Tactile acuity of fingertips and hand representation size in human Area 3b and Area 1 of the primary somatosensory cortex.

Intracortical mapping in monkeys revealed a full body map in all four cytoarchitectonic subdivisions of the contralateral primary somatosensory cortex (S1), as well as positive associations between spatio-tactile acuity performance of the fingers and their representation field size especially within cytoarchitectonic Area 3b and Area 1. Previous non-invasive investigations on these associations in humans assumed a monotonous decrease of representation field size from index finger to little finger although the field sizes are known to change in response to training or in disease. Recent developments improved noninvasive functional mapping of S1 by a) adding a cognitive task during repetitive stimulation to decrease habituation to the stimuli, b) smaller voxel size of fMRI-sequences, c) surface-based analysis accounting for cortical curvature, and d) increase of spatial specificity for fMRI data analysis by avoidance of smoothing, partial volume effects, and pial vein signals. We here applied repetitive pneumatic stimulation of digit 1 (D1; thumb) and digit 5 (D5; little finger) on both hands to investigate finger/hand representation maps in the complete S1, but also in cytoarchitectonic Areas 1, 2, 3a, and 3b separately, in 21 healthy volunteers using 3T fMRI. The distances between activation maxima of D1 and D5 were evaluated by two independent raters, blinded for performance parameters. The fingertip representations showed a somatotopy and were localized in the transition region between the crown and the anterior wall of the post central gyrus agreeing with Area 1 and 3b. Participants were comprehensively tested for tactile performance using von Freyhair filaments to determine cutaneous sensory thresholds (CST) as well as grating orientation thresholds (GOT) and two-point resolution (TPD) for spatio-tactile acuity testing. Motor performance was evaluated with pinch grip performance (Roeder test). We found bilateral associations of D1-D5 distance for GOT thresholds and partially also for TPD in Area 3b and in Area 1, but not if using the complete S1 mask. In conclusion, we here demonstrate that 3T fMRI is capable to map associations between spatio-tactile acuity and the fingertip representation in Area 3b and Area 1 in healthy participants.

Nephila edulis-breeding and care under laboratory conditions.

Due to fascinating mechanical and biological characteristics spider silk is of great interest in many research fields. Among the orb-weavers Nephila edulis is one of the species used as source for natural spider silk in laboratories. Under appropriate conditions, animals can be kept and bred easily. This manuscript gives information about the spiders' natural habitat, behavior, and breeding and compares them with the established methods and conditions within a research laboratory. Keeping conditions and methods of rearing are described in detail. Within a keeping facility with reliable supply of food, cannibalism rate is significantly reduced and spiders mate all year long. Cohabitants of the genus Steatoda are routinely found in laboratory keeping. While these small spiders do not pose a threat to Nephila edulis, cellar spiders (family Pholcidae) have to be extracted as they have been observed hunting for Nephila spiders.

Activity and safety of crizotinib in patients with alveolar soft part sarcoma with rearrangement of TFE3: European Organization for Research and Treatment of Cancer (EORTC) phase II trial 90101 'CREATE'.

Background: Alveolar soft part sarcoma (ASPS) is an orphan malignancy associated with a rearrangement of transcription factor E3 (TFE3), leading to abnormal MET gene expression. We prospectively assessed the efficacy and safety of the MET tyrosine kinase inhibitor crizotinib in patients with advanced or metastatic ASPS. Patients and methods: Eligible patients with reference pathology-confirmed ASPS received oral crizotinib 250 mg bd. By assessing the presence or absence of a TFE3 rearrangement, patients were attributed to MET+ and MET- sub-cohorts. The primary end point was the objective response rate (ORR) according to local investigator. Secondary end points included duration of response, disease control rate (DCR), progression-free survival (PFS), progression-free rate, overall survival (OS) and safety. Results: Among 53 consenting patients, all had a centrally confirmed ASPS and 48 were treated. A total of 45 were eligible, treated and assessable. Among 40 MET+ patients, 1 achieved a confirmed partial response (PR) that lasted 215 days and 35 had stable disease (SD) as best response (ORR: 2.5%, 95% CI 0.6% to 80.6%). Further efficacy end points in MET+ cases were DCR: 90.0% (95% CI 76.3% to 97.2%), 1-year PFS rate: 37.5% (95% CI 22.9% to 52.1%) and 1-year OS rate: 97.4% (95% CI 82.8% to 99.6%). Among 4 MET- patients, 1 achieved a PR that lasted 801 days and 3 had SD (ORR: 25.0%, 95% CI 0.6% to 80.6%) for a DCR of 100% (95% CI 39.8% to 100.0%). The 1-year PFS rate in MET- cases was 50% (95% CI 5.8% to 84.5%) and the 1-year OS rate was 75% (95% CI 12.8% to 96.1%). One patient with unknown MET status due to technical failure achieved SD but stopped treatment due to progression after 17 cycles. The most common crizotinib-related adverse events were nausea [34/48 (70.8%)], vomiting [22/48 (45.8%)], blurred vision [22/48 (45.8%)], diarrhoea (20/48 (41.7%)] and fatigue [19/48 (39.6%)]. Conclusion: According to European Organization for Research and Treatment of Cancer (EORTC) efficacy criteria for soft tissue sarcoma, our study demonstrated that crizotinib has activity in TFE3 rearranged ASPS MET+ patients. Clinical trial number: EORTC 90101, NCT01524926.

Urinary Lipidomics: evidence for multiple sources and sexual dimorphism in healthy individuals.

Urinary lipidomics may add new valuable biomarkers to the diagnostic armamentarium for early detection of metabolic and kidney diseases. Sources and composition of urinary lipids in healthy individuals, however, have not been investigated in detail. Shotgun lipidomics was used to quantify lipidomic profiles in native urine samples from 16 individuals (eight men, eight women) collected in five fractions over 24 h. All probands were comprehensively characterized by urinary and clinical indices. The mean total urinary lipid concentration per sample was 0.84 µM in men and 1.03 µM in women. We observed significant intra- and interindividual variations of lipid concentrations over time, but failed to detect a clear circadian pattern. Based on quantity and subclass composition it seems very unlikely that plasma serves as major source for the urinary lipidome. Considering lipid metabolites occurring in at least 20% of all samples 38 lipid species from 7 lipid classes were identified. Four phosphatidylserine and one phosphatidylethanolamine ether species (PE-O 36:5) were detectable in almost all urine samples. Sexual dimorphism has been found mainly for phosphatidylcholines and phosphatidylethanolamines. In men and in women urinary lipid species were highly correlated with urinary creatinine and albumin excretion, reflecting glomerular filtration and tubular transport processes. In women, however, lipid species deriving from urinary cells and cellular constituents of the lower genitourinary tract considerably contributed to the urinary lipidome. In conclusion, our study revealed the potential of urinary lipidomics but also the complexity of methodological challenges which have to be overcome for its implementation as a routine diagnostic tool for renal, urological and metabolic diseases.

Activity and safety of crizotinib in patients with advanced clear-cell sarcoma with MET alterations: European Organization for Research and Treatment of Cancer phase II trial 90101 'CREATE'.

BACKGROUND: Clear-cell sarcoma (CCSA) is an orphan malignancy, characterized by a specific t(12;22) translocation, leading to rearrangement of the EWSR1 gene and overexpression of MET. We prospectively investigated the efficacy and safety of the tyrosine kinase inhibitor crizotinib in patients with advanced or metastatic CCSA. PATIENTS AND METHODS: Patients with CCSA received oral crizotinib 250 mg twice daily. Primary end point was objective response rate (ORR), secondary end points included duration of response, disease control rate (DCR), progression-free survival (PFS), progression-free rate (PFR), overall survival (OS), OS rate and safety. The study design focused on MET+ disease with documented rearrangement of the EWSR1 gene by fluorescence in situ hybridization. RESULTS: Among 43 consenting patients with the local diagnosis of CCSA, 36 had centrally confirmed CCSA, 28 of whom were eligible, treated and assessable. Twenty-six out of the 28 patients had MET+ disease, of whom one achieved a confirmed partial response and 17 had stable disease (SD) (ORR 3.8%, 95% confidence interval: 0.1-19.6). Further efficacy end points in MET+ CCSA were DCR: 69.2% (48.2% to 85.7%), median PFS: 131 days (49-235), median OS: 277 days (232-442). The 3-, 6-, 12- and 24-month PFR was 53.8% (34.6-73.0), 26.9% (9.8-43.9), 7.7% (1.3-21.7) and 7.7% (1.3-21.7), respectively. Among two assessable MET- patients, one had stable disease and one had progression. The most common treatment-related adverse events were nausea [18/34 (52.9%)], fatigue [17/34 (50.0%)], vomiting [12/34 (35.3%)], diarrhoea [11/34 (32.4%)], constipation [9/34 (26.5%)] and blurred vision [7/34 (20.6%)]. CONCLUSIONS: The PFS with crizotinib in MET+ CCSA is similar to results achieved first-line in non-selected metastatic soft tissue sarcomas with single-agent doxorubicin. The PFS is similar to results achieved with pazopanib in previously treated sarcoma patients. CLINICAL TRIAL NUMBER: EORTC 90101, EudraCT number 2011-001988-52, NCT01524926.

Influence of direct or indirect contact for the cytotoxicity and blood compatibility of spider silk.

Spider silk became one of the most-researched biomaterials in the last years due to its unique mechanical strength and most favourable chemical composition for tissue engineering purposes. However, standardized analysis of cytocompatibility is missing. Therefore, the aim of this study was to investigate hemolysis, cytotoxicity of native spider silk as well as influences on the cell culture medium. Changes of cell culture medium composition, osmolarity as well as glucose and lactate content were determined via ELISA measurement. Possible hemolysis and cytotoxicity in vitro of spider silk were performed via measurement of hemoglobin release of human red blood cells or relative metabolic activity of L929 fibroblasts, respectively, according to international standard procedures. In ELISA measurement, no significant changes in medium composition could be found in this study. Spider silk was not hemolytic in direct and indirect testing. However, a borderline cytotoxicity according to definitions was found in indirect cytotoxicity testing. Nevertheless, in direct cytotoxicity testing, relative metabolic activity measurement revealed that spider silk is not cytotoxic under these conditions. This is the first study to conduct standardized tests regarding cytotoxicity and hemolysis of native spider silk, which might be considered inert in cell culture. As neither hemolysis nor cytotoxicity was found in direct contact in standardized procedures, safety in biomedical applications may be assumed. The indirect cytotoxicity seems to play a minor role in vivo. However, a borderline toxicity was revealed, suggesting potential leachables not yet identified. Displays one of the weaving frames used in this study after seeding with the single drop technique described herein.

Follow-up with primary care providers for elevated glycated haemoglobin identified at the dental visit.

OBJECTIVES: This study examined patient experiences after receiving elevated diabetes screening values using blood collected at a dental clinic. It explores patients' reactions to screening, whether or not they sought recommended medical follow-up, and facilitating factors and barriers to obtaining follow-up care. METHODS: At the comprehensive care clinics at a large, urban College of Dentistry in the United States, haemoglobin A1C (HbA1C) values were obtained from 379 study participants who had not been previously diagnosed with diabetes. In all, 169 (44.6%) had elevated HbA1C values. We analysed quantitative and qualitative data concerning these patients' follow-up with primary care providers (PCPs). RESULTS: We were able to contact 112 (66.3%) of the 169 study participants who had an elevated HbA1C reading. Of that group, 61 (54.5%) received recommended follow-up care from a PCP within 3 months, and an additional 28 (25.0%) said they intended to seek such care. Qualitative themes included the following: the screening letter - opportunity or burden, appreciation for the 3-month follow-up call and barriers to medical follow-up that included the following: lack of knowledge about diabetes, not understanding the importance of follow-up, busyness, financial concerns, fear and denial. CONCLUSIONS: Quantitative and qualitative data demonstrate that dentists, dental hygienists and nurses are well poised to discover and translate new models of patient-centred, comprehensive care to patients with oral and systemic illness.

What is the role of routine follow-up for localised limb soft tissue sarcomas? A retrospective analysis of 174 patients.

BACKGROUND: There are neither prospective data nor agreement on the optimal routine follow-up procedures in patients treated for soft tissue sarcoma of the limb. METHODS: Data on 174 consecutive patients with a soft tissue sarcoma of the limb undergoing follow-up by oncologists at a single centre from 2003 to 2009 were included in this analysis. The rate and site of recurrence and mode of detection were analysed. Outcome of the patients was assessed. RESULTS: Eighty-two patients (47%) experienced relapse of any type. Isolated local recurrence occurred in 26 patients and local relapse with synchronous pulmonary metastases in five patients. Local recurrences were detected clinically in 30 of these 31 patients; magnetic resonance imaging identified only one local recurrence. Twenty-eight patients developed isolated lung metastases; in nine patients these were amenable to resections, seven of whom are currently free of disease after treatment. Lung metastases were detected by chest x-ray (CXR) in 19 patients, computed tomography scanning in 3 patients, and clinically in 11 patients. Twenty-three patients developed non-pulmonary metastases. More than 80% of relapses occurred in the first 2 years of follow-up; however, later recurrences were also observed. CONCLUSIONS: Routine follow-up CXR can detect lung metastases suitable for surgical resection, although the optimal interval of imaging has yet to be defined. Local relapse is almost always detected by patients or physicians, and routine scanning of the primary site is of doubtful benefit. Patient and physician education to detect local relapse may be helpful. Prospective evaluation of follow-up is recommended.

Noise and age-related hearing loss: a study of 40 123 gold miners in South Africa.

OBJECTIVE AND DESIGN: This retrospective cohort study aimed to describe the differential effect of noise exposure and age-related hearing loss in a large sample of gold miners in South Africa. STUDY SAMPLE: Audiological data of 40 123 South African mine workers were investigated. Data of a non-noise-exposed control group (n = 6162) and group exposed to underground noise (≥ 85 dB A (TWA) (n = 33 961) were included. Within these two larger noise-exposed groups two homogenous exposure groups (HEG) were also selected for analyses, namely the driller group (n = 4399) and the administration group (administrative workers) (n = 2211). Participants were categorized in terms of noise exposure, age, and race. RESULTS: Significantly different thresholds (worse for underground noise group) with respect to the median for all frequencies after adjusting for age was evident between the noise-exposed and control groups (ANCOVA). The largest differences in hearing thresholds between the noise-exposed and control groups were observed at 3 and 4 kHz in the age group 36 to 45 years. Administration and driller group differed significantly (driller group worse results) with respect to the mean LFA512 and HFA346 after adjusting for age (ANCOVA). Black males had significantly better high-frequency hearing compared with white male counterparts but significantly worse low-frequency hearing. CONCLUSION: Age was the most important influence on hearing thresholds for the noise and control groups. Race was shown to be a very significant factor determining susceptibility to NIHL and ARHL.

Interdental cleaning among persons with diabetes: relationships with individual characteristics.

OBJECTIVES: Given the existence of many potential oral health complications for adults with diabetes (especially for those who do not practise regular oral self-care), and the specific importance of regular interdental cleaning, the research determined the proportion of U.S. adults with diabetes who practise daily interdental cleaning and their socio-demographic, economic and oral health characteristics related to this practice. METHODS: Analyses were conducted using data collected from 573 dentulous adults with diabetes ≥ 30 years who participated in the U.S. 2009-2010 National Health and Nutrition Examination survey. Using complex sample survey software, findings were extrapolated to >15 million U.S. adults. Descriptive statistics were used to determine the frequency of interdental cleaning, and chi-square tests were used to identify salient individual characteristics related to this practice. RESULTS: 41.2% reported that they never used any interdental device, while 24.8% indicated that they practised interdental cleaning daily. Statistically significant relationships (P < 0.05) with daily interdental cleaning included female sex, ever having had treatment for gum disease and using mouthwash daily for a dental problem. CONCLUSIONS: Because so many adults with diabetes do not practise regular interdental cleaning, and in view of the important role that dental hygienists fulfil as oral healthcare educators, there is a great need for dental hygienists to teach and motivate adults with diabetes to practise regular interdental cleaning. This need is especially great for subgroups of these adults who are men, have not been treated for periodontitis and do not regularly use a mouthwash for dental problems.

Chlamydia trachomatis prevalence, genotype distribution and identification of the new Swedish variant in Southern Germany.

PURPOSE: In Germany, reliable data about the prevalence of urogenital Chlamydia trachomatis infections, causative genotypes, as well as corresponding clinical, demographic and behavioural information are sparse. We, therefore, performed a prospective prevalence study including 1,003 sexually active volunteers of a Southern German city. METHODS: Study participants completed a standardised questionnaire and provided first void urine samples for analysis. Our screening strategy included the performance of two nucleic acid amplification tests with different target genes, enabling the detection of the new Swedish variant of C. trachomatis (nvCT). Direct genotyping of positive specimens was performed by sequence analysis of the ompA gene. RESULTS AND CONCLUSION: The overall prevalence of C. trachomatis infection was 4.2 % in women and 4.6 % in men. A relatively high prevalence of 8.3 % was found in men older than 25 years. Never using condoms was an independent risk factor for infection. The most common symptom was discharge; however, 64.5 % of infected females and all of the infected men were asymptomatic, supporting the need for screening programmes. The most frequently encountered genotypes were E (46.5 %), F (20.9 %) and K (14.0 %). Since the nvCT was detected in one female student, this is one of the rare studies that reports on the molecular identification of nvCT apart from Sweden.

Diabetes screening at the periodontal visit: patient and provider experiences with two screening approaches.

OBJECTIVES: This study examined patient and dental provider experiences during the periodontal visit of diabetes screening approaches involving the collection of gingival crevicular blood (GCB) and finger stick blood (FSB) for haemoglobin A1c (HbA1c) testing. METHODS: At a large, urban, US periodontics and implant clinic, FSB samples from 120 patients and GCB samples from 102 of these patients were collected on special blood collection cards and sent to a laboratory for HbA1c testing, with test results sent to the patients from the laboratory. Quantitative and qualitative data from patients and qualitative data from providers were collected and analysed. RESULTS: Quantitative and qualitative data support the feasibility and acceptability of the approaches described. Themes that arose from the interviews with providers and patients include 'a good chance to check', 'patient choice', 'FSB versus GCB testing' and 'a new way of interacting and viewing the dental visit'. CONCLUSIONS: Periodontal patients and dental providers believe that the dental visit is an opportune site for diabetes screening and generally prefer GCB to FSB collection. HbA1c testing is well tolerated, convenient and acceptable to patients, and GCB testing reduces time and liability obstacles for dental providers to conduct diabetes screening.

Intraosseous Venous Malformations of the Head and Neck.

Intraosseous venous malformations represent a subtype of venous vascular malformations that arise primarily in bone. In the head and neck, intraosseous venous malformations are most frequently found in the skull, skull base, and facial skeleton, with location at the geniculate ganglion of the facial nerve perhaps the most widely recognized. These non-neoplastic lesions are characterized by dilated venous channels with characteristic internal bony spicules on CT but may present with a more complex appearance on MR imaging and may share features with more aggressive lesions. Further confounding the imaging-based diagnosis of intraosseous venous malformation is the frequent misrepresentation of these lesions as hemangiomas in the radiology and clinical literature, as well as in daily practice. Because most intraosseous venous malformations can be left alone, their correct diagnosis may spare a patient unnecessary concern and intervention.

High-Resolution T2-Weighted Imaging for Surveillance in Postoperative Vestibular Schwannoma: Equivalence with Contrast-Enhanced T1WI for Measurement and Surveillance of Residual Tumor.

BACKGROUND AND PURPOSE: Patients with surgically resected vestibular schwannoma will undergo multiple postoperative surveillance examinations, typically including postcontrast sequences. The purpose of this study was to compare high-resolution T2WI with gadolinium T1WI in the postoperative assessment of vestibular schwannoma. MATERIALS AND METHODS: This was a retrospective study of patients with a history of resected vestibular schwannoma at a single institution. High-resolution T2WI and gadolinium T1WI were independently evaluated for residual disease. In addition, 3D and 2D measurements were performed in the group of patients with residual tumor. Statistical analysis was performed to evaluate the agreement between sequences on the binary assessment (presence/absence of tumor on initial postoperative examination) and to evaluate the equivalence of measurements for the 2 sequences on 3D and 2D quantitative assessment in individuals with residual disease. RESULTS: One hundred forty-eight patients with retrosigmoid-approach resection of vestibular schwannomas were included in the final analysis. There was moderate-to-substantial agreement between the 2 sequences for the evaluation of the presence versus absence of tumor (Cohen κ coefficient = 0.78; 95% CI, 0.68-0.88). The 2 sequences were significantly equivalent for 2D and 3D quantitative assessments (short-axis P value = .021; long-axis P value = .015; 3D P value = .039). CONCLUSIONS: In this retrospective study, we demonstrate moderate-to-substantial agreement in the categoric assessment for the presence versus absence of tumor and equivalence between the 2 sequences for both 2D and volumetric tumor measurements as performed in the subset of patients with measurable residual. On the basis of these results, high-resolution T2WI alone may be sufficient for early postoperative imaging surveillance in this patient population.

A Gamified Social Media-Based Head and Neck Radiology Education Initiative of the American Society of Head and Neck Radiology: Viewership and Engagement Trends at 3 Years.

BACKGROUND AND PURPOSE: Social media has made inroads in medical education. We report the creation and 3-year (2018-2021) longitudinal assessment of the American Society of Head and Neck Radiology Case of the Week (#ASHNRCOTW), assessing viewership, engagement, and impact of the coronavirus disease 2019 (COVID-19) pandemic on this Twitter-based education initiative. MATERIALS AND METHODS: Unknown cases were tweeted from the American Society of Head and Neck Radiology account weekly. Tweet impressions (number of times seen), engagements (number of interactions), and new followers were tabulated. A social media marketing platform identified worldwide distribution of Twitter followers. Summary and t test statistics were performed. RESULTS: #ASHNRCOTW was highly visible with 2,082,280 impressions and 203,137 engagements. There were significantly greater mean case impressions (9917 versus 6346), mean case engagements (1305 versus 474), case engagement rates (13.06% versus 7.76%), mean answer impressions (8760 versus 5556), mean answer engagements (908 versus 436), answer engagement rates (10.38% versus 7.87%), mean total (case + answer) impressions (18,677 versus 11,912), mean total engagements (2214 versus 910), and total engagement rates (11.79% versus 7.69%) for cases published after the pandemic started (all P values < .001). There was a significant increase in monthly new followers after starting #ASHNRCOTW (mean, 134 versus 6; P < .001) and significantly increased monthly new followers after the pandemic started compared with prepandemic (mean, 178 versus 101; P = .003). The American Society of Head and Neck Radiology has 7564 Twitter followers throughout 130 countries (66% outside the United States). CONCLUSIONS: Social media affords substantial visibility, engagement, and global outreach for radiology education. #ASHNRCOTW viewership and engagement increased significantly during the COVID-19 pandemic.

The root meristem is shaped by brassinosteroid control of cell geometry.

Growth extent and direction determine cell and whole-organ architecture. How they are spatio-temporally modulated to control size and shape is not well known. Here we tackled this question by studying the effect of brassinosteroid (BR) signalling on the structure of the root meristem. Quantification of the three-dimensional geometry of thousands of individual meristematic cells across different tissue types showed that the modulation of BR signalling yields distinct changes in growth rate and anisotropy, which affects the time that cells spend in the meristem and has a strong impact on the final root form. By contrast, the hormone effect on cell volume was minor, establishing cell volume as invariant to the effect of BR. Thus, BR has the highest effect on cell shape and growth anisotropy, regulating the overall longitudinal and radial growth of the meristem, while maintaining a coherent distribution of cell sizes. Moving from single-cell quantification to the whole organ, we developed a computational model of radial growth. The simulation demonstrates how differential BR-regulated growth between the inner and outer tissues shapes the meristem and thus explains the non-intuitive outcomes of tissue-specific perturbation of BR signalling. The combined experimental data and simulation suggest that the inner and outer tissues have distinct but coordinated roles in growth regulation.

Phase I/II study of single-agent lenvatinib in children and adolescents with refractory or relapsed solid malignancies and young adults with osteosarcoma (ITCC-050)☆.

BACKGROUND: We report results from the phase I dose-finding and phase II expansion part of a multicenter, open-label study of single-agent lenvatinib in pediatric and young adult patients with relapsed/refractory solid tumors, including osteosarcoma and radioiodine-refractory differentiated thyroid cancer (RR-DTC) (NCT02432274). PATIENTS AND METHODS: The primary endpoint of phase I was to determine the recommended phase II dose (RP2D) of lenvatinib in children with relapsed/refractory solid malignant tumors. Phase II primary endpoints were progression-free survival rate at 4 months (PFS-4) for patients with relapsed/refractory osteosarcoma; and objective response rate/best overall response for patients with RR-DTC at the RP2D. RESULTS: In phase I, 23 patients (median age, 12 years) were enrolled. With lenvatinib 14 mg/m2, three dose-limiting toxicities (hypertension, n = 2; increased alanine aminotransferase, n = 1) were reported, establishing 14 mg/m2 as the RP2D. In phase II, 31 patients with osteosarcoma (median age, 15 years) and 1 patient with RR-DTC (age 17 years) were enrolled. For the osteosarcoma cohort, PFS-4 (binomial estimate) was 29.0% [95% confidence interval (CI) 14.2% to 48.0%; full analysis set: n = 31], PFS-4 by Kaplan-Meier estimate was 37.8% (95% CI 20.0% to 55.4%; full analysis set) and median PFS was 3.0 months (95% CI 1.8-5.4 months). The objective response rate was 6.7% (95% CI 0.8% to 22.1%). The patient with RR-DTC had a best overall response of partial response. Some 60.8% of patients in phase I and 22.6% of patients in phase II (with osteosarcoma) had treatment-related treatment-emergent adverse events of grade ≥3. CONCLUSIONS: The lenvatinib RP2D was 14 mg/m2. Single-agent lenvatinib showed activity in osteosarcoma; however, the null hypothesis could not be rejected. The safety profile was consistent with previous tyrosine kinase inhibitor studies. Lenvatinib is currently being investigated in osteosarcoma in combination with chemotherapy as part of a randomized, controlled trial (NCT04154189), in pediatric solid tumors in combination with everolimus (NCT03245151), and as a single agent in a basket study with enrollment ongoing (NCT04447755).

Chemotherapy with 5-fluorouracil, cisplatin and streptozocin for neuroendocrine tumours.

BACKGROUND: The role of chemotherapy for neuroendocrine tumours remains controversial and there is no standard regimen. METHOD: We report the outcome for a consecutive series of chemonaive patients with metastatic or locally advanced neuroendocrine tumours treated with a combination of 5-fluorouracil (500 mg m(-2)), cisplatin (70 mg m(-2)) and streptozocin (1000 mg m(-2)) (FCiSt) administered three weekly for up to six cycles. Patients were assessed for radiological response, toxicity and survival. RESULTS: In the 79 patients assessable for response, treatment with FCiSt was associated with an overall response rate of 33% (38% for pancreatic primary sites and 25% for non-pancreatic primary sites). Stable disease occurred in a further 51%, with progression in 16%. The median time to progression was 9.1 months and median overall survival was 31.5 months. The most common grade 3-4 toxicity was neutropaenia (28% patients) but grade 3-4 infection was rare (7%). The most frequent non-haematological grade 3-4 toxicity was nausea and vomiting (17%). Prognostic factors included Ki-67, mitotic index, grade and chromogranin A, whereas response to chemotherapy was predicted by mitotic index, grade and alpha-fetoprotein. CONCLUSIONS: FCiSt is an effective regimen for neuroendocrine tumours with an acceptable toxicity profile. Grade and mitotic index are the best predictors of response.