Jessica C. Lloyd

Effect of intermittent fasting on prostate cancer tumor growth in a mouse model

Caloric restriction (CR) has been shown to have anti-cancer properties. However, CR may be difficult to apply in humans secondary to compliance and potentially deleterious effects. An alternative is intermittent CR, or in the extreme case intermittent fasting (IF). In a previous small pilot study, we found 2 days per week of IF with ad libitum feeding on the other days resulted in trends toward prolonged survival of mice bearing prostate cancer xenografts. We sought to confirm these findings in a larger study. A total of 100 (7- to 8-week-old) male severe combined immunodeficiency mice were injected subcutaneously with 1 × 105 LAPC-4 prostate cancer cells. Mice were randomized to either ad libitum Western Diet (44% carbohydrates, 40% fat and 16% protein) or ad libitum Western Diet with twice-weekly 24 h fasts (IF). Tumor volumes and mouse bodyweights were measured twice weekly. Mice were killed when tumor volumes reached 1000 mm3. Serum and tumor were collected for analysis of the insulin/insulin-like growth factor 1 (IGF-1) hormonal axis. Overall, there was no difference in mouse survival (P=0.37) or tumor volumes (P⩾0.10) between groups. Mouse body weights were similar between arms (P=0.84). IF mice had significantly higher serum IGF-1 levels and IGF-1/IGFBP-3 ratios at killing (P<0.001). However, no difference was observed in serum insulin, IGFBP-3 or tumor phospho-Akt levels (P⩾0.39). IF did not improve mouse survival nor did it delay prostate tumor growth. This may be secondary to metabolic adaptations to the 24 h fasting periods. Future studies are required to optimize CR for application in humans.

Variation in definitions of urinary tract infections in spina bifida patients: a systematic review.

OBJECTIVE: Urinary tract infections (UTIs) are a common source of morbidity among children with spina bifida (SB) and are a frequently reported outcome in studies of this patient population. However, the criteria for a diagnosis of UTI are often not stated. We evaluated the literature on SB patients for the criteria that authors use to define parameters in reporting UTI outcomes. METHODS: Embase and Medline were queried with the medical subject heading terms “spinal dysraphism,” “myelomeningocele,” “infection,” and “urinary tract infection.” A second search with the exploded term “spina bifida” and “urinary tract infection” was performed. Original research studies reporting a UTI outcome in SB patients were included and evaluated by 2 independent reviewers for the presence of a UTI definition and diagnostic criteria. RESULTS: We identified 872 publications, of which 124 met inclusion criteria. Forty-five of 124 (36.3%) studies reporting UTI as an outcome provided a definition of UTI. Of 124 studies, 28 (22.6%) were published in pediatric journals and 69 (55.6%) in urology journals. A definition of UTI was provided in 11 (39.3%) and 26 (37.7%) studies, respectively. “Fever, culture, and symptoms” defined a UTI in 17 of 45 studies. Journal category and presence of UTI definitions did not correlate (P = .71). CONCLUSIONS: Explicit definitions for UTI are heterogeneous and infrequently applied in studies of SB patients, limiting study reliability and estimates of true UTI rates in this population. Future studies will benefit from the development and application of a standard definition for UTI in this population.

Low-Carbohydrate Diets and Prostate Cancer: How Low Is "Low Enough"?

Previous studies indicate that carbohydrate intake influences prostate cancer biology, as mice fed a no-carbohydrate ketogenic diet (NCKD) had significantly smaller xenograft tumors and longer survival than mice fed a Western diet. As it is nearly impossible for humans to consume and maintain NCKD, we determined whether diets containing 10% or 20% carbohydrate kcal showed similar tumor growth as NCKD. A total of 150 male severe combined immunodeficient mice were fed a Western diet ad libitum, injected with the human prostate cancer cell line LAPC-4, and then randomized 2 weeks later to one of three arms: NCKD, 10% carbohydrate, or 20% carbohydrate diets. Ten mice not injected were fed an ad libitum low-fat diet (12% fat kcal) serving as the reference in a modified-paired feeding protocol. Mice were sacrificed when tumors reached 1,000 mm3. Despite consuming extra calories, all mice receiving low-carbohydrate diets were significantly lighter than those receiving a low-fat diet (P < 0.04). Among the low-carbohydrate arms, NCKD-fed mice were significantly lighter than the 10% or 20% carbohydrate groups (P < 0.05). Tumors were significantly larger in the 10% carbohydrate group on days 52 and 59 (P < 0.05), but at no other point during the study. Diet did not affect survival (P = 0.34). There were no differences in serum insulin-like growth factor-I or insulin-like growth factor binding protein-3 at sacrifice among the low-carbohydrate arms (P = 0.07 and P = 0.55, respectively). Insulin was significantly lower in the 20% carbohydrate arm (P = 0.03). LAPC-4 xenograft mice fed a low-carbohydrate diet (10–20% carbohydrate kcal) had similar survival as mice consuming NCKD (0% carbohydrate kcal). Cancer Prev Res; 3(9); 1124–31. ©2010 AACR.

Fish Oil Slows Prostate Cancer Xenograft Growth Relative to Other Dietary Fats and is Associated with Decreased Mitochondrial and Insulin Pathway Gene Expression

BACKGROUND:Previous mouse studies suggest that decreasing dietary fat content can slow prostate cancer (PCa) growth. To our knowledge, no study has yet compared the effect of multiple different fats on PCa progression. We sought to systematically compare the effect of fish oil, olive oil, corn oil and animal fat on PCa progression.METHODS:A total of 96 male severe combined immunodeficient mice were injected with LAPC-4 human PCa cells. Two weeks following injection, mice were randomized to a Western diet based on fish oil, olive oil, corn oil or animal fat (35% kilocalories from fat). Animals were euthanized when tumor volumes reached 1000 mm3. Serum was collected at death and assayed for PSA, insulin, insulin-like growth factor-1 (IGF-1), IGF-1-binding protein-3 and prostaglandin E-2 (PGE-2) levels. Tumors were also assayed for PGE-2 and cyclooxygenase-2 levels, and global gene expression was analyzed using Affymetrix microarrays.RESULTS:Mice weights and tumor volumes were equivalent across groups at randomization. Overall, fish oil consumption was associated with improved survival relative to other dietary groups (P=0.014). On gene expression analyses, the fish oil group had decreased signal in pathways related to mitochondrial physiology and insulin synthesis/secretion.CONCLUSIONS:In this xenograft model, we found that consuming a diet in which fish oil was the only fat source slowed tumor growth and improved survival compared with that in mice consuming diets composed of olive oil, corn oil or animal fat. Although prior studies showed that the amount of fat is important for PCa growth, this study suggests that the type of dietary fat consumed may also be important.

Preoperative predictors of blood loss at the time of radical prostatectomy: results from the SEARCH database

The literature contains conflicting data on preoperative predictors of estimated blood loss (EBL) at radical retropubic prostatectomy (RRP). We sought to examine preoperative predictors of EBL at the time of RRP among patients from the SEARCH database to lend clarity to this issue. A total of 1154 patients were identified in the SEARCH database who underwent RRP between 1988 and 2008 and had EBL data available. We examined multiple preoperative factors for their ability to predict EBL using multivariate linear regression analysis. Median EBL was 900 ml (s.d. 1032). The 25th and 75th percentile for EBL were 600 and 1500 ml, respectively. EBL increased significantly with increasing body mass index (BMI) and increasing prostate size and decreased with more recent year of RRP (all P<0.001). The mean-adjusted EBL in normal-weight men (BMI<25 kg/m2) was 807 ml compared to 1067 ml among severely obese men (BMI⩾35 kg/m2). Predicted EBL for men with the smallest prostates (<20 g) was 721 ml, compared to 1326 ml for men with prostates ⩾100 g. Finally, statistically significant differences between centers were observed, with mean-adjusted EBL ranging from 844 to 1094 ml. Both BMI and prostate size are predictors of increased EBL. Prostate size is of particular note, as a nearly twofold increased EBL was seen from the smallest (<20 g) to the largest prostates (⩾100 g). Over time, average EBL significantly decreased. Finally, significant differences in EBL were observed between centers. Patients with multiple risk factors should be forewarned they are at increased risk for higher EBL, which may translate into a greater need for blood transfusion.

Effect of Isocaloric Low-Fat Diet on Prostate Cancer Xenograft Progression in a Hormone-Deprivation Model

PURPOSE Previous mouse studies suggesting that low fat diets slow prostate cancer growth often used corn oil (omega-6), which enhances prostate cancer growth, as the primary fat. Using a saturated fat based diet we previously found no significant difference in tumor growth between low and high fat fed SCID mice (Taconic Farms, Hudson, New York) xenografted with LAPC-4 cells. Whether similar results would hold in a castration model is unclear. MATERIALS AND METHODS A total of 80 male SCID mice were fed a Western diet (40% fat and 44% carbohydrate) and injected with LAPC-4 human prostate cancer cells. When tumors were 200 mm(3), the mice were castrated and randomized to an isocaloric Western or a low fat diet (12% fat and 72% carbohydrate). Animals were sacrificed when tumors were 1,000 mm(3). Serum was collected and assayed for prostate specific antigen, insulin, insulin-like growth factor 1 and insulin-like growth factor binding protein 3. Tumors were assayed for total and phosphorylated Akt. RESULTS Mouse weight was equivalent in the 2 groups. Overall dietary group was not significantly associated with survival (log rank p = 0.32). There were no statistically significant differences in prostate specific antigen (p = 0.53), insulin-like growth factor axis parameters (each p >0.05) or p-Akt-to-t-Akt ratios (p = 0.22) between the groups at sacrifice. CONCLUSIONS In this xenograft model we found no difference in tumor growth or survival between low fat vs Western fed mice when the fat source was saturated fat. These results conflict with those of other studies in which corn oil was used to show that low fat diets delay prostate cancer growth, suggesting that fat type may be as important as fat amount in the prostate cancer setting.

Estimated blood loss as a predictor of PSA recurrence after radical prostatectomy: Results: from the SEARCH database

Study Type – Diagnosis (exploratory cohort)
 Level of Evidence 2b

Variation in use of nephron-sparing surgery among children with renal tumors

OBJECTIVE Given the negative long-term effects of renal insufficiency, nephron-sparing surgery (NSS) is increasingly discussed for the treatment of pediatric renal tumors. We sought to examine variation in practice patterns of NSS among children with renal tumors. MATERIALS AND METHODS We performed a retrospective cohort analysis of claims data for pediatric inpatient admissions captured by the Kids Inpatient Database (1997-2009). We identified children with renal tumors who underwent surgery, including radical nephrectomy (RN) and NSS. We used multivariable logistic regression to assess the relationship between use of NSS and various clinical, demographic, and geographic predictors of interest. RESULTS We identified 10,108 pediatric inpatient admissions for renal tumors. Of these, 1657 were surgical admissions, with 1501 patients (90.5%) undergoing RN and 156 (9.5%) undergoing NSS. On multivariable analysis, NSS was associated only with a concomitant diagnosis of renal insufficiency (relative ratio [RR] 3.37, p = 0.01) and surgery in the Northeastern USA (RR 3.07, p = 0.03). Race/ethnicity, age, payer type, procedure year, and other non-clinical factors were not significantly associated with NSS. CONCLUSION In a large, nationwide pediatric cohort, RN remains the most common surgical intervention for renal tumors. NSS is significantly associated with a diagnosis of renal insufficiency, but not non-clinical factors such as patient gender or race.

Incidence of Breakthrough Urinary Tract Infection in Hospitalized Infants Receiving Antibiotic Prophylaxis

Urinary tract infections (UTIs) are a source of substantial morbidity in children in the neonatal intensive care unit. The incidence of UTIs that occur in critically ill infants during a course of antibiotic prophylaxis (i.e., breakthrough urinary tract infections [BUTIs]) is not known. We investigated the incidence of BUTI in a cohort of infants hospitalized on prophylactic antibiotics in neonatal intensive care units. Predictors of BUTI were evaluated using multivariable Cox regression. Out of 716 787 infants, 631 (0.09%) were prescribed 821 courses of antibiotic prophylaxis. Among this cohort, 60 infants (9.5%) suffered a total of 65 BUTIs. Of all prophylactic antibiotic courses, 65/821 (7.9%) were complicated by BUTI. Klebsiella, Enterobacter, and Escherichia coli species were the most common causes of BUTI. There was no statistically significant difference (P = .78) in BUTI incidence among the 4 antibiotics assessed (amoxicillin, cephalexin, nitrofurantoin, or trimethoprim-sulfamethoxazole).

Utility Estimation for Pediatric Vesicoureteral Reflux: Methodological Considerations Using an Online Survey Platform.

Purpose: The advent of online task distribution has opened a new avenue for efficiently gathering community perspectives needed for utility estimation. Methodological consensus for estimating pediatric utilities is lacking, with disagreement over whom to sample, what perspective to use (patient vs parent) and whether instrument induced anchoring bias is significant. We evaluated what methodological factors potentially impact utility estimates for vesicoureteral reflux. Materials and Methods: Cross‐sectional surveys using a time trade‐off instrument were conducted via the Amazon Mechanical Turk® (https://www.mturk.com) online interface. Respondents were randomized to answer questions from child, parent or dyad perspectives on the utility of a vesicoureteral reflux health state and 1 of 3 “warm‐up” scenarios (paralysis, common cold, none) before a vesicoureteral reflux scenario. Utility estimates and potential predictors were fitted to a generalized linear model to determine what factors most impacted utilities. Results: A total of 1,627 responses were obtained. Mean respondent age was 34.9 years. Of the respondents 48% were female, 38% were married and 44% had children. Utility values were uninfluenced by child/personal vesicoureteral reflux/urinary tract infection history, income or race. Utilities were affected by perspective and were higher in the child group (34% lower in parent vs child, p <0.001, and 13% lower in dyad vs child, p <0.001). Vesicoureteral reflux utility was not significantly affected by the presence or type of time trade‐off warm‐up scenario (p = 0.17). Conclusions: Time trade‐off perspective affects utilities when estimated via an online interface. However, utilities are unaffected by the presence, type or absence of warm‐up scenarios. These findings could have significant methodological implications for future utility elicitations regarding other pediatric conditions.