Culture of 3D bioprinted bone constructs requires an increased fluid dynamic stimulation.

In vitro flow-induced mechanical stimulation of developing bone tissue constructs has been shown to favor mineral deposition in scaffolds seeded with cells directly exposed to the fluid flow. However, the effect of fluid dynamic parameters, such as shear stress (SS), within 3D bioprinted constructs is still unclear. Thus, this study aimed at correlating the SS levels and the mineral deposition in 3D bioprinted constructs, evaluating the possible dampening effect of the hydrogel. Human mesenchymal stem cells (hMSCs) were embedded in 3D bioprinted porous structures made of alginate and gelatin. 3D bioprinted constructs were cultured in an osteogenic medium assessing the influence of different flow rates (0, 0.7 and 7 ml/min) on calcium and collagen deposition through histology, and bone volume (BV) through micro-computed tomography. Uniform distribution of calcium and collagen was observed in all groups. Nevertheless, BV significantly increased in perfused groups as compared to static control, ranging from 0.35±0.28 mm3, 11.90±8.74 mm3 and 25.81±5.02 mm3 at week 3 to 2.28±0.78 mm3, 22.55±2.45 mm3 and 46.05±5.95 mm3 at week 6 in static, 0.7 and 7 ml/min groups, respectively. SS values on construct fibers in the range 10-100 mPa in 7 ml/min samples were twice as high as those in 0.7 ml/min samples showing the same trend of BV. The obtained results suggest that it is necessary to enhance the flow-induced mechanical stimulation of cell-embedding hydrogels to increase the amount of mineral deposited by hMSCs, compared to what is generally reported for the development of in vitro bone constructs. STATEMENT OF SIGNIFICANCE: In this study, we evaluated for the first time how the hydrogel structure dampens the effect of flow-induced mechanical stimulation during the culture of 3D bioprinted bone tissue constructs. By combining computational and experimental techniques we demonstrated that those shear stress thresholds generally considered for culturing cells seeded on scaffold surface, are no longer applicable when cells are embedded in 3D bioprinted constructs. Significantly, more bone volume was formed in constructs exposed to shear stress values generally considered as detrimental than in constructs exposed shear stress values generally considered as beneficial after 3 weeks and 6 weeks of dynamic culture using a perfusion bioreactor.

The Clean Care Contest: promoting hand hygiene among healthcare and medical students.

INTRODUCTION: Despite continuing efforts, compliance rates and knowledge of best practices in hand hygiene remain disappointing. Recognizing that conventional educational tools seem out of touch with young people and that the med and messages contents need refreshing, the Italian Study Group of Hospital Hygiene of the Italian Society of Hygiene, Preventive Medicine and Public Health devised a novel approach to promote the creation of innovative educational tools for improving knowledge of, and compliance with, hand hygiene rules among healthcare and medical students. METHODS: A contest in creating educational material on hand hygiene practices involved university students of nursing and medicine, and of other healthcare degrees. Students from the universities of the GISIO network were invited to create educational material (e.g., videos, posters, presentations, leaflets, and screensavers) to be presented by May 5th 2019 during the World Hand Hygiene Day / Save Lives: Clean Your Hands Global Annual Initiative of the World Health Organization). A local and a national winners were awarded. RESULTS: Three different local and national contests were performed during 2016, 2017 and 2018. During the three-year period, more than 270 educational tools have been developed: 130 (48%) were judged useful for hand hygiene promotion campaigns. The most frequent projects participating in the contests were videos (39%), posters (29%), leaflets (14%), and others (18%) submitted by more than 1,500 students of nursing (40%), medicine (31%), dentistry (7%), and of other healthcare courses in 14 universities. Products were evaluated by a local committee and, subsequently, local winners represented their University in a national contest. CONCLUSIONS: The contest provided a framework for the creation of innovative and potentially effective educational tools via an engaging approach that leveraged student creativity. Given the need to improve compliance rates, this study suggests that new ways can be advantageously explored to teach hand hygiene procedures and increase awareness of the importance of their consistent use among healthcare and medical students.

A systematic review and Meta-analysis on the association between Hand-Foot Syndrome (HFS) and Cancer Chemotherapy Efficacy.

Hand-foot syndrome (HFS) is a common skin toxicity of traditional chemotherapies. Some studies showed that HFS has an association with progression-free survival (PFS) and the overall survival (OS). So far, there is not available any systematic literature reviews or meta-analysis aimed to assess the associations between HFS, PFS and OS. For this reason, this study aims to quantitatively summarize, critically review, and interpret the recent literature related to the associations between HFS and efficacy of chemotherapy in terms of PFS and OS. Queries shaped by PICOM framework, a systematic search of three electronic databases (PubMed, Scopus, and Science Direct) was carried out for the period between January 2010 and December 2017. Quantitative data pooling was based on the calculation of Hazard Ratio (HR) with 95% Confidence Interval (95% CI) for the OS and PFS associated to the presence of HFS, through the data of original publications. Five papers were included in this systematic review for the quantitative data pooling. Patients with HFS showed improved PFS (HR = 0.532 [0.431-0.656]; p = 0.000) and improved OS (HR = 0.522 [0.427-0.638]; p = 0.000). HFS causes a reduction of compliance with oncology treatments. Healthcare providers should use this result as a trigger to foster patients' coping and the one of their family caregivers, enhancing their adherence to cancer treatments.

Epidemiology of intensive care unit-acquired sepsis in Italy: results of the SPIN-UTI network.

BACKGROUND: Sepsis is the major cause of mortality from any infectious disease worldwide. Sepsis may be the result of a healthcare associated infection (HAI): the most frequent adverse events during care delivery especially in Intensive Care Units (ICUs). The main aim of the present study was to describe the epidemiology of ICU-acquired sepsis and related outcomes among patients enrolled in the framework of the Italian Nosocomial Infections Surveillance in ICUs - SPIN-UTI project. STUDY DESIGN: Prospective multicenter study. METHODS: The SPIN-UTI network adopted the European protocols for patient-based HAI surveillance. RESULTS: During the five editions of the SPIN-UTI project, from 2008 to 2017, 47.0% of HAIs has led to sepsis in 832 patients. Overall, 57.0% episodes were classified as sepsis, 20.5% as severe sepsis and 22.5% as septic shock. The most common isolated microorganisms from sepsis episodes were Acinetobacter baumannii, Klebsiella pneumoniae and Pseudomonas aeruginosa. The case fatality rate increased with the severity of sepsis and the mean length of ICU-stay was significantly higher in patients with ICU-acquired sepsis than in patients without. CONCLUSION: Our study provides evidence that ICU-acquired sepsis occurs frequently in Italian ICU patients and is associated with a high case fatality rate and increased length of stay. However, in order to explain these findings further analyses are needed in this population of ICU patients.

A multicentre study on epidemiology and prevention of needle stick injuries among students of nursing schools.

INTRODUCTION: Among the health professions with a long period of training, the students of the Nursing Bachelor's Degree are the most exposed to biological risk resulting from accidents, in particular with needles and cutting edges. The aim of the study was to estimate the frequency and the circumstances for the occurrence of needle stick injuries, as a knowledge base for targeted prevention interventions. METHODS: The study was carried out between May and July 2017 in 11 Universities in Italy and 1 in Albania (associated with the "Tor Vergata" University of Rome). An anonymous semi-structured questionnaire was proposed to 1st (second semester), 2nd and 3rd year students of Nursing Bachelor's Degree. RESULTS: A total of 2742 questionnaires were collected. The average age of participants was 22.9 years (median 22, range 19-60 years), 73% of whom were females. A total of 381 injuries were reported. Three hundred and sixteen students (11.8%) underwent at least 1 injury (12.7% among females, 9.7% among males); 41 students declared two or more injuries; four students did not report the number of injuries occurred. The first injury occurred, as an average, 17 days after the start of the internship (median 15 days) and, in 25% of the cases, during the first 9 days. The highest percentage of accidents occurred during the first internship (25.3% of the total) and decreased with the progress of the training path. The injuries occurred in 38% of cases during drug preparation, 24% when disposing of sharp devices, 15% while re-capping needles, 13% during blood sampling and 10% in other circumstances. In 51.2% of cases, the needle was not sterile. Among the nursing students who suffered a needle stick injury, 58.1% declared that they had performed the post-exposure prophylaxis. 96% of students stated to be vaccinated against Hepatitis B virus. Amongst the students who had their serological status checked (74%), 18% stated the antibody titre was not protective. 49.8% of students answered to have been trained in advance on the correct procedures to avoid needle stick and cutting edges injuries in each clinical ward attended, 41.2% referred that this occurred only in some wards and 10% in no ward at all. CONCLUSION: The results of this study show a high percentage of needle stick injuries in students of the Nursing Bachelor's Degree. Therefore, there is a need for careful reflection on the most effective methods of targeted training acquisition of knowledge, skills and behavioural models useful for the exercise of the profession.

Tackling muscle fibrosis: From molecular mechanisms to next generation engineered models to predict drug delivery.

Muscle fibrosis represents the end stage consequence of different diseases, among which muscular dystrophies, leading to severe impairment of muscle functions. Muscle fibrosis involves the production of several growth factors, cytokines and proteolytic enzymes and is strictly associated to inflammatory processes. Moreover, fibrosis causes profound changes in tissue properties, including increased stiffness and density, lower pH and oxygenation. Up to now, there is no therapeutic approach able to counteract the fibrotic process and treatments directed against muscle pathologies are severely impaired by the harsh conditions of the fibrotic environment. The design of new therapeutics thus need innovative tools mimicking the obstacles posed by the fibrotic environment to their delivery. This review will critically discuss the role of in vivo and 3D in vitro models in this context and the characteristics that an ideal model should possess to help the translation from bench to bedside of new candidate anti-fibrotic agents.

Industrialization of a perfusion bioreactor: Prime example of a non-straightforward process.

Bioreactors are essential enabling technologies for the translation of advanced therapies medicinal products from the research field towards a successful clinical application. In order to speed up the translation and the spread of novel tissue engineering products into the clinical routine, tissue engineering bioreactors should evolve from laboratory prototypes towards industrialized products. In this work, we thus challenged the industrialization process of a novel technological platform, based on an established research prototype of perfusion bioreactor, following a GMP-driven approach. We describe how the combination of scientific background, intellectual property, start-up factory environment, wise industrial advice in the biomedical field, design, and regulatory consultancy allowed us to turn a previously validated prototype technology into an industrial product suitable for serial production with improved replicability and user-friendliness. The solutions implemented enhanced aesthetics, ergonomics, handling, and safety of the bioreactor, and they allowed compliance with the fundamental requirements in terms of traceability, reproducibility, efficiency, and safety of the manufacturing process of advanced therapies medicinal products. The result is an automated incubator-compatible device, housing 12 disposable independent perfusion chambers for seeding and culture of any perfusable tissue. We validated the cell seeding process of the industrialized bioreactor by means of the Design of Experiment approach, whilst the effectiveness of perfusion culture was evaluated in the context of bone tissue engineering.

Italian version of Nursing Students' Perception of Instructor Caring (I-NSPIC): assessment of reliability and validity.

BACKGROUND: Clinical experience is an essential component of nursing education since it provides students with the opportunity to construct and develop clinical competencies. Instructor caring is a pivotal facilitator at the forefront of clinical education, playing a key and complex educating role in clinical sectors. For these reasons the aims of this study was to assess the validity and reliability of the Italian version of NSPIC (I-NSPIC). METHODS: A validation multicentre study was conducted in three different Italian universities. A total of 333 nursing students were enrolled in the 2014/2015 academic year. Exploratory factor analysis (EFA) with oblique rotation was performed to test the construct validity of I-NSPIC. The Cronbach's alpha coefficient and test retest via Intraclass Correlation Coefficient (ICC) analyses were done to assess the internal consistency and stability of the scale. A Spearman's correlation with another scale (CLES-T) was used to examine the concurrent validities. RESULTS: Four factors (control versus flexibility, supportive learning climate, confidence through caring, appreciation of life meaning and respectful sharing) were identified in EFA. The Cronbach's alpha value showed that I-NSPIC was a reliable instrument (α = 0.94) and the ICC coefficient was satisfactory. CONCLUSION: The I-NSPIC is a valid instrument for assessing the perception of instructor caring in Italian nursing students. It may also prove helpful in promoting the caring ability of nursing students and in increasing the caring interactions in the relationship between instructor and nursing students. The knowledge emerged from this study provide important insight in developing effective training strategies in the clinical training of undergraduate nursing students.

Definition of criteria and indicators for the prevention of Healthcare-Associated Infections (HAIs) in hospitals for the purposes of Italian institutional accreditation and performance monitoring.

BACKGROUND: Healthcare-associated infections (HAIs) are an important issue in terms of quality of care. HAIs impact patient safety by contributing to higher rates of preventable mortality and prolonged hospitalizations. In Italy, analysis of the currently available accreditation systems shows a substantial heterogeneity of approaches for the prevention and surveillance of HAIs in hospitals. The aim of the present study is to develop and propose the use of a synthetic assessment tool that could be implemented homogenously throughout the nation. METHODS: An analysis of nine international and of the 21 Italian regional accreditation systems was conducted in order to identify requirements and indicators implemented for HAI prevention and control. Two relevant reviews on this topic were further analyzed to identify additional evidence-based criteria. The project team evaluated all the requirements and indicators with consensus meeting methodology, then those applicable to the Italian context were grouped into a set of "focus areas". RESULTS: The analysis of international systems and Italian regional accreditation manuals led to the identification respectively of 19 and 14 main requirements, with relevant heterogeneity in their application. Additional evidence-based criteria were included from the reviews analysis. From the consensus among the project team members all the standards were compared and 20 different thematic areas were identified, with a total of 96 requirements and indicators for preventing and monitoring HAIs. CONCLUSIONS: The study reveals a great heterogeneity in the definition of accreditation criteria between the Italian regions. The introduction of a uniform, synthetic assessment instrument, based on the review of national and international standards, may serve as a self-assessment tool to evaluate the achievement of a minimum standards set for HAIs prevention and control in healthcare facilities. This may be used as an assessment tool by the Italian institutional accreditation system, also useful to reduce regional disparities.

Nursing students' clinical competencies: a survey on clinical education objectives.

BACKGROUND: Developing clearly defined competencies and identifying strategies for their measurement remain unfortunately a critical aspect of nursing training. In the current international context, which continues to be characterised by deep economic crisis, universities have a fundamental role to play in redefining the educational goals to respond to the expectations of certain geographical areas of interest, as underscored in the Bologna Process (Joint Declaration of the European Ministers of Education Convened in Bologna 19 June 1999). DESIGN AND AIM OF STUDY: The aim of this observational study was to examine the clinical learning context of nursing students using a tool developed by a team of teachers for the analysis of clinical learning. METHODS: Redefinition of the clinical learning objectives with reference to the competencies set out in the questionnaire validated by Venturini et al. (2012) and the subsequent use of the tool created by the team of teachers for students in the first, second and third-year courses of the 2013/14 academic year, covering all the internships called for in those years. RESULTS: All nursing students enrolled in the first, second and third year of the nursing undergraduate degree program at the University of Pavia (no. 471) participated in this survey. A total of 1,758 clinical internships were carried out: 461 for the first year, 471 for the second year and 826 for the third year. Setting objectives, beginning with the educational offerings in the several clinical contexts, represents a strong point for this process. The results highlight a level of heterogeneity and complexity intrinsic to the University of Pavia educational system, characterized by clinical settings with different clinical levels (Research hospital and other traditional hospitals) that offering different levels of training. CONCLUSIONS: The use of the self-evaluation form for clinical learning made it possible to perform real-time observations of the training activities of the entire student body. An educational model structured in this way allows the student to develop their capacity for critical thinking. For educational activities, such a self-evaluation form represents an ideal instrument for identifying areas in need of improvement. This explorative study, carried out by means of a self-evaluation form, is the first-step toward the development of an educational programme that is more uniform and easily traceable within the academic system.

Social media and nurse education: an integrative review of the literature.

INTRODUCTION: The exponential advance of social media has touched all areas of society, no exception for the professional and personal lives of healthcare people. The issue to be considered is not whether or not social media are being used, but how they are used. The line between proper and improper use, and even abuse, of social media is a subtle one. Thus, the key issue is to be aware of the tool that is being used and this should be supported with suitable training for healthcare professionals and, at an even earlier stage, for students at healthcare training institutions during their studies. OBJECTIVE: To describe, through an integrative review of the literature, the use of social media by teachers and students during teaching activity and practical training courses. MATERIALS AND METHODS: An integrative review of the literature was conducted in October 2014. The literature search was performed by consulting the main biomedical databases: PubMed, CINAHL and Embase. RESULTS: The literature search brought up a total of 854 citations. 804 abstracts were excluded as they were not relevant. Of the remaining 50, 31 were excluded for not meeting the general criteria and, hence, only 19 articles were included. Two aspects emerged from the works selected: the use and potential of social media in nursing education and the ethical and professional implications of their use. CONCLUSIONS: The analysis of the literature reveals two areas for further investigation: evaluating the level of moral awareness in nursing education with regards to the use of Web 2.0 communication tools and implementing teaching methods to promote the construction and development of moral reasoning in professionals.

The students' reasons to choose a nursing degree program: an Italian exploratory study.

BACKGROUND: From the international literature very interesting cues emerge about students' motivations to choose a Nursing Degree Program. Unfortunately, this phenomenon is largely unexplored in Italy. An observational study was conducted at the University of Pavia, with the aim to investigate the reasons underpinning the students' choice to enter a Nursing Degree Program. METHODS: A semi-structured, self-administrated questionnaire was used for this single-center cross-sectional study. The questionnaire was aimed to investigate the reasons underpinning the students' choice to enter a Nursing Degree Program, using both open-ended and close-ended multiple choice questions. Descriptive statistics have been used to describe collected data. Open-ended response analysis was conducted through an exploratory and qualitative analysis of language. RESULTS: Response rate was 71% (196/275). Our study results highlighted a variety of reasons that encourage students to begin a Nursing Degree Program: the feeling of usefulness (80%), the desire to help and to care people (78%), the interest in the sciences (71%), the compassion to the suffering people (66%). We also identified 4 categories that describe which characteristics a nurse should have according to the students' point of view: expertise; personal characteristics; to experience the professional life as a social function and to have interest in the health field. CONCLUSIONS: Students' answers indicate that often the choice to enter a Nursing Degree Program is not supported by clear ideas and strong motivations. We consider it crucial to provide a realistic image of the nursing role and opportunities for career development, so that students can have the right elements to make a conscious choice. There is a need for more qualitative research to explore the reasons why students choose the Nursing Degree Program; moreover, to identify, from the beginning of the course, those students who are in crisis of motivation, in order to adopt support strategies that could enable them to successfully achieve academic career.

Is fibromyalgia a cause of failure in the treatment of a painful shoulder?

PURPOSE: This study aims to review the incidence of fibromyalgia in a cohort of patients who were treated for shoulder pain and address whether a concomitant fibromyalgia could have had detrimental effect on outcomes. METHODS: The treatment of 286 consecutive patients for shoulder pain was reviewed. RESULTS: Eighteen patients (6.3 %) were diagnosed as having fibromyalgia, but in 13 of them (72 %), the diagnosis was initially missed. Five patients received a total of 11 surgeries for treatment of the shoulder. At an average follow-up of 15 months (range 12-27), the average new Oxford shoulder score (OS score) was 49 % (range 6-87 %). The average physical component of the Short-Form-12 Healthy Survey (SF-12) was 36 (range 21-55), and the mental component 30 (range 15-46). The Summary Outcome Determination score (SOD score) was 1.3 (range-3 to 6). CONCLUSIONS: Fibromyalgia occurs relatively frequently in patients who complain of shoulder pain and it can be a cause of failure in the treatment of concomitant painful shoulder conditions.

Prevention in the workplace and training of personnel: new methodological approaches.

In Italy since 15 years huge investments in term of human, material and economical resources have been allocated to prevention. However epidemiological data show unsatisfactory results. It's necessary and urgent to modify the general learning of prevention in order to increase all the actors involved in social and productive system. The aim of our project is to improve competencies and knowledge concerning hygiene in the workplace and prevention of nursing personnel, using cooperative-learning model, concerning the ways of transmission of infectious diseases, so that they will be able to develop their activities and being motivated in the adoption of safety proceedings. The results indicate, in all the participants groups, an improvement of their skills and knowledge about the correct behavioural procedures to limit biological hazards for themselves and for their patients. We observed increased motivation and awareness, a greater ability to take action when they see the adoption of inadequate or incorrect procedures by colleagues.

Identification of patients at high risk for hypocalcemia after total thyroidectomy.

Hypocalcemia is a major post-operative complication of total thyroidectomy, causing severe symptoms and increasing hospitalization time. The primary cause is secondary hypo-parathyroidism following damage to, or devascularisation of, one or more parathyroid glands during surgery. Aim of the study was to develop a simple and reliable method for predicting post-operative hypocalcemia in total thyroidectomy patients. A retrospective analysis was made of immediate pre-operative and early post-operative calcium levels in 100 patients. It was found that a marked decrease in blood calcium, immediately after surgery, was a sensitive predictor of hypocalcemia. In a subsequent prospective series of 67 patients, the efficacy was assessed of early administration of calcium plus Vitamin D in reducing symptomatic hypocalcemia in patients in whom the difference (Δ) between pre- and post-operative blood calcium was ≥ 1.1 mg/dl. This treatment was part of a protocol in which normo-calcemic patients were discharged immediately after drainage removal (third post-operative day). In the retrospective series, 84% of patients who developed hypocalcemia had Δ ≥ 1.1 and 54% of patients who did not develop hypocalcemia had Δ < 1.1 (p < 0.0001). Mean duration of hospitalization was 6.2 days. In the prospective series, 76% of patients who developed hypocalcemia had Δ ≥ 1.1 mg/dl; of the patients who did not develop hypocalcemia 75% had Δ < 1.1 mg/dl (p = 0.0013); mean hospitalization was 4.7 days (p < 0.0001). Use of the 1.1 mg/dl cut-off for deciding whether to start early prophylaxis allowed most patients to avoid symptomatic hypocalcemia (and the associated anxiety), while permitting a significantly reduced hospital stay, resulting in lower hospitalization costs.

Assessment of QT liabilities in drug development.

Since the publication, in 1997, of the CPMP (Committee for Proprietary Medicinal Products) Points to Consider document on "The assessment of potential for QT prolongation by non-cardiovascular medicinal products," both regulatory bodies and the pharmaceutical industry have paid increasing attention to the conduct of careful preclinical studies on the subject. Regulatory attention has focused on the drafting of Safety Pharmacology guidelines through the ICH (International Conference on Harmonization) process, which resulted in approval by the ICH and acceptance by the three main regions (USA, Europe, and Japan) of the ICH S7A guideline. The guideline does not deal only with cardiovascular studies and does not provide guidance on QT investigations. This part has been deferred to a second guideline (ICH S7B). Nevertheless, pharmaceutical companies have implemented screening strategies aimed at selecting compounds that do not present QT liabilities. These strategies can differ according to the pharmaceutical class, while experimental models differ according to the stage of development of the compound. Several in vitro models are employed in discovery (radioligand binding, high-throughput patch clamp, efflux, and fluorescence assays). These models, coupled with in silico methods, allow companies to screen a high number of compounds. Other in vitro models, applied later in the R&D process (action potential duration, APD, in Purkinje fibers or papillary muscle and the isolated heart) are useful in better describing the activity of compounds on cardiac ion channels. The most robust and accepted in vivo test is represented by telemetry studies in conscious non-rodents.

Selectivity enhancement induced by substitution of non-natural analogues of arginine and lysine in arginine-based thrombin inhibitors.

Seven non-natural analogues of arginine and lysine have been substituted in an established arginine-based thrombin inhibitor. Four of the new compounds exhibited significant thrombin inhibition (K(i)'s 0.53-3.95 microM) and were subsequently tested for selectivity against trypsin. The two best compounds gave selectivity ratios of 962 and 525 (trypsin/thrombin), improving upon the parent compound.

Progress report on the palliative therapy of 100 patients with neoplastic effusions by intracavitary low-dose interleukin-2.

OBJECTIVE: Several cytokines, particularly IL-2 and interferons, are thought to be effective in the palliative therapy of neoplastic effusions. We report on the activity and toxicity of intracavitary administration of low-dose IL-2 in a case series of 100 cancer patients with neoplastic effusions. METHODS: One hundred patients with advanced solid tumors and neoplastic effusions underwent IL-2 intracavitary injection as first-line treatment. The most common sites of fluid accumulation were pleura (n = 68), peritoneum (n = 21) and pericardium (n = 11). Breast cancer, lung cancer and mesothelioma were the most frequent neoplasms in our series. One cycle consisted of intracavitary IL-2 at 6,000,000 IU on days 1 and 7. RESULTS: According to Paladine's criteria, an objective clinical response was achieved in 72% (complete response in 27% and partial response in 45%), with a median duration of 5 months (range: 1-11 months). The peritoneum was the least responsive site for neoplastic effusion reduction. IL-2 intracavitary injection was well tolerated in all patients; the only toxicity observed was fever >38 degrees C in 6% of the patients. CONCLUSION: This study shows that intracavitary injection of IL-2 represents a feasible, well-tolerated and effective therapy of neoplastic fluid accumulation. Further studies are needed in order to compare the effectiveness of intracavitary IL-2 with other standard treatments.

PNU-159548, a novel cytotoxic antitumor agent with a low cardiotoxic potential.

PURPOSE: PNU-159548 (4-demethoxy-3'-deamino-3'aziridinyl-4'-methylsulphonyl-daunorubicin), a derivative of the anticancer idarubicin, has a broad spectrum of antitumoral activity in vitro and in vivo attributable to its DNA intercalating and alkylating properties. The present study was conducted to determine the cardiotoxic activity of PNU-159548 relative to doxorubicin in a chronic rat model sensitive to anthracycline-induced cardiomyopathy. METHODS: Young adult male rats were allocated to the following treatment groups: group 1, PNU-159548 vehicle control (colloidal dispersion); group 2, doxorubicin control (saline); groups 3, 4, 5, 6, and 7, PNU-159548 at 0.12, 0.25, 0.50, 0.75, and 1.0 mg/kg, respectively; and group 8, 1.0 mg/kg doxorubicin. Treatments were administered intravenously once weekly for 4 weeks (first sacrifice time) or for 7 weeks (rats killed at weeks 8, 12, 22, 27, or 35). Body weights, organ weights, serum chemistry, hematology, serum troponin-T, and cardiac histopathology were followed throughout the study. RESULTS: Doxorubicin caused irreversible cardiomyopathy evident at week 4 in some rats and progressing in severity in all rats by week 8. There were also marked myelotoxicity, increased liver and kidney weights, testicular atrophy, and about 20% mortality by week 27 in doxorubicin-treated rats. The deaths were attributed to cardiomyopathy and/or nephropathy. PNU-159548 caused a dose-dependent myelotoxicity, with the dose of 0.5 mg/kg per week being equimyelotoxic to 1.0 mg/kg per week doxorubicin. PNU-159548 also caused an increase in liver weight that was reversible and a non-reversible testicular atrophy but, unlike doxorubicin, had no effect on kidney weight. At equimyelotoxic doses, the cardiotoxicity caused by PNU-159548, expressed as the mean total score, was less than one-twentieth of that induced by doxorubicin, and much less than that predicted on the basis of its content of idarubicin, which is in turn markedly less cardiotoxic than doxorubicin. CONCLUSIONS: The novel cytotoxic antitumor derivative, PNU-159548, is significantly less cardiotoxic than doxorubicin at equimyelosuppressive doses. The combination of intercalating and alkylating activities within the same molecule without the cardiotoxic side effects of anthracyclines makes PNU-159548 an excellent candidate for clinical development in oncology.

Pharmacological and toxicological aspects of 4-demethoxy-3'-deamino-3'-aziridinyl-4'-methylsulphonyl-daunorubicin (PNU-159548): a novel antineoplastic agent.

4-demethoxy-3'-deamino-3'-aziridinyl-4'-methylsulphonyl-daunorubicin (PNU-159548) belongs to a novel class of antitumor compounds (termed alkycyclines) and is currently undergoing Phase II clinical trial. In the present study, we investigated the in vitro and in vivo antitumor activity, the pharmacokinetics, and the toxicological profile of this compound. PNU-159548 showed good cytotoxic activity in murine and human cancer cells growing in vitro, with an average concentration for 50% growth inhibition of 15.8 ng/ml. The drug showed strong antitumor efficacy in vivo after i.v. and p.o. administration against rapidly proliferating murine leukemias and slowly growing transplantable human xenografts. At non-toxic doses, PNU-159548 produced complete regression and cures in ovarian, breast, and human small cell lung carcinomas. Fourteen of 16 models studied, including colon, pancreatic, gastric, and renal carcinomas, astrocytoma and melanoma, were found to be sensitive to PNU-159548. In addition, PNU-159548 was effective against intracranially implanted tumors. Toxicological studies revealed myelosuppression as the main toxicity in both mice and dogs. The maximum tolerated doses, after a single administration, were 2.5 mg/kg of body weight in mice, 1.6 mg/kg in rats, and 0.3 mg/kg in dogs. In the cyclic studies, the maximum tolerated doses were 0.18 mg/kg/day (cumulative dose/cycle: 0.54 mg/kg) in rats and 0.05 mg/kg/day (cumulative dose/cycle: 0.15 mg/kg) in dogs. PNU-159548 showed minimal cardiotoxicity, when compared with doxorubicin in the chronic rat model at a dose level inducing similar myelotoxicity. Animal pharmacokinetics, carried out in mice, rats, and dogs, was characterized by high volumes of distribution, plasma clearance of the same order of the hepatic blood flow, and short terminal half-life. These findings support the conclusion that PNU-159548 is an excellent candidate for clinical trials in the treatment of cancer.