; p = N.S.). Median survival time of all patients was 29 months; subjects with minimal residual disease and good performance status before treatment had higher survival (48 vs. 22 months-p0.05 and 29 vs. 9 months-p0.05, respectively). Median time to progression was 25 months. After a median follow-up of 60 months, 15 (28%) patients were alive, 14 of whom disease-free. Toxicity was moderate with a particularly low incidence of nephrotoxicity and no case of serious long-lasting neuropathy. These findings suggest that the described combination has an efficacy comparable to other CDDP-containing combinations, using 2, 3 or more drugs, with a low incidence of acute serious toxicities and of disabling delayed sequelae.

In order to evaluate the response to immunization of HIV-infected children we studied the humoral response to an enhanced potency inactivated poliovaccine (E-IPV) of 43 children born of HIV seropositive mothers. All these subjects have been followed for 32 (15-48) months in order to ascertain their infection status. After a course of 2 doses of E-IPV, 88% of children had neutralizing antibody (n.a.) titers greater than 1:4 to the 3 poliovirus serotypes and 100% to at least 2 polio strains. No statistically significant differences both as rates of n.a. positive subjects and as antibody levels were found between HIV infected children and those who lost HIV antibodies. The poorest response was observed in subjects with full-blown immunodeficiency (CD4 less than 1000/mm3, reduced response to PWM). Sixteen children also received a booster dose of vaccine one year after the completion of the primary cycle. Infected and non-infected subjects responded to the same extent with high levels of n.a. to this immunization. Interestingly, the recall dose was also able to induce high n.a. titers in those HIV infected children who showed significant decreases of n.a. titers in the months following the end of the primary cycle.

Presently only about 6% of liver cancers are curable, namely those most delimited and surgically resectable. The aim of our project is to investigate the possibility of curing patients with unresectable liver-only cancers, either primary or secondary to a resectable primary malignancy, consisting mainly of hepatocellular carcinoma and liver metastases from colonic carcinoma. The curability of liver cancers would increase by nearly 30% (1, 2) and in Italy about 3400 patients per year could be saved (3). To reach this goal a specifically targeted treatment on both organ and neoplastic tissue should be realized. In fact conventional therapies (systemic chemotherapy, external radiotherapy) are only palliative, because of their hepatic or systemic toxicity. Also more selective approaches, through a loco-regional or tumour focused application (e.g. intra-arterial chemotherapy, radioimmunotherapy), still give poor results because they lack one of the two required selectivities (1,2). Besides, the liver is not removable or artificially replacable and cancer contraindicates liver transplantation (4, 5).

The increased incidence of malignancies associated with AIDS has been the subject of several reports in the North American literature: besides Kaposi’s sarcoma and other tumours, such as squamous carcinoma of the tongue and cloacogenic carcinoma of the anorectum [1–22], malignant lymphomas have been demonstrated to be one of the major problems among the neoplastic complications of AIDS [12–24]. According to the North American experience, non-Hodgkin’s lymphomas in patients with AIDS or AIDS-related clinical conditions present at an advanced stage in which lesions are concentrated in extranodal and often unusual locations, notably the CNS. Disease confined to the lymph nodes is uncommon. These lymphomas are predominantly high-grade B-cell neoplasms classified as immunoblastic and Burkitt’s-like lymphomas. A variety of severe opportunistic infections and Kaposi’s sarcoma affect these patients. At the same time, the association with AIDS is strengthened by the regular demonstration of reversed ratios of helper (T4+) and suppressor (T8+) lymphocytes in the peripheral blood and by the presence of antibodies to human immune deficiency virus (HIV) [22]. The prognosis is dismal: response to chemotherapy does not positively affect median survival. Mortality rates analysed by histological grade are higher than the currently reported rates for comparable patient populations [18].