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Background: Robotic-assisted thoracic surgery has been shown as a safe and feasible surgical procedure to treat a broad range of thoracic malignancies with a shorten hospital stay, a quicker return to normal daily activities and superior quality of life compared to open approach. Nonetheless, its utilization has predominantly been restricted to the average surgical intervention. In the latest years, given the technological improvements and the advanced skills of the "robotic" surgeons, this approach has been applied to more complex and challenging procedures (e.g., advanced stages/ after neoadjuvant therapies). The aim of this study is to show the results and the advantages of redo thoracic procedures performed with a robot-assisted approach., Methods: Retrospective analysis of a prospectively collected database (2017-2019). We analysed the first case series undergoing robotic approach (totally endoscopic) in patients who underwent previous surgery and/or radiotherapy for thoracic malignancies., Results: Nine patients (M/F =5/4) with a median age of 73 years underwent robotic procedures after previous radical surgery (n=6) or radiation therapy treatment (n=3). The mean time interval between the two interventions was 96.12 months (range, 7-444 months). The conversion rate was 0%. No postoperative death occurred. Only one complication arose (air leaking) treated conservatively. The median length of stay and chest tube duration were 5 days (range, 4-10 days) and 2 days (range, 2-5 days). The 30-, 60- and 90-day mortality was 0%. With a median follow-up of 10 months (range, 2-12 months), all patients are currently alive, disease free, and with an overall survival and a disease-free survival of 10 months., Conclusions: The robotic surgery is a safe and feasible approach in case of redo-robotic surgery, showing good outcomes, permitting a fast return to full daily activity, and enabling the patients to rapidly undergo adjuvant treatments, when required., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/med-20-47). FM is an official proctor for Intuitive Surgical. The other authors have no conflicts of interest to declare., (2020 Mediastinum. All rights reserved.)

Introduction: Surgical resection with minimally invasive approach is the gold standard for both definitive diagnosis and treatment of solitary pulmonary nodules (SPNs); however, it can be difficult to pinpoint small, deep, or subsolid nodes without palpating lung parenchyma. The primary endpoint of this study is showing that radioguided surgery is a cost-effective strategy to improve the effectiveness of video-thoracoscopic localization/resection of SPNs/ground-glass opacities (GGOs). Secondary endpoints are analyzing the morbidity of this technique and tips and tricks to better manage this method., Methods: SPN smaller than 20 mm and/or with a distance from the visceral pleura ≥5 mm underwent minimally invasive resection after computed tomography-guided injection of a solution composed of 0.1/0.2 mL of 99Tc-labeled human serum albumin microspheres and 0.1 mL of nonionic contrast. In the operating theater, a collimated probe connected to a gamma ray detector allowed localization of the target area., Results: Between 1997 and 2018, a total of 451 patients with SPN/GGO underwent minimally invasive surgery with a radioguided technique at our hospital. The mean SPN diameter was 13 mm (range, 5-20 mm), and the mean distance from the visceral pleura was 15 mm (range, 6-29 mm). The mean time to a localizing nodule was 3 minutes (range, 1-5 minutes). No significant injection-related complications were reported; only 3.3% of patients (15 of 451) developed pneumothorax. Both 30- to 60-day and 90-day mortality were 0%. The rate of postoperative complications was 2.53% (prolonged air leak). The conversion rate to thoracotomy was 1.55% (7 of 451)., Conclusions: Our 20-year experience shows that radioguided thoracoscopic surgery is a safe and feasible strategy to treat suspicious SPN/GGO, with a success rate of 98%., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The original version of this article, unfortunately, contained an error. In Fig. 2 - panel d, incorrect image was published and this is now presented correctly in this article.

Background: There is a paucity of robust clinical data on major postoperative complications following robotic-assisted resection for primary lung cancer. This study assessed the incidence and outcomes of patients who experienced major complications after robotic anatomic pulmonary resection., Methods: This was a multicenter, retrospective review of patients who underwent robotic anatomic pulmonary resection between 2002 and 2018. Major complications were defined as grade III or higher complications according to the Clavien-Dindo classification. Statistical analysis was performed based on patient-, surgeon-, and treatment-related factors., Results: During the study period, 1264 patients underwent robotic anatomic pulmonary resections, and 64 major complications occurred in 54 patients (4.3%). Univariate analysis identified male sex, forced expiratory volume in 1 second, diffusion capacity of the lung for carbon monoxide, neoadjuvant therapy, and extent of resection as associated with increased likelihood of a major postoperative complication. Patient age, performance status, body mass index, reoperation status, and surgeon experience did not have a significant impact on major complications. Patients who experienced at least 1 major complication were at higher risk for an intensive care unit stay of >24 hours (17.0% vs 1.4%; P < .001) and prolonged hospitalization (8.5 days vs 4 days; P < .001). Patients who experienced a major postoperative complication had a 14.8% risk of postoperative death., Conclusions: In this series, the major complication rate during the postoperative period was 4.3%. A number of identified patient- and treatment-related factors were associated with an increased risk of major complications. Major complications had a significant impact on mortality and duration of stay., (Copyright © 2019 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Pulmonary metastasectomy is considered a potentially curative treatment for selected patients with metastatic colorectal cancer (CRC). Several prognostic factors have been analysed, but to date, it is still not well defined which is the optimal resection margin during lung metastasectomy (LM). This study analyses the long-term results and prognostic factors after LM in CRC patients with particular attention to the resection margins. Primary endpoint of this study is to assess the correlation between resection margins and long-term outcomes., Methods: Observational cohort study on all proven cases of CRC lung metastases (2000-2016) resected with curative intent in a single centre., Results: The series included 210 consecutive patients (M/F 133/77) with a mean age of 65.4 (± 9.96) years, 75% (159/210) of them with a solitary metastasis. Mean size of metastasis was 2.57 cm (± 1.45). One hundred sixty-eight patients underwent wedge resections (80%) and lymphadenectomy was carried out in 90 cases (42.9%). With a mean follow-up of 56 months (range 5-192), we observed a 1-, 3- and 5-year overall survival (OS) of 95%, 74% and 54%, respectively. The patients were divided into three groups according to the resection margin distance from the tumour: (a) ≥ 2 cm (145 cases); (b) < 2, ≥ 1 cm (37 cases); and (c) < 1 cm (12 cases). The OS was significantly different between the three groups (p = 0,020); univariate and multivariate analyses showed that a narrow resection margin was an independent prognostic factor of worse survival (p = 0.006 and HR 3.4 p = 0.009)., Conclusions: Long-term survival of patients after LM is strongly associated with a greater distance between the lesion and the resection margin.

Background: Intraoperative catastrophes during robotic anatomical pulmonary resections are potentially devastating events. The present study aimed to assess the incidence, management, and outcomes of these intraoperative catastrophes for patients with primary lung cancers., Methods: This was a retrospective, multiinstitutional study that evaluated patients who underwent robotic anatomical pulmonary resections. Intraoperative catastrophes were defined as events necessitating emergency thoracotomy or requiring an additional unplanned major surgical procedure. Standardized data forms were collected from each institution, with questions on intraoperative management strategies of catastrophic events., Results: Overall, 1810 patients underwent robotic anatomical pulmonary resections, including 1566 (86.5%) lobectomies. Thirty-five patients (1.9%) experienced an intraoperative catastrophe. These patients were found to have significantly higher clinical TNM stage (P = .031) and lower forced expiratory volume in 1 second (81% vs 90%; P = .004). A higher proportion of patients who had a catastrophic event underwent preoperative radiotherapy (8.6% vs 2.3%; P = .048), and the surgical procedures performed differed significantly compared with noncatastrophic patients. Patients in the catastrophic group had higher perioperative mortality (5.7% vs 0.5%; P = .018), longer operative duration (195 minutes vs 170 minutes; P = .020), and higher estimated blood loss (225 mL vs 50 mL; P < .001). The most common catastrophic event was intraoperative hemorrhage from the pulmonary artery, followed by injury to the airway, pulmonary vein, and liver. Detailed management strategies were discussed., Conclusions: The incidence of catastrophic events during robotic anatomical pulmonary resections was low, and the most common complication was pulmonary arterial injury. Awareness of potential intraoperative catastrophes and their management strategies are critical to improving clinical outcomes., (Copyright © 2019 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objective(s): Robotic lobectomy is becoming a widespread surgical procedure in NSCLC treatment, but data on oncologic outcomes is still lacking. The aim of this study was to analyze long term oncologic results of robotic lobectomy for non small lung cancer., Methods: Clinical records of consecutive NSCLC patients underwent robotic major surgery, between January 2010 and December 2015, were collected and analyzed., Results: We analyzed data of 212 patients (127 male and 85 female), with a median age of 66.3 years. The median follow-up time was 40.3 months (range 4-83). The median disease free survival was 66.3 months. Free disease survival stage-correlated was 75.6 months for stage I, 42.3 months for stage II, 51.2 months for stage III and 10.3 months for stage IV. The median overall survival was 78.6 months. Overall survival stage-correlated was 82 months for stage I, 73.5 months for stage II, 61.4 months for stage III and 41.3 months for stage IV., Conclusions: This study suggests high safety level, positive post-operative and oncologic outcomes for patients NSCLC underwent robotic major surgery, also in advanced stages., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Robotic surgery has the features to represent the future of surgery, considering the rapid evolution of its technology and the resulting in the surgical field. In the last years, the robotic technique in thoracic surgery has progressively become widespread in the word, particularly for the treatment of the mediastinal and pulmonary lesions. The development of technology in the robotic system has been associated with the improvement of intraoperative and postoperative results. Due to the satisfying results and increasing experience and confidence with the robotic technique, surgeons are consequently enlarging the surgical indication, moving to increasingly challenging cases. Thoracic robotic surgery is being affirmed as a safe technique also for those complex cases, which in the past were considered a matter solely for open surgery. In fact, robotic surgery is increasingly associated with positive surgical results and guarantees less traumatism and a fast recovery to the patients. These positive results have resulted from the evolution of the technique, which has developed in parallel with the evolution of the technology, exploiting to its best the latest features of the robotic system. These features, such as the fluorescence-detection tool or the robotic stapler, have been aiding the surgeon to maximise the safety and feasibility of the application of the robotic technique to thoracic surgery., Competing Interests: Conflicts of Interest: Prof. F Melfi is an official proctor for Intuitive Surgical. The other authors have no conflicts of interest to declare.

Background: Open pulmonary resection is considered the gold standard treatment of early-stage non-small cell lung cancer (NSCLC). However, in the last decades, the use of minimal-invasive techniques has given promising results. Survival in lung cancer, after surgery, depends on the number of pathological nodes (pN), thus lymph nodal upstaging can be considered a surrogate for surgical quality of the procedure. Several studies have demonstrated a lower rate of upstaging in video-assisted thoracic surgery than in open surgery, suggesting an approach-related difference in lymphadenectomy. Features of robotic technique could consent a lymph nodal dissection similar to open surgery. The aim of the study is to compare nodal upstaging between thoracotomy and robotic approaches to evaluate the oncologic radicality., Methods: Between January 2013 and December 2016, 212 consecutive cN0 NSCLC patients underwent lobectomy and lymphadenectomy (N1 + N2 stations) by either thoracotomy (Open Group) or robotic surgery (Robotic Group)., Results: Lobectomy and lymphadenectomy were performed in 106 cN0-cN1 NSCLC patients by robotic surgery and in 106 cN0-cN1 NSCLC patients by open surgery. A mean of 14.42 ± 6.99 lymph nodes was removed in the Robotic Group (RG) and a mean of 14.32 ± 7.34 nodes in the Open Group (OG). Nodal upstaging was observed in 22 (20.75%) RG patients and in 19 OG (17.92%) patients., Conclusions: Robotic lobectomy for clinical N0-N1 NSCLC appears to be equivalent to thoracotomy in terms of efficacy of lymph node dissection and nodal upstaging. Given that the nodal upstaging is a surrogate of quality of surgery, we can consider robotic lobectomy an appropriate procedure which ensures similar result to the open approach.

Aim: We report two cases of the very rare Primary Acquired Grynfeltt Hernia. The related abdominal wall defects were repaired, by open surgery, placing a partially absorbable plug and mesh. The observation and management of these two new cases prompted us to review the literature with the purpose of suggesting the most appropriate surgical approach and technique., Matherial of Study: A 60 years old female patient showing a swelling at the left lumbar region, and a 76 years old male patient showing evidence of a tumefaction located at the right lumbar region, were diagnosed at our department with Primary Acquired Grynfeltt Hernia., Results: Postoperative courses were uneventful and the patients were discharged from hospital respectively on the third and second postoperative day. Follow-up at thirty days, six months, two and three years showed no signs of recurrence., Discussion: Primary Acquired Grynfeltt Hernia is one of the rarest abdominal hernias. In literature there are no comparative studies showing which type of surgical approach should be preferred for this specific abdominal wall defect. In our department, open surgery was successfully performed for the treatment of two new cases of Primary Acquired Grynfeltt Hernias and, second time in literature, partially absorbable plug and mesh were placed in order to repair the causative abdominal wall defect., Conclusion: Based on our experience and literature review, we consider open hernia repair with partially absorbable plug and mesh as an appropriate and advisable surgical approach for not complicated cases of Primary Acquired Grynfeltt Hernia. Surgery is performed rapidly, effortlessly and securely if the patient is under general anesthesia, in lateral decubitus position with the operating table flexed at the level of the iliac crest., Key Words: Primary Acquired Grynfeltt Hernia, Lumbar Hernia.

The aim of the present study was to externally validate the European System for Cardiac Operative Risk Evaluation (EuroSCORE) II (ESII) in patients undergoing percutaneous coronary intervention (PCI) and to compare its performance with that of its previously released versions, named additive (addES) and logistic EuroSCORE (logES). A total of 537 patients undergoing PCI were analyzed by different measurements of discrimination, calibration, and global accuracy. A significant gradient in all-cause mortality was seen with all the models at 30 days, 1 year, and 5 years, with the exception of the ESII at 30 days. The ESII had the lowest area under the receiver operating characteristic curve at all time points compared with its previous version, being 0.83 (vs 0.90 for both addES and logES) at 30 days, 0.75 (vs 0.82 for both addES and logES) at 1 year, and 0.69 (vs 0.77 for addES and 0.76 for logES) at 5 years. However, the ESII displayed a better calibration than the logES at 30 days, whereas both scores were miscalibrated at 1 and 5 years. The Brier score displayed similar global accuracy between the ESII and logES. In conclusion, the ESII is better calibrated than the logES at 30 days but does not represent a step forward in discrimination and global accuracy compared with its previous versions for predicting early- and long-term mortality of patients undergoing PCI., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The 8th Annual Meeting of the International Society for Stem Cell Research (ISSCR) placed a particular emphasis on topics related to the engineering of induced pluripotent stem cells through reprogramming of mammalian somatic cells, embryonic and adult stem cells of different species, tissue regeneration, stem cell transplantation and cancer stem cells. This report provides an overview on the standpoint of stem cell research programs, which is based on the proceedings of the meeting., (Copyright 2010 Prous Science, S.A.U. or its licensors. All rights reserved.)

Background: Management of displaced femoral neck fracture in elderly patients is challenging due to the patient's high risk profile, poor quality bone stock and muscle weakness., Materials and Methods: Fifty-one patients with displaced (Garden 3-4) intracapsular femoral neck fractures were treated with a newly designed Fixion expandable stem hemiarthroplasty implant and followed thereafter for a minimum of 6 months., Results: Thirty patients (58.8%) had concomitant diseases graded 3-4 by the ASA scoring system. Two patients (4.8%) incurred deep wound infections that necessitated hardware removal. One case (2.6%) of dislocation was treated by closed reduction. Forty-two patients (82.4%) survived >6 months and cooperated with the study protocol. Mild groin/thigh pain was reported by 11 patients (26.2%). Twenty-six (61.9%) had lost 1-2 out of 4 grades of mobility., Conclusions: Fixion implant may be considered a further step in the evolution of femoral joint hemiarthroplasty. In the short term, it has proven to be as effective as cemented implant and to be user-friendly for the surgeon. It is also anticipated to be feasible whenever revision is required.

The focus of the seventh annual meeting of the International Society for Stem Cell Research was placed on several topics, such as cancer stem cells, stem cell transplantation, tissue regeneration, biology of embryonic and adult stem cells of various species and production of induced pluripotent stem cells via reprogramming of mammalian somatic cells. This report provides an overview of stem cell research, based on the proceedings of the meeting., (Copyright 2009 Prous Science, S.A.U. or its licensors. All rights reserved.)

Effective gene-based interventions for the treatment of genetic disorders, neurodegenerative diseases and cardiovascular maladies require longterm transgene expression in target cells. Integrating viral vector systems based on the genera of the retroviridae and on adeno-associated virus are suitable tools, as the integration of viral vector genomes into the cellular chromosomal DNA allows for a more stable and long-lasting transgene expression than episomal gene-delivery models. Two nonviral gene-delivery systems with integrating properties have also been developed. These are based on the Sleeping Beauty DNA transposon system and on the Streptomyces bacteriophage integrase phiC31. However, the integration of recombinant vector systems may damage the natural genetic arrangement of the target cell. Such genetic alterations are termed insertional mutagenesis, which might result in malignant cell transformation. Insertional mutagenesis caused leukemia in five patients who participated in clinical trials for the treatment of severe combined immunodeficiency (SCID)-X1; sadly, one of the patients died. Gene therapists had to assess the real risk-versus-benefit ratio for the use of retroviral vectors in patients and devise novel strategies to minimize the occurrence of insertional mutagenesis-related malignancies. In this respect, a particular emphasis was placed on the engineering of enhancer-less self-inactivating retroviridae-based systems., (Copyright 2009 Prous Science, S.A.U. or its licensors. All rights reserved.)

Recent findings showed certain specific factors had the ability to reprogram in vitro human somatic cells, which in turn could generate pluripotent stem cells. Remarkably, somatic cell-derived pluripotent stem cells recapitulated the features of human embryonic stem cells, as demonstrated independently by two groups of investigators. The reprogramming of somatic cells may represent an alternative to the controversial use of human embryonic stem cells in transplantation therapy and in a variety of other applications, such as generation of cellular models for human diseases and for drug research and development. However, the intrinsic expression of epigenetic reprogramming factors in somatic cells requires the use either of lentiviral- or retroviral-mediated gene transfer, which may cause insertional mutagenesis-induced malignancies. In summary, the recent achievements for the in vitro reprogramming of human somatic cells to a pluripotent state can be considered an important advancement in stem cell research. As for future clinical applications in regenerative medicine, it is necessary to tackle the issue of insertional mutagenesis, which is associated with all types of integrating gene delivery systems. Another critical issue is the control of the tumorigenic potential of somatic cell-derived pluripotent stem cells. As it stands, the newly developed technology can be used to engineer useful models for the study of human diseases and development of novel therapeutics., (Copyright 2008 Prous Science, S.A.U. or its licensors. All rights reserved.)

Background: Roentgenographic and functional outcomes of expandable self locking intramedullary nailing and platelet rich plasma (PRP) gel in the treatment of long bone non-unions are reported., Materials and Methods: Twenty-two patients suffering from atrophic diaphyseal long bone non-unions were enrolled in the study. Patients were treated with removal of pre-existing hardware, decortication of non-union fragments, and fixation of pseudoarthrosis with expandable intramedullary nailing (Fixion, Disc'O Tech, Tel Aviv, Israel). At surgery, PRP was placed in the pseudoarthrosis rim., Results: The thirteen-month follow-up showed 91% (20/22 patients) of patients attaining bony union. The average time to union was 21.5 weeks. No infection, neurovascular complication, rotational malalignment, or limb shortening >4 mm were observed. The healing rate of non-unions was comparable to that observed in previous studies but with a lower complication frequency., Conclusions: The combined use of self locking intramedullary nailing and PRP in the management of atrophic diaphyseal long bone non-unions seems to produce comparable results with less complications than previously reported. Further data are warranted to investigate the single contribution of PRP gel and Fixion nail.

Nonviral-mediated gene transfer was used in human gene therapy clinical trials that dealt with the treatment of inherited or acquired genetic disorders and cancer. Several preclinical studies are currently ongoing to employ nonviral vectors in genetic immunization programs for a variety of infectious diseases. The interest in nonviral-mediated gene transfer is motivated by two main reasons: (I) nonviral-based vectors do not derive from infectious agents and are minimally toxic; and (II) they can be easily produced in large quantities. However, the main drawbacks of nonviral-mediated gene transfer are related to low transfection efficiency of target cells, especially in vivo, and to the transient nature of transgene expression. These drawbacks render nonviral-mediated gene transfer not particularly suitable for the treatment of pathological conditions that require long-term transgene expression, such as neurodegenerative disorders and inherited or acquired genetic diseases. On these grounds, the optimal application of nonviral-mediated gene transfer is in immunotherapy for cancer and infectious diseases, as a transient expression of the transgene might be sufficient to trigger effective and durable host immune responses. The purpose of this review is to summarize the standpoint of nonviral vector development.

Stem cell research has greatly contributed to the field of oncology with the identification and isolation of cancer stem cells from a variety of tumors. The discovery of rare subpopulations of cancer stem cells has indeed entirely changed the focus of cancer research. Normal adult stem cells and cancer stem cells can both self-renew and undergo a differentiation program that, in turn, gives rise to a high number of differentiated cells. Adult stem cells and their malignant counterparts share almost all of the same intrinsic and extrinsic factors to regulate self-renewal, differentiation and proliferation pathways. Fractions of normal and cancer stem cells are naturally more resistant to toxic injuries than any other cell type. Overall, these observations lead to the conclusion that adult stem or progenitor cells can eventually become malignant by generating cancer stem cells, which are responsible for the development and maintenance of the tumor mass. In addition, chemo-resistant cancer stem cells may cause the relapse of the disease following an apparent beneficial treatment. Indeed, the study of the biology of cancer stem cells might lead to the improvement of preventive cancer diagnosis and to the development of novel therapeutics, which must be designed to selectively target malignant stem cells without affecting normal adult stem cells.

The high immunogenicity of recombinant adenoviral vectors is one of the major issues in the field of gene therapy. Adenoviral-based vectors are susceptible both to cytotoxic T-lymphocyte and humoral immune responses. In addition, leaky adenoviral genes also render transduced cells susceptible to host immune responses. These are the main reasons why adenoviral-based vectors are not suitable to correct genetic disorders, which require long-term expression of the transgene. Another limit to long-term transgene expression is posed by the fact that adenoviral-based vectors do not integrate their genome into the cellular chromosomal DNA of transduced cell populations. As it stands, adenoviral-mediated gene transfer is a promising tool for cancer therapy and for genetic immunization programs against infectious diseases, provided that host immune responses are carefully controlled., (Copyright 2006 Prous Science)

The role of adult stem cells in tissue regeneration has attracted much interest because of its enormous therapeutic potential. Adult stem cells reside in every tissue of the body and have the ability to self-renew and to give rise to a high number of differentiated progeny. These are indeed the essential steps in tissue regeneration, which in some cases occurs constitutively, whereas in other cases happens in response to an injury. The identification of the key factors involved in self-renewal and differentiation pathways is at the top of the agenda of stem cell biologists. Interestingly, a number of factors that govern the fate of adult stem cells also play a role in malignant cell transformation, such as the Wnt cascade, Oct-4, Bmi-1 and Evi1. In addition, rare subpopulations of cancer stem cells were identified for leukemia and other solid tumors. These rare fractions of cancer stem cells are in large part responsible for maintaining the tumor mass, as they have the capacity to self-renew and to generate a high number of progeny via differentiation program. These findings can be considered a major breakthrough in cancer research. Currently, oncologists and stem cell biologists have two main goals: i) the assessment of the consistency of the line that divides adult stem cells and carcinogenesis; ii) to better characterize the biology of cancer stem cells. This new line of investigation may allow for the development of novel therapeutics and cancer diagnostics., (2005 Prous Science)

Lentiviral-based vectors have been widely used lately in preclinical studies and for the in vitro genetic manipulation of embryonic and adult stem cells. They allow for the transduction of nondividing cells and for stable gene expression. On these grounds, lentiviral vectors look promising for eventual applications for the gene-based treatment of neurological disorders, cardiopathies and inherited or acquired genetic diseases. The best developed and characterized lentiviral vector system is based on the human immunodeficiency virus type 1 (HIV-1). However, safety concerns preclude any possible application of HIV-1-derived vectors in clinical trials. For this reason, gene therapists are currently improving the design of other lentiviral vectors, such as feline immunodeficiency virus, equine anemia infectious virus and Visna virus. These lentiviruses are not pathogenic in humans and are only distantly related to primate Retroviridae. This review summarizes the achievements in improving the design of lentiviral vector systems that are not based on HIV-1., ((c) 2005 Prous Science. All rights reserved.)

The possibility of regenerating tissues would provide an effective therapeutic tool for the treatment of many pathological conditions, including neurological diseases, spinal cord injuries, cardiopathies, diabetes, hematological illnesses and genetic disorders. While stem cells may have the potential of regenerating a variety of tissues, as indicated by a number of groundbreaking but preliminary reports, ethical issues and safety considerations seem to preclude the use of human embryonic stem cells in the clinical setting. Adult stem cells might circumvent the issues posed by embryonic stem cells, although the potential plasticity of adult stem cells is under scrutiny because of many conflicting and contradictory reports in the field of stem cell research. Indeed, many aspects of the biology of stem cells are still not known. In this respect, stem cell biologists have to address several pressing issues. A better understanding of stem cell biology would almost certainly allow for the establishment of efficient and reliable cell transplantation experimental programs in the clinic.

The achievement of efficient regulation and/or tissue-specific gene expression is one of the major goals for gene therapists. A number of inducible systems and tissue-specific promoters are currently available. Studies in vitro and in vivo have shown promising results in controlling gene expression. However, the achievement of efficient gene regulation in patients is still an open question. This review describes the main inducible systems and tissue-specific promoters in view of their potential therapeutic applications., ((c) 2004 Prous Science. All rights reserved.)

The receptor for the insulin-like growth factor-1 (IGF-1R) controls a wide variety of cellular functions. IGF-1R is a tyrosine kinase receptor that is activated by the binding of a ligand to the extracellular domain. There are three ligands for IGF-1R: IGF-I, IGF-II and insulin at supraphysiological concentrations. The binding of the ligand activates the catalytic activity of the tyrosine kinase domain, which in turn causes the autophosphorylation of IGF-1R. As a consequence of autophosphorylation, the activated IGF-1R sends a potent mitogenic signal to the cell nucleus. It has been clearly shown that an overexpressed and activated IGF-1R is quasi-obligatory for the establishment of a malignant cell phenotype. Interestingly, the targeting of IGF-1R can reverse the malignant phenotype in cancer cells, without affecting the biology of normal cells. For these reasons, IGF-1R seems to be a very promising candidate target for cancer therapy. In addition, IGF-1R protects cells from apoptosis and promotes cell growth and proliferation. However, more recent studies have also shown that IGF-1R regulates cell adhesion and motility, and, in certain cellular contexts, can induce differentiation. Indeed, the biology of the IGF-1R appears more complex than previously thought. The goal of this review is to describe the multiple functions displayed by IGF-1R in cell biology.

The latest generation of lentiviral vectors based on HIV-1 is one of the most efficient tools for gene transduction of mammalian cells. However, the possible employment of HIV-based vectors in clinical trials is a very controversial issue, mainly due to safety and ethical concerns. HIV-1 is a lethal pathogenic agent, which induces AIDS. Genetic vectors must derive either from viruses that are not pathogenic in humans, or that eventually just cause mild illnesses. Patients exposed to HIV-based vectors will test seropositive to certain components of HIV-1. In addition, there might be other possible adverse effects in patients that cannot be predicted, as many aspects of the pathogenesis of AIDS have not been completely understood yet. On these grounds, it seems necessary to improve the design of other lentiviral vectors, which derive from viruses that are not pathogenic in humans and are distantly related to primate retroviridae.

Gene transfer technology has many potential applications in medicine. Phase I and phase II gene-based clinical trials have been conducted for the treatment of cancer, monogenic disorders, some neurodegenerative illnesses, cardiopathies and infectious diseases. A phase I gene therapy clinical trial has recently been approved for the treatment of Parkinson's disease, while preclinical studies are in progress to develop gene-based interventions for the treatment of Alzheimer's disease and Huntington's disease, amyotrophic lateral sclerosis, spinal cord injury, and diabetes type 1 and type 2. A number of gene transfer models have been generated for gene therapy and genetic immunization programs. Vector design is addressing several pressing issues in the matter of gene delivery improvement, stabilization of transgene expression and safety. This is necessary in order to achieve efficient gene-based therapeutic interventions. Indeed, considerable progress has been reported in the field of vector design, which has produced some encouraging results in clinical trials and preclinical studies. However, vector design should be further developed to allow for the successful application of gene transfer technology in therapy. This review summarizes the latest achievements and controversies in clinical trials and preclinical studies in the field of gene therapy., ((c) 2003 Prous Science. All rights reserved.)