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.

Evidence for existence of polyol pathway in cultured rat mesangial cells.

The accumulation of polyols has been previously found in renal glomeruli isolated from streptozocin-induced diabetic (STZ-D) rats, although the intraglomerular polyol pathway has not been exactly localized. Because we have previously observed mesangial cell dysfunction in STZ-D rats, we examined whether the polyol pathway exists in mesangial cells as a possible candidate of the cause of cellular dysfunction. The activities of two polyol pathway enzymes, aldose reductase and sorbitol dehydrogenase, were clearly detected in the crude homogenate of cultured mesangial cells at higher levels than those of whole glomeruli when DL-glyceraldehyde or D-fructose was used as substrate. When cells were incubated in medium containing 55 mM glucose or galactose, a large amount of sorbitol or galactitol was accumulated intracellularly. The accumulation of polyols was effectively blocked by an aldose reductase inhibitor, ICI 128436. These results suggest that the polyol pathway exists in mesangial cells of rat glomeruli and may play a role in the development of mesangial cell dysfunction found in STZ-D rats.

Diagnostic pattern for neuroses in China, Japan, and the United States.

To investigate the diagnostic patterns for neuroses in China, Japan, and the United States, the authors showed videotapes and brief written case histories of six Chinese patients to psychiatrists and psychiatrists-in-training in Beijing, Tokyo, and Honolulu. In cases with a well-distinguished clinical picture the diagnoses were congruent in the three countries. Diagnostic disagreement occurred in cases with symptoms of decline in mental function, which were overwhelmingly diagnosed as neurasthenia by the Chinese clinicians, and cases with situational stress, which were diagnosed as adjustment reaction by the Americans. This illustrates that different professional concepts and classification systems are used in different countries.

Transethnic adoption and personality traits: a lesson from Japanese orphans returned from China to Japan.

The authors interviewed 25 Japanese who had been left as orphans in China at the end of World War II and who had recently returned to Japan with their Chinese spouses after almost four decades. It was found that even though they had been raised as Chinese culturally for almost their entire lives, most of these subjects had retained certain Japanese personality traits and social behavior from early childhood, and these characteristics distinguished them from their Chinese counterparts.

Glucose inhibits myo-inositol uptake and reduces myo-inositol content in cultured rat glomerular mesangial cells.

Although activation of polyol pathway has been proposed as one of the etiologic factors of diabetic complications, precise mechanism of the effect of polyol accumulation is still unclear. In order to test the hypothesis that there is an association of polyol pathway with myo-inositol metabolism, we measured myo-inositol content in cultured rat glomerular mesangial cells. By exposing the cells to high concentrations of glucose, intracellular myo-inositol content was reduced from 12.39 +/- 0.64 nmol/mg protein at 0 mmol/L glucose to 6.54 +/- 0.38 nmol/mg protein at 27.5 mmol/L glucose and 4.88 +/- 0.43 nmol/mg protein at 55 mmol/L glucose. This decrease of myo-inositol content was partially prevented by co-incubation with aldose reductase inhibitor, sorbinil. To examine further the mechanism of myo-inositol depletion, myo-inositol uptake by mesangial cells was studied. Major myo-inositol uptake process was sodium-dependent, saturable, and ouabain sensitive with Vmax of 171 pmol/mg protein/20 min and Km of 33 mumol/L. Sodium-dependent myo-inositol uptake was significantly inhibited by glucose in a dose-dependent manner only when glucose was present during uptake experiment, and kinetic analysis revealed the inhibition was competitive. Aldose reductase inhibition failed to prevent inhibitory effect of glucose on myo-inositol uptake. These data suggest that myo-inositol content of glomerular mesangial cells, which is reduced by high concentrations of glucose, is maintained by two processes: a glucose-sensitive but sorbitol-insensitive process, sodium-dependent myo-inositol uptake; and a sorbitol (aldose reductase) sensitive process, myo-Inositol depletion under high glucose condition may induce dysfunction of mesangial cells seen in diabetes.

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.

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.

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 comparative study of children's television programmes: American and Japanese.

American Children's Stories on Television (ACSTV) and Japanese counterparts (JCSTV) were analysed with emphasis on the transcultural element, according to the main theme and the features of the key characters. The most common theme of both ACSTV and JCSTV was authority. The authority figure in ACSTV was viewed as a competitor, while in JCSTV it was viewed as being evil. The intimacy of the mother-child relationship was prominent in JCSTV. In ACSTV, individualism was emphasised, while in JCSTV group affiliation was more emphasised.

A mental health survey of the Vietnamese refugee in Japan.

A mental health survey was conducted using the Cornell Medical Index (CMI) on Vietnamese refugees who have resettled in Japan. 64.5% of the females and 37.2% of the males displayed emotional disturbance. The refugees with life-threatening and/or concentration camp experience had significantly higher CMI scores than those without it (t test, P less than 0.05). CMI scores of the group residing in Japan for 4-5 years are markedly lower than the group residing there for 2-3 years (F test, P less than 0.05).

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.

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.

[Measurement of renal plasma flow and glomerular filtration rates in diabetic subjects].

To clarify the problem in the measurement of renal plasma flow and glomerular filtration rates in diabetes, the effect of glucose on the determination of para-aminohippuric acid (PAH) and inulin was examined. The concentration of urinary PAH in glucosuric diabetic subjects decreased after the storage of urine samples because of the glycation of PAH. Therefore, glucose must be removed by the acid treatment before the determination of the concentrations of urinary PAH. Since glucose can interfere with the assay of inulin, the sample must be treated with NaOH prior to the determination of the inulin concentration. GFR of the subjects with type 2 diabetes was next examined. GFR in the subjects with a duration of diabetes less than 10 years was significantly higher than that in the subjects with a duration of diabetes more than 10 years. Thus, the subjects with short-term type 2 diabetes may present with hyperfiltration similar to the subjects with short-term type 1 diabetes.

[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.

[A study of the measurement of p-aminohippurate in diabetic subjects].

Glomerular filtration rate has been found to be elevated in the early stage of insulin-dependent diabetes mellitus and has been proposed to play a pathogenetic role in the development of diabetic nephropathy. However, the reports about the change in renal plasma flow (RPF) among diabetic subjects were inconsistent, suggesting that the presence of hyperglycemia may in some way interfere the procedures of RPF measurement. Recently, it has been reported that the glucose in the urine may react with p-aminohippurate (PAH), a widely used marker for RPF measurement, and influence the chemical measurement of PAH, misleading the result of RPF value. In fact, we obtained the decrease of PAH value in urine samples obtained from diabetic subjects during the storage for one week in frozen condition. In order to clarify the factors which may influence the glucose-PAH reaction, we have conducted various in vitro studies. The decrease of PAH values was dose-dependent to urine glucose. The pH of the test solution or urine was also found to greatly influence the result of PAH measurement when glucose was present. The analysis of glucose-PAH reactants by HPLC suggested that the amino residue of PAH might be reacted with glucose, producing the glycation product (Schiff base). The rate of glycation of PAH was time- and pH-dependent. However, when the reaction time was prolonged at the last step of PAH measurement after the addition of the acid solution, the decrease of PAH value was gradually corrected reaching to the theoretical value in 7 hours.(ABSTRACT TRUNCATED AT 250 WORDS)

[Diagnostic imagings of mediastinal mass].

Conventional postero anterior and lateral chest radiographs constitute the first examination of the mediastinum. A well-penetrating radiograph of 130KV or more is needed to optimally, demonstrate the lung-mediastinal borders as well as air-containing structures in the central thorax. Many mediastinal lesions that are obscure on conventional films are clearly demonstrated by CT, which clearly separates structures in the axial plane. The extent and localization of tumor can be more easily determined by CT than by other techniques. Conventional chest tomography has been popular in the past, but with the advent of CT scanning, this procedure has little in evaluating a mediastinal mass if CT is available. Nuclear scan using gallium 67 is fairly accurate in identifying inflammatory lesions and malignant tumors, but with the advent of CT such studies have little if any use in the mediastinum. The list of CT indications conforms somewhat to the report published by the Society of Computed Body Tomography, with some modifications. CT examination of the mediastinum has become one of the most useful complementary modalities in the diagnostic field and often not only is it complementary, but it may be an alternative to other X-ray studies, isotope scanning, or mediastinoscopy.