Microsatellite polymorphism of steroid hormone synthesis gene CYP11A1 is associated with advanced prostate cancer

It is widely recognized that androgen biosynthesis and metabolism are associated with the development and progression of prostate cancer. The human CYP11A1 gene (CYP11A1) encodes the P450scc enzyme, which mediates the first step in sex steroid hormone synthesis. The gene contains a (tttta)n-5 bp tandem repeat microsatellite polymorphism located at 528 bp upstream of the translation initiation site and the CYP11A1 mRNA level may be modulated by the polymorphism. Recent studies suggested that the absence of the shortest (tttta)4 allele of the CYP11A1 polymorphism was associated with a risk of polycystic ovary syndrome and with a hyperandrogenic state in polycystic ovary syndrome patients. In our study which included 278 prostate cancer patients, 213 benign prostatic hyperplasia (BPH) patients and 299 male controls, we explored the association between the CYP11A1 polymorphism and prostate cancer on the hypothesis that the presence of the (tttta)4 allele may increase the risk of the development or progression of prostate cancer. In addition, we measured the serum levels of 6 steroid hormones or their metabolite (i.e., testosterone, free-testosterone, estrone, estradiol, dehydroepiandrosterone and androstendione) in 156 control males subjects and compared those with and without the (tttta)4 allele. The polymorphism was evaluated by PCR amplification of a 145-170 bp fragment followed by polyacrylamid gel electrophoresis. The CYP11A1 allele consisted of 4, 6, 7, 8 and 9 (tttta)-5 bp repeats. There was no significant difference in the genotype frequency as for the presence of the (tttta)4 allele between prostate cancer patients and male controls, and between prostate cancer patients and BPH patients. However, there was a significant difference in the genotype frequency in relation to the disease status. Prostate cancer patients without the (tttta)4 allele had an increased risk of metastatic disease (stage D) compared to those with the (tttta)4 allele [adjusted odds ratio (aOR)=1.76, 95% confidence interval (Cl)=1.07-2.90 and p =0.026]. Patients without the (tttta)4 allele had an increased risk of high grade prostate cancer (Gleason score 8 or more, or poorly differentiated cancer) compared to those with the (tttta)4 allele (aOR=1.79, 95% Cl=1.08-2.97 and p =0.025). No significant difference in the serum levels of 6 steroid hormones or their metabolites was found in the presence or absence of the (tttta)4 allele. Our results suggest that the CYP11A1 polymorphism may have a significant influence on the development of advanced and/or high grade prostate cancer and the absence of the CYP11A1 (tttta)4 allele, i.e., the homozygosity for the (tttta)6 or longer allele, could be a useful marker for the prediction of disease progression of prostate cancer.     

A novel combination antimetabolite, TAS-102, exhibits antitumor activity in FU-resistant human cancer cells through a mechanism involving FTD incorporation in DNA

TAS-102 is a new antimetabolite agent composed of a alpha, alpha, alpha-trifluorothymidine (FTD; 1 M) and thymidine phosphorylase inhibitor (TPI; 0.5 M). Here, we investigated the antitumor effect and mechanism of TAS-102 against 5-FU, or FdUrd, resistant human cancer cell lines. The respective tumor growth inhibition rate of orally administered FTD against 5-FU-resistant NUGC-3 was about 70% at a dose level of 200 mg/kg/day; this value was comparable to that against the parental NUGC-3. On the other hand, the tumor inhibition rates of 5-FU, FdUrd, and TS-1 against 5-FU-resistant NUGC-3 were lower than those against parental NUGC-3. Similar observations were made in an FdUrd-resistant human colorectal cancer cell line (DLD-1). TAS-102 was also effective in 5-FU-less sensitive human pancreatic cancer cell lines (PAN-12 and BxPC-3) and human esophagus cancer (T.T.) when compared with 5-FU or UFT. Our hypothesis was that a relatively short and high dosage of TAS-102 results in an additional mechanism of FTD incorporation into DNA other than thymidylate synthase (TS) inhibition. We then examined the effects of FTD on DNA at the cellular level. After treatment with FTD or FdUrd, the DNA fragmentation pattern was examined using filter elution and in situ nick translation. Treatment with FTD for 2 h resulted in marked DNA fragmentation. When the tumor cells were treated with FTD for 72 h or with FdUrd for 2 or 72 h, only a small amount of DNA fragmentation was observed, and the appearance of the tumor cells did not differ markedly from that of untreated cells. Moreover, the DNA fragmentation rate in the TAS-102 treatment group was significantly higher than that in the control group in vivo. These results suggest that when tumor cells are exposed to high concentrations of FTD for short periods of time, FTD manifests its antitumor activity primarily through the induction of DNA fragmentation after FTD incorporation into the DNA. We conclude that TAS-102 is expected to manifest antitumor effects against 5-FU-resistant tumors that are similar to those exerted in 5-FU-sensitive tumors.     

T393C polymorphism of GNAS1 associated with the autonomic nervous system in young, healthy Japanese subjects

1. T393C polymorphism of the gene encoding the Gs-protein alpha-subunit (GNAS1) has been reported recently to be associated with hypertension in which dysfunctions of the autonomic nervous system (ANS) are closely involved. In the present study, the association of this polymorphism with ANS activity was investigated in young, healthy Japanese males. 2. Four hundred and one subjects were genotyped for the T393C polymorphism of GNAS1 by polymerase chain reaction-restriction fragment length polymorphism. Autonomic nervous system activity during supine rest and when standing was assessed in 137 subjects by electrocardiogram R-R interval power spectral analysis. 3. One hundred and fifty-four subjects (38.4%) were homozygous for the T allele (TT), 188 (46.9%) were heterozygous (TC) and 59 (14.7%) were homozygous for the C allele (CC). There were no significant differences as to genotype among the clinical characteristics investigated. In power spectral analysis of heart rate variability, the high-frequency component and parasympathetic nervous system (PNS) index during supine rest were significantly lower in TT and TC carriers than in CC carriers. Furthermore, the increase in heart rate and the responsiveness of sympathetic nervous system index and PNS index to postural change from supine rest to standing were significantly lower in TT and TC carriers than in CC carriers. 4. These observations suggest that the GNAS1 T393C polymorphism is associated with ANS activity in youth, so that it may be useful as a genetic marker for future pathogenesis of hypertension. Follow-up studies are necessary to clarify the prevalence rates of hypertension among 393T allele carriers in the present study.     

Irregularity of photoreceptor layer after successful macular hole surgery prevents visual acuity improvement

PURPOSE: To investigate the association between a photoreceptor irregularity and visual acuity (VA) after macular hole (MH) surgery. DESIGN: Prospective observational case series. METHODS: Twenty-four eyes with an idiopathic MH that resolved after vitreous surgery were examined by new optical coherence tomography (OCT 3000). The images were divided into regular photoreceptor, detected as a straight line above the retinal pigment epithelium reflex, and irregular, which cannot be detected by it. RESULTS: Regular images were observed in 12 eyes (80%) and irregular images in 3 eyes (20%) with good VA (>or=0.7). Regular images were seen in 3 eyes (33%) and irregular images in 6 eyes (67%) with poor VA (<0.7). The percentage of regular images in the group with good VA was significantly higher than that in the group with poor VA (P <.05). CONCLUSION: A photoreceptor irregularity after MH surgery may prevent VA improvement.     

A new technique of fixing a costal coaptation pin after resection of rib segment

The Poly-L-lactide costal coaptation pin is an effective device in chest wall reconstruction. However, fixation is sometimes incomplete, despite the use of the costal coaptation pin. We report here the use of two suture techniques for the fixation of the incised ribs with costal coaptation and discuss the effectiveness of these procedures. We used the Poly-L-lactide costal coaptation pin in 174 cases of posterolateral thoracotomies with two suture methods. In one method the rib was generally fixed with suture only (L-method, n = 30), and in the H-method pairs of holes were made at the end of the incised ribs for ligating with sutures (H-method, n = 144). The effectiveness of each method was evaluated based on the degree of fixation and lateral shift 24 months postoperatively. Lateral shift was none in 114 (79.2%) cases using the H-method and 18 (60.0%) cases using the L-method. Fixation was good in 131 (91.0%) cases using the H-method but in only 20 (66.7%) cases using the L-method. H-method was significantly more effective than the L-method of costal coaptation. The H-method was very effective for fixing incised ribs and is convenient for use by thoracic surgeons.     

A clinicopathological study of resected adenocarcinoma 2 cm or less in diameter

Background

The biological behavior of small adenocarcinoma is different in each patient and these are especially enormous differences when evaluating solid tumors and nonsolid tumors.

Methods

A total of 159 adenocarcinomas 2 cm or less in diameter were studied. Several clinicopathological factors were retrospectively analyzed.

Results

The diameter of the primary tumors was less than 1 cm in 47 patients, 1-1.5 cm in 49 patients, and 1.5-2 cm in 63 patients, respectively. Almost all patients (147) were pathologic N0 and there were 12 node-positive patients (7.5%). Lymph-node involvement was observed in 1 patient with a tumor diameter measuring less than 1 cm and in 11 patients with a tumor diameter measuring 1-2 cm. According to Noguchi' s classification, 33 patients belonged to class A or B, 71 patients belonged to class C, and 55 patients belonged to class D, E, or F. The ratio of ground-glass opacity (GGO) area in the main tumor in high resolution computed tomography was classified into two groups with a threshold of 50%. There were 44 patients with a GGO ratio of equal to or greater than 50%, none of which indicated lymph-node metastasis or tumor recurrence during follow-up (5-year survival = 100%). On the contrary among 115 patients with a GGO ratio less than 50%, lymph-node involvement was indicated in 12 patients (10.4%) and the 5-year survival rate was 83.9%.

Conclusions

The biological malignancy of small adenocarcinomas might be accurately evaluated by the proportion of GGO area as well as the Noguchi classification.     

Gene therapy via blockade of monocyte chemoattractant protein-1 for renal fibrosis

Monocyte chemoattractant protein (MCP)-1, also termed monocyte chemotactic and activating factor (MCAF)/CCL2, plays an important role in progressive organ fibrosis. It was hypothesized that MCP-1, through its cognate receptor, CCR2, regulates the pathogenesis and is therapeutically of importance for renal fibrosis. To achieve this goal, the therapeutic efficacy and efficiency in renal fibrosis induced by a unilateral ureteral obstruction nephropathy model in mice by the blockade of MCP-1/CCR2 signaling was studied. The delivery of N-terminal deletion mutant of the human MCP-1 gene, 7ND, into a skeletal muscle ameliorated renal fibrosis by resulting in decrease in the deposit of type I collagen and in reduced expression of TGF-beta. Concomitantly, gene transfer of 7ND reduced the cell infiltration, most of which were CCR2-positive macrophages, followed by the decrease in MCP-1 expression in the diseased kidneys. These observations suggest that MCP-1 through CCR2 signaling is responsible for Mphi recruitment, which augments downstream events, resulting in renal fibrosis. Moreover, these findings imply that gene therapy against MCP-1/CCR2 signaling via the mutant gene transferred strategy may serve a beneficial therapeutic application for renal fibrosis.     

Guidelines for the treatment of lung cancer with lymph node involvement

Lung cancer with mediastinal lymph node involvement has a poor prognosis, especially when treated with surgery alone. Such cases are considered to be managed best by multimodality treatment. Some randomized trials showed positive results of induction chemotherapy and adjuvant chemotherapy in locally advanced lung cancer, but more evidence is needed to create the standard treatment for stage III lung cancer. A combination of chemotherapy and radiotherapy remain the standard of care for patients with obvious N2 disease, and the role of surgery following induction chemotherapy or chemo-radiotherapy in advanced stage III patients will be evaluated in phase III trials. Enrollment of patients in prospective clinical trials is strongly recommended to clarify unresolved issues in this clinical setting.     

Outcome of the perioperative use of percutaneous cardiopulmonary support for adult cardiac surgery: factors affecting hospital mortality

Percutaneous cardiopulmonary bypass support (PCPS) has become a widespread standard modality for the treatment of circulatory collapse; however, its clinical use for postcardiotomy low cardiac output syndrome (LOS) has been reported to be unsatisfactory. We reviewed the clinical outcomes of twenty-three patients undergoing cardiac surgery and treated with PCPS. Solitary coronary artery grafting was undertaken for nine patients, while three had concomitant procedures. The remaining patients underwent valvular surgery. The indications for PCPS were preoperative shock in two patients and postcardiotomy LOS or shock in twenty-one patients. All patients except one underwent an intraaortic balloon pump. Sixteen of the twenty-three patients (69.6%) were weaned from PCPS and twelve patients (52.2%) reached hospital discharge. A univariate analysis revealed that risk factors for hospital mortality were age older than seventy years (P = 0.05), PCPS running time (P = 0.017), low cardiac function at the institution of PCPS (P = 0.004), and urine output within the initial 24 h (P = 0.041). The cardiac index (CI) in survivors was improved within 24 h, and eleven of the twelve survivors were weaned off PCPS within 48 h, whereas ten of the twelve nonsurvivors required PCPS for more than 48 h (P = 0.0006). There is little possibility of weaning patients from PCPS who do not show any signs of hemodynamic recovery within 48 h after its institution. Limited use of PCPS within 48 h may be applicable for postcardiotomy patients, but other cardiopulmonary support, such as a left ventricular assist device, may be required when hemodynamic recovery is not obtained within 48 h.