Prednisone metabolism in recipients of kidney or liver transplants and in lung recipients receiving ketoconazole

BACKGROUND: Actual prednisone exposure in low-dose prednisone regimens, in part determined by cytochrome P450 metabolism, has been shown to be important for allograft survival. METHODS: Prednisolone (the principal active metabolite of prednisone) metabolism was determined in eight nontransplant patients and in transplant recipients receiving oral prednisone maintenance therapy (20 kidney and 6 liver recipients receiving cyclosporine [CsA] and eight lung recipients receiving ketoconazole and CsA or tacrolimus [FK506]). RESULTS: Prednisolone area under the curve (AUC)-dose-normalized (PNAUCn) to 1 mg/kg was 8,288+/-1,513 ng.hr/mL in kidney recipients, versus 4,826+/-999 ng/mL per hr in healthy subjects (P<0.001); it was also increased in liver recipients versus healthy subjects (11,456+/-1,214 ng.hr/mL, P<0.001). Liver recipients also metabolized prednisolone more slowly than kidney recipients (P<0.001). PNAUCn in lung recipients was similar in kidney recipients despite the effect of ketoconazole to slow CsA metabolism. In kidney transplant recipients, the rate of CsA metabolism was correlated with the rate of prednisolone metabolism (r=0.54, P=.026). Basal cortisol levels in all transplant recipients were lower than in healthy subjects, suggesting more prednisolone exposure in transplant patients. CONCLUSIONS: Prednisolone metabolism is slower in solid-organ transplant recipients than in healthy subjects. The slower metabolism of prednisolone, particularly in liver recipients, may help explain the immunologic effectiveness of low-dose prednisone regimens in these patients.     

Early results of bladder-cancer screening in a high-risk population of heavy smokers

OBJECTIVE

To report first results of an early bladder‐cancer detection programme, and to evaluate the detection rate and the diagnostic value of the tests used.

SUBJECTS AND METHODS

Urine samples of 183 screened subjects with a history of smoking of ≥40 pack‐years were collected for analysis with a urinary dipstick test for haematuria, the nuclear matrix protein‐22 test (BladderChek®, Matritech, Inc., Newton, MA, USA), voided urine cytology and a molecular cytology test (UroVysion, Abbott Molecular Inc., Des Plaines, IL, USA). Participants with at least one positive test result had a further evaluation including cystoscopy and radiological imaging. The subjects’ risk factors, test results and histological findings were analysed.

RESULTS

In all, 75 subjects had at least one positive test result and were evaluated further; abnormal histological findings were detected in 18 (24% of those who had cystoscopy, 9.8% of the original 183), 15 of those in the urinary bladder, with pTaG1 (one), carcinoma in situ (two), dysplastic lesions (11) and one an inverted papilloma. In the upper urinary tract, two urothelial tumours (pTaG1 and pTxN2G3) and one renal cell carcinoma (pT1G2) were detected by computed tomography. In summary, six of 183 subjects (3.3%) had a histologically confirmed malignant tumour and another 12 (6.6%) were identified with a possible pre‐cancerous lesion of the urinary tract. The urinary dipstick, BladderChek, cytology and UroVysion detected (i.e. were true‐positive in) nine (50%), one (6%), seven (39%) and 11 (61%) of the 18 tumours found, while they failed to detect nine (50%), 17 (94%), 11 (61%) and seven (39%) of these lesions, respectively. Omitting the urine dipstick test, the BladderChek, cytology or UroVysion from the test setting could have spared 40, five, two or one subjects(s) from unnecessary invasive interventions; however, three, none, two or six lesions, would have been missed. More positive screening tests per subject was associated with a higher probability of a (pre)‐malignant lesion.

CONCLUSION

Screening a high‐risk group with a history of smoking of ≥40 pack‐years showed a significant proportion (3.3%) with malignancy. These first results are encouraging and warrant continuation of the screening programme. In this series the most efficient screening tool was the combination of UroVysion, cytology and urinary dipstick testing. Of special scientific interest will be the follow‐up of those patients with a possible pre‐cancerous lesion.     

Pathological features of Gleason score 6 prostate cancers in the low and intermediate range of prostate‐specific antigen level: is there a difference?

OBJECTIVE

To assess the pathological features of Gleason score 6 prostate cancers after radical prostatectomy in the low (<4 ng/mL) and intermediate range of prostate‐specific antigen level (4–10 ng/mL), as such prostate cancers are considered to be well differentiated tumours with a low risk for recurrence after therapy.

PATIENTS AND METHODS

In all, 1354 patients with T1c prostate cancer and PSA levels of <10.0 ng/mL had a radical retropubic prostatectomy. Patients with Gleason score 6 tumours were divided into two groups, those with PSA levels of <4 and 4.0–10.0 ng/mL. Extracapsular extension, positive surgical margins, biochemical recurrence (BCR) and mean time to BCR were evaluated.

RESULTS

Of the 1354 patients, there were 437 (32.3%) with Gleason score 6 prostate cancers. Patients in the low PSA group had less extraprostatic disease than those with a higher level (5.9% vs 14.5%) and both groups had an almost equal proportion of positive surgical margins (9.4% vs 11.0%). In the low PSA group there was statistically significantly shorter BCR than in the high PSA group, with a mean time to BCR of 1.7 vs 3.1 years.

CONCLUSIONS

These results show a statistically significantly higher rate of extraprostatic disease and earlier BCR in men with a high than a low PSA level even in Gleason score 6 prostate cancer. As the rate of BCR and extracapsular extension are significantly related to prostate cancer mortality, these findings further support the concept of screening using low PSA levels.     

S-Classification of Sentinel Lymph Node Predicts Axillary Nonsentinel Lymph Node Status in Patients with Breast Cancer

Background One-half of breast cancer patients with positive sentinel lymph node (SN) have no further metastases in the axillary lymph node basin. The aim of the present study was to identify patients with positive SN who are unlikely to have further metastases in the axillary lymph node basin, using a new classification of SN, namely the S-classification. Methods Specimens of positive SN were subjected to a pathological review according to the previously published S-classification. S-stages of positive SN were correlated with the status of further metastases in the axillary lymph node basin after axillary lymph node dissection (ALND). Results Of 117 patients who underwent sentinel lymph node biopsy, 36 (30.8%) had a positive SN and were subjected to level I and II ALND. The occurrence of positive nonsentinel nodes was significantly related to the S-stage of SN. No patient with stage SI had additional metastases in the nonsentinel lymph nodes, while 14.3% of patients with SII stage disease and 60.9 % of patients with SIII disease had other non-SN that were metastatic. Conclusion S-stages of positive SN are highly predictive for axillary nonsentinel node status. Especially patients with SI sentinel node metastases appear to be at low risk for further nonsentinel node metastases.     

The prevalence of peripheral arterial disease and medial arterial calcification in patients with chronic renal failure: requirements for diagnostics

BACKGROUND: Knowledge of the prevalence of peripheral arterial disease (PAD) in patients with chronic renal failure (CRF) is limited because of a lack of uniformity in disease definition and recognition. Furthermore, little is known of the prevalence of medial arterial calcification (MAC) in patients with CRF. Our goal is to study the prevalence of PAD and MAC defined by ankle brachial index (ABI) or toe brachial index (TBI) measurements in a Finnish population of patients with CRF consisting of predialysis and dialysis patients, as well as renal transplant recipients. METHODS: We examined 136 patients with CRF and 59 control subjects. Fifty-nine of the patients with CRF had moderate to severe predialysis CRF, 36 patients were on dialysis treatment, and 41 were renal transplant recipients. Mean age of patients was 51.9 +/- 11.5 years, and 39 patients (29%) had diabetes. ABI and TBI were measured by means of photoplethysmography. The definition of PAD required an ABI value of 0.90 or less, a TBI value of 0.60 or less, or a previous positive lower-extremity angiogram result. ABI values of 1.3 or greater or incompressible arteries at ankle level indicated MAC. The presence of claudication was determined by an interview. RESULTS: Prevalences of PAD on this study were 22.0% in patients with predialysis CRF, 30.6% in patients on dialysis treatment, 14.6% in renal transplant recipients, and 1.7% in the control group (P = 0.001). Prevalences of MAC were 23.7%, 41.7%, 23.1%, and 3.4% (P < 0.001), respectively. Only 9 patients had claudication, and 6 of those patients had PAD. CONCLUSION: Both asymptomatic PAD and MAC are common in patients with CRF. Therefore, we recommend the use of both ABI and TBI measurements in the evaluation of PAD in patients with CRF.     

Gamma Knife surgery for adrenocorticotropic hormone-producing pituitary adenomas after bilateral adrenalectomy

OBJECT: Patients with adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas may require a bilateral adrenalectomy to treat their Cushing's disease. Approximately one third of these patients, however, will experience progressive enlargement of the residual pituitary adenoma, develop hyperpigmentation, and have an elevated level of serum ACTH. These patients with Nelson's syndrome can be treated with Gamma Knife surgery (GKS). METHODS: The prospectively collected University of Virginia Gamma Knife database of patients with pituitary adenomas was reviewed to identify all individuals with Nelson's syndrome who were treated with GKS. Twenty-three patients with a minimum of 6 months of follow up were identified in the database. These patients were assessed for tumor control (that is, lack of tumor growth over time) with neuroimaging studies (median follow-up duration 22 months) and for biochemical normalization of their ACTH levels (median follow-up duration 50 months). Neuroimaging follow-up studies were available for 22 patients, and endocrine follow up was available for 15 patients in whom elevation of ACTH levels was documented prior to GKS. In the 22 patients in whom neuroimaging follow-up studies were available, 12 had a decrease in tumor size, eight had no tumor growth, and two had an increase in tumor volume. Ten of 15 patients with elevated ACTH levels prior to GKS showed a decrease in their ACTH levels at last follow up; three of these 10 patients achieved normal ACTH levels (< 50 pg/ml) and the other five patients with initially elevated values had an increase in ACTH levels. Ten patients were thoroughly evaluated for post-GKS pituitary function; four were found to have new pituitary hormone deficiency and six did not have hypopituitarism after GKS. One patient suffered a permanent third cranial nerve palsy and four patients are now deceased. CONCLUSIONS: Gamma Knife surgery may control the residual pituitary adenoma and decrease ACTH levels in patients with Nelson's syndrome. Delayed hypopituitarism or cranial nerve palsies can occur after GKS. Patients with Nelson's syndrome require continued multidisciplinary follow-up care. Given the difficulties associated with management of Nelson's syndrome, even the modest results of GKS may be helpful for a number of patients.     

Self-reported volume of radical prostatectomies among urologists in the USA

OBJECTIVE: To evaluate the variability in the volume of radical retropubic prostatectomy (RP) performed by urologists in the USA, and the physician characteristics that predict RP volume, as previous studies showed that individual surgeon volume for RP is associated with clinical outcomes. METHODS: In a nationwide, representative survey of 2000 urologists who treat prostate carcinoma in the USA, we asked respondents to indicate a numerical range of RPs they perform each year (none, 1-10, 11-30, and >30, the last which we defined as 'high volume'). We then identified characteristics of the provider and practice associated with a high volume of RPs. Supplementing survey results with other national data, we estimated the proportion of all RPs in the USA performed by 'high-volume' urologists. RESULTS: The survey response rate was 66.1% (1313 urologists) with no differences between the respondents and non-respondents for the measured demographic variables. Among urologists who performed RPs (89.1% of the sample), 37.3% did < or = 10, 46.9% 11-30 and 15.8% >30 RPs/year. Academic and urological oncology fellowship-trained urologists were, respectively, 41% and 27% more likely than private-practice and non-fellowship-trained urologists to have a high volume of RPs. Of all RPs performed yearly in the USA, only an estimated 46.1% were by high-volume urologists. CONCLUSION: A significant proportion of urologists report a RP volume that might be associated with higher rates of cardiac, respiratory, vascular, wound-healing, and genitourinary complications. Further study is needed to characterize the possible relationships between RP volume and tumour recurrence, survival, and long-term erectile dysfunction and incontinence.     

Perforated Diverticulitis with Generalized Peritonitis: Low Stoma Rate Using a “Damage Control Strategy”

Purpose

Optimal surgical management of perforated diverticulitis of the sigmoid colon has yet to be clearly defined. The purpose of this study was to evaluate efficacy of a “Damage Control Strategy” (DCS).

Materials and methods

Patients with perforated diverticulitis of the sigmoid colon complicated by generalized peritonitis (Hinchey III and IV) surgically treated according to a damage control strategy between May 2011 and February 2017 were enrolled in the present multicenter retrospective cohort study. Data were collected at three surgical centers. DCS comprises a two-stage concept: [1] limited resection of the perforated colon segment with oral and aboral blind closure during the emergency procedure and [2] definitive reconstruction at scheduled second laparotomy (anastomosis???loop ileostomy or a Hartmann’s procedure) after 24–48?h.

Results

Fifty-eight patients were included into the analysis [W:M 28:30, median age 70.1 years (30–92)]. Eleven patients (19%) initially presented with fecal peritonitis (Hinchey IV) and 47 patients with purulent peritonitis (Hinchey III). An anastomosis could be created during the second procedure in 48 patients (83%), 14 of those received an additional loop ileostomy. In the remaining ten patients (n?=?17%), an end colostomy was created at second laparotomy. A fecal diversion was performed in five patients to treat anastomotic complications. Thus, altogether, 29 patients (50%) had stoma at the end of the hospital stay. The postoperative mortality was 9% (n?=?5), and median postoperative hospital stay was 18.5 days (3–66). At the end of the follow-up, 44 of 53 surviving patients were stoma free (83%).

Conclusion

The use of the Damage Control strategy leads to a comparatively low stoma rate in patients suffering from perforated diverticulitis with generalized peritonitis.

     

Hyperbaric oxygen therapy improves angiogenesis and bone formation in critical sized diaphyseal defects

Besides the use of autologous bone grafting several osteoconductive and osteoinductive methods have been reported to improve bone healing. However, persistent non‐union occurs in a considerable number of cases and compromised angiogenesis is suspected to impede bone regeneration. Hyperbaric oxygen therapy (HBO) improves angiogenesis. This study evaluates the effects of HBO on bone defects treated with autologous bone grafting in a bone defect model in rabbits. Twenty‐four New‐Zealand White Rabbits were subjected to a unilateral critical sized diaphyseal radius bone defect and treated with autologous cancellous bone transplantation. The study groups were exposed to an additional HBO treatment regimen. Bone regeneration was evaluated radiologically and histologically at 3 and 6 weeks, angiogenesis was assessed by immunohistochemistry at three and six weeks. The additional administration of HBO resulted in a significantly increased new bone formation and angiogenesis compared to the sole treatment with autologous bone grafting. These results were apparent after three and six weeks of treatment. The addition of HBO therapy to autologous bone grafts leads to significantly improved bone regeneration. The increase in angiogenesis observed could play a crucial role for the results observed. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:513–520, 2015.