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).

Precision analysis for the determination of steric mass action parameters using eight tobacco host cell proteins.

Plants are advantageous as biopharmaceutical manufacturing platforms because they allow the economical and scalable upstream production of proteins, including those requiring post-translational modifications, but do not support the replication of human viruses. However, downstream processing can be more labor-intensive compared to fermenter-based systems because the product is often mixed with abundant host cell proteins (HCPs). Modeling chromatographic separation can minimize the number of process development experiments and thus reduce costs. An important part of such modeling is the sorption isotherm, such as the steric mass action (SMA) model, which describes the multicomponent protein-salt equilibria established in ion-exchange systems. Here we purified ten HCPs, including 2-Cys-peroxiredoxin, from tobacco (Nicotiana tabacum and N. benthamiana). For eight of these HCPs, we obtained sufficient quantities to determine the SMA binding parameters (KSMA and ν) under different production-relevant conditions. We studied the parameters for 2-Cys-peroxiredoxin on Q-Sepharose HP in detail, revealing that pH, resin batch and buffer batch had little influence on KSMA and ν, with coefficients of variation (COVs) less than 0.05 and 0.21, respectively. In contrast, the anion-exchange resins SuperQ-650S, Q-Sepharose FF and QAE-550C led to COVs of 0.69 for KSMA and 0.05 for ν, despite using the same quaternary amine functional group as Q-Sepharose HP. Plant cultivation in summer vs winter resulted in COVs of 0.09 for KSMA and 0.02 for ν, revealing a small impact compared to COVs of 17.15 for KSMA and 0.20 for ν when plants were grown in different settings (climate-controlled phytotron vs greenhouse). We conclude that plant cultivation can substantially affect protein properties and the resulting SMA parameters. Accordingly, plant growth but also protein purification and characterization for chromatography model building should be tightly controlled and well documented.

[Pheochromocytoma and paraganglioma : Importance of diagnostic imaging]. / Phäochromozytom und Paragangliom : Stellenwert der bildgebenden Diagnostik.

CLINICAL BACKGROUND: If pheochromocytoma (PC) or paraganglioma (PGL) is diagnosed based on serologic studies, imaging is required to locate the adrenal mass for further management. Besides pathognomonic hormonal findings, PC/PGL can exhibit typical imaging features. However, PC/PGL can also show morphological overlap with other pathologies. STANDARD RADIOLOGICAL METHODS: The modality of choice for evaluation of PC is CT. In case of extra-adrenal location, MRI is superior to CT. Imaging with PET-CT provides complementary information in the differentiation of PC/PGL and is recommended as the imaging modality of choice for malignant PC/PGL. 68Ga-DOTATATE (or 68Ga-DOTATOC/ 68Ga-DOTANOC) PET-CT has high sensitivity for SDHx-mutated PC/PGL and serves for planning of radioreceptor therapy with somatostatin analogues. In contrast, 123I-metaiodobenzylguanidine (MIBG) scintigraphy is important in assessing the potential efficacy of radioreceptor therapy with MIBG. METHODICAL DETAILS: The CT protocol for PC evaluation should include non-enhanced, arterial, portal-venous and late phases; the latter for the evaluation of wash-out. Recent studies indicate non-enhanced CT alone may be sufficient to rule out PC. For MRI, in- and opposed-phase sequences should be additionally acquired. PRACTICAL RECOMMENDATIONS: A relevant proportion of PC is diagnosed incidentally. Therefore, imaging of PC will gain further importance. Recent studies show better response rates of PC/PGL after radioreceptor therapy with somatostatin analogues (177Lu-DOTATATE) than with MIBG. Therefore, 68Ga-DOTATATE PET-CT gains further importance-for diagnostic imaging and therapy planning.

[Update on endocrine hypertension]. / Update endokrine Hypertonie.

Endocrine disorders are the most common causes of secondary hypertension. Early diagnosis and specific treatment are crucial for improvement of the prognosis. This article provides an overview on which clinical constellations point to an increased risk of secondary causes of hypertension. These include spontaneous hypokalemia, young age at onset of hypertension, adrenal incidentaloma and therapy refractive arterial hypertension. The basic diagnostics include determination of the aldosterone to renin ratio, measurement of free plasma metanephrines and a 1 mg dexamethasone suppression test. Borderline results require repeated control testing and/or confirmatory testing under standardized test conditions. In cases of repeatedly conspicuous results referral to a specialized clinic should be considered for further clarification and confirmation of the diagnosis. Imaging diagnostics may constitute an adjunct to laboratory testing after the diagnosis has been confirmed. Therapeutic algorithms vary depending on the underlying endocrine disease.

Extraskeletal osteosarcoma: A European Musculoskeletal Oncology Society study on 266 patients.

PURPOSE: Prognosis of extraskeletal osteosarcoma (ESOS) is reported to be poorer than that of skeletal osteosarcoma. This multicenter retrospective study aimed to evaluate factors influencing ESOS prognosis. PATIENTS AND METHODS: Members of the European Musculoskeletal Oncology Society (EMSOS) submitted institutional data on patients with ESOS. RESULTS: Data from 274 patients treated from 1981 to 2014 were collected from 16 EMSOS centres; 266 patients were eligible. Fifty (18.7%) had metastases at diagnosis. Of 216 patients with localised disease, 211 (98%) underwent surgery (R0 = 70.6%, R1 = 27%). Five-year overall survival (OS) for all 266 patients was 47% (95% CI 40-54%). Five-year OS for metastatic patients was 27% (95% CI 13-41%). In the analysis restricted to the 211 localised patients who achieved complete remission after surgery 5-year OS was 51.4% (95% CI 44-59%) and 5-year disease-free survival (DFS) was 43% (95% CI 35-51%). One hundred twenty-one patients (57.3%) received adjuvant or neoadjuvant chemotherapy and 80 patients (37.9%) received radiotherapy. A favourable trend was seen for osteosarcoma-type chemotherapy versus soft tissue sarcoma-type (doxorubicin ± ifosfamide) regimens. For the 211 patients in complete remission after surgery, patient age, tumour size, margins and chemotherapy were positive prognostic factors for DFS and OS by univariate analysis. At multivariate analysis, patient age (≤40 years versus >40 years) (P = 0.05), tumour size (P = 0.0001) and receipt of chemotherapy (P = 0.006) were statistically significant prognostic factors for survival. CONCLUSION: Patient age and tumour size are factors influencing ESOS prognosis. Higher survival was observed in patients who received perioperative chemotherapy with a trend in favour of multiagent osteosarcoma-type regimen which included doxorubicin, ifosfamide and cisplatin.

Efficacy of pyramided Bt proteins Cry1F, Cry1A.105, and cry2Ab2 expressed in Smartstax corn hybrids against lepidopteran insect pests in the northern United States.

Commercial field corn (Zea mays L.) hybrids transformed to express some or all of the lepidopteran insect-resistant traits present in SmartStax corn hybrids were evaluated for insecticidal efficacy against a wide range oflepidopteran corn pests common to the northern United States, during 2008 to 2011 at locations in 15 states. SmartStax hybrids contain a pyramid of two Bacillus thuringiensis (Bt) derived events for lepidopteran control: event TC1507 expressing Cry1F protein and MON 89034 expressing CrylA.105 + Cry2Ab2. These studies focused on characterization of the relative efficacy of each event when expressed alone or in combination, and compared with non-Bt hybrid. Corn hybrids containing pyramided insecticidal proteins Cry1F + Cry1A.105 + Cry2Ab2 (SmartStax) consistently showed reduced plant feeding damage by a wide range of lepidopteran larvae compared with single event and non-Bt hybrids. Corn hybrids expressing TC1507 or MON 89034 as single or pyramided events were consistently efficacious against Ostrinia nubilalis (Hübner). SmartStax hybrids had less injury from Agrotis ipsilon (Hufnagel) and Striacosta albicosta (Smith) than corn hybrids containing only event MON 89034 but were not more efficacious than single event TC1507 hybrids. Corn hybrids with event MON 89034 provided better control of Helicoverpa zea (Boddie), than event TC1507 alone. Spodoptera frugiperda (J.E. Smith) efficacy was higher for hybrids with pyramid events and single events compared with the non-Bt hybrids. The spectra of activity of events TC1507 and MON 89034 differed. The combination of TC1507 + MON 89034 provided redundant control of some pests where the spectra overlapped and thereby are expected to confer a resistance management benefit.

Evaluation of corn hybrids expressing Cry34Ab1/Cry35Ab1 and Cry3BbL against the western corn rootworm (Coleoptera: Chrysomelidae).

Studies were conducted across nine U.S. states, over 5 yr, to characterize the efficacy of transgenic corn (Zea mays L.) hybrids producing insecticidal proteins derived from Bacillus thuringiensis (Bt) for control of western corn rootworm, Diabrotica virgifera virgifera Le Conte. Hybrids tested had the same genetic background, contained one of two single events (DAS-59122-7 expressing Cry34Ab1/Cry35Ab1 or MON 88017 expressing Cry3Bb1) or a pyramid consisting of both rootworm-active events (SmartStax traits) and were compared with a non-Bt near isoline. Frequency analyses of root feeding data showed that hybrids containing both events sustained less root damage (0-3 node injury scale) than hybrids containing either event alone. The levels of root protection provided by MON 88017 and DAS-59122-7 were not different from each other. Efficacy was also evaluated based on consistency of protection, based on the proportion of plants with root ratings of either < or = 0.25 or < 1.00 on the node injury scale. The combination of two modes of action in SmartStax provided greater product consistency over a single mode of action at the 0.25 level and all hybrids producing Bt proteins provided equally high consistency at the 1.00 level. Overall these data show single and multiple mode of action hybrids provided high, consistent protection over the past 5 yr across the trial geography; however, pyramiding the rootworm Bt events provided greater and more consistent root protection. These findings also support that pyramided traits like SmartStax (Cry3Bb1 + Cry34Ab1/Cry35Ab1) remain a viable strategy for delaying resistance to either trait.

Evaluation of corn hybrids expressing Cry1F, cry1A.105, Cry2Ab2, Cry34Ab1/Cry35Ab1, and Cry3Bb1 against southern United States insect pests.

Studies were conducted across the southern United States to characterize the efficacy of multiple Bacillus thuringiensis (Bt) events in a field corn, Zea mays L., hybrid for control of common lepidopteran and coleopteran pests. Cry1F protein in event TC1507 and Cry1A.105 + Cry2Ab2 proteins in event MON 89034 were evaluated against pests infesting corn on above-ground plant tissue including foliage, stalks, and ears. Cry34Ab1/Cry35Ab1 proteins in event DAS-59122-7 and Cry3Bb1 in event MON 88017 were evaluated against the larvae of Mexican corn rootworm, Diabrotica virgifera zeae Krysan and Smith, which occur below-ground. Field corn hybrids containing Cry1F, Cry1A.105 + Cry2Ab2, Cry34Ab1/Cry35Ab1, and Cry3Bb1 insecticidal proteins (SmartStax) consistently demonstrated reductions in plant injury and/or reduced larval survivorship as compared with a non-Bt field corn hybrid. Efficacy provided by a field corn hybrid with multiple Bt proteins was statistically equal to or significantly better than corn hybrids containing a single event active against target pests. Single event field corn hybrids provided very high levels of control of southwestern corn borer, Diatraea grandiosella (Dyar), lesser cornstalk borer, Elasmopalpus lignosellus (Zeller), and fall armyworm, Spodoptera frugiperda (J.E. Smith), and were not significantly different than field corn hybrids with multiple events. Significant increases in efficacy were observed for a field corn hybrid with multiple Bt events for sugarcane borer, Diatraea saccharalis (F.), beet armyworm, Spodoptera exigua (Hübner), corn earworm, Helicoverpa zea (Boddie), and Mexican corn rootworm. Utilization of field corn hybrids containing multiple Bt events provides a means for managing insect resistance to Bt proteins and reduces non-Bt corn refuge requirements.

[Progressive dyspnoea in two patients with carcinoid syndrome]. / Progrediente Dyspnoe bei Karzinoidsyndrom.

In patients with carcinoid syndrome, there has always to be considered cardiac impairment. We report about two patients with hepatic and bone metastases of a neuroendocrine tumor of the midgut, who suffered from progressive dyspnea. This was caused in both cases by a right-to-left atrial shunt, in case 1 based on a patent foramen ovale (PFO), in case 2 based on a secundum atrial septal defect. Symptoms were significantly reduced by percutaneous closure of PFO and ASD, respectively. Right-to-left atrial shunt was facilitated by right-sided carcinoid induced endocardial fibrosis with the consequence of severe tricuspid regurgitation, leading to an increase of right atrial pressure.

Quantification of Cry1Ac and Cry1F Bacillus thuringiensis insecticidal proteins in selected transgenic cotton plant tissue types.

Quantitative enzyme-linked immunosorbent assays were used to characterize the geographical (locations) and temporal (through 6 wk) expression of CrylAc, from Bacillus thuringiensis variety kurstaki, and Cry1F, from B. thuringiensis variety aizawai, in transgenic cotton, Gossypium hirsutum L., plant structures. Terminal leaves, squares (flower buds), flowers, bolls (fruit), and mature leaves located five and eight nodes below the terminal apex were sampled during weeks 2, 4, and 6 after the initiation of anthesis. The effect of location (environment) significantly influenced protein expression levels, although similar trends were observed across locations. Cry1F was expressed at levels greater (1.1-29.0-fold) than that for CrylAc in all structures with exception to flowers. In contrast, the level of CrylAc in flowers was generally greater than Cry1F. Within each sampling period, concentrations of Cry1F in mature leaves (five and eight node) were greater than that for other structures. Expression was also greater for older, eight-node mature leaves than younger, five-node mature leaves. CrylAc expression in bolls was lowest compared with terminal leaves, squares, flowers, and mature leaves, which expressed at similar concentrations. Cry1F expression increased through time for mature leaves and terminal leaves; whereas, a decline in Cry1Ac protein concentration was observed for terminal leaves and bolls. The data presented here provides a means to understand observed levels of efficacy (patterns of insect damage) by comparing the spatial and temporal dynamics of expression for Cry1Ac and Cry1F in PhytoGen 440W transgenic cotton.

Efficacy of transgenic cotton expressing Cry1Ac and Cry1F insecticidal protein against heliothines (Lepidoptera: Noctuidae).

Cotton, Cossypium hirsutum L, plants expressing Cry1Ac and Cry1F (Phytogen 440W) insecticidal crystal proteins of Bacillus thuringiensis (Bt) Berliner, were evaluated against natural populations of tobacco budworm, Heliothis virescens (F.), and bollworm, Helicoverpa zea (Boddie) (Lepidoptera: Noctuidae), across 13 southern U.S. locations that sustained low, moderate, and high infestations. The intrinsic activity of Phytogen 440W was compared with nontreated non-Bt cotton (PSC355) and with management strategies in which supplemental insecticides targeting heliothines were applied to Phytogen 440W and to PSC355 cotton. Infestations were composed primarily of bollworm, which is the least sensitive of the heliothine complex to Cry toxins. Therefore, damage recorded in these studies was primarily due to bollworm. Greater than 75% of all test sites sustained heliothine infestations categorized as moderate to high (10.6-64.0% peak damaged bolls in nontreated PSC355). Phytogen 440W, alone or managed with supplemental insecticide applications, reduced heliothine-damaged plant terminals, squares (flower buds), flowers, and bolls equal to or better (1.0-79.0-fold) than managing a non-Bt cotton variety with foliar insecticides across all infestation environments. Rarely (frequency of < or = 11% averaged across structures), sprayed Phytogen 440W reduced damaged structures compared with nontreated Phytogen 440W. Protection against heliothine-induced plant damage was similar across the three levels of infestation for each viable management strategy, with exception to damaged squares for nontreated Phytogen 440W. In situations of moderate to high heliothine infestations, cotton plants expressing Cry1Ac and Cry1F may sustain higher levels of damage compared with that same variety in low infestations. No significant difference in yield was observed among heliothine management strategies within each infestation level, indicating cotton plants may compensate for those levels of plant damage. These findings indicate Phytogen 440W containing Cry1Ac and Cry1F provided consistent control of heliothines across a range of environments and infestation levels.

No influence of immunosuppression on insulin sensitivity and beta-cell function in living donor liver transplantation.

In liver transplantation alterations of glucose metabolism are common but not well understood. Influence of immunosuppression is widely presumed but has not proven until now. Using a frequently sampled intravenous glucose tolerance test with a minimal modeling technique of glucose disappearance we analyzed insulin sensitivity (SI) and beta-cell function (first and second phase of pancreatic beta-cell secretion, Phi 1 and Phi 2) in living donor liver transplantation of the right lobe. Initial immunosuppression in recipients was done with tacrolimus, prednisolone, and basiliximab induction. Donors and recipients were investigated before and 10 days, 6 months, and 1 year after operation. Normal SI of controls (donors before operation) decreased markedly 10 days after right lobectomy to SI 2.22 +/- 0.35 x 10(-4) min(-1) x microU/mL (P < .001); Phi 2 was compensatory increased. All parameters normalized within 1 year. Recipients were insulin-resistant with hyperinsulinemia before transplantation. After transplantation no parameter was significantly different from donors; all normalized equally to donors over 1-year follow-up. Thus, immunosuppression in recipients has no influence on glucose metabolism because liver function itself seems to play a more pronounced role than known until now.

[Incidence of fungal involvement in nail psoriasis]. / Häufigkeit des Pilzbefalles bei Nagelpsoriasis.

BACKGROUND AND OBJECTIVE: Because it is clinically so similar, onychomycosis is one of the most important differential diagnostic considerations in psoriatic nail changes. We determined the frequency of fungal involvement in nails of psoriatic patients. PATIENTS/METHODS: Fungal colonization of the nails of psoriatic patients with and without clinically obvious nail changes was investigated in a collective of 250 patients compared to a group of 102 non-psoriatic persons. RESULTS: There was no significant difference in the frequency of nail colonization with dermatophytes and moulds between healthy persons and psoriatics. Yeasts were more commonly found in psoriatic nails. CONCLUSIONS: Nail changes in psoriatic patients are mostly caused by psoriasis. However secondary colonization by yeasts is more common in psoriatic nails than in the general population. It remains to be clarified why dermatophytes are not more common in psoriatic nails.

The use of itraconazole to treat cutaneous fungal infections in children.

BACKGROUND: Cutaneous mycoses such as tinea capitis, onychomycosis and some cases of tinea corporis/cruris, and tinea pedis/manus require oral antifungal therapy. There is relatively limited data regarding the use of the newer oral antifungal agents, e.g. itraconazole, in the treatment of these mycoses in children. OBJECTIVE: We wished to determine the efficacy and safety of itraconazole continuous therapy in the management of cutaneous fungal infections in children. METHODS: Children with cutaneous mycoses were treated with itraconazole in an open-label manner in 4 studies. For tinea capitis, the treatment regimens using itraconazole continuous therapy were: study 1, 3 mg/kg/day for 4 or 8 weeks; study 2, 5 mg/kg/day for 6 weeks, and study 3, 5 mg/kg/ day for 4 weeks. In a different trial, study 4, itraconazole continuous therapy 5 mg/kg/day was used to treat toenail onychomycosis (duration: 12 weeks), tinea corporis/ cruris (duration: 1 week) and tinea pedis/manus (duration: 2 weeks). RESULTS: The efficacy rates at follow-up 12 weeks from the start of therapy in children with tinea capitis treated using the itraconazole continuous regimen were: clinical cure (CC) and mycological cure (MC) in study 1 (n = 10, Trichophyton violaceum all patients), CC 50%, MC 86%; in study 2 (n = 35, Microsporum canis 22 patients, Trichophyton sp. 12 patients), CC 82.8%, MC 80%, and in study 3 (n = 16, M. canis 11 patients, Trichophyton sp. 5 patients), (CC 66.7%, MC 78.5%. Itraconazole was also effective in the treatment of dermatomycoses in 24 children (study 4). The CC and MC rates at the follow-up 8 weeks from the start of therapy in children with dermatomycoses and 12 months in children treated for onychomycosis were: onychomycosis (n = 1, T. rubrum), CC 100%, MC 100%; tinea corporis (n = 12, M. canis 10 patients), CC 100%, MC 90%; tinea cruris (n = 3, Trichophyton sp. 2 patients), CC 100%, MC 100%; tinea manus (n = 1, T. rubrum), CC 100%, MC 100%, and tinea pedis (n = 7, T. rubrum), CC 100%, MC 100%). Adverse effects consisted of a cutaneous eruption in 1 (1.2%) of the 85 children, with mild, transient, asymptomatic elevation of liver function tests (less than twice the upper limit of normal) in 2 (3.4%) of 58 children in whom monitoring was performed. CONCLUSIONS: Itraconazole is effective and safe in the treatment of tinea capitis and other cutaneous fungal infections in children.

Continuous itraconazole treatment for onychomycosis and dermatomycosis: an overview of safety.

Over the past 10 years, itraconazole has been used to treat more than 34 million patients worldwide. We present a review of the safety of various continuous itraconazole schedules used in the treatment of dermatomycosis and onychomycosis. Data from controlled clinical trials and extensive post-marketing surveillance show that itraconazole has an impressive safety profile at a dose of 50-200 mg/day for 1-4 weeks for dermatomycosis and 200 mg/day for 3 months for onychomycosis. In addition, itraconazole is safe to use in diabetic patients with dermatomycosis or onychomycosis. Short-term, intermittent itraconazole regimens, which may offer additional benefits in terms of safety and cost, have now been introduced.