Development of a Pediatric Fertility Preservation Program: A Report From the Pediatric Initiative Network of the Oncofertility Consortium

Infertility is known to decrease quality of life among adults. In some cases, infertility is caused by medical conditions and/or treatments prescribed in childhood, and using methods to protect or preserve fertility may expand future reproductive possibilities. Structured programs to offer counseling about infertility risk and fertility preservation options are essential in the care of pediatric patients facing fertility-threatening conditions or treatments, yet multiple barriers to program development exist. This report was developed from the institutional experiences of members of the Pediatric Initiative Network of the Oncofertility Consortium, with the intent of providing guidance for health care providers aiming to establish programs at institutions lacking pediatric fertility preservation services. The mechanics of building a fertility preservation program are discussed, including essential team members, target populations, fertility preservation options (both established and experimental), survivorship issues, research opportunities, and ethical considerations. Common barriers to program development and utilization, including low referral rates and financial concerns, are also discussed, and recommendations made for overcoming such barriers.     

Ischaemic preconditioning of the graft in adult living related right lobe liver transplantation: impact on ischaemia�Creperfusion injury and clinical relevance

Background

Ischaemic preconditioning (IPC) of the right liver graft in the donor has not been studied in adult-to-adult living related liver transplantation (LRLT).

Objective

To assess the IPC effect of the graft on ischaemia reperfusion injury in the recipient and compare recipient and donor outcomes with and without preconditioned grafts.

Patients and methods

Alternate patients were transplanted with right lobe grafts that were (n =22; Group _Precond) or were not (n =22; Group _Control) subjected to IPC in the living donor. Liver ischaemia–reperfusion injury, liver/kidney function, morbidity/mortality rates and outcomes were compared. Univariate and multivariate analyses were performed to identify factors predictive of the aspartate aminotransferase (AST) peak and minimum prothrombin time.

Results

Both groups had similar length of hospital stay, morbidity/mortality, primary non-function and acute rejection rates. Post-operative AST (P =0.8) and alanine aminotransferase (ALT) peaks (P =0.6) were similar in both groups (307 ± 189 and 437 ± 302 vs. 290 ± 146 and 496 ± 343, respectively). In univariate analysis, only pre-operative AST and warm ischemia time (WIT) were significantly associated with post-operative AST peak (in recipients). In multivariate analysis, the graft/recipient weight ratio (P =0.003) and pre-operative bilirubin concentration (P =0.004) were significantly predictive of minimum prothrombin time post-transplantation.

Conclusions

Graft IPC in the living related donor is not associated with any benefit for the recipient or the donor and its clinical value remains uncertain.     

A necrotic skin lesion in a dialysis patient after the initiation of warfarin therapy: a difficult diagnosis

Necrotic skin lesions are unfortunately common in patients with end stage renal disease undergoing dialysis therapy. We present a case of a necrotic skin lesion in a peritoneal dialysis patient shortly after the initiation of warfarin therapy for atrial fibrillation. We discuss and contrast distinguishing features of two diagnostic possibilities: warfarin skin necrosis (WSN) and calcific uremic arteriopathy (CUA) in terms of clinical presentation, risk factors and pathology. Lastly, we outline the importance of establishing a diagnosis as treatment regimens differ substantially.     

The role of secreted frizzled-related protein 2 expression in prostate cancer

O’Hurley G, Perry A S, O’Grady A, Loftus B, Smyth P, O’Leary J J, Sheils O, Fitzpatrick J M, Hewitt S M, Lawler M & Kay E W
(2011) Histopathology  59 , 1240–1248
The role of secreted frizzled‐related protein 2 expression in prostate cancer Aims: Improved prostate cancer (PCa)‐specific biomarkers are urgently required to distinguish between indolent and aggressive disease, in order to avoid overtreatment. In this study, we investigated the prostatic tissue expression of secreted frizzled‐related protein (SFRP)‐2. Methods and results: Following immunohistochemical analysis on PCa tissue microarrays with samples from 216 patients, strong/moderate SFRP‐2 expression was observed in epithelial cells of benign prostatic hyperplasia, and negative/weak SFRP‐2 expression was observed in the majority of tumour epithelia. However, among Gleason grade 5 carcinomas, 40% showed strong/moderate SFRP‐2 expression and 60% showed negative SFRP‐2 expression in epithelial cells. Further microscopic evaluation of Gleason grade 5 tumours revealed different morphological patterns, corresponding with differential SFRP‐2 expression. The first subgroup (referred to as Type A) appeared to have a morphologically solid growth pattern, whereas the second subgroup (referred to as Type B) appeared to have a more diffuse pattern. Furthermore, 100% (4/4) of Type A patients experienced biochemical recurrence, as compared with 0% (0/6) of Type B patients. Conclusions: These results imply: (i) that there is a loss of SFRP‐2 expression from benign to malignant prostate glands; and (ii) differential SFRP‐2 expression among two possible subgroups of Gleason grade 5 tumours.     

A moderately high fat diet promotes salt-sensitive hypertension in obese zucker rats by impairing nitric oxide production

The objective of this research was to examine the contribution of a moderately high fat (MHF) diet to the development of salt-sensitive hypertension in obese Zucker rats. Lean and obese Zucker rats were fed either a MHF diet or a diet of standard rat chow (control diet) for 10 weeks. From week 4 through week 10, the drinking water was supplemented with 1% NaCl. Blood pressure was measured weekly, and urinary excretion of nitric oxide metabolites (NO(x)) was determined at weeks 4 and 10. At week 10, renal nitric oxide synthase (NOS) activity was assessed in kidney homogenates. Blood pressures of obese, but not lean, rats on the MHF fat diet were significantly increased by salt-supplementation, whereas blood pressures of rats on the control diet were not appreciably affected. NO(x) excretion was increased in response to salt-supplementation in rats on the control diet, with the effect being particularly dramatic in obese rats. After salt-supplementation, NO(x) excretion by rats on the MHF diet was lower than rats on the control diet. In obese rats on the MHF diet, this decrease in NO production was accompanied by a reduction in renal NOS activity. These results indicate that obese rats are more inclined than lean rats to develop diet-induced hypertension in response to a moderately high fat, salt-supplemented diet. Furthermore, they suggest that MHF diet-induced defects in NO production may promote the salt-sensitivity of blood pressure in obese Zucker rats, which appear to require more NO to maintain blood pressure during a salt challenge.     

Phase II trial of fenretinide (NSC 374551) in patients with recurrent small cell lung cancer

Background Alterations in retinoid signaling appear to be involved in the pathogenesis of small cell lung cancer (SCLC). Fenretinide [N-(4-hydroxyphenyl)retinamide], a synthetic retinoid, inhibits the growth of SCLC cells in vitro via the induction of apoptosis. Since these data suggested that SCLC is the adult solid tumor that is most susceptible to fenretinide, a trial to evaluate the clinical activity of fenretinide in patients with SCLC was considered the definitive test of its clinical potential in adult oncology. Methods Patients with progressive SCLC after one or two prior chemotherapy regimens and a performance status of 0–2 were eligible for the study. Patients with stable, treated brain metastases were eligible. Fenretinide 900 mg/m² twice daily was administered orally on days 1–7 of each 21-day cycle. Blood and saliva were collected pre-treatment and on day 7 of cycle 1 to measure fenretinide and retinol levels by high-pressure liquid chromatography (HPLC). Results Nineteen patients were enrolled. Fifteen patients had one prior chemotherapy regimen and four patients had two prior regimens. The median time from diagnosis to enrollment was 10 months. A median of two cycles of fenretinide was administered. There were no objective responses, but four of 17 evaluable patients (24%) had stable disease after 2–17 cycles. The median time to treatment failure was 5.7 weeks overall, while the four patients with stable disease demonstrated treatment failure at 11, 13, 19, and 52 weeks. Median survival was 25 weeks, with one patient alive 22 months after the start of treatment. The 1-year survival rate was 29%. Toxicity included mild, reversible visual changes (haziness, altered night vision), grade 1–3 nausea/vomiting, and grade 1–2 diarrhea. The mean day 7 plasma fenretinide level was 2.90 ± 1.66 μg/ml (7.40 ± 4.25 μM; n = 14). The mean pre-treatment and day 7 plasma retinol levels were 0.47 ± 0.16 μg/ml and 0.05 ± 0.07 μg/ml (n = 8), respectively. The mean day 7 salivary fenretinide level was 0.08 ± 0.18 μg/ml, with no correlation between salivary and plasma drug levels. Conclusions Fenretinide is well tolerated in patients with SCLC and stabilization of disease was noted in 24% of patients with this aggressive disease. However, after the first stage of enrollment, the response rate did not meet criteria to proceed with full trial accrual. Plasma concentrations of fenretinide that induce cytotoxicity in vitro in SCLC cell lines are clinically achievable, but there were no objective responses. Non-invasive drug monitoring using saliva underestimates systemic exposure.