The Multidisciplinary Approach for the Diagnosis of Laryngohyoid Lesions: a Systematic Literature Review and Meta-Analysis.

Background: The diagnosis of neck lesions remains a medico-legal diagnostic challenge because of the complexity of the anatomical relationship of the neck's organs and their anthropometric morphological variability. We compared the multidisciplinary approach using autopsy and postmortem computed tomography (PMCT), postmortem fine preparation (PMFP), postmortem micro-computed tomography (micro-CT), and postmortem magnetic resonance (PMMR) with the performance of a single diagnostic method among them evaluating the significance of different results. The multidisciplinary approach significantly reduced the number of unidentified neck lesions. The analysis demonstrates the need to better define the scan protocols and compose forensic guidelines for radiological application. The results of this study point out the need to compare the different diagnostic approaches in deceased subjects to better define the radiological scan protocol based on a multidisciplinary approach, including autopsy and radiological methods and the radiological scan protocols. Methods: We performed a systematic electronic search of retrospective scientific articles in PubMed, the Scopus database, and the Cochrane Library. The following combinations of words were used: "hyoid fracture"; "comparison between PMCT AND autopsy"; "hyoid fracture PMCT AND autopsy"; "hyoid bone fracture AND forensic imaging"; "hyoid fracture AND PMCT"; "neck fracture PMCT AND autopsy"; "laryngohyoid lesions"; "postmortem CT AND autopsy in strangulation"; "postmortem AND strangulation Signs "; "strangulation virtopsy"; and "strangulation AND MRI". We selected 16 articles that were published between March 2003 and June 2020. We conducted a meta-analysis with R software to evaluate the rates. We obtained related confidence intervals and a forest plot. Results: Thyroid cartilage damages were significantly more common than hyoid bone fractures (61.7% vs 42.2%) in a sample of 128 subjects. The synergic uses of autopsy/PMCT, autopsy/PMFP, autopsy/microCT, and autopsy/PMMR revealed significantly higher rates than a single investigation. We analyzed the PMCT scan data. The scan parameters evaluated were as follows: row, scan sample, reconstruction, kernel, slice thickness, kVp, and mAs. A lack of uniformity in the application of the protocol was observed. Conclusion: Further studies are needed to better define the radiological scan protocols and to draw guidelines to identify the appropriate radiological methods in relation to the specific case.

Autologous adipose-derived stromal vascular fraction and platelet concentrates for the treatment of complex perianal fistulas.

BACKGROUND: Complex perianal fistulas are a major challenge for modern surgery since 10-35% of patients have functional problems after treatment. Sphincter-saving techniques have a wide range of efficacy (10-80%). We hypothesised that autologous adipose-derived stromal vascular fraction in combination with platelet rich plasma is a new therapeutic strategy with enhanced cure and function preservation rates. METHODS: Adult patients with complex cryptoglandular perianal fistulas were treated with injection of autologous adipose-derived stromal vascular fraction in combination with platelet rich plasma around and inside the fistulous tract between May 2018 and April 2019 at the General and Emergency Surgery Operative Unit of the University Hospital "P. Giaccone" of Palermo. Fistulas were confirmed by magnetic resonance imaging. Patients completed the Short Form-36 score on quality of life and the Wexner and Vaizey scores on faecal incontinence, and they were functionally studied using a three-dimensional anorectal manometry. The clinical and functional follow-up was performed at 1 year and 2 years after surgery. RESULTS: Nine patients (4 males, 5 females; median age 42 years [19-63 years]) with high trans-sphincteric or horseshoe fistulas were treated. The average number of previous surgeries per patient was 4.8. At 1 year follow-up, 77.7% of patients were cured, while at 2 years there was 1case of relapse. The variation in Short Form-36 score in cured patients was not significant (p = 0.0936). No statistically significant differences were found in continence scores. CONCLUSIONS: The proposed treatment is a treatment option that preserves sphincter integrity and function, potentially avoiding postoperative incontinence and the need of repeated treatments.

Validation of the Meet-URO score in patients with metastatic renal cell carcinoma receiving first-line nivolumab and ipilimumab in the Italian Expanded Access Program.

BACKGROUND: The Meet-URO score allowed a more accurate prognostication than the International Metastatic RCC Database Consortium (IMDC) for patients with pre-treated metastatic renal cell carcinoma (mRCC) by adding the pre-treatment neutrophil-to-lymphocyte ratio and presence of bone metastases. MATERIALS AND METHODS: A post hoc analysis was carried out to validate the Meet-URO score on the overall survival (OS) of patients with IMDC intermediate-poor-risk mRCC treated with first-line nivolumab plus ipilimumab within the prospective Italian Expanded Access Programme (EAP). We additionally considered progression-free survival (PFS) and disease response rates. Harrell's c-index was calculated to compare the accuracy of survival prediction. RESULTS: Overall the EAP included 306 patients, with a median follow-up of 12.2 months, median OS was not reached, 1-year OS was 66.8% and median PFS was 7.9 months. By univariable analysis, both the IMDC score and the two additional variables of the Meet-URO score were associated with either OS or PFS (P < 0.001 for all comparisons). The four Meet-URO risk groups (G) had 1-year OS of 92%, 72%, 50% and 21% for G2 (29.1% of patients), G3 (28.8%), G4 (33.0%) and G5 (9.1%), respectively. OS was significantly shorter in each consecutive G (P = 0.001 for G3, P < 0.001 for both G4 and G5 compared to G2). Similarly, Meet-URO Gs 2-5 showed decreasing median PFS and response rates. The Meet-URO score showed the highest c-index for both OS (0.73) and PFS (0.67). Limitations include the post hoc nature of this analysis and the lack of a comparative arm to assess predictive value. CONCLUSION: The Meet-URO score appeared to show better prognostic classification than the IMDC alone in patients with mRCC at IMDC intermediate-poor risk treated with first-line nivolumab and ipilimumab.

Utility of post mortem computed tomography in clivus fracture diagnosis. Case illustration and literature review.

Clivus fractures are usually associated with head blunt trauma due to traffic accident and falls. A 23 - year-old man died immediately after a smash-up while he was stopping on his motorcycle. Post-mortem Computed tomography (PMCT), performed before autopsy, revealed a complex basilar skull base fractures associated with brainstem and cranio-vertebral junction injuries, improving the diagnostic performance of conventional autopsy. Imaging data were re-assessable and PMCT offers the possibility to perform multiplanar and volume rendered reconstructions, increasing forensic medicine knowledge related to traumatic injuries.

A facile method to determine pore size distribution in porous scaffold by using image processing.

Image processing permits scientists to investigate morphological properties of three-dimensional structures starting from their bi-dimensional gray-scale representation. In many cases porous structure with complex architecture has to be designed in order to attempt specific properties such in the case of scaffold for tissue engineering. Traditional morphological characterization, like scanning electron microscopy, should be coupled with quantitative information such as pore size distribution (PSD) in order to get a deeper understanding of the influence of the porous structure on tissue regeneration processes and on other related applications, it is remarkable to study a quantitative analysis of porosity and of pores dimension. In this work it was developed as a software able to accomplish the segmentation of images containing pores of any geometry in a semi-automatic way with the aim to measure the PSD. Case study constituted by PLA porous scaffolds with different pore size was adopted. Results indicate that image processing methods well fit the pore size features of PLA scaffolds, overcoming the limits of the more invasive porosimetry techniques.

Dose-finding/phase II trial: bevacizumab, immunotherapy, and chemotherapy (BIC) in metastatic renal cell cancer (mRCC). Antitumor effects and variations of circulating T regulatory cells (Treg).

The aim of this study was to explore the efficacy and toxicities of a combined regimen of bevacizumab plus immunotherapy and chemotherapy (BIC) and the circulating T regulatory cells (Treg) in metastatic renal cell cancer (mRCC). Nephrectomized mRCC patients were enrolled into a multicenter single-arm dose-finding study with five escalated dose levels of chemotherapy with intravenous gemcitabine and 5-fluorouracil associated with fixed intravenous doses of bevacizumab, subcutaneous low doses of interleukin-2, and interferon-α-2a. An expanded cohort (phase II study) was treated at the recommended dose for additional safety and efficacy information according to minimax Simon two-stage design. Blood samples for Treg were collected and evaluated by fluorescence-activated cell sorting (FACS) analysis on cycle 1. Fifty-one patients were entered to receive one of five dose levels. Median age was 58 years (male 67 %, pretreated 49 %): 15 patients were low risk according to Memorial Sloan-Kettering Cancer Center (MSKCC) criteria, while 27 and nine were respectively intermediate- and high-risk patients. More frequent grade 3 and 4 toxicities included nonfebrile neutropenia, thrombocytopenia, and fever. Among patients evaluable for response (49), 29.5 % had partial response and 37 % stable disease. Overall median time to progression and median overall survival were 8.8 and 22.67 months, respectively. We observed a rapid increase in the percentage of Treg after immunotherapy and a reduction after bevacizumab only in patient who obtained a partial response or stable disease. The BIC was feasible, well tolerated, and shown interesting activity. Further studies are needed to explore if Treg could have a role in clinical response in mRCC treated with bevacizumab.

Comparison of iodinated contrast media for the assessment of atherosclerotic plaque attenuation values by CT coronary angiography: observations in an ex vivo model.

OBJECTIVE: To compare the influence of different iodinated contrast media with several dilutions on plaque attenuation in an ex vivo coronary model studied by multislice CT coronary angiography. METHODS: In six ex vivo left anterior descending coronary arteries immersed in oil, CT (slices/collimation 64×0.625 mm, temporal resolution 210 ms, pitch 0.2) was performed after intracoronary injection of a saline solution, and solutions of a dimeric isosmolar contrast medium (Iodixanol 320 mgI ml(-1)) and a monomeric high-iodinated contrast medium (Iomeprol 400 mgI ml(-1)) with dilutions of 1/80 (low concentration), 1/50 (medium concentration), 1/40 (high concentration) and 1/20 (very high concentration). Two radiologists drew regions of interest in the lumen and in calcified and non-calcified plaques for each solution. 29 cross-sections with non-calcified plaques and 32 cross-sections with calcified plaques were evaluated. RESULTS: Both contrast media showed different attenuation values within lumen and plaque (p<0.0001). The correlation between lumen and non-calcified plaque values was good (Iodixanol r=0.793, Iomeprol r=0.647). Clustered medium- and high-concentration solutions showed similar plaque attenuation values, signal-to-noise ratios (SNRs) (non-calcified plaque: medium solution SNR 31.3±15 vs 31.4±20, high solution SNR 39.4±17 vs 37.4±22; calcified plaque: medium solution SNR 305.2±133 vs 298.8±132, high solution SNR 323.9±138 vs 293±123) and derived contrast-to-noise ratios (p>0.05). CONCLUSION: Differently iodinated contrast media have a similar influence on plaque attenuation profiles. ADVANCES IN KNOWLEDGE: Since iodine load affects coronary plaque attenuation linearly, different contrast media may be equally employed for coronary atherosclerotic plaque imaging.

Prognostic outcome of routine clinical noninvasive multidetector-row computed tomography coronary angiography in patients with suspected coronary artery disease: a 2-year follow-up study.

PURPOSE: The aim of the study was to assess the prognostic value of multidetector-row CT coronary angiography (MDCT-CA) in patients with suspected coronary artery disease (CAD) in a routine clinical context. MATERIALS AND METHODS: A total of 125 patients (82 men, age 57.4±10.3 years) with suspected CAD underwent MDCT-CA. All patients were assessed for cardiovascular risk factors, symptoms and coronary calcium score. A 2-year follow-up study for the occurrence of major adverse cardiac events was performed. RESULTS: According to the Morise pretest score, 76 patients (60.8%) were at intermediate risk. Patients with suspected CAD presented the following prognostic outcome (p<0.0001): in 41 patients with normal coronary arteries at MDCT-CA, the event rate was 0%; five of 49 patients with nonobstructive CAD had major cardiac events; two of 35 patients with obstructive CAD suffered cardiac death and 19 underwent revascularisation. At multivariate analysis, the presence of obstructive CAD is the only significant independent prognostic variable (hazard ratio, 10.1393; 95% confidence interval 3.2189-31.9379; p<0.0001). CONCLUSIONS: Routine clinical MDCT-CA provides an excellent prognostic value at 2-year follow-up in patients with normal coronary arteries. The cardiac event rate increases with CAD severity.

Prevalence of myocardial bridging and correlation with coronary atherosclerosis studied with 64-slice CT coronary angiography.

PURPOSE: This study aimed to assess the prevalence and characteristics of myocardial bridging in patients who underwent multislice computed tomography coronary angiography (MSCT-CA) and to evaluate the correlation between bridged coronary segments and atherosclerosis. MATERIALS AND METHODS: A total of 277 patients (mean age 60+/-11 years) we consecutively examined with 64-slice MSCT-CA for suspected or known coronary atherosclerosis were retrospectively reviewed for myocardial bridging. Segments proximal and distal to the bridging were evaluated for atherosclerotic plaque, as were the remaining coronary segments. RESULTS: Myocardial bridging was present in 82 patients (30%, mean age 59+/-12). Bridges were of variable length (<1 cm 58%; 1-2 cm 32%; >2 cm 10%) and depth (superficial 69%, intramyocardial 31%) and frequently localised in the mid-distal segment of the left anterior descending artery (95%). Myocardial bridging cannot be considered a significant risk factor for coronary atherosclerosis (odds ratio 0.49) compared with traditional cardiovascular risk factors. Coronary segments proximal to the bridge showed no atherosclerotic disease (33%), positive remodelling (27%), <50% stenosis (20%) or >50% stenosis (20%). We identified 12 noncalcified, 32 mixed and 17 calcified plaques. The distal segments were significantly less affected (p<0.0001). CONCLUSIONS: MSCT-CA is a reliable, noninvasive method that is able to depict myocardial bridging and associated atherosclerotic plaque in the proximal segments.

Videofluorography swallow study of patients with systemic sclerosis.

PURPOSE: This study was undertaken to evaluate the role of the videofluorographic (VFG) swallow study in patients with systemic sclerosis. MATERIALS AND METHODS: Over a 23-month period, 45 women (mean age 58 years, range 27-76 years) with a known diagnosis of systemic sclerosis and a history of dysphagia underwent a dynamic and morphological study of the oral, pharyngeal and oesophageal phases of swallowing with videofluorography. All examinations were performed with a remote-controlled digital C-arm device with 16-in image intensifier, 0.6- to 1.2-mm focal spot range and maximum tube voltage of 150 kVp in fluorography and 120 kVp in fluoroscopy. Cineradiographic sequences were acquired for the swallow study with 12 images per second and matrix 512 x 512 after the ingestion of boluses of high-density (250% weight/volume) barium. The evaluation of oesophageal peristalsis was documented with digital cineradiographic sequences with six images per second in the upright and supine positions during the swallowing of barium (60% weight/volume), and the water siphon test was performed with the patient in the supine position to evaluate the presence of gastro-oesophageal reflux disease (GORD). All patients subsequently underwent laryngoscopy, endoscopy and pH monitoring, and the data thus obtained were processed and compared. RESULTS: The VFG swallow study identified alterations of epiglottal tilting associated with intraswallowing laryngeal penetration in 26 patients (57.8%), pooling of contrast agent in the valleculae and pyriform sinuses in 23 (51.1%) and radiographic signs of nonspecific hypertrophy of the lingual and/or palatine tonsils in 18 (40%). The study of the oesophageal phase revealed the presence of altered peristalsis in all patients, and in particular, 36 patients (80%) showed signs of atony. Altered oesophageal clearing mechanisms were evident in all 45 patients, sliding hiatus hernia in 43 (93%) and GORD in 44 (97%). CONCLUSIONS: Our study demonstrated that in patients with systemic sclerosis, there is no primary alteration of the oral or pharyngeal phase of swallowing. In addition, alterations of epiglottal tilting associated with laryngeal penetration of contrast agent were found to be secondary to chronic GORD. Indeed, in 40% of patients, radiographic signs were found that indicated nonspecific hypertrophy of the lingual tonsil and/or palatine tonsils and nonspecific signs of chronic pharyngeal inflammation, and GORD was identified in 93% of patients, which in 40% of cases extended to the proximal third of the oesophagus. The data obtained were confirmed in 85% of cases with pH monitoring and in all cases with laryngoscopy.

Influence of heart rate in the selection of the optimal reconstruction window in routine clinical multislice coronary angiography.

PURPOSE: The aim of our study was to assess the influence of heart rate on the selection of the optimal reconstruction window with 40-slice multidetector-row computed tomography (40-MDCT) coronary angiography. MATERIALS AND METHODS: We studied 170 patients (114 men, age 60+/-11.3 years) with suspected or known coronary artery disease with 40-MDCT coronary angiography. Patients [mean heart rate (HR) 62.9+/-9.3 bpm, range 42-94 bpm] were clustered in two groups (group A: HR 65 bpm). Multiphase reconstruction data sets were obtained with a retrospective electrocardiogram (ECG)-gated 40-MDCT coronary angiography scan from 0% to 95% every 5% of the R-R interval. Two radiologists in consensus evaluated the best data sets for diagnostic purposes. RESULTS: In group A, the optimal reconstruction windows were at 70% (55/110, 71/110 and 69/110 for the right coronary artery, left anterior descending and the left circumflex, respectively) and 75% (26/110, 28/110 and 28/110, respectively) of the R-R interval. In group B, a wide range of reconstruction windows were employed, both in the end-systolic phase at 40% (32/60, 18/60 and 17/60, for the right coronary artery, left anterior descending and circumflex, respectively) and diastolic phases at 70% (12/60, 22/60 and 19/60, respectively). Six scans were excluded due to severe respiratory artefacts. CONCLUSIONS: Optimal position of the image reconstruction window relative to the cardiac cycle is significantly influenced by the heart rate during scanning. Diastolic reconstruction phases often allowed an optimal assessment in group A. Reconstruction phases from 30% to 45% are advisable for higher heart rates.

Multislice human organ extraction based on GVF.

Segmentation techniques based on active contours algorithm are widely used in medical imaging. Unfortunately, they require a lot of parameters to be used and this can represent an issue for those physicians with not much informatics skills. This paper proposes a software tool which allows to segment multiple slice can differ organ extraction setting a small number of parameters. Moreover, the tool offers the functionality to perform a multiple segmentation the same time, so that an entire volume composed by hundreds slices can be segmented.

Digital cineradiographic study of swallowing in patients with amyotrophic lateral sclerosis.

PURPOSE: This study was performed to evaluate the usefulness of digital cineradiography in detecting swallowing disorders in dysphagic patients affected by amyotrophic lateral sclerosis (ALS) with a view to planning an adequate therapeutic approach. MATERIAL AND METHODS: From January 2005 to September 2006, 23 patients (10 men and 13 women; mean age 41.3+/-8.6 years) affected by ALS were evaluated with digital cineradiography to assess the grade of dysphagia. All patients were classified using the Hillel ALS Severity Scale (ALSSS). All examinations were performed with radiocontrolled equipment provided with a digital C-arm. RESULTS: The cineradiographic technique enabled us to differentiate patients with disorders of the oral (17/23) and/or pharyngeal (19/23) swallowing phase from those without swallowing dysfunction (4/23). In 14/23 patients, passage of contrast medium into the upper airways was observed during swallowing, whereas in 5/23 cases, aspiration of contrast medium into the lower airways was recorded. CONCLUSIONS: The videofluoroscopic swallowing study has high diagnostic capabilities in the evaluation of swallowing disorders, as it is able to identify the degree and causes of impairment. In addition, the study proved useful for planning speech therapy and for follow-up in patients with ALS.

Forty-slice MDCT enteroclysis: evaluation after oral administration of isotonic solution in Crohn's disease.

OBJECTIVE: The aim of this study was to evaluate the accuracy of multidetector computed tomography (MDCT) enteroclysis after oral hyperhydration with isotonic solution in detecting bowel wall alterations in patients with Crohn's disease. MATERIALS AND METHODS: Twenty-eight patients with a diagnosis of Crohn's disease established by ileocolonoscopy and histology were enrolled in the study; 15 patients with negative ileocolonoscopy served as controls. In all cases, MDCT enteroclysis was performed after oral administration of 2,000 ml of isotonic solution and intravenous administration of N-butylscopolamine. Axial, isotropic multiplanar and volume-rendered reconstructions were used to evaluate bowel wall thickness, ulceration, contrast enhancement, extraparietal involvement and possible complications. RESULTS: MDCT enteroclysis identified the typical signs of Crohn's disease in 26 patients (92.8%), with sensitivity of 92.8%, specificity of 100%, positive predictive value 100% and negative predictive value 75%. CONCLUSIONS: MDCT enteroclysis after oral hyperhydration with isotonic solution showed a high level of accuracy in detecting small bowel changes in patients with Crohn's disease. It can be considered a safe and effective alternative to conventional radiography and small-bowel spiral computed tomography enema, especially in patients who refuse nasojejunal intubation.

Gastrointestinal stromal tumour: 40-row multislice computed tomography findings.

PURPOSE: The purpose of this study was to describe the findings and evaluate the role of multidetector (40-slice) computed tomography (MDCT) in the preoperative assessment of gastrointestinal stromal tumours (GISTs). MATERIALS AND METHODS: Thirteen patients with histologically proven GIST (size: 4-30 cm; mean: 9 cm) underwent 40-slice MDCT after the ingestion of 1,000 ml of water. Images were obtained before and 70 s after intravenous injection of 120 ml of iodinated contrast agent. Two experienced radiologists reviewed the CT findings to evaluate lesion site, size, margins, attenuation, growth pattern, enhancement pattern, ascites, lymphadenopathy, direct invasion to adjacent organs and distant metastasis. Multiplanar maximum intensity projection and three-dimensional (3D) reconstructions were also obtained. RESULTS: Seven out of 13 GISTs were located in the jejunumileum, 3/13 in the stomach, 2/13 in the rectum and in one case, the origin remained unknown. Eleven out of 13 were exophytic, and ten had well-defined borders. Two out of 13 showed calcifications. Thirteen out of 13 exhibited inhomogeneous enhancement due to areas of necrosis and cystic degeneration. Direct invasion to adjacent organs (n=3), ascites (n=3), and liver (n=1) and peritoneal (n=1) metastases were also detected. Bowel obstruction, vascular invasion and lymphadenopathy were never seen. CONCLUSIONS: MDCT allowed reliable preoperative assessment of GIST, providing useful clues for lesion characterisation.

The GENIUS web portal--an easy way to access the Grid.

OBJECTIVE: The development of computational Grids is making huge amounts of computing power and data storage available for a lot of scientific applications. At this stage of development, the use of the Grid is mainly based on Command Line Interface (CLI) tools that are not very friendly and can be considered an obstacle to the use of these powerful tools. The objective of this paper is to present a solution to this problem. METHODS: To ease the access of new users to the grid the GENIUS (Grid Enabled web eNvironment for site Independent User job Submission) grid portal has been jointly developed by INFN and NICE within the context of both the Italian INFN Grid and the European DataGrid Projects. Here we devote particular care to the description of job creation and submission and the services for transparent access to user's data and applications. RESULTS: Using GENIUS, the obstacle of complicated CLI can be overtaken and simple web interfaces can be built for specific user communities and applications. Here we show examples in the field of bio-medical applications. CONCLUSIONS: The use of Grid can be made easy with the use of Grid portals such as GENIUS.

Quality of life evaluation in a randomised trial of chemotherapy versus bio-chemotherapy in advanced melanoma patients.

This study analyses the health related quality of life (HRQOL) of advanced melanoma patients, in a randomised trial comparing bio-chemotherapy (bio-CT) versus chemotherapy (CT). The trial enrolled 178 patients and the median survival was not statistically different between the two arms. HRQOL was assessed at baseline and before each cycle of therapy, using the Rotterdam Symptom Checklist (RSCL) questionnaire completed with 140 patients. At baseline, overall quality of life and psychological distress scores were the most impaired, compared with the normal population. During treatment, the difference between the two arms in the changes from baseline was statistically significant (P=0.03) only in the overall quality of life score, with a decrease of 6.28 points in the bio-CT arm. The mean values decreased significantly in all domains in bio-CT arm, but only in activity level and physical symptom distress scores in the CT arm. Testing HRQOL variables and prognostic clinical factors in a Cox model, only the serum level of lactic dehydrogenase, baseline overall quality of life and the physical symptom distress scores remained significant independent prognostic factors for survival. A score of less than 75 points in the overall quality of life and in the physical symptom distress domains was associated with a Hazard Ratio (HR) of 2.31 (95% Confidence Interval (CI): 1.09-4.90) and 1.92 (95% CI: 1.10-3.36), respectively.

Topoisomerase I inhibitors combination chemotherapy in non-small cell lung cancer.

In the last years, the main topoisomerase I inhibitors (TP1-I) (i.e. topotecan and irinotecan) have been used in combination chemotherapy in non-small cell lung cancer. Several drugs (also alternative to cisplatin) have been used in combination with TP1-I, but to date the higher remission rate obtained with combinations is not translated into a more prolonged survival in comparison with TP1-I given alone. On the other hand, the toxicity of TP1-I combinations is greater than those of TP1-I used alone. The superior efficacy of combinations versus TP1-I used alone remains an open question. Furthermore, the best schedule for TP1-I has not been completely elucidated. Randomised studies are few (only two phase III trials) and only controlled studies will be able to clarify the best TP1-I combination regimen.