Mogamulizumab-induced photosensitivity in patients with mycosis fungoides and other T-cell neoplasms.

BACKGROUND: Mogamulizumab (Mog) is a defucosylated, therapeutic monoclonal antibody, targeting CCR4 and was first approved in Japan for the treatment of adult T-cell leukaemia/lymphoma (ATLL), followed by cutaneous T-cell lymphoma and peripheral T-cell lymphoma. OBJECTIVE: To retrospectively investigate development of photosensitivity in patients with mycosis fungoides and other T-cell neoplasms after treatment with Mog. METHODS: We treated seven cutaneous lymphoma patients with Mog. Upon combination treatment with narrow-band UVB, we noticed that four patients developed photosensitivity dermatitis following Mog therapy, including two cases of mycosis fungoides, one case of adult T-cell leukaemia/lymphoma and one case of EB virus-associated T-cell lymphoproliferative disorder. Phototest was performed with UVA and UVB, and immunohistochemical staining for CD4, CD8 and Foxp3 was conducted in both photosensitivity and lymphoma lesions. RESULTS: Phototest revealed that the action spectrum of the photosensitivity was UVB in three cases and both UVB and UVA in one case. Histopathologically, the photosensitive lesions were characterized by a lichenoid tissue reaction with a CD8+ T cell-dominant infiltrate, sharing the feature with chronic actinic dermatitis, an autoreactive photodermatosis with a cytotoxic T-cell response. Foxp3+ regulatory T cells (Tregs) were decreased in the photosensitivity lesions compared with the lymphoma lesions. CONCLUSION: Increased incidence of photosensitivity reaction was observed during Mog treatment. Decreased number of Tregs in the lesional skin suggests that this reaction is possibly induced by autoreactive cytotoxic T cells.

Fibrinolysis in Living Donor Liver Transplantation Recipients Evaluated Using Thromboelastometry: Impact on Mortality.

BACKGROUND: Inadequate hemostasis during living donor liver transplantation (LDLT) is mainly due to coagulopathy but may also include fibrinolysis. The purpose of this study was to determine the incidence of fibrinolysis and assess its relevance to mortality in LDLT. METHODS: The incidence and prognosis of fibrinolysis were retrospectively studied in 76 patients who underwent LDLT between April 2010 and February 2013. Fibrinolysis was evaluated and defined by maximum lysis (ML) >15% within a 60-minute run time using thromboelastometry (ROTEM). RESULTS: Fibrinolysis was observed in 19 of the 76 (25%) patients before the anhepatic (pre-anhepatic) phase and was developed in 24 (32%) patients during and after the anhepatic (post-anhepatic) phase. In these 43 patients who had fibrinolysis, spontaneous recovery occurred in 29 patients (73%) within 3 hours after reperfusion of the liver graft. Recovery with tranexamic acid was noted in 2 patients with fibrinolysis in the post-anhepatic phase. Thrombosis in the portal vein and liver artery was noted in 14 patients, and the incidence was significantly greater in patients with post-anhepatic fibrinolysis than in those with pre-anhepatic fibrinolysis (P = .0017). Fibrinolysis that developed in the pre-anhepatic phase was associated with increased 30-day and 6-month mortalities (P = .0003 and .0026, respectively). CONCLUSIONS: Fibrinolysis existed and developed in a large percentage of patients during LDLT. Thrombosis in the portal vein and hepatic artery was more common in patients with fibrinolysis in the post-anhepatic phase. Fibrinolysis that developed in the pre-anhepatic phase was associated with increased 30-day and 6-month mortalities.

Diastolic dysfunction of the left ventricle is associated with pulmonary edema after renal transplantation.

BACKGROUND: Post-operative pulmonary complications are associated with high mortality and graft loss in renal transplantation recipients. Left ventricular diastolic dysfunction is not uncommon in patients with chronic renal failure, including those with preserved left ventricular systolic function. The purpose of this study was to determine the relationship between left ventricular diastolic dysfunction and incidence of post-operative pulmonary edema in renal transplantation recipients with preserved left ventricular systolic function. METHODS: Pre-operative left ventricular function and incidence of pulmonary edema were retrospectively studied in 209 patients who underwent living-donor renal transplantation between January 2010 and October 2012. Left ventricular systolic and diastolic functions were evaluated by ejection fraction and E/E' ratio, retrospectively, using transthoracic echocardiography. Pulmonary edema was defined by evidence of pulmonary congestion on the chest X-ray together with PaO2 /FiO2 ratio < 300 mmHg. RESULTS: Eleven out of 190 (5.8%) renal transplantation patients with preserved left ventricular systolic function developed post-operative pulmonary edema. Patients with pulmonary edema had a significantly higher geometric mean (95% confidence interval) of E/E' ratio than those without pulmonary edema [17.8 (14.1-22.5) vs. 11.1 (10.6-11.7), P = 0.001]. CONCLUSION: Pre-operative left ventricular diastolic dysfunction correlated with the development of post-operative pulmonary edema in renal transplantation recipients. Meticulous intraoperative volume therapy is important to avoid post-operative pulmonary edema in such patients.

Inhibition of T helper 2 chemokine production by narrowband ultraviolet B in cultured keratinocytes.

BACKGROUND: Narrowband ultraviolet B (NB-UVB) has recently been used for the treatment of various skin disorders. Its effects on the production of cytokines and chemokines by keratinocytes are unknown. OBJECTIVES: To investigate the effect of NB-UVB on production of chemokines and proinflammatory cytokines by keratinocytes in comparison with broadband (BB)-UVB. METHODS: Normal human epidermal keratinocytes (or the human keratinocyte cell line HaCaT in some experiments) at semiconfluency were irradiated with NB-UVB at 10, 100, 500 or 1000 mJ cm(-2) or BB-UVB at 10 or 100 mJ cm(-2). The cultures were maintained in the presence or absence of interferon (IFN)-gamma at 200 U mL(-1). The 72-h culture supernatants were analysed by enzyme-linked immunosorbent assay to quantify T helper (Th)1 chemokines (IFN-inducible protein 10 and monokine induced by IFN-gamma), Th2 chemokines [macrophage-derived chemokine (MDC) and thymus and activation-regulated chemokine (TARC)] and proinflammatory cytokines [interleukin (IL)-1alpha and tumour necrosis factor (TNF)-alpha]. The expression of mRNA for these molecules was simultaneously assessed by reverse transcriptase-polymerase chain reaction. The culture supernatants were also tested for their chemotactic activity for Th1 and Th2 cells. The two UVB sources were compared on the basis of their minimal erythemal doses and clinically used doses. RESULTS: Although both NB-UVB and BB-UVB increased the production of IL-1alpha and TNF-alpha, the augmentative effect of NB-UVB was less than that of BB-UVB. Both wavelength ranges of UVB enhanced or had no effect on Th1 chemokine production, but suppressed the production of Th2 chemokines MDC and TARC. This was confirmed by chemotactic assay, which showed decreased chemotactic activity for Th2 cells by the culture supernatants from NB-UVB-irradiated keratinocytes. CONCLUSIONS: NB-UVB reduces the production of Th2 chemokines without excess production of proinflammatory cytokines, suggesting its therapeutic effectiveness on Th2-mediated skin disorders as well as its relative safety in clinical usage.

Innate immunity mediated by epidermal keratinocytes promotes acquired immunity involving Langerhans cells and T cells in the skin.

Skin is an immunological organ consisting of epidermal cells, i.e. keratinocytes and Langerhans cells (LCs, antigen-presenting dendritic cells), and both innate and acquired immune systems operate upon exposure of the skin to various external microbes or their elements. To explore the relationship between innate and acquired immunities in the skin, we investigated whether Toll-like receptor (TLR) ligation of epidermal cells enhances the ability of LCs to present a specific antigen to T cells in mice. LC-containing epidermal cells were incubated with CpG oligonucleotide (TLR9 ligand) modified with trinitrophenyl hapten, and cultured with hapten-primed CD4(+) T cells. TLR9 ligand was capable of enhancing the hapten-presenting ability of LCs when LC-enriched epidermal cells, but not purified LCs, were used as the LC source, suggesting that bystander keratinocytes play a role in the enhancement of LC function. Cultivation of freshly isolated epidermal cells with CpG promoted the expression of major histocompatibility complex (MHC) class II and CD86 molecules on LCs. CpG enhanced the production of interleukin (IL)-1alpha, granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumour necrosis factor (TNF)-alpha by primarily cultured keratinocytes. The addition of a cocktail of neutralizing antibodies against these cytokines abrogated the CpG-promoted, antigen-presenting ability of LC-enriched epidermal cells. Moreover, the addition of culture supernatants from CpG-stimulated keratinocytes restored the ability of purified LCs. Our study demonstrated that although the direct effect of CpG on LCs is minimal, LC function can be up-regulated indirectly by cytokines released by CpG-stimulated keratinocytes. This also implies that innate immunity evoked by TLR ligation of keratinocytes enhances acquired immunity comprising LCs and T cells.

Purpuric adult T-cell leukaemia/lymphoma: expansion of unusual CD4/CD8 double-negative malignant T cells expressing CCR4 but bearing the cytotoxic molecule granzyme B.

A 78-year-old Japanese woman with adult T-cell leukaemia/lymphoma (ATL) presented with an unusual purpuric and erythematous eruption on the face and trunk. Immunohistochemical and flow cytometric analyses showed that the tumour cells were CD4/CD8 double-negative, and expressed CCR4 T-helper (Th) 2 chemokine receptors. Despite these features, the cells aberrantly produced granzyme B, which is a cytotoxic molecule usually produced by CD8(+) cytotoxic T cells, natural killer cells, or occasionally by Th1 cells. In a purpuric lesion, extravasation of erythrocytes was associated with an infiltrate of these cytotoxic tumour cells. Our case suggests phenotypical and functional heterogeneity of tumour cells in ATL, which may be closely related to the clinical appearance of the skin eruption.

Evidence for polyclonal infection of Epstein-Barr virus in a patient with primary cutaneous anaplastic large cell lymphoma.

We report a case of CD30 + primary cutaneous anaplastic large cell lymphoma. The lymphoma cells were shown to express the Epstein-Barr virus (EBV)-encoded small RNAs by in situ hybridization and to have EBV genomes by PCR, whereas no monoclonal band was detected by Southern blot analysis using the EBV terminal repeat probe. These data suggested polyclonal infection by EBV, which provides evidence that EBV plays little part in the pathogenesis of this tumour even in the infected cases.

Differential response to low temperature of two Delta6 fatty acid desaturases from Mucor circinelloides.

A recently identified Delta6 fatty acid desaturase in Mucor rouxii shows a low sequence homology (approximately 24% at the amino acid level) to that isolated from Mortierella alpina, but is phylogenetically closer to a plant enzyme, suggesting the occurrence of Delta6 desaturase isozymes in Mucorales molds. In the present study, two types of Delta6 desaturases, mcD6-1 ( Mo. alpina type) and mcD6-2 ( M. rouxii type), were cloned from Mucor circinelloides. When the cloned genes were expressed in the yeast Saccharomyces cerevisiae in the presence of a linoleic acid substrate (C18:2Delta9, 12), a newly generated gamma-linolenic acid (C18:3Delta6, 9, 12) was detected in the cells, which confirmed the suspected enzymatic function of the recombinant protein. This is the first report of Delta6 desaturase isozymes present in one organism. Northern analysis demonstrated that the amount of mcD6-2 mRNA was less than half of that of mcD6-1 mRNA in cells grown at 28 degrees C. However, upon cultivation of the cells at 15 degrees C for 0.5-1 h, mcD6-2 mRNA rapidly increased by up to 1.5-fold and then gradually decreased. By contrast, mcD6-1 transcripts levels did not fluctuate significantly for 1 h after the temperature shift, but declined by 75% over the next 2 h. The gamma-linolenic acid content in total fatty acid from M. circinelloides decreased at 28 degrees C, but was maintained at approximately 30% at 15 degrees C. These data suggest that Delta6 desaturase isozymes play physiologically distinct roles in the maintenance of cellular lipids and adaptation to low temperature.

[A case of squamous cell carcinoma that developed on chronic tar dermatosis].

A 79-year-old Japanese man visited our clinic for evaluation of a large tumor on the left wrist and multiple keratotic tumors. He had handled creosote oil, which is a purified product of coal tar production, for 50 years. Physical examinations revealed poikiloderma with multiple hyperkeratotic tumors on the back of his hand and forearm bilaterally, and a cauliflower-like tumor, 80 x 60 x 15 mm in size, on the left wrist. Histopathologically, the large tumor showed a proliferation of atypical squamoid cells with many keratinization foci, indicating well-differentiated squamous cell carcinoma.

The tumor cells (FA-6) established from a pancreatic cancer associated with humoral hypercalcemia of malignancy: a simultaneous production of parathyroid hormone-like activity and transforming growth factor activity.

Human pancreatic cancer cells (FA-6) producing bone resorbing factor were established in culture. A biopsied lymphnode from a patient with pancreatic cancer associated with humoral hypercalcemia of malignancy (HHM) was transplanted to nude mice, and the cells producing high parathyroid hormone (PTH)-like activity were selected by a limited dilution from outgrowth of the xenografts of the tumor grown in nude mice. The conditioned media contained an activity to stimulate the resorption of mouse calvaria in vitro which was indomethacin-insensitive. The conditioned media had both alpha-type and beta-type transforming growth factor (TGF) activity but no interleukin-1 activity. TGF-alpha activity was co-eluted with PTH-like activity from gel-chromatography at around 15 kDa. The FA-6 cells now established are the first cells of pancreatic cancer associated with HHM producing both PTH-like and TGF-alpha activities along with bone resorbing activity.

Promotion of calcification by imidazole and its suppression by diltiazem in the growth cartilage of rats with HEBP induced rickets.

The object of our experiments was to determine the effect of imidazole on the growth cartilage of rats with HEBP induced rickets. When HEBP (1-hydroxyethylidene-1, 1-bisphophonic acid) was given to young rats in large doses over a short period, rickets was consistently produced. We found that imidazole had a calcification promoting action in the growth plate cartilage where there had been an increase in thickness due to the inhibition of calcification. In an attempt to clarify the mechanism of accelerated calcification due to imidazole, the effects of diltiazem, a calcium antagonist, were observed; it was found to suppress the accelerated calcification. If diltiazem inhibits the entry of calcium ions into the cells of the growth cartilage, as it does in smooth muscle and myocardial cells, then our results indicate that intracellular concentrations of calcium may play an important role in the accelerated calcification due to imidazole.