Unique natural history of an EGFR mutated adenocarcinoma.

BACKGROUND: Supportive care alone cannot be indicated for cancers for which established standard therapy exists unless there is a specific reason. Due to the refusal of standard therapy by the patient after proper explanation of the therapy, we experienced a long-term follow-up of >10 years with supportive care alone in an epidermal growth factor receptor (EGFR) mutated lung cancer patient. CASE: A 70-year-old woman was referred due to the right lung with some ground glass opacities (GGOs). One of the GGOs which was resected in another hospital had been confirmed to be EGFR mutation-positive lung adenocarcinoma. Although EGFR-tyrosine kinase inhibitor (TKI) was explained to be the standard therapy, the patient refused receiving the therapy and wished to follow up imaging of the remaining GGOs. During the follow-up period of 13 years, the each GGO showed a gradual increase. The doubling time of the largest GGO and that of serum carcinoembryonic antigen was > 2,000 days, respectively. CONCLUSION: Although very rare, some of EGFR mutated lung adenocarcinoma might have a very slow progression. Clinical course of this patient provides useful information to the clinical practice of future patients who may have similar clinical courses.

Late-onset pulmonary and cardiac toxicities in a patient treated with immune checkpoint inhibitor monotherapy.

BACKGROUND: Immune checkpoint inhibitors (ICPIs) can cause immune-related adverse events (irAEs) in organs throughout the body. Of the irAEs, ICPI-induced interstitial lung disease (ILD) is the most notable one that can be life-threatening. No less than that, ICPI-induced cardiac irAEs are serious ones and are recently attracting attention. IrAEs usually develop within a few months after the initiation of ICPI treatment, but some of them occur after a long period of time from the start of treatment. CASE: A 60-year-old male patient with squamous cell carcinoma developed ICPI-induced ILD more than 2 years after the initiation of ICPI therapy. A few months after the ICPI-induced ILD improved, he developed heart failure, which was presumed to be caused by impaired cardiac ejection. Both irAEs improved without administration of corticosteroids. CONCLUSION: Although rare, these irAEs may appear even after a long period of time from the start of administration, and chest physicians should be careful of late-onset irAEs.

A mutein of human basic fibroblast growth factor TGP-580 accelerates colonic ulcer healing by stimulating angiogenesis in the ulcer bed in rats.

Previously, we reported that TGP-580, a mutein of human basic fibroblast growth factor (bFGF), accelerated the healing of gastric and duodenal ulcers in rats. In the present study, we examined the effect of TGP-580 on the healing of colonic ulcers. In male Sprague Dawley rats, ulcers were induced in the colon 6 cm from the anus by enema of 50 µl of 3% N-ethylmaleimide, a sulfhydryl alkylator. The lesions were examined under a dissecting microscope (x10). The concentration of bFGF in the ulcerated colon was measured by enzyme immunoassay, and both the distribution of bFGF and the density of microvessels in the ulcer bed were examined by immunohistochemical staining. The content of bFGF in the ulcerated colon was markedly increased associated with ulcer healing, and ulcer healing was significantly delayed by intravenous administration of a monoclonal antibody for bFGF (MAb 3H3) once daily for 10 days. In the ulcer bed, many cells such as fibroblasts, vascular endothelial cells and macrophages were positively stained with bFGF antiserum. TGP-580, human bFGF or dexamethasone was given intracolonally twice daily for 10 days, starting the day after ulcer induction. TGP-580 (0.2 - 20 µg/ml, 200 µl/rat) dose-dependently accelerated ulcer healing, and its effect was more than 10 times stronger than that of human bFGF. Density (µm/0.01 mm(2)) of microvessels in the ulcer bed was significantly increased by treatment with TGP-580, and there was a good correlation between the density of microvessels and the decrease of ulcerated area (R(2) = 0.633). On the other hand dexamethasone (20 µg/ml) inhibited angiogenesis in the ulcer bed and delayed ulcer healing. These results suggest that angiogenesis in the ulcer bed plays an important role in ulcer healing, and that bFGF mutein TGP-580 accelerated colonic ulcer healing, at least in part, by stimulating angiogenesis, whereas glucocorticoids may delay the healing by inhibiting angiogenesis.

Relationship between the Peripheral Lymphocyte Response to Mycophenolic Acid in vitro and the Level of ATP in Peripheral CD4+ Lymphocytes before and after Renal Transplantation.

OBJECTIVE: The lymphocyte immunosuppressant sensitivity test has been used to predict the pharmacodynamics of immunosuppressive drugs for the purpose of preventing acute rejection and infection after renal transplantation. On the other hand, measuring the ATP levels in peripheral CD4+ lymphocytes is also able to monitor the risks of rejection and infection in transplant recipients. In the present study, we examined the relationship between the mycophenolic acid pharmacodynamics and the ATP levels in peripheral lymphocytes before and after renal transplantation. METHODS: We examined both the pharmacological efficacy of mycophenolic acid and the lymphocyte ATP levels before and 2, 4 and 6 weeks after the operation in 20 renal transplant recipients. The drug's pharmacological efficacy was evaluated by the 50% inhibitory concentration of the drug against the in vitro proliferation of peripheral blood lymphocytes activated by T cell mitogen. The ATP levels in peripheral CD4+ lymphocytes were measured by the Immuknow assay kit. The relationships between the mycophenolic acid pharmacodynamics and ATP levels in peripheral lymphocytes were examined in these recipients. RESULTS: The immunosuppressive effects of mycophenolic acid against mitogen-activated lymphocyte proliferation were significantly and positively correlated with the lymphocyte ATP levels, but only at 6 weeks after transplantation. The relationship was not significant before or at 2 or 4 weeks after the operation. CONCLUSION: Our present data raised the possibility that evaluating the pharmacological efficacy of mycophenolic acid pre-transplantation and monitoring the ATP level 6 weeks after transplantation can predict the risk of rejection and/or infection in renal transplant recipients.

Comparison of renal biomarkers with glomerular filtration rate in susceptibility to the detection of gentamicin-induced acute kidney injury in dogs.

Fourteen renal biomarkers were compared with measurement of glomerular filtration rate (GFR) in detecting acute kidney injury (AKI) in beagle dogs given gentamicin (40 mg/kg/day by subcutaneous injection) for 7 consecutive days. Serum and urinary biomarkers were measured before administration of gentamicin and then on days 4 and 8 after starting administration. GFR was derived by use of a simplified equation. Increased urinary cystatin C and decreased GFR occurred from day 4 and were detected before increases in blood urea nitrogen (BUN) and serum creatinine concentrations and changes in other urinary parameters. The closest correlation was between urinary cystatin C and GFR. At termination, microscopical examination revealed extensive necrosis of proximal tubular epithelium with hyaline casts in the kidney of treated dogs. These data indicate that urinary cystatin C is the most sensitive index of kidney injury and GFR reflects the kidney functional mass.

Nitrate-dependent ferrous iron oxidation by anaerobic ammonium oxidation (anammox) bacteria.

We examined nitrate-dependent Fe(2+) oxidation mediated by anaerobic ammonium oxidation (anammox) bacteria. Enrichment cultures of "Candidatus Brocadia sinica" anaerobically oxidized Fe(2+) and reduced NO3(-) to nitrogen gas at rates of 3.7 ± 0.2 and 1.3 ± 0.1 (mean ± standard deviation [SD]) nmol mg protein(-1) min(-1), respectively (37°C and pH 7.3). This nitrate reduction rate is an order of magnitude lower than the anammox activity of "Ca. Brocadia sinica" (10 to 75 nmol NH4(+) mg protein(-1) min(-1)). A (15)N tracer experiment demonstrated that coupling of nitrate-dependent Fe(2+) oxidation and the anammox reaction was responsible for producing nitrogen gas from NO3(-) by "Ca. Brocadia sinica." The activities of nitrate-dependent Fe(2+) oxidation were dependent on temperature and pH, and the highest activities were seen at temperatures of 30 to 45°C and pHs ranging from 5.9 to 9.8. The mean half-saturation constant for NO3(-) ± SD of "Ca. Brocadia sinica" was determined to be 51 ± 21 µM. Nitrate-dependent Fe(2+) oxidation was further demonstrated by another anammox bacterium, "Candidatus Scalindua sp.," whose rates of Fe(2+) oxidation and NO3(-) reduction were 4.7 ± 0.59 and 1.45 ± 0.05 nmol mg protein(-1) min(-1), respectively (20°C and pH 7.3). Co-occurrence of nitrate-dependent Fe(2+) oxidation and the anammox reaction decreased the molar ratios of consumed NO2(-) to consumed NH4(+) (ΔNO2(-)/ΔNH4(+)) and produced NO3(-) to consumed NH4(+) (ΔNO3(-)/ΔNH4(+)). These reactions are preferable to the application of anammox processes for wastewater treatment.

Quantitation of human herpesvirus-6 (HHV-6) DNA in a cord blood transplant recipient with chromosomal integration of HHV-6.

Chromosomal integration of the human herpesvirus-6 (HHV-6) genome (CIHHV-6) is an important consideration if HHV-6 DNA is detected during the course of transplantation. A 4-year-old girl with refractory anemia with excess blasts type-2 was diagnosed with CIHHV-6 before a cord blood transplantation. HHV-6 DNA was serially quantitated by polymerase chain reaction assay in the transplant period. The possibility of HHV-6 reactivation in a transplant recipient with CIHHV-6 was suspected in our case.

Individual differences in prothrombin time-international normalized ratio variation following coadministration of the anticancer agents S-1 and warfarin: 3 case reports.

OBJECTIVE: We report three cases of elevated prothrombin time-international normalized ratios (PT-INR) following the initiation of coadministration of warfarin and S-1, a preparation containing tegafur (FT), gimeracil (CDHP), and oteracil potassium (Oxo). CASE SUMMARIES: The three cases included 2 men and 1 woman aged 79, 71, and 54 y, respectively. PT-INRs were in the range of 2.0 - 3.0 before therapy but were elevated to values in the range of 3.79 - 4.92 within 8 - 17 days after initiating the coadministration of warfarin (1.5 - 3.5 mg/d) and S-1 (80 - 120 mg/d). When the drug interactions in Cases 1 - 3 were evaluated using the Drug Interaction Probability Scale, each of these cases was assessed as "probable". DISCUSSION: The drug interaction between warfarin and S-1 presumably leads to elevated PT-INR because the 5-fluorouracil (5-FU), which is metabolite of FT in S-1, inhibits the metabolic processing of S-warfarin by cytochrome P450 (CYP) 2C9. However, individual differences in the metabolic production of 5-FU from FT because of genetic polymorphisms in CYP2A6 and individual variation in the levels of renal function may lead to complications when 5-FU is coadministered with warfarin as compared to when 5-FU is administered alone. CONCLUSION: It is essential that the dosage level of warfarin is appropriately adjusted by frequent PT-INR measurements when warfarin and S-1 are coadministered.

Histone acetylation by CBP and p300 at double-strand break sites facilitates SWI/SNF chromatin remodeling and the recruitment of non-homologous end joining factors.

Non-homologous end joining (NHEJ) is a major repair pathway for DNA double-strand breaks (DSBs) generated by ionizing radiation (IR) and anti-cancer drugs. Therefore, inhibiting the activity of proteins involved in this pathway is a promising way of sensitizing cancer cells to both radiotherapy and chemotherapy. In this study, we developed an assay for evaluating NHEJ activity against DSBs in chromosomal DNA in human cells to identify the chromatin modification/remodeling proteins involved in NHEJ. We showed that ablating the activity of the homologous histone acetyltransferases, CBP and p300, using inhibitors or small interfering RNAs-suppressed NHEJ. Ablation of CBP or p300 impaired IR-induced DSB repair and sensitized lung cancer cells to IR and the anti-cancer drug, etoposide, which induces DSBs that are repaired by NHEJ. The CBP/p300 proteins were recruited to sites of DSBs and their ablation suppressed acetylation of lysine 18 within histone H3, and lysines 5, 8, 12, and 16 within histone H4, at the DSB sites. This then suppressed the recruitment of KU70 and KU80, both key proteins for NHEJ, to the DSB sites. Ablation of CBP/p300 also impaired the recruitment of BRM, a catalytic subunit of the SWI/SNF complex involved in chromatin remodeling at DSB sites. These results indicate that CBP and p300 function as histone H3 and H4 acetyltransferases at DSB sites in NHEJ and facilitate chromatin relaxation. Therefore, inhibition CBP and p300 activity may sensitize cancer cells to radiotherapy and chemotherapy.

Induction of insulin-like growth factor-I by interleukin-17F in bronchial epithelial cells.

BACKGROUND: Increased expression of IL-17F has been noted in the airway of asthmatic patients, but its role in asthma has not been fully elucidated. Insulin-like growth FACTOR-I (IGF-I) is known to be involved in airway remodelling and inflammation, while its regulatory mechanisms remain to be defined. OBJECTIVE: To further clarify the biological function of IL-17F, we investigated whether IL-17F is able to regulate the expression of IGF-I in bronchial epithelial cells. METHODS: Bronchial epithelial cells were stimulated with IL-17F in the presence or absence of T-helper type 2 cytokines. Various kinase inhibitors were added to the culture to identify the key signalling events leading to the expression of IGF-I, in conjunction with the use of short interfering RNAs (siRNAs) targeting mitogen- and stress-activated protein kinase (MSK) 1, p90 ribosomal S6 kinase (p90RSK), and cyclic AMP response element-binding protein (CREB). RESULTS: IL-17F significantly induced IGF-I gene and protein expression, and co-stimulation with IL-4 and IL-13 augmented its production. MAP kinase kinase (MEK) inhibitors and the Raf1 kinase inhibitor significantly inhibited IGF-I production, and the combination of PD98059 and Raf1 kinase inhibitor showed further inhibition. Overexpression of Raf1 and Ras dominant-negative mutants inhibited its expression. MSK1 inhibitors significantly blocked IL17F-induced IGF-I expression. Moreover, transfection of the siRNAs targeting MSK1, p90RSK, and CREB blocked its expression. CONCLUSIONS: In bronchial epithelial cells, IL-17F is able to induce the expression of IGF-I via the Raf1-MEK1/2-ERK1/2-MSK1/p90RSK-CREB pathway in vitro.

Transmission of chromosomally integrated human herpesvirsus 6 (HHV-6) variant A from a parent to children leading to misdiagnosis of active HHV-6 infection.

Only a handful of cases of chromosomally integrated human herpesvirus 6 (CI-HHV-6) have been reported, suggesting that this phenomenon is rare. We here present a familial case of HHV-6 variant A (HHV-6A) transmission through a generation, which was identified in the setting of allogeneic hematopoietic stem cell transplantation (HSCT). A 31-year-old man with myelodysplastic syndrome underwent allogeneic HSCT from a human leukocyte antigen-identical sibling, and was found to be continuously yielding high copy numbers of HHV-6A DNA in plasma evaluated by real-time polymerase chain reaction (PCR). Antiviral therapy with ganciclovir or foscarnet failed to decrease the copy numbers. HHV-6A DNA was detected in the patient's buccal mucosa and hair follicles, and was also detected in the plasma, whole blood, and buccal mucosa of the patient's father and 2 siblings, but not in his mother. The sequences of HHV-6A DNA isolated from all family members were identical. Since monitoring of HHV-6 by PCR has been widely introduced to the field of HSCT, transplant physicians should be aware of such an alternative form of HHV-6 transmission, particularly when HHV-6A is detected.

[Infective endocarditis with acute embolism to the lower extremity artery caused by a vegetation: report of a case].

Successful surgical treatment of a case of infective endocarditis with embolism to a lower extremity artery is reported. A 71-year-old man was referred to our hospital for the treatment of infective endocarditis. Echocardiography showed a vegetation on the non-coronary cusp of the aortic valve measuring 19 mm in diameter. We planned surgical treatment, including aortic valve replacement, however, embolism of a lower extremity artery by the vegetation occurred during the waiting period for the operation. We removed the offending vegetation from the popliteal artery and replaced the peccant aortic valve with a prosthetic valve in separate operations. The postoperative course was uneventful and the patient was transferred to another hospital on the 33rd day after the valve replacement surgery.

[Surgical removal of native aortic valve thrombosis associated with acute myocardial infarction and protein C deficiency; report of a case].

Native aortic valve thrombosis is an uncommon event. We describe the case of a 76-year-old man who suffered acute myocardial infarction associated with native aortic valve thrombosis diagnosed by cardiac catheterization. Since the thrombus was localized on the right coronary cusp and occluded right coronary artery, rescue revascularization was performed using perfusion catheter, which was continuously engaged to the right coronary artery. Operation was immediately performed under cardiopulmonary bypass. After incision of ascending aorta, thrombus was removed easily and aortic valve was preserved without degenerative change. Histological study showed a typical thrombus without any specific findings. He had a good clinical course and discharged 9 days after the operation. He had no history of heart valve disease, left heart catheterization or bacterial endocarditis. Since laboratory data showed 41% in protein C antigen and 32% of protein C activity, he was diagnosed of protein C deficiency. Our report emphasize that this thrombus formation may be caused by protein C deficiency.

Do Recent Advances in MR Technologies Contribute to Better Gamma Knife Radiosurgery Treatment Results for Brain Metastases?

The detection of intracerebral lesions has improved greatly with advancements in MR imaging, especially the greater sensitivity of the 1.5 Tesla unit versus the older 1.0 Tesla unit. We aimed to determine whether improvements in MR imaging have actually improved diagnostic capabilities and treatment outcomes in gamma knife radiosurgery (GKRS) for brain metastases (METs). Ours was a retrospective study of a consecutive series of 1179 patients (441 females, 738 males, mean age: 63 years, range: 19-92 years) with brain METs who underwent GKRS from 1998 to 2004. Our treatment policy was to irradiate all lesions visible on MR images during a single GKRS session. Mean and median tumor numbers were seven and three (range; 1-74). The 1179 patients were divided into two groups: a 1.0 T-group of 660 patients examined using a 1.0 Tesla MR unit before August,2002, and a 1.5 T-group of 519 examined using a 1.5 Tesla MR unit after September 2002. In the 1.5 T-group, lesion volumes as small as 0.004 cc were detected with a 5 mm slice thickness. The corresponding lesion size was 0.013 cc in the 1.0 T-group. One or more lesions invisible on a 5 mm slice study were additionally detected on a 2 mm slice study in 47.8% of patients in the 1.0 T-group and 25.2% in the 1.5 T-group (p<.0001). The median survival time (MST) in the 1.5 T-group was significantly longer than that in the 1.0 T-group (8.4 vs. 6.3 months, p=.0004). Due to biases in patient numbers between the two groups, we analyzed subgroups with KPS of 80% or better, no neurological deficits, stable primary tumors, lung cancer, tumor numbers of four or less and tumor volumes of 10.0 cc or smaller. In every subgroup analysis, the MSTs of the 1.5-Tesla group were significantly longer than those of the 1.0-Tesla group. The prognosis of a cancer patient is undoubtedly influenced by multiple factors. Nevertheless, we conclude that application of the 1.5 Tesla MR unit has had a favorable impact on diagnosis and GKRS treatment results in patients with brain METs.

Lafutidine can improve the quality of gastric ulcer healing in humans: a randomized, controlled, multicenter trial.

Improving the quality of ulcer healing (QOUH) is one of the valid methods of prevention of relapse of gastric ulcers. We investigated the effect of lafutidine on the QOUH of gastric ulcer compared with famotidine in a randomized, multi-centre controlled trial. Consecutive 80 patients with a gastric ulcer were randomly assigned to receive twice daily either lafutidine (10 mg) or famotidine (20 mg) for 12 weeks. Esophagogastroduodenoscopy was performed to examine the ulcer healing rate and rate of flat type ulcer scars using dye-contrast. The gastric ulcer healing rate was 92.1% in the lafutidine group (35/38) and 94.7% in the famotidine group (36/38). The rate of flat-type ulcer scars was significantly higher in the lafutidine group (68.4%, 26/38) than in the famotidine group (42.1%, 16/38) (P = 0.021). In conclusion, the present study demonstrated that lafutidine, as compared to famotidine, yields a significantly superior QOUH in patients with gastric ulcers in the clinical setting.

Increased levels of KL-6 and subsequent mortality in patients with interstitial lung diseases.

OBJECTIVES: KL-6 is a specific marker in patients with interstitial lung diseases (ILDs); however, the relationship between elevated levels of KL-6 and subsequent mortality is not well defined. To determine if elevated serum levels of KL-6 are associated with increased mortality, and to identify the most suitable cut-off level of KL-6 by which to distinguish between good prognosis and poor prognosis, we evaluated the prognostic significance of serum KL-6 levels in patients with stable-state ILDs. METHODS: Two hundred and nineteen patients diagnosed with ILDs (152 with idiopathic interstitial pneumonia and 67 with collagen disease-associated pulmonary fibrosis) at Tsukuba University Hospital from April 1999 to October 2005 were entered in this study. Serum KL-6 levels in patients with ILDs were measured with a commercially available enzyme immunoassay kit, and these patients were then followed up. RESULTS: During the follow-up period, 58 of the 219 patients died of respiratory failure. Patients who died during this period had higher levels of KL-6 than did those who did not (P = 0.0004). The receiver operating characteristic curve analysis showed 1000 U mL(-1) as the most suitable cut-off level by which to distinguish between the two groups of patients. The 95% specificity serum KL-6 level with poor outcome was 2750 U mL(-1). In univariate and multivariate analysis, elevated serum KL-6 (>1000 U mL(-1)) in the stable state indicated poor prognosis (P = 0.0005, log-rank test; P = 0.0001, Cox proportional hazard model). CONCLUSIONS: Elevated KL-6 level may provide simple, yet valuable information by which to identify patients with ILDs who are at increased risk for subsequent mortality.