Medically and economically appropriate follow-up schedule for prostate cancer patients after radical prostatectomy

BACKGROUND: Our goal was to determine the optimal frequency and method of follow-up after radical prostatectomy to minimize medical cost without adversely affecting patients. METHODS: Two hundred and twenty-one patients who underwent a radical prostatectomy with or without adjuvant androgen deprivation from 1989 to 1999 were selected for the study. Eighty percent of the patients received postoperative androgen deprivation. Tumor recurrence was strictly defined as detectable serum prostate specific antigen (PSA) and/or clinical findings such as local tumor detection or bone metastasis. Thirty of 221 patients experienced tumor recurrence. Risk of tumor recurrence, procedures for detection of recurrence, and PSA doubling time after biochemical failure were analyzed. RESULTS: None of the 30 patients who were examined showed definitive local recurrence or metastatic sites on the imaging study at the time of initial PSA detection, and there were no observed recurrences in the absence of detectable serum PSA. In patients who showed elevated PSA within 12 months after radical prostatectomy, PSA levels rapidly increased with doubling times ranging from 1.2 to 13.7 months. Excluding those patients, the doubling time of PSA levels ranged from 2.8 to 31.5 months. CONCLUSIONS: Prostate specific antigen screening is sufficient to detect treatment failure after radical prostatectomy, irrespective of adjuvant hormone therapy. Based on the calculated doubling time, the longest advisable interval between checks of PSA levels is estimated to be four months within the first year after radical prostatectomy, and biannually or annually thereafter. Continuously elevated PSA levels or clinical symptoms indicate surveys for local recurrences and distant metastases.     

Prevention of Ventricular Arrhythmia and Calcium Dysregulation in a Catecholaminergic Polymorphic Ventricular Tachycardia Mouse Model Carrying Calsequestrin‐2 Mutation

Arrhythmia Prevention in CPVT . Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a familial arrhythmic syndrome caused by mutations in genes encoding the calcium‐regulation proteins cardiac ryanodine receptor (RyR2) or calsequestrin‐2 (CASQ2). Mechanistic studies indicate that CPVT is mediated by diastolic Ca²⁺ overload and increased Ca²⁺ leak through the RyR2 channel, implying that treatment targeting these defects might be efficacious in CPVT. Method and results: CPVT mouse models that lack CASQ2 were treated with Ca²⁺‐channel inhibitors, β‐adrenergic inhibitors, or Mg²⁺. Treatment effects on ventricular arrhythmia, sarcoplasmic reticulum (SR) protein expression and Ca²⁺ transients of isolated myocytes were assessed. Each study agent reduced the frequency of stress‐induced ventricular arrhythmia in mutant mice. The Ca²⁺ channel blocker verapamil was most efficacious and completely prevented arrhythmia in 85% of mice. Verapamil significantly increased the SR Ca²⁺ content in mutant myocytes, diminished diastolic Ca²⁺ overload, increased systolic Ca²⁺ amplitude, and prevented Ca²⁺ oscillations in stressed mutant myocytes. Conclusions: Ca²⁺ channel inhibition by verapamil rectified abnormal calcium handling in CPVT myocytes and prevented ventricular arrhythmias. Verapamil‐induced partial normalization of SR Ca²⁺ content in mutant myocytes implicates CASQ2 as modulator of RyR2 activity, rather than or in addition to, Ca²⁺ buffer protein. Agents such as verapamil that attenuate cardiomyocyte calcium overload are appropriate for assessing clinical efficacy in human CPVT . (J Cardiovasc Electrophysiol, Vol. 22, pp. 316‐324, March 2011)     

SERUM CONCENTRATION OF UNSATURATED THYROXINE-BINDING GLOBULIN IN HYPER- AND HYPOTHYROIDISM

The concentration of serum thyroxine (T4)-binding globulin (TBG) not binding T4 (unsaturated TBG, u-TBG) was determined in hyper- and hypothyroidism. u-TBG was expressed as the product of TBG concentration and the ratio of free TBG capacity to maximal TBG capacity as determined by reverse-flow electrophoresis. u-TBG concentration in normal sera (n = 40) was 15.5 +/- 2.3 mg/l (mean +/- SD), or 257 +/- 38 nmol/l for a molecular weight of TBG of 60 000 daltons. u-TBG levels were significantly lower in hyperthyroidism (7.1 +/- 2.3 mg/l, n = 16, P less than 0.001) and higher in hypothyroidism (21.7 +/- 5.0 mg/l, n = 22, P less than 0.001). Based on partial correlation analysis, u-TBG was inversely correlated to serum T4 (r = -0.586, P less than 0.001), but not correlated to triiodothyronine (T3) (r=-0.180, NS). There was a reciprocal correlation between u-TBG concentration and the T3 uptake value (r = 0.748, P less than 0.001). There was also a reciprocal correlation of u-TBG with both % free T4 (r = 0.425, P less than 0.001) and % free T3 (r = 0.377, P less than 0.001), when the data were subjected to partial correlation analysis. These results provide the values for u-TBG concentration in hyper- and hypothyroidism, and support the concept that the free fractions of serum thyroid hormones may be determined by the number of binding sites of the TBG molecule that are not saturated with T4 in hyper-and hypothyroidism.     

A Novel Missense Mutation Causing a G487R Substitution in the S2–S3 Loop of Human ether‐à‐go‐go‐Related Gene Channel

hERG(G487R) Channel . Introduction: Mutations of human ether‐à‐go‐go‐related gene (hERG), which encodes a cardiac K⁺ channel responsible for the acceleration of the repolarizing phase of an action potential and the prevention of premature action potential regeneration, often cause severe arrhythmic disorders. We found a novel missense mutation of hERG that results in a G487R substitution in the S2–S3 loop of the channel subunit [hERG(G487R)] from a family and determined whether this mutant gene could induce an abnormality in channel function. Methods and Results: We made whole‐cell voltage‐clamp recordings from HEK‐293T cells transfected with wild‐type hERG [hERG(WT)], hERG(G487R), or both. We measured hERG channel‐mediated current as the “tail” of a depolarization‐elicited current. The current density of the tail current and its voltage‐ and time‐dependences were not different among all the cell groups. The time‐courses of deactivation, inactivation, and recovery from inactivation and their voltage‐dependences were not different among all the cell groups. Furthermore, we performed immunocytochemical analysis using an anti‐hERG subunit antibody. The ratio of the immunoreactivity of the plasma membrane to that of the cytoplasm was not different between cells transfected with hERG(WT), hERG(G487R), or both. Conclusion: hERG(G487R) can produce functional channels with normal gating kinetics and cell‐surface expression efficiency with or without the aid of hERG(WT). Therefore, neither the heterozygous nor homozygous inheritance of hERG(G487R) is thought to cause severe cardiac disorders. hERG(G487R) would be a candidate for a rare variant or polymorphism of hERG with an amino acid substitution in the unusual region of the channel subunit. (J Cardiovasc Electrophysiol, Vol. 23, pp. 1246–1253, November 2012)     

Susceptibility of experimental autoimmune hepatitis in transgenic mice overexpressing the c-H-ras gene

Results from a recent study of ours have demonstrated the significant role of the wild-type ras gene in the development of hepatocellular carcinoma in rasH2 mice having prototype human c-H- ras genes. Chronic cell death and regeneration have been considered to work as co-carcinogens with wild-type ras gene overexpression in this model. To elucidate a role of gene overexpression in the occurrence of chronic inflammation, we tried to induce inflammation in the liver of rasH2 mice by immunizing them with the supernatant of a freshly prepared syngenic liver homogenate. Immunization resulted in a dense inflammatory infiltrate in the portal tract and focal necrosis with spots of fatty or foamy degeneration in the transgenic mouse liver; however, these observations were less frequently observed in non-transgenic mouse liver. Monocytes, granulocytes and plasma cell infiltration were observed in the livers of transgenic mice. An immunohistochemical study showed that CD3-positive lymphocytes also infiltrated the liver. The inflammatory infiltrate was still present in the transgenic liver 24 weeks after the last injection, but little infiltrate was observed at the same time in non-transgenic mice. No hepatic tumours could be produced over the 6 months duration of the study and the results are only preliminary. However, these results do suggest that overexpression of wild-type ras is partially responsible for the occurrence of autoimmune chronic hepatitis.     

A comparative study of nucleolar organizer region, proliferating cell nuclear antigen and epidermal growth factor receptor staining in colon tumours

Several studies have reported that proliferating cell nuclear antigen (PCNA), nucleolar organizer regions (NOR) and epidermal growth factor receptor (EGF-R) are cellular proliferation parameters in malignant tumours. However, the correlation of EGF-R with PCNA and NOR has not been reported in colon tumours. To clarify this, we investigated the correlation of the expression of EGF-R with PCNA and NOR in colonic epithelial tumours. Using immunohistochemical staining and one-step silver staining techniques, the expressions of EGF-R-, PCNA- and NOR-associated protein were studied in paraffin sections from five normal mucosae, 10 adenomas with mild atypia, 16 adenomas with moderate atypia, 32 adenomas with severe atypia including carcinoma in situ and 47 with invasive colon carcinomas. Significant differences were found among the respective degrees of atypia in Ag-NOR counts, PCNA labelling index (LI), and the expression of EGF-R. However, there were no significant differences among the Ag-NOR counts of the severe atypia and invasive carcinoma. There was a significant positive correlation between Ag-NOR counts and PCNA LI (P<0.001). The Ag-NOR counts and PCNA LI in EGF-R-positive cases were higher than in EGF-R-negative cases (P<0.001). These results indicate that each of the parameters increased significantly with the increase in atypia and the progression of cancer. Epidermal growth factor receptor provokes an exacerbation of protein synthesis and the cell cycle in colonic epithelial tumours.     

Antibiotic prophylaxis in radical prostatectomy: 1-day versus 4-day treatments

OBJECTIVE: The standard protocol of antibiotic prophylaxis in radical prostatectomy remains to be established. We retrospectively compared the occurrence of perioperative infections following radical prostatectomy between two different protocols of antibiotic prophylaxis. METHODS: This study included 106 cases of radical retropubic prostatectomy managed on the clinical pathways. Two different protocols of antibiotic prophylaxis were used in otherwise identical pathways. Between January and December 2004, 50 patients received a second generation cephem, cefotiam, for 4 days, beginning 30 min before surgery (4-day group), whilst between December 2004 and July 2005, only two doses of cefotiam were given on the day of operation in 56 patients (1-day group). The incidence of surgical site infection (SSI) and remote infection (RI) was retrospectively investigated. RESULTS: Superficial incisional SSI occurred in one (1.8%) patient in the 1-day group, whereas no patient in the 4-day group developed SSI. No RI was observed in either the 1-day or 4-day group. Intravenous antibiotics were administered besides the pathway in a patient in the 1-day group because unexplained fever more than 38 degrees C continued postoperative day (POD) 2 through POD 4 without signs of SSI or RI. Excluding this case, postoperative more than 38 degrees C was rare and transient after POD 2. CONCLUSION: The incidence of SSI and RI was low and not significantly different between the 1-day and 4-day groups. Therefore, the 1-day protocol of prophylactic antibiotic treatment seems adequate for preventing perioperative infections in radical prostatectomy.