Larotrectinib in adult patients with solid tumours: a multi-centre, open-label, phase I dose-escalation study.

BACKGROUND: NTRK1, NTRK2 and NTRK3 gene fusions (NTRK gene fusions) occur in a range of adult cancers. Larotrectinib is a potent and highly selective ATP-competitive inhibitor of TRK kinases and has demonstrated activity in patients with tumours harbouring NTRK gene fusions. PATIENTS AND METHODS: This multi-centre, phase I dose escalation study enrolled adults with metastatic solid tumours, regardless of NTRK gene fusion status. Key inclusion criteria included evaluable and/or measurable disease, Eastern Cooperative Oncology Group performance status 0-2, and adequate organ function. Larotrectinib was administered orally once or twice daily, on a continuous 28-day schedule, in increasing dose levels according to a standard 3 + 3 dose escalation scheme. The primary end point was the safety of larotrectinib, including dose-limiting toxicity. RESULTS: Seventy patients (8 with tumours with NTRK gene fusions; 62 with tumours without a documented NTRK gene fusion) were enrolled to 6 dose cohorts. There were four dose-limiting toxicities; none led to study drug discontinuation. The maximum tolerated dose was not reached. Larotrectinib-related adverse events were predominantly grade 1; none were grade 4 or 5. The most common grade 3 larotrectinib-related adverse event was anaemia [4 (6%) of 70 patients]. A dose of 100 mg twice daily was recommended for phase II studies based on tolerability and antitumour activity. In patients with evaluable TRK fusion cancer, the objective response rate by independent review was 100% (eight of the eight patients). Eight (12%) of the 67 assessable patients overall had an objective response by investigator assessment. Median duration of response was not reached. Larotrectinib had limited activity in tumours with NTRK mutations or amplifications. Pharmacokinetic analysis showed exposure was generally proportional to administered dose. CONCLUSIONS: Larotrectinib was well tolerated, demonstrated activity in all patients with tumours harbouring NTRK gene fusions, and represents a new treatment option for such patients. CLINCALTRIALS.GOV NUMBER: NCT02122913.

Selective RET kinase inhibition for patients with RET-altered cancers.

Background: Alterations involving the RET kinase are implicated in the pathogenesis of lung, thyroid and other cancers. However, the clinical activity of multikinase inhibitors (MKIs) with anti-RET activity in RET-altered patients appears limited, calling into question the therapeutic potential of targeting RET. LOXO-292 is a selective RET inhibitor designed to inhibit diverse RET fusions, activating mutations and acquired resistance mutations. Patients and methods: Potent anti-RET activity, high selectivity, and central nervous system coverage were confirmed preclinically using a variety of in vitro and in vivo RET-dependent tumor models. Due to clinical urgency, two patients with RET-altered, MKI-resistant cancers were treated with LOXO-292, utilizing rapid dose-titration guided by real-time pharmacokinetic assessments to achieve meaningful clinical exposures safely and rapidly. Results: LOXO-292 demonstrated potent and selective anti-RET activity preclinically against human cancer cell lines harboring endogenous RET gene alterations; cells engineered to express a KIF5B-RET fusion protein -/+ the RET V804M gatekeeper resistance mutation or the common RET activating mutation M918T; and RET-altered human cancer cell line and patient-derived xenografts, including a patient-derived RET fusion-positive xenograft injected orthotopically into the brain. A patient with RET M918T-mutant medullary thyroid cancer metastatic to the liver and an acquired RET V804M gatekeeper resistance mutation, previously treated with six MKI regimens, experienced rapid reductions in tumor calcitonin, CEA and cell-free DNA, resolution of painful hepatomegaly and tumor-related diarrhea and a confirmed tumor response. A second patient with KIF5B-RET fusion-positive lung cancer, acquired resistance to alectinib and symptomatic brain metastases experienced a dramatic response in the brain, and her symptoms resolved. Conclusions: These results provide proof-of-concept of the clinical actionability of RET alterations, and identify selective RET inhibition by LOXO-292 as a promising treatment in heavily pretreated, multikinase inhibitor-experienced patients with diverse RET-altered tumors.

T-Cell type acute lymphoblastic leukemia following cyclosporin A therapy for aplastic anemia.

Cyclosporin A (CsA) is used to prevent rejection in transplantation and to treat autoimmune and hematologic diseases such as aplastic anemia. However, the tumor growth-promoting effect of CsA remains controversial. We report the case of a 24-year-old man who developed acute lymphoblastic leukemia of precursor-T-cell origin after 75 months of treatment with CsA for aplastic anemia. The surface antigen phenotype of his leukemic cells was CD2+, CD3+, CD5+, CD7+, CD4-, CD8-, CD10-, CD20-, CD34-, CD41-, and CD56-. Southern blot analysis revealed a monoclonal rearrangement of T-cell receptor-Jgamma nongermline fragments in HindIII digestion.

Mental health in Asia: social improvements and challenges.

Remarkable improvements in economic conditions and a considerable upgrade in the quality of life have been observed in many parts of Asia during the past several decades. At the same time, many mental health challenges face the people of Asia. Various social mental health indexes are reviewed here, with available data from China, Japan, Korea, Singapore, Malaysia, and other Asian societies. The data are compared with data from the United States, Australia in the Pacific Rim, and some other Western countries to examine patterns of similarity or difference between East and West in the process of modernization. Common trends in mental health issues associated with rapid sociocultural change observed in different Asian societies are discussed, as well as the relative shortage of mental health personnel available in many Asian societies. It is emphasized that, in addition to expanding psychiatric services, there is an even more urgent need to promote mental health knowledge and concern through education in the general population. Mental health needs to be cultivated and maintained by social forces and cultural strengths. It is stressed that there is a challenge for Asian people to advance mental health beyond economic development in the 21st century.

[Marginal zone lymphoma associated with Sjögren's syndrome and hepatitis C virus infection].

A 64-year-old female was admitted in May 1997, because of salivary gland swelling. Histology of the right parotid gland revealed malignant lymphoma, diffuse medium-sized B-cell type, and she was treated with local radiotherapy and chemotherapy. She was rehospitalized in April 1998, because of recurrence of lymphoma in the stomach and the sigmoid colon. She had splenomegaly and lymphadenopathy (neck and inguinal). Laboratory findings revealed marked elevation of rheumatoid factor and RNA of hepatitis C virus. A diagnosis of Sjogren's syndrome was made by dryness and the histological findings of labial biopsy. Marginal zone B-cell lymphoma mainly consisted of centrocyte-like cells and lymphoepithelial lesions, and CD 20 and IgM-kappa were positive with immunohistochemical staining. Lymphoma involved the gut and spleen. We discuss the correlation of malignant lymphoma with Sjogren's syndrome and HCV infection.

[Histiocytic necrotizing lymphadenitis (Kikuchi-Fujimoto's disease) accompanied by hemophagocytosis and salivary gland swelling in a patient with systemic lupus erythematosus].

After 2 years of steroid therapy that had effectively controlled her systemic lupus erythematosus, a 37-year-old woman presented with fever, erythema (face, upper chest), and low CH50. Increased oral steroid (prednisolone from 15 mg to 40 mg) and intravenous methylprednisolone (mPSL) (80 mg for 3 days) alleviated these symptoms except for the fever. Subsequently, the patient's fever worsened and leukocytopenia, abnormal liver function, lymphadenopathy (neck, axilla), and salivary gland swelling developed. Lymph node histology revealed features characteristic of Kikuchi-Fujimoto's disease (KFD). Laboratory examinations showed WBC 600/microliter, Hb 9.5 g/dl, platelets 90,000/microliter, GOT 766 IU/l, GPT 646 IU/l, LDH 4,228 IU/l, TG 1,622 mg/dl, and ferritin 6,330 ng/ml. Serum interferon gamma was also elevated (673 U/ml). Because a bone marrow smear revealed hemophagocytosis, mPSL pulse therapy (1 g for 3 days) was started for treatment of hemophagocytic syndrome. The fever promptly disappeared, and the patient's clinical symptoms resolved within 2 weeks. The abnormal laboratory data related to KFD and hemophagocytosis returned to normal within 4 weeks after the initiation of mPSL pulse therapy. We speculated that the hemophagocytosis and salivary gland involvement in this patient were also symptoms of KFD. This case indicated that corticosteroid pulse therapy is effective for KFD with serious clinical symptoms.

Random number generation deficit in schizophrenia characterized by oral vs written response modes.

To characterize the deficit in random number generation in schizophrenia with respect to control of sensory information processing, the present study employed a random number generation task using 10 digits (0 to 9) and compared two response modes (oral and written) with different amounts of sensory availability about the previous choices of the subject. Analysis indicated that the increased availability of previous information in the written response mode may exacerbate an aspect of the deficit in random number generation in schizophrenia reflecting the disturbance in control of sensory information processing. The comparison of performance in written and oral response modes may be useful in assessing schizophrenic psychopathology.

Optimization of excimer-forming two-probe nucleic acid hybridization method with pyrene as a fluorophore.

A previously presented homogeneous assay method, named the excimer-forming two-probe nucleic acid hybridization (ETPH) method, is based on specific excimer formation between two pyrenes attached at the neighboring terminals of two sequential probe oligonucleotides complementary to a single target. In this study, we investigated assay conditions and optimal molecular design of probes for intense excimer emission using a pyrenemethyliodoacetamide-introduced 16mer probe, a pyrene butanoic acid-introduced 16merprobe and a target 32mer. The length of the linker between the pyrene residue and the terminal sugar moiety remarkably influenced the quantum efficiency of excimer emission; the pair of linker arms of these two probes was optimal. The quantum efficiency was also dependent upon the concentrations of dimethylformamide and NaCl added to the assay solution. Spectroscopic measurements and T m analysis showed that an optimal configuration of the two pyrene residues for intense excimer emission might be affected by pyrene-pyrene interaction, pyrene-duplex interaction (intercalation/stacking) and solvent conditions as a whole. We then demonstrated the practicality of the ETPH method with the optimal hybridization conditions thus attained by determining that the concentration of 16S rRNA in extracts from Vibrio mimicus ATCC 33655 cells in exponential growth phase is 18 500 16S rRNA molecules/cell on average.

Clinical experience of functional electrical stimulation in complete paraplegia.

Percutaneous intramuscular electrodes and a portable multichannel system were used to restore the function of the paralyzed lower extremities in six patients with complete paraplegia. The total number of inserted electrodes was 168. All of the patients could stand, two could walk in parallel bars, and two could walk with a walker. The rate of breakage of electrodes was only 0.6% in our series. There were 10 (6.0%) superficial infections, and 10 (6.0%) movement of electrodes which required reimplantation. The results suggest that the ultrafine intramuscular electrode is practical for long term use with paraplegic patients. Although the system can be used for paraplegic patients during the activities of daily living, it will be necessary to develop a closed-loop controller to reduce the amount of stimulation to the extensor muscles and extend the endurance of upright activity to reduce fatigue.

Nucleic acid hybridization accompanied with excimer formation from two pyrene-labeled probes.

We developed a novel nucleic acid hybridization method based on excimer formation. We used two different 16-mer oligonucleotide probes that had a combined continuous-sequence run that was complementary to a target 32-mer. Prior to hybridization, the adjacent terminal ends (i.e. the 3'-terminal of one probe and the 5'-terminal of the other probe) were each labeled with one pyrene residue. When these probes simultaneously hybridized to the target, a 495 nm broad fluorescence band was produced. The intensity of this band increased as the intensity of the pyrene monomer bands decreased, indicating that the 495 nm band was attributed to the pyrene excimer. The excimer fluorescence, easily differentiated from the monomer bands for emission wavelength, opens up a new way to perform homogeneous hybridization assays and in vivo imaging of nucleic acids.

Restoration and analysis of standing-up in complete paraplegia utilizing functional electrical stimulation.

OBJECTIVE: Restoration of stand-up motion in patients with complete paraplegia utilizing multichannel functional electrical stimulation, and analysis of the restored motion. DESIGN: Nonrandomized control trial. SETTING: General community, a referral center, institutional practice, and ambulatory care: PATIENTS: Twelve volunteer samples were used for the collection of normal data. Two complete paraplegics received treatment for the restoration of stand-up motion. MAIN OUTCOME MEASURES: The electromyogram, joint angle, and floor reaction force were investigated during standing-up with arms crossed in front of the chest, and hands-assisted standing-up using parallel bars. The maximum knee joint torque during standing-up without hands-assists was calculated using a three-segment link model. Standing-up motion in complete paraplegics was restored, and then analyzed using the three-dimensional floor reaction force and the hip, knee, and ankle angles. RESULTS: Main muscles used to stand up were the quadriceps, tibialis anterior, and paraspinal muscles. Hands-assists reduced the muscle activity and the vertical floor reaction force. Peak muscle activity was less during hands-assisted standing-up, except for the rectus femoris and the iliopsoas muscle. The maximum knee joint torque during standing-up was 1.6Nm/kg for both knees. Two complete paraplegics were able to stand up smoothly from a wheelchair based on stimulation data obtained from normal subjects. The characteristic pattern during standing-up was knee flexion preceding extension. CONCLUSION: Stand-up motion was restored utilizing electromyogram data and knee joint torque data from normal subjects.

Excimer formation by hybridization using two pyrene-labeled oligonucleotide probes.

Pyrene excimer formation was achieved in an aqueous solution by nucleic acid hybridization. We used two different 16-mer oligonucleotide probes which had a combined continuous-sequence run complimentary to a target 32-mer. Prior to hybridization, the adjacent terminal ends (i.e., the 3'-terminal of one probe and the 5'-terminal of the other probe) were each labeled with one pyrene residue. The simultaneous hybridization of the probes to the target induced a 495-nm broad fluorescence band characteristic for pyrene excimer. Temperature and molecular configurations of the hybrid influenced the excimer formation.

The effect of an aldose reductase inhibitor (Epalrestat) on diabetic nephropathy in rats.

In order to clarify the possible contribution of the abnormal polyol pathway to the development of diabetic nephropathy, the effect of aldose reductase inhibitor on renal function and morphology was examined in streptozotocin (STZ)-induced diabetic rats. Six months after STZ injection, glomerular filtration rate and renal plasma flow showed marked decline with significant increase in nuclear-free mesangial area (MA) and relative mesangial area (RMA; MA per glomerular area) in diabetic rats. Oral administration of an aldose reductase inhibitor, Epalrestat, prevented renal hypofunction and mesangial expansion in diabetic rats without influencing the levels of blood glucose. These results suggest that the abnormal polyol pathway in diabetic rats is closely related to the development of mesangial expansion, a morphologic representative of diabetic glomerulopathy, and renal hypofunction.

Evaluation of the radiographic efficacy of iomeprol.

Iomeprol, a new nonionic contrast medium, was administered at concentrations of 300 mgI/ml, 350 mgI/ml, and 400 mgI/ml to 1939 Japanese patients. The radiographic efficacy, the incidence of heat sensation and the incidence of pain were evaluated. The radiographic efficacy was rated as excellent in 80.6% and good in 17.5% of 1017 cases of conventional arteriography, excellent in 75.6% and good in 22.2% of 267 cases of IADSA or IVDSA, excellent in 78.3% and good in 19.6% of 384 cases of intravenous urography and excellent in 68.6% and good in 28.8% of 271 cases of CT enhancement. There was no statistical difference in radiographic efficacy between the sites of arteriography. Heat sensation was mild or moderate in 43.4% and severe in 0.2% of cases requiring intra-arterial injection, and mild or moderate in 50.7% of cases requiring intravenous injection. There were no cases of severe heat sensation following intravenous injection. The incidence of pain was low (mild 4.2%, moderate 0.7% and severe 0.1%) with intra-arterial injections. It is concluded that iomeprol is an excellent radiographic contrast medium for intravenous urography, CT enhancement and various forms of angiography.

Assessment of the side-effects of iomeprol.

Adverse reactions were investigated in a group of 1918 patients enrolled in a study for the clinical assessment of iomeprol. The incidence of adverse reactions in the group was 5.3%. Dermatological symptoms were the principal adverse reactions. No previously unreported side-effects from iodinated contrast media were detected. Most adverse reactions were of slight or moderate intensity and most appeared within 3 h of the injection. The examinations which elicited a comparatively high frequency of adverse reactions were cerebral angiography, abdominal angiography, peripheral angiography, intravenous urography and thoracic angiography. No significant sex differences were noted with respect to the occurrence of adverse reactions, but such effects were more frequent among younger patients, among patients with allergic conditions and among patients who had previously received iodinated contrast media. As regards the manner of injection of iomeprol, there were no definite trends in terms of the iodine concentration used or the quantity of contrast medium injected, but the incidence of adverse reactions was comparatively high for intravenous as compared with intra-arterial injection.

[A social psychiatric study on foreign-born inpatients at Tokyo Metropolitan Matsuzawa hospital].

The authors carried out a chart review study of 293 foreign-born patients who were admitted to Tokyo Metropolitan Matsuzawa Hospital from January 1986 to December 1992. We divided the subjects into three groups according to their living status in Japan, Immigrant group: 66 long-term residents, Resident group: 188 short-term residents with purposes of work or study, and Visitor group: 39 temporary visitors for sightseeing or business. The subjects came from 43 countries in the world, 70.3% (206/293) of whom were those from Asian countries. The subjects grew in number every year and the noticeable feature was a drastic increase in the number of Resident group (e.g. 6 patients in 1986, 63 in 1992). The mean duration (SD) of hospitalization for Immigrant group was the longest among the groups (Immigrant group: 58.7 (55.0) days, Resident group: 31.9 (35.0) days, Visitor group: 19.0 (16.3) days). The frequent diagnoses at discharge based on ICD-9, were schizophrenia (59.7%) and reactive psychosis (19.1%). The significantly larger proportion of Visitor group had previous psychiatric histories in their homeland than other groups (Visitor group: 56.4%, Immigrant group: 24.2%, Resident group: 23.9%). 70.0% (205/293) of the subjects could not use Japanese in usual settings and the number of them had been increasing every year. This communication difficulty had caused serious inconvenience in the treatment. All of Visitor group, and 71.8% (135/188) of Resident group could not receive social securities, and there were difficulties for them to raise money for their medical treatment and living expenses. 92.3% among Visitor group, 91.0% of Resident group and 21.2% of Immigrant group returned to their homeland after inpatient treatment. The result indicated that we must immediately establish the interpreter dispatch system for foreign-born patients and that of the social securities guaranteeing their medical care and living expenses.

[Measurement of the center of gravity using the link model for controlling functional electrical stimulation].

The purpose of this study is to better understand the reliability of using the link model when determining the center of gravity. We measured the centers of gravity using both the link model and the floor reaction force in 11 healthy subjects. Dempster's and Clauser's anthropometric data were used in measuring the center of gravity by the link model, and these results were compared with those measured by the floor reaction force. The motion area of the center of gravity during quiet standing was determined by experimental data, using the link model calculation. Joint torque was measured using Cybex II in one paraplegic patient who was treated by functional electrical stimulation (FES). We discuss whether the paraplegic patient can stand safely in a determined center of gravity motion area. Displacements of the center of gravity measured by the link model were very close to those obtained by the floor reaction force. The parameters of body segments proposed by Dempster were more reasonable than those of Clauser. The maximum differences of the center of gravity between those measured by the link model using Dempster's data and those measured by the floor reaction force, were 1.47 cm for the fore-aft direction, 1.85 cm for the lateral direction, and 2.34 cm for the vertical direction. The torque caused by electrical stimulation was stronger than that calculated by the link model during quiet standing. Our results suggest that the link model system that measures displacement of the center of gravity using Dempster's data, is clinically applicable for the closed-loop control system of FES.

Effects of collagen concentration on epithelial differentiation: in vitro analysis with a mucosal tissue model.

Using collagen, epithelial cells, and fibroblasts isolated from the rabbit oral mucosa, a mucosal tissue model was prepared in vitro. Using this model, the effects of the collagen concentration on growth and differentiation of epithelial cells were studied. A positive correlation was found to exist between the collagen concentration and growth as well as the differentiation of epithelial cells. Further, above a 8.6% concentration of collagen, formation of the epithelial process and the basement membrane at the border between the epithelial layer and the connective tissue was noted. A conclusion was drawn that the collagen concentration in the extracellular matrix is deeply related to the growth and differentiation of mucosal epithelial cells. At the same time, it can be said that the successful completion of this research project endorsed the reliability of our methodology for the study of mucosa.