Clinical Effect of Switching from a Luteinizing Hormone-Releasing Hormone Agonist to an Antagonist in Patients with Castration-Resistant Prostate Cancer and Serum Testosterone Level ≥ 20 ng/dl

Introduction

The efficacy of conversion from a luteinizing hormone-releasing hormone agonist to an antagonist was evaluated prospectively in patients with castration-resistant prostate cancer.

Materials and Methods

From October 2012 to December 2014, 8 cases with a serum testosterone level ≥ 20 ng/dl during following androgen deprivation therapy were enrolled and received degarelix monthly. The primary end-pointgoal was to determine the effective prostate-specific antigen response rate. The secondary end-pointgoal was to assess the proportion of cases with a decrease in serum testosterone level to < 20 ng/ml.

Results

One patient achieved a complete response, with a prostate-specific antigen level of 0.02 ng/ml at the nadirend of the study. The effective response rate was 25.0% (2/8), and the proportion of cases with prostate-specific antigen decline was 62.5% (5/8). In 5/8 cases (5/8, 62.5%), serum testosterone levels declined to < 20 ng/dl.

Conclusion

Switching to a luteinizing hormone-releasing hormone antagonist in patients with testosterone levels ≥ 20 ng/dl may be an option in sequential androgen deprivation therapy for some patients.Key Words: Castration-resistant, Degarelix, Prostatic neoplasms, Luteinizing hormone-releasing hormone, Testosterone     

Prognostic factors in patients with ipsilateral pulmonary metastasis from non-small cell lung cancer.

OBJECTIVE: Pulmonary metastasis of non-small cell lung cancer is classified as an advanced disease stage, with limited indications for surgical treatment. However, the prognosis of patients with pulmonary metastasis of non-small cell lung cancer is better than that of patients with distant metastases. The purpose of the present study was to analyze and detect possible prognostic factors in surgically treated patients with ipsilateral pulmonary metastasis of non-small cell lung cancer. METHODS: Among 1198 patients with non-small cell lung cancer who underwent surgery at Kurashiki Central Hospital (Okayama, Japan) from April 1982 to March 2004, a total of 48 (4.0%) patients with pathologically diagnosed ipsilateral pulmonary metastasis were retrospectively evaluated. The median follow-up time was 20.5 months (range 1-103 months) and 37 patients (77.1%) were completely followed up until their death or more than 5 years after the operation. RESULTS: Among the 48 patients, 31 (64.6%) patients had metastatic nodules in the same lobe as the primary tumor (PM1) and 17 (35.4%) patients had metastatic nodules in different ipsilateral lobes (PM2). There was no significant difference in survival between patients with PM1 and the other patients with pT4-stage IIIB, or between patients with ipsilateral PM2 and the other patients with stage IV. Univariate analysis of postoperative survival stratified according to clinicopathologic factors revealed significant differences for the radicality of resection (complete vs. incomplete), tumor size (0-30 vs. >30mm) and pathological nodal (pN) factor (among pN0, pN1 and pN2-3). Multivariate analysis revealed that tumor size (0-30 vs. >30mm) and pN factor (pN0-1 vs. pN2-3) were independent prognostic factors. CONCLUSIONS: The results of our study suggest that undergoing a complete resection, having a tumor size of 30mm or less and having no mediastinal lymph node metastases were better prognostic factors for surgically treated patients with ipsilateral pulmonary metastasis of non-small cell lung cancer.     

Conjunctival nodules associated with Vogt-Koyanagi-Harada disease

Background To report on conjunctival nodules as an unusual manifestation of Vogt-Koyanagi-Harada disease. Methods A 24-year-old woman presented with a two-month history of bilateral conjunctival injection and gradually decreased vision. Ophthalmological examinations revealed bilateral granulomatous uveitis and bulbar conjunctival nodules, and a biopsy of the conjunctival nodules was performed. Results The biopsy specimens showed noncaseating granulomas. The major components of the infiltrating lymphocytes were CD8-positive T cells. Topical corticosteroid therapy reduced the anterior segment inflammation, and the conjunctival nodules disappeared within a week. Afterwards, the patient demonstrated bilateral retinal detachments, sunset glow fundus and alopecia, and, therefore, was diagnosed to have Vogt-Koyanagi-Harada disease four months after the first symptoms. Conclusions Conjunctival nodules may represent the primary manifestation of Vogt-Koyanagi-Harada disease. Financial disclosure: none.     

Analysis of idiopathic thrombocytopenic purpura patients with antiglycoprotein IIb/IIIa or Ib autoantibodies

We analyzed the immunological characteristics of patients with idiopathic thrombocytopenic purpura (ITP) and antiglycoprotein (GP) IIb/IIIa or GPIb autoantibodies. Among 101 ITP patients, 32 had anti-GPIIb/IIIa and 19 had anti-GPIb autoantibodies. Thrombocytopenia was more severe in patients with anti-GPIb autoantibodies than in patients without these autoantibodies, whereas ITP patients with anti-GPIIb/IIIa autoantibodies did not develop severe thrombocytopenia. Patients with anti-GPIb autoantibodies showed significant increases of platelet-associated IgM and platelet-associated C3 in comparison with patients without the autoantibodies, despite there being no significant difference in the platelet-associated IgG levels. The lymphocyte subsets and the blastogenic response in patients with anti-GPIb autoantibodies were also significantly different from those in the patients without these autoantibodies. Furthermore, severe purpura and a poor response to prednisolone were far more common in the patients with anti-GPIb autoantibodies. Activation of the complement system and/or functional abnormalities of lymphocytes thus appear to be involved in the development of thrombocytopenia in ITP patients with anti-GPIb autoantibodies, and such antibodies may be associated with a particularly severe form of ITP.     

Changes in serum levels of metalloproteinases and their inhibitors by treatment of chronic hepatitis C with interferon

We treated 18 patients with chronic hepatitis C by recombinant interferon-α (6 MIU for 24 weeks). In seven patients, serum aminotransferase levels declined to normal (responders). To evaluate the effect of interferon on matrix metalloproteinases (MMPs) and their inhibitors, namely tissue inhibitors of metalloproteinases (TIMPs), the serum levels of these enzymes were determined by enzyme immunoassay (EIA) using a specific monoclonal antibody. In responders, there was a tendency, but not a significant one, towards either an increase in serum MMP 1 levels or a decrease in serum TIMP 1 levels. In contrast, in nonresponders, both a significant decrease in MMP 1 and MMP 3 and a significant increase in TIMP 1 were observed. The number of cases of either increase in serum MMP levels or decrease in serum TIMP levels was significantly larger in responders than in nonresponders. Furthermore, the ratio of MMP 1 to TIMP 1 significantly increased in responders, suggesting that the balance between matrix formation and degradation in hepatic fibrosis tended to move toward degradation. These data indicate that interferon may exert a beneficial effect on hepatic fibrosis in parallel with improvement of aminotransferase activity.     

Cathepsins B and L Increased during Response of Periodontal Ligament Cells to Mechanical Stress In Vitro

Cathepsin is a typical and well-characterized lysosomal cysteine protease that, under pathological conditions, is involved in tissue destruction. A recent immunocytochemical study demonstrated that cathepsins B (CAB) and L (CAL) were localized in the periodontal ligament (PDL) of the rat molar, and they were expressed in compressed sites during experimental tooth movement. Further, we demonstrated previously that the levels of CAB and CAL in gingival crevicular fluid increased during orthodontic tooth movement. Therefore, CAB and CAL may play important roles in the process of collagen degradation during orthodontic tooth movement, and our in vitro study examined the secretion of CAB and CAL in PDL cells following mechanical stress. PDL cells were subjected to 0.5, 1.0, 2.0, or 3.0 g/cm² of compression force or an increase in surface area by tension force of 0.28%, 0.95%, 1.72%, or 2.50% for 24 hr. For detection of CAB and CAL in conditioned medium, commercially available ELISA kits were used. We found compression and tension significantly increased the secretions of both CAB and CAL in PDL cells, which were exhibited in a time- and force magnitude-dependent manner. The compression-stimulated secretion of CAB was increased approximately 3-fold and that of CAL 4-fold, as compared with the control. Further, tension-stimulated secretion of CAB was increased by 1.5-fold and that of CAL 2-fold compared with the control. When analyzed using a semiquantitative polymerase chain reaction assay, CAB and CAL mRNA were increased in response to both compression and tension forces. These findings demonstrated that mechanical stress (compression and tension forces) causes an increase in secretion of CAB and CAL in PDL cells in vitro.     

Alteration of the Intestinal Environment by Lubiprostone Is Associated with Amelioration of Adenine-Induced CKD

The accumulation of uremic toxins is involved in the progression of CKD. Various uremic toxins are derived from gut microbiota, and an imbalance of gut microbiota or dysbiosis is related to renal failure. However, the pathophysiologic mechanisms underlying the relationship between the gut microbiota and renal failure are still obscure. Using an adenine-induced renal failure mouse model, we evaluated the effects of the ClC-2 chloride channel activator lubiprostone (commonly used for the treatment of constipation) on CKD. Oral administration of lubiprostone (500 µg/kg per day) changed the fecal and intestinal properties in mice with renal failure. Additionally, lubiprostone treatment reduced the elevated BUN and protected against tubulointerstitial damage, renal fibrosis, and inflammation. Gut microbiome analysis of 16S rRNA genes in the renal failure mice showed that lubiprostone treatment altered their microbial composition, especially the recovery of the levels of the Lactobacillaceae family and Prevotella genus, which were significantly reduced in the renal failure mice. Furthermore, capillary electrophoresis–mass spectrometry-based metabolome analysis showed that lubiprostone treatment decreased the plasma level of uremic toxins, such as indoxyl sulfate and hippurate, which are derived from gut microbiota, and a more recently discovered uremic toxin, trans-aconitate. These results suggest that lubiprostone ameliorates the progression of CKD and the accumulation of uremic toxins by improving the gut microbiota and intestinal environment.     

Angiotensin II receptor blocker prevents increased arterial stiffness in patients with essential hypertension.

BACKGROUND: High pulse wave velocity (PWV) is related to cardiovascular risk in essential hypertension (EHT). It is reported that short-term treatment with an angiotensin II receptor blocker (ARB) decreases PWV, as well as blood pressure (BP), and increases the serum adiponectin, known as an adipocytokine, which has an anti-atherosclerotic effect. However, it is not known whether long-term treatment with ARB prevents the increase in PWV independently of the reduction of BP, and whether adiponectin is related to the chronic effect of ARB on PWV. METHODS AND RESULTS: In order to examine the short-term effect of ARB on PWV, 9 subjects with EHT had PWV measured before and after treatment with an ARB for 1 month. The treatment significantly reduced PWV and BP. For evaluation of the long-term effect of ARB therapy, 56 consecutive subjects with EHT who were already taking anti-hypertensive drugs other than an angiotensin-converting enzyme inhibitor had their PWV measured. We divided the EHT subjects into 2 groups: (1) the ARB group (EHT treated with an ARB for at least 6 months) and (2) the control group (EHT treated with anti-hypertensive drugs other than an ARB). Although there was no significant difference between the 2 groups in BP, age or body mass index, the PWV value in the ARB group was significantly lower than that in the control group. Moreover, the serum adiponectin concentration in the ARB group was significantly higher than that in the control group. CONCLUSIONS: Long-term treatment with ARB inhibits the progression of arterial stiffness independent of BP reduction. One of the mechanisms may be related to the increased serum adiponectin concentration after treatment with an ARB.