[Surgical uprighting of partially impacted second molars]. / Chirurgisch oprichten van deels geïmpacteerde tweede molaren.

Eruption of mandibular second molars usually occurs around the age of 12. Incomplete eruption of second molars in such young patients can lead to loss of the molars, due to caries, root resorption or periodontal pathology. When a pathology of this kind develops, the treatment option for a mesially impacted molar is often to extract the tooth. If tooth eruption is, however, monitored closely by the dentist and/or orthodontist, early treatment can be considered in order to preserve the tooth. Partially impacted second molars can be placed in a functional anatomical position by surgical uprighting and repositioning. As long as certain conditions are met, this results in sound functionality with preservation of the full dentition. In cases of incomplete eruption, this treatment option should therefore be considered by dentists and orthodontists before extracting the second molars.

[Multidisciplinary treatment of amelogenesis imperfecta]. / Multidisciplinaire behandeling van amelogenesis imperfecta.

A healthy 13-year-old patient with amelogenesis imperfecta was referred by her orthodontist to the joint consultation hour (Center for Specialised Dentistry and Oral and Maxillofacial Surgery). In addition to her amelogenesis imperfecta, she was diagnosed with a class 2 malocclusion and a mandibular hypoplasia. She was treated successfully through a multidisciplinary approach.

How can schistosome circulating antigen assays be best applied for diagnosing male genital schistosomiasis (MGS): an appraisal using exemplar MGS cases from a longitudinal cohort study among fishermen on the south shoreline of Lake Malawi.

We provide an update on diagnostic methods for the detection of urogenital schistosomiasis (UGS) in men and highlight that satisfactory urine-antigen diagnostics for UGS lag much behind that for intestinal schistosomiasis, where application of a urine-based point-of-care strip assay, the circulating cathodic antigen (CCA) test, is now advocated. Making specific reference to male genital schistosomiasis (MGS), we place greater emphasis on parasitological detection methods and clinical assessment of internal genitalia with ultrasonography. Unlike the advances made in defining a clinical standard protocol for female genital schistosomiasis, MGS remains inadequately defined. Whilst urine filtration with microscopic examination for ova of Schistosoma haematobium is a convenient but error-prone proxy of MGS, we describe a novel low-cost sampling and direct visualization method for the enumeration of ova in semen. Using exemplar clinical cases of MGS from our longitudinal cohort study among fishermen along the shoreline of Lake Malawi, the portfolio of diagnostic needs is appraised including: the use of symptomatology questionnaires, urine analysis (egg count and CCA measurement), semen analysis (egg count, circulating anodic antigen measurement and real-time polymerase chain reaction analysis) alongside clinical assessment with portable ultrasonography.

Added diagnostic value of broad-range 16S PCR on periprosthetic tissue and clinical specimens from other normally sterile body sites.

AIMS: Evaluation of 16S PCR in addition to the standard culture to improve the pathogen detection rate in clinical specimens. METHODS AND RESULTS: Microbiological culture and direct 16S PCR was performed on specimens from suspected prosthetic joint infection patients (cohort-1) and on tissues and fluids from other normally sterile body sites (cohort-2). Based on clinical and microbiological data, the detection rate for both methods was assessed, assuming no superiority of either 16S PCR or culture. In cohort-1, 469 specimens were obtained. Culture was positive in 170 (36·2%) specimens, 16S PCR detected 70 (41·2%) of those pathogens. Additionally, 16S PCR detected pathogens in 13 of 299 (4·3%) culture-negative specimens. In cohort-2, pathogens were cultured in 52 of 430 (12·1%) specimens and 16S PCR revealed those pathogens in 32 (61·5%) specimens. 16S PCR detected pathogens in 31 of 378 (8·2%) culture-negative specimens. CONCLUSIONS: Overall, the yield with 16S PCR was low. For cohort-1 16S PCR detected pathogens in 4·3% of culture-negative specimens, where this was 8·2% for cohort-2. SIGNIFICANCE AND IMPACT OF THE STUDY: Although direct 16S PCR cannot replace culture, it may offer a valuable additional diagnostic option for detection of difficult to culture micro-organisms in culture-negative clinical specimens.

Multiplex real-time PCR for diagnosing malaria in a non-endemic setting: a prospective comparison to conventional methods.

Almost a decade ago our diagnostic laboratory implemented an in-house real-time PCR for the detection of Plasmodium DNA to diagnose malaria in parallel with conventional diagnostics, i.e., microscopy (thick and thin smears), quantitative buffy coat microscopy (QBC), and a rapid diagnostic test (RDT). Here we report our experiences and make a comparison between the different diagnostic procedures used in this non-endemic setting. All patients during the period February 2009-December 2017 suspected of malaria were prospectively tested at the moment of sample collection. Both PCR and conventional malaria diagnostics were carried out on a total of 839 specimens from 825 patients. In addition, three Plasmodium falciparum (Pf) patients were closely followed by real-time PCR and microscopy after treatment. Overall, 56 samples (55 patients) tested positive by real-time PCR, of which six were missed by microscopy and seven by QBC. RDT showed fairly good results in detecting Pf, whereas specificity was not optimal. RDT failed to detect 10 of 17 non-Pf PCR positive specimens. One Plasmodium malariae patient would have been missed if only conventional diagnostic tests had been used. The high sensitivity of the PCR was confirmed by the number of PCR positive, microscopy negative post-treatment samples. In conclusion, within our routine diagnostic setting, malaria real-time PCR not only showed a high level of agreement with the conventional methods used, but also showed higher sensitivity and better specificity. Still, for complete replacement of the conventional procedures in a non-endemic setting, the time-to-results of the real-time PCR is currently too long.

[A PhD completed. Bilateral sagittal split osteotomy: risk factors for complications and predictability of the splitter-separator technique]. / Serie: Hora est. De bilaterale sagittale splijtings­osteotomie: risicofactoren voor complicaties en voorspelbaarheid van de splijttang-splijtheveltechniek.

Bilateral sagittal split osteotomy (BSSO) is a surgical technique to correct hypoplasia, hyperplasia or asymmetry of the mandible. The risk of complications associated with BSSO with splitter and separators, the so-called splitter-separator technique, and the predictability of this technique were analysed. The average incidence of complications associated with classic BSSO techniques was determined by a review of the literature. With classic techniques, a bad split occurred in 2.3% of the operated sides, removal of osteosynthesis material on account of complaints in 11.2% of patients, and permanent neurosensory disturbances in the area of the mental nerve in 33.9% of patients. The incidence of complications for BSSO with splitter and separators is a bad split in 2.0% of the operated sides, necessary removal of osteosynthesis material in 5.6% of patients, and permanent neurosensory disturbances of the lower lip in 9.9% of patients. Removal of the third molars during BSSO may result in an increased chance of bad split but does not increase the risk of other complications. In conclusion, BSSO with splitter and separators is a reliable technique, with a remarkably low incidence of permanent neurosensory disturbances of the lower lip.

[Replacing heavily damaged molars with the use of 3D-techniques]. / Vervanging van ernstig beschadigde molaren met behulp van 3D-technieken.

Seriously damaged molars can be replaced by autotransplantation with the help of 3D techniques. In the present case, involving an 18-year old patient, 18, 38 and 48 were used to replace, respectively, 14, 36 and 37. Preoperatively, the width of the crowns and the root development of 18, 38 and 48 were analysed using 3D imaging. During the autotransplantation procedure, the new alveoli are formed with the help of replicas of the donor molars printed in 3D, in order to prevent iatrogenic damage to the actual donor molars.. The extra-alveolar time was less than 2 minutes for all donor molars. Postoperative follow-up showed physiologic integration of the transplanted molars. There was no ankylosis. Autotransplantation with the help of 3D techniques makes it possible to perform complex procedures with good results.

Opisthorchis felineus negatively associates with skin test reactivity in Russia-EuroPrevall-International Cooperation study.

BACKGROUND: Most studies on the relationship between helminth infections and atopic disorders have been conducted in (sub)tropical developing countries where exposure to multiple parasites and lifestyle can confound the relationship. We aimed to study the relationship between infection with the fish-borne helminth Opishorchis felineus and specific IgE, skin prick testing, and atopic symptoms in Western Siberia, with lifestyle and hygiene standards of a developed country. METHODS: Schoolchildren aged 7-11 years were sampled from one urban and two rural regions. Skin prick tests (SPT) and specific IgE (sIgE) against food and aeroallergens were measured, and data on allergic symptoms and on demographic and socioeconomic factors were collected by questionnaire. Diagnosis of opisthorchiasis was based on PCR performed on stool samples. RESULTS: Of the 732 children included, 34.9% had opisthorchiasis. The sensitization to any allergen when estimated by positive SPT was 12.8%, while much higher, 24.0%, when measured by sIgE. Atopic symptoms in the past year (flexural eczema and/or rhinoconjunctivitis) were reported in 12.4% of the children. SPT was positively related to flexural eczema and rhinoconjunctivitis, but not to wheezing. Opisthorchiasis showed association with lower SPT response, as well as borderline association with low IgE reactivity to any allergen. However, the effect of opisthorchiasis on SPT response was not mediated by IgE, suggesting that opisthorchiasis influences SPT response through another mechanism. Opisthorchiasis also showed borderline association with lower atopic symptoms. CONCLUSIONS: There is a negative association between a chronic helminth infection and skin prick test reactivity even in a developed country.

[Incision of the third molar in the Netherlands. Incision tech-niques for the removal of impacted third molars in the mandible.] / Incisietechnieken bij verwijdering van geïmpacteerde derde molaren in de onderkaak.

Various incision techniques to remove impacted third molars in the mandible have been described, for example, the flap incision, the envelope incision, the distal incision and the modified envelope incision. The aim of this study was to record the incision techniques used by oral and maxillofacial surgeons in the Netherlands for the removal of impacted third molars in the mandible. All members of the Dutch Association of Oral and Maxillofacial Surgery (NVMKA) received a questionnaire. In this questionnaire, the surgeons specified their standard incision technique for the removal of, respectively, mesially impacted, upright, or distally impacted mandibular third molars. Of the 323 questionnaires sent, 172 were returned (53,3% response rate). The flap incision and the distal incision were the most frequently used incisions by oral and maxillofacial surgeons (including residents) in the Netherlands. The academic centre seems to have a lasting impact on the preferred way of removing an impacted third molar. It also seems that an oral and maxillofacial surgeon more frequently removes a third molar in the mandible from a sitting position than a resident.

Helminths are positively associated with atopy and wheeze in Ugandan fishing communities: results from a cross-sectional survey.

BACKGROUND: Parasitic helminths are potent immunomodulators and chronic infections may protect against allergy-related disease and atopy. We conducted a cross-sectional survey to test the hypothesis that in heavily helminth-exposed fishing villages on Lake Victoria, Uganda, helminth infections would be inversely associated with allergy-related conditions. METHODS: A household survey was conducted as baseline to an anthelminthic intervention trial. Outcomes were reported wheeze in last year, atopy assessed both by skin prick test (SPT) and by the measurement of allergen-specific IgE to dust mites and cockroach in plasma. Helminth infections were ascertained by stool, urine and haemoparasitology. Associations were examined using multivariable regression. RESULTS: Two thousand three hundred and sixteen individuals were surveyed. Prevalence of reported wheeze was 2% in under-fives and 5% in participants ≥5 years; 19% had a positive SPT; median Dermatophagoides-specific IgE and cockroach-specific IgE were 1440 and 220 ng/ml, respectively. S. mansoni, N. americanus, S. stercoralis, T. trichiura, M. perstans and A. lumbricoides prevalence was estimated as 51%, 22%, 12%, 10%, 2% and 1%, respectively. S. mansoni was positively associated with Dermatophagoides-specific IgE [adjusted geometric mean ratio (aGMR) (95% confidence interval) 1.64 (1.23, 2.18)]; T. trichiura with SPT [adjusted odds ratio (aOR) 2.08 (1.38, 3.15)]; M. perstans with cockroach-specific IgE [aGMR 2.37 (1.39, 4.06)], A. lumbricoides with wheeze in participants ≥5 years [aOR 6.36 (1.10, 36.63)] and with Dermatophagoides-specific IgE [aGMR 2.34 (1.11, 4.95)]. No inverse associations were observed. CONCLUSIONS: Contrary to our hypothesis, we found little evidence of an inverse relationship between helminths and allergy-related outcomes, but strong evidence that individuals with certain helminths were more prone to atopy in this setting.

A Novel Approach for Computer-Assisted Template-Guided Autotransplantation of Teeth With Custom 3D Designed/Printed Surgical Tooling. An Ex Vivo Proof of Concept.

PURPOSE: The aim of this study was to introduce a novel method for accurate autotransplantation with computer-assisted guided templates and assembled custom-designed surgical tooling and to test the feasibility and accuracy of this method ex vivo. MATERIALS AND METHODS: A partially edentulous human mandibular cadaver was scanned with a cone-beam computed tomography (CBCT) system and an intraoral scan system. The 3-dimensional (3D) data of this cadaver were imported into specialized software and used to analyze the region of the recipient site and the donor tooth was selected. Subsequently, congruent to the donor tooth, custom surgical tools and a surgical guided template were designed and 3D printed. The guided osteotomy was performed and the donor tooth was transplanted. To evaluate the planned position of the donor tooth in relation to the position of the transplanted donor tooth, the mandible with the transplanted donor tooth was rescanned with the CBCT system and software matching was applied to measure the accuracy of the procedure. RESULTS: The angular deflection of the transplanted donor tooth in relation to the planned donor tooth position was 3.1°. When comparing the 3D positions of the shoulder, there was a deviation of 1.25 mm and an apical deviation of 0.89 mm. CONCLUSION: With the use of currently available technology, it is feasible to accurately plan and create in a virtual simulation a donor tooth position with congruent custom surgical tools and to transfer this to a clinical setting with 3D printing. However, further research on multiple levels is needed to explore this novel approach.

[Autotransplantation 2.0. Considerations, results and the latest techniques]. / Autotransplantatie 2.0. Overwegingen, uitkomsten en nieuwste technieken.

Autotransplantation is a valuable technique offering a physiological type of tooth replacement to patients with missing teeth. Teeth with open apices (50-75% apical closure) will regenerate with vitality following autotransplantation. The success rate following an autotransplantation is 82%. The remaining 18% can usually still be treated successfully with a simple additional treatment. The tooth survival rate 10 years after autotransplantation is higher than 90%. The use of 3D techniques makes it possible to create a pre-operative replica of the donor tooth. With this, a new alveolus can be prepared at the transplant site even before extraction. This technique reduces the extra-alveolar time for the donor tooth and minimises the possibility of iatrogenic damage. This results in a streamlined procedure, enabling better planning with better results.

[The 3D printed drilling template for bilateral sagittal osteotomy]. / De 3D-geprinte boormal voor de bilaterale sagittale splijtingsosteotomie.

The bilateral sagittal osteotomy (BSSO) is a widely used surgical technique within orthognatic surgery. The specific osteotomy design may vary from clinic to clinic. The best position of the bone cuts in a BSSO continues to be a point of discussion and probably differs from patient to patient. In addition, standardisation in, for example, research may be desirable. Pre-operative planning using a drilling template in order to position the planned individual saw cuts during BSSO can be of value. To achieve this goal, a pre-operative 3D printed biocompatible drilling template was manufactured for 1 patient on the basis of pre-operative planning. The difference between the pre-operatively determined bone cuts with the assistance of the drilling template and the actual bone cuts was still large.

Pazopanib exposure decreases as a result of an ifosfamide-dependent drug-drug interaction: results of a phase I study.

BACKGROUND: The vascular endothelial growth factor receptor (VEGFR) pathway plays a pivotal role in solid malignancies and is probably involved in chemotherapy resistance. Pazopanib, inhibitor of, among other receptors, VEGFR1-3, has activity as single agent and is attractive to enhance anti-tumour activity of chemotherapy. We conducted a dose-finding and pharmacokinetic (PK)/pharmacodynamics study of pazopanib combined with two different schedules of ifosfamide. METHODS: In a 3+3+3 design, patients with advanced solid tumours received escalating doses of oral pazopanib combined with ifosfamide either given 3 days continuously or given 3-h bolus infusion daily for 3 days (9 g m(-2) per cycle, every 3 weeks). Pharmacokinetic data of ifosfamide and pazopanib were obtained. Plasma levels of placental-derived growth factor (PlGF), vascular endothelial growth factor-A (VEGF-A), soluble VEGFR2 (sVEGFR2) and circulating endothelial cells were monitored as biomarkers. RESULTS: Sixty-one patients were included. Pazopanib with continuous ifosfamide infusion appeared to be safe up to 1000 mg per day, while combination with bolus infusion ifosfamide turned out to be too toxic based on a variety of adverse events. Ifosfamide-dependent decline in pazopanib exposure was observed. Increases in PlGF and VEGF-A with concurrent decline in sVEGFR2 levels, consistent with pazopanib-mediated VEGFR2 inhibition, were observed after addition of ifosfamide. CONCLUSION: Continuous as opposed to bolus infusion ifosfamide can safely be combined with pazopanib. Ifosfamide co-administration results in lower exposure to pazopanib, not hindering biological effects of pazopanib. Recommended dose of pazopanib for further studies combined with 3 days continuous ifosfamide (9 g m(-2) per cycle, every 3 weeks) is 800 mg daily.

Long-term responders and survivors on pazopanib for advanced soft tissue sarcomas: subanalysis of two European Organisation for Research and Treatment of Cancer (EORTC) clinical trials 62043 and 62072.

BACKGROUND: Pazopanib recently received approval for the treatment of certain soft tissue sarcoma (STS) subtypes. We conducted a retrospective analysis on pooled data from two EORTC trials on pazopanib in STS in order to characterize long-term responders and survivors. PATIENTS AND METHODS: Selected patients were treated with pazopanib in phase II (n = 118) and phase III study (PALETTE) (n = 226). Combined median progression-free survival (PFS) was 4.4 months; the median overall survival (OS) was 11.7 months. Thirty-six percent of patients had a PFS ≥ 6 months and were defined as long-term responders; 34% of patients survived ≥18 months, defined as long-term survivors. Patient characteristics were studied for their association with long-term outcomes. RESULTS: The median follow-up was 2.3 years. Patient characteristics were compared among four subgroups based on short-/long-term PFS and OS, respectively. Seventy-six patients (22.1%) were both long-term responders and long-term survivors. The analysis confirmed the importance of known prognostic factors in metastatic STS patients treated with systemic treatment, such as performance status and tumor grading, and additionally hemoglobin at baseline as new prognostic factor. We identified 12 patients (3.5%) remaining on pazopanib for more than 2 years: nine aged younger than 50 years, nine females, four with smooth muscle tumors and nine with low or intermediate grade tumors at initial diagnosis. The median time on pazopanib in these patients was 2.4 years with the longest duration of 3.7 years. CONCLUSIONS: Thirty-six percent and 34% of all STS patients who received pazopanib in these studies had a long PFS and/or OS, respectively. For more than 2 years, 3.5% of patients remained progression free under pazopanib. Good performance status, low/intermediate grade of the primary tumor and a normal hemoglobin level at baseline were advantageous for long-term outcome. NCT00297258 (phase II) and NCT00753688 (phase III, PALETTE).

Doxorubicin-based adjuvant chemotherapy in soft tissue sarcoma: pooled analysis of two STBSG-EORTC phase III clinical trials.

BACKGROUND: The EORTC-STBSG coordinated two large trials of adjuvant chemotherapy (CT) in localized high-grade soft tissue sarcoma (STS). Both studies failed to demonstrate any benefit on overall survival (OS). The aim of the analysis of these two trials was to identify subgroups of patients who may benefit from adjuvant CT. PATIENTS AND METHODS: Individual patient data from two EORTC trials comparing doxorubicin-based CT to observation only in completely resected STS (large resection, R0/marginal resection, R1) were pooled. Prognostic factors were assessed by univariate and multivariate analyses. Patient outcomes were subsequently compared between the two groups of patients according to each analyzed factor. RESULTS: A total of 819 patients had been enrolled with a median follow-up of 8.2 years. Tumor size, high histological grade and R1 resection emerged as independent adverse prognostic factors for relapse-free survival (RFS) and OS. Adjuvant CT is an independent favorable prognostic factor for RFS but not for OS. A significant interaction between benefit of adjuvant CT and age, gender and R1 resection was observed for RFS and OS. Males and patients >40 years had a significantly better RFS in the treatment arms, while adjuvant CT was associated with a marginally worse OS in females and patients <40 years. Patients with R1 resection had a significantly better RFS and OS favoring adjuvant CT arms. CONCLUSION: Adjuvant CT is not associated with a better OS in young patients or in any pathology subgroup. Poor quality of initial surgery is the most important prognostic and predictive factor for utility of adjuvant CT in STS. Based on these data, we conclude that adjuvant CT for STS remains an investigational procedure and is not a routine standard of care.

Outcome of patients with sarcoma and other mesenchymal tumours participating in phase I trials: a subset analysis of a European Phase I database.

BACKGROUND: Although sarcomas account for only 1% of all solid tumours, patients with sarcomas comprise a larger proportion of patients entering phase I trials, due to the limited number of registered or active drugs for these diseases. To help in patient selection, we evaluated the utility of the predictive Royal Marsden Score which had been derived in carcinoma patients. In addition, we analysed efficacy and toxicity regarding the sarcoma population enrolled in phase I trials. PATIENTS AND METHODS: We used data from a European Database comprising 2182 patients treated in phase I trials in 14 European institutions between 2005 and 2007. RESULTS: One hundred and seventy-eight patients diagnosed with advanced sarcoma or other mesenchymal tumours were identified and accounted for 217 phase I trial participations during the study period. Histological type, class of drug, number of metastatic sites, high serum lactate dehydrogenase activity (LDH), low albumin and high white blood cell count were independent prognostic factors. Poor performance status (PS), liver metastases and high leucocyte count were associated with increased risk of early death. The class of drug used was the strongest predictor of progression-free survival (PFS) duration, inhibitors of angiogenesis and histone deacetylase giving the best results. Poor PS, high serum LDH and low lymphocyte count correlated with shorter PFS. In this heterogeneous population, PFS with investigational agents appeared comparable with that previously published for patients receiving standard treatments beyond first line. CONCLUSION: Prognostic factors in sarcoma patients do not differ from a broader phase I population. Efficacy measures suggest that some patients with sarcoma derive benefit from therapy in this setting which could therefore be considered for patients with no remaining standard therapeutic option.

MiR-17-92 and miR-221/222 cluster members target KIT and ETV1 in human gastrointestinal stromal tumours.

BACKGROUND: Gastrointestinal stromal tumours (GIST) are characterised by high expression of KIT and ETV1, which cooperate in GIST oncogenesis. Our aim was to identify microRNAs that are deregulated in GIST, have a role in GIST pathogenesis, and could potentially be used as therapeutic tool. METHODS: Differentially expressed microRNAs between primary GIST (n=50) and gastrointestinal leiomyosarcomas (GI-LMS, n=10) were determined using microarrays. Selected microRNA mimics were transfected into GIST-882 and GIST-T1 cell lines to study the effects of microRNA overexpression on GIST cells. Luciferase reporter assays were used to establish regulation of target genes by selected microRNAs. RESULTS: MiR-17-92 and miR-221/222 cluster members were significantly (P<0.01) lower expressed in GIST vs GI-LMS and normal gastrointestinal control tissues. MiR-17/20a/222 overexpression in GIST cell lines severely inhibited cell proliferation, affected cell cycle progression, induced apoptosis and strongly downregulated protein and--to a lesser extent--mRNA levels of their predicted target genes KIT and ETV1. Luciferase reporter assays confirmed direct regulation of KIT and ETV1 by miR-222 and miR-17/20a, respectively. CONCLUSION: MicroRNAs that may have an essential role in GIST pathogenesis were identified, in particular miR-17/20a/222 that target KIT and ETV1. Delivering these microRNAs therapeutically could hold great potential for GIST management, especially in imatinib-resistant disease.

Growth modulation index as metric of clinical benefit assessment among advanced soft tissue sarcoma patients receiving trabectedin as a salvage therapy.

BACKGROUND: The growth modulation index (GMI) is the ratio of time to progression with the nth line (TTP(n)) of therapy to the TTP(n)(-1) with the n-1th line. GMI >1.33 is considered as a sign of activity in phase II trials. PATIENTS AND METHODS: This retrospective analysis evaluated the concordance between the GMI and the efficacy outcomes in 279 patients with advanced soft tissue sarcoma (ASTS) treated with trabectedin 1.5 mg/m² (24-h infusion every 3 weeks) in four phase II trials. RESULTS: One hundred and forty-two (51%) patients received one prior line and 137 ≥ 2 lines. The median TTP(n) was 2.8 months (range 0.2-26.8), whereas the median TTP(n)(-1) was 4.0 months (0.3-79.5). The median GMI was 0.6 (0.0-14.4). Overall, 177 patients (63%) had a GMI <1; 21 (8%) a GMI equal to 1-1.33 and 81 (29%) a GMI >1.33, which correlated with the median overall survival in those patients (9.1, 13.9 and 23.8 months, respectively, P = 0.0005). A high concordance rate between the GMI and response rate (P < 0.0001) and progression-free survival (PFS, P < 0.0001) was observed. Good performance status (PS) was the only factor associated with GMI >1.33 (PS = 0; P < 0.04). CONCLUSIONS: A high GMI was associated with favorable efficacy outcomes in patients treated with trabectedin. Further research is needed to assess GMI as an indicator in this setting.

Prediction of early death among patients enrolled in phase I trials: development and validation of a new model based on platelet count and albumin.

BACKGROUND: Selecting patients with 'sufficient life expectancy' for Phase I oncology trials remains challenging. The Royal Marsden Hospital Score (RMS) previously identified high-risk patients as those with ≥ 2 of the following: albumin <35 g l(-1); LDH > upper limit of normal; >2 metastatic sites. This study developed an alternative prognostic model, and compared its performance with that of the RMS. METHODS: The primary end point was the 90-day mortality rate. The new model was developed from the same database as RMS, but it used Chi-squared Automatic Interaction Detection (CHAID). The ROC characteristics of both methods were then validated in an independent database of 324 patients enrolled in European Organization on Research and Treatment of Cancer Phase I trials of cytotoxic agents between 2000 and 2009. RESULTS: The CHAID method identified high-risk patients as those with albumin <33 g l(-1) or ≥ 33 g l(-1), but platelet counts ≥ 400.000 mm(-3). In the validation data set, the rates of correctly classified patients were 0.79 vs 0.67 for the CHAID model and RMS, respectively. The negative predictive values (NPV) were similar for the CHAID model and RMS. CONCLUSION: The CHAID model and RMS provided a similarly high level of NPV, but the CHAID model gave a better accuracy in the validation set. Both CHAID model and RMS may improve the screening process in phase I trials.