High incidence and early onset of nivolumab-induced pneumonitis: four case reports and literature review.

BACKGROUND: Nivolumab, an anti-programmed cell death-1 (PD-1) monoclonal antibody used as an immune checkpoint inhibitor, is commonly employed for its anti-tumor effects against various types of malignant tumors. However, its administration is complicated by immune-related adverse events (irAEs), including pneumonitis. CASE PRESENTATION: We present a case series of four patients with malignant melanoma, non-small cell lung cancer, and hypopharyngeal carcinoma who demonstrated pneumonitis induced by nivolumab, and further review clinicopathological characteristics of these patients in comparison with those of previously reported patients with nivolumab-induced pneumonitis. In our series, 20% of patients who were treated with nivolumab developed pneumonitis, all of which occurred approximately 2 weeks after the initiation of nivolumab treatment. Prompt recognition of the nivolumab-induced pneumonitis allowed for successful resolution. Computed tomography scan images of the patients demonstrated predominantly cryptogenic organizing pneumonia patterns. All patients were males, who had been heavily treated with antitumor drugs prior to nivolumab. CONCLUSIONS: Our case series showed that nivolumab had a high incidence of drug-induced pneumonitis with early onset, supporting the need for renewed attention to nivolumab-induced pneumonitis, particularly in patients with a history of heavy antitumor treatments.

Association between polymorphisms in the SPINK5 gene and atopic dermatitis in the Japanese.

Atopy, which is characterized by increased levels of immunoglobulin E (IgE) against common environmental allergens, is considered the strongest predisposing factor for asthma and atopic dermatitis (AD). Mutations in the gene encoding serine protease inhibitor Kazal-type 5 (SPINK5) are responsible for Netherton syndrome, a rare skin disorder characterized by greatly elevated IgE levels with atopic manifestations. A recent study of Caucasian AD families showed that maternally derived alleles of the SPINK5 gene are associated with development of AD and asthma, suggesting the parent-of-origin effect for the development of atopic diseases in the SPINK5 gene. We studied the possible association of the SPINK5 gene for the development of atopic diseases by determining the genotypes of five polymorphisms in a Japanese population. Ttransmission disequilibrium tests revealed an association of SPINK5 polymorphisms with AD but not with asthma. Our data indicate that the SPINK5 gene is associated with AD across ethnicities.

Mutation and association analysis of the interferon regulatory factor 2 gene (IRF2) with atopic dermatitis.

Interferon regulatory factor 2 (IRF-2) is a member of a family of transcriptional factors involved in the modulation of cellular responses to interferons (IFNs) and viral infection as well as in the regulation of cell growth and transformation. Irf2 knockout mice show T helper 1 (Th1) cell development defect and spontaneous development of an inflammatory skin disease. To determine if there are any mutations in IRF2 associated with development of atopic dermatitis (AD), we screened for mutations in the 5' flanking and coding regions of IRF2 in AD patients and control subjects by single-strand conformational polymorphism (SSCP) analysis. We found three mutations in the promoter region ([-829C>T, -830C>T], -684C>T, and -467G>A), one silent mutation in exon 9 (921G>A), and a 10-bp deletion in the 3' untranslated region (1739[ATCCC]8>6). Among them, the -467G allele and the haplotype of the -467G, 921A, and 1739(ATCCC)8 alleles were transmitted preferentially to AD-affected children (P = 0.02 and P = 0.007, respectively). Our data suggest that IRF-2 plays some role in the development of AD in the Japanese population.

[Analysis of factors influencing on Anisakis specific IgE antibodies].

Anisakis-specific IgE (AsIgE) was examined in 84 cases of acute urticaria (AU) and 100 cases of atopic dermatitis (AD). Gender, age, disease category (AU or AD) and serum IgE value of the patients were compared with AsIgE. Univariate analysis showed that there was significant correlation between age and AsIgE, and between serum IgE and AsIgE. Serum IgE was significantly higher in AD than in AU. Age was significantly higher in AU than in AD. AsIgE was positive value in 26 cases (31%) of AU and 25 cases (25%) of AD. There were no significant differences between them. In these cases, however, AsIgE was significantly higher in AU than in AD. Percentage of patients with high AsIgE value (> class 2) was significantly higher in AU (20 cases, 24%) than in AD (3 cases, 3%). Multivariate analysis using discriminant analysis and logistic regression analysis showed that the most influential factor on AsIgE was disease category (relative risk = 16.87), and the second was age (relative risk = 1.05). Serum IgE and gender were considered not to influence on AsIgE. It is possible that Anisakis or related antigens have something to do with urticaria in AU patients with high AsIgE value.

Individual solvation numbers around the nickel(II) ion in an N,N-dimethylformamide and N,N-dimethylacetamide mixture determined by Raman spectrophotometry.

Individual solvation numbers around the nickel(II) ion have been determined by titration Raman spectroscopy in N,N-dimethylformamide (DMF) and N,N-dimethylacetamide (DMA) mixtures at 298 K. The in-plane bending vibration (delta(O=C-N)) of DMF and the stretching vibration (v(N-CH3)) of DMA were used in the present analysis. These Raman bands of solvent molecules shift to higher frequencies upon coordination of the solvent molecules to the metal ion. By analyzing the band intensities of free and bound solvent molecules with increasing concentration of the metal ion, the solvation number around the metal ion can be evaluated. Because the individual solvation numbers of DMF and DMA around the nickel(II) ion in the mixture are determined independently, the total solvation number is obtained as their sum. It was found that the total solvation number remains 6 in all mixtures of the DMA mole fraction x = 0 - 1. Although DMF and DMA have practically the same electron-pair donor capacities, the nickel(II) ion prefers DMF to DMA, and an equal solvation number is attained at x = 0.75. This is ascribed to the solvation steric effect of DMA.

Formation of Copper(II) Thiocyanato and Cadmium(II) Iodo Complexes in Micelles of Nonionic Surfactants with Varying Poly(ethylene oxide) Chain Lengths.

Formation of copper(II) thiocyanato and cadminum(II) iodo complexes in micelles of poly(ethylene oxide) (PEO)-type nonionic surfactants with varying PEO chain lengths of 9.5 (Triton X-100), 30 (Triton X-305), and 40 (Triton X-405) has been studied by titration spectrophotometry and calorimetry at 298 K. In a given surfactant solution, all data obtained were analyzed by assuming formation of ternary complexes MX(n)Y(m)((2-n)+) (M = Cu(II),Cd(II); X = SCN(-), I(-); Y = surfactant), and the complexes thus form in aqueous phase (m = 0) or in micelles (m = 1). In the Cu(II)-SCN(-) system, spectrophotometric data obtained by varying concentrations of the surfactant can be explained well in terms of formation of Cu(NCS)(2)Y in micelles and Cu(NCS)(+) and Cu(NCS)(2) in an aqueous phase, and it turned out that formation constant of Cu(NCS)(2)Y increases with increasing PEO chain length. In the Cd(II)-I(-) system, the formation of CdI(3)Y(-) and CdI(4)Y(2-) is concluded in micelles, and that of CdI(+), CdI(3)(-), and CdI(4)(2-) in an aqueous phase. Interestingly, formation enthalpies of CdI(3)Y(-) and CdI(4)Y(2-) become significantly less negative with increasing PEO chain length. This suggests that transfer of the complexes from aqueous solution to a hydrophobic octylphenyl (OP) moiety in micelles is significantly more exothermic than that to a hydrophilic PEO one. Thermodynamic parameters of transfer of CdI(3)(-) and CdI(4)(2-) from aqueous solution to the OP and PEO moieties of micelles have been evaluated. Copyright 2000 Academic Press.

Comparison of phototoxicity mechanism between pulsed and continuous wave irradiation in photodynamic therapy.

A study has been conducted in which HeLa cells are incubated with hematoporphyrin derivative (HpD) for 1 h (1 microgram/ml of HpD in PBS) to compare the use of continuous wave (CW) and pulsed laser (10 Hz repetition rate and 7-9 ns pulse width) light for photodynamic therapy. Cytotoxic effects on the cells are evaluated by the 3-(4,5-dimethyl-2-thiazolyl)-2-5-diphenyl-2H-tetrazolium bromide (MTT) assay and the fluorescein diacetate (FDA)/propidium iodide (PI) stain method using a flow cytometer. The type of cell death is estimated by analysis of the DNA content and observation of the nuclear morphology. The cytotoxicity ratio of cells irradiated by pulsed laser light is estimated to be lower than that for CW laser light. The viability of cells that received pulsed laser light gradually decreases, whereas no significant changes are found in the cells irradiated with CW laser light with the elapse of post-irradiation time. The type of cell death differs between the pulsed and CW laser light irradiations. These findings suggest that the cytotoxic efficacy of the excitation light source is displayed by the difference in the type of cell death, namely apoptosis or necrosis.

Metastasis of esophageal carcinoma manifesting as whitlow-like lesions.

A rare case of phalangeal metastasis of esophageal carcinoma in an 81-year-old man is described. The patient developed a tender, red, and swollen right index finger. From the clinical features, he was erroneously diagnosed with whitlow at first and treated with antibiotics with no success. A bone X-ray showed that the distal phalanx of the index finger was completely dissolved. Histopathological examination revealed proliferation of squamous cell carcinoma into the deep dermis. It is important to understand that the phalangeal metastases commonly display inflammatory symptoms that mimic acute infection.

Papillary eccrine adenoma: immunohistochemical studies of keratin expression.

Despite various studies, there are serious disagreements about the cellular differentiation of papillary eccrine adenoma. In the present study, 2 specimens of papillary eccrine adenoma were analyzed by immunohistochemical techniques, using a panel of monoclonal antibodies against keratins, to elucidate its differentiation. Histopathologically, the tumor was composed of multiple tubular structures lined by two or more layers of epithelial cells. The luminal cells of the tubules were flattened or cuboidal. The former were noted in large dilated tubules. The latter were usually observed in small-to-moderate-sized tubules, and formed intraluminal papillary projections in some tubules. Immunohistochemically, there were two kinds of cuboidal cells in the luminal layers of the tubules. Most of the large dilated tubules and some of the small-to-moderate-sized tubules expressed immunophenotypes similar to those of the eccrine dermal duct. The other tubular structures, including the small tubules resembling those of syringoma, expressed immunophenotypes similar to those of the transitional portions between the dermal ducts and the secretory segments of eccrine glands. From the above comparative studies, papillary eccrine adenoma is considered to differentiate towards the dermal duct and the transitional portions between the dermal ducts and the secretory segments of eccrine glands.

[Transthoracic Doppler echocardiographic detection of intramyocardial coronary artery flow in humans using high frequency transducer].

The use of transthoracic color and pulsed Doppler echocardiography to detect intramyocardial coronary artery flow in humans was evaluated in 18 normal healthy subjects (mean age 54 years) and in 16 patients with hypertrophic cardiomyopathy (HCM; mean age 59 years) to measure the intramyocardial coronary artery flow velocity at the ventricular septum and the apex using a 10-5 or 7-4 MHz transducer. Linear inflow color Doppler signals which passed the interventricular septum were demonstrated in 15 of 18 normal subjects (83%) and 15 of 16 patients with HCM (94%). The phasic flow velocities measured by pulsed Doppler echocardiography consisted of two forward flow signals in mid-systole (S-wave) and holodiastole (D-wave), and were obtained in 11 of 18 in normal subjects (61%) and 14 of 16 patients with HCM (88%). The mean peak velocities of the S- and D-waves in patients with HCM (mean [+/-SD] 27 +/- 9 and 86 +/- 23 cm/sec, respectively) were significantly (p < 0.05) higher than those in normal subjects (18 +/- 4 and 54 +/- 11 cm/sec, respectively). At the apex, linear inflow color Doppler signals which passed the myocardium perpendicularly during the whole diastole were demonstrated in 14 of 18 normal subjects (78%) and all 16 patients with HCM (100%). The phasic flow velocities were measured by pulsed Doppler echocardiography in 10 of 18 normal subjects (56%) and 15 of 16 patients with HCM (94%). The mean peak velocities in patients with HCM (74 +/- 27 cm/sec) were significantly (p < 0.05) higher than those in normal subjects (33 +/- 13 cm/sec). Transthoracic color and pulsed Doppler echocardiography can detect intramyocardial coronary artery flow in humans at the interventricular septum and the apex noninvasively.

Thiocyanato and Iodo Complexation of Cadmium(II) Ions in Micellar Solutions of a Nonionic Surfactant Triton X-100

Complexation of the cadmium(II) ion with thiocyanate and iodide ions have been studied by precise titration calorimetry in micellar solutions of a nonionic surfactant Triton X-100 containing 0.4 mol dm-3 NaClO4 as a constant ionic medium at 298 K. With regard to the Cd(II)-SCN- system, the formation of [Cd(NCS)]+ and [Cd(NCS)(SCN)] in aqueous solution and [Cd(NCN)2(SCN)]- in micelles was established, though the complexation in micelles is not extensive. With the Cd(II)-I- system, the formation of [CdI]+, [CdI3]-, and [CdI4]2- was established in aqueous solution together with the formation of [CdI2], [CdI3]-, and [CdI4]2- in micelles. It is revealed that the complexation in micelles is accompanied by relatively large and negative enthalpies, which is ascribed to the enthalpies of transfer of [CdI3]- and [CdI4]2- from aqueous solution to micelles. This suggests that a hydrophobic complex with no capacity to form strong hydrogen bonds in water is favored in micelles.

[Quantitative evaluation of aqueous flare in psoriasis using a laser flare-cell meter].

We evaluated aqueous humor protein concentration in psoriasis using a laser flare-cell meter, which can quantify aqueous flare precisely and objectively. Psoriatic severity was evaluated on the basis of psoriasis area and severity index (PASI) score. Aqueous flare was measured in 40 eyes of 20 psoriasis patients (sixteen psoriasis vulgaris, three guttate psoriasis, and one psoriatic arthritis) and 28 eyes of 14 normal controls. Aqueous flare value was significantly higher in psoriatic patients than in normal controls (p < 0.01). There was no difference between psoriasis vulgaris and the other types of psoriasis. Aqueous flare value was higher in patients with psoriatic history longer than 10 years than in those with less than 10 years (p < 0.05), and also higher in patients with severe psoriasis (PASI score > 10) than in those with mild psoriasis (PASI score < 10) (p < 0.05). But no statistically significant differences in aqueous flare value were found among cyclosporin, etretinate, and psoralen ultra violet A therapies. These findings strongly suggest that patients suffering from psoriasis have slight damage of the blood-aqueous barrier even if they have no ocular symptoms, and that the degree of blood-aqueous barrier damage increases with time and severity of psoriasis.

DNA-ploidy abnormalities are a reflection of the metastatic potential of malignant melanoma. Microfluorometric DNA analysis.

Using DAPI (4',6-diamidino-2-phenylindole)-DNA microfluorometry, we examined the nuclear DNA-ploidy abnormalities of 15 primary malignant melanomas and their 20 corresponding metastases. They all presented the aneuploid DNA histographic pattern. When the DNA index value was calculated as the reflection of DNA-ploidy abnormalities, it was found to be significantly higher in the metastases (2.07 +/- 0.50) than in the primary tumors (1.76 +/- 0.50) (p < 0.01). Sixteen (80%) of the metastatic tumors had a higher DNA index value than their primary tumors, whereas the remaining four (20%) had a lower value. The difference in the DNA index values between the primary and metastatic tumors did not correlate to any other conventional prognostic variables (e.g. histologic type, level, and thickness). When we added 15 non-metastatic melanomas to the above 15 primary melanomas and evaluated the predictors for metastasis using multivariate stepwise logistic regression analysis, the DNA index value of the primary melanomas was found to be the most reliable risk factor. These results suggest that primary melanoma cell populations, having high DNA index values, are usually responsible for subsequent metastasis, and that hence, DNA-ploidy abnormalities of primary melanomas are likely to provide useful information for patient potential with regard to metastasis.

In situ right internal thoracic artery graft via transverse sinus for revascularization of posterolateral wall: early results in 116 cases.

The in situ right internal thoracic artery graft brought through the transverse sinus was used to revascularize the posterolateral wall in 116 patients. Its advantages were assessed retrospectively. The graft was anastomosed to the circumflex marginal branch in 70 patients (60%) or to the posterolateral branch in 41 patients (35%). One patient died (mortality rate 0.9%). Perioperative myocardial infarction occurred outside the territory of the right internal thoracic artery graft in 10 patients, four of whom required mechanical support for hemodynamic deterioration. Postoperative early angiography in 114 patients found the graft to be patent in 97.4%. The ratio of the diameter of the right internal thoracic artery to that of the recipient marginal branch was 0.94 +/- 0.18 (n = 69), and that to the posterolateral branch was 0.88 +/- 0.18 (n = 37) (not significantly different). Results of a postoperative stress test were abnormal in one patient (1/96 tested patients). This retrospective study suggests that the right internal thoracic artery brought through the transverse sinus to revascularize the posterolateral wall provided excellent early patency and good clinical results, even to the most distally located branches. This continues to be our procedure of choice for patients with multivessel coronary disease.