Intratumoral inflammation is associated with more aggressive prostate cancer

Purpose

Inflammation may play a role in the development and progression of many cancers, including prostate cancer. We sought to test whether histological inflammation within prostate cancer was associated with more aggressive disease.

Methods

The slides of prostatectomy specimens were reviewed by a board-certified pathologist on 287 men from a Veterans Affairs Medical Center treated with radical prostatectomy from 1992 to 2004. The area with the greatest tumor burden was scored in a blinded manner for the degree of inflammation: absent, mild, or marked. We used logistic and Cox proportional hazards regression analysis to examine whether categorically coded inflammation score was associated with adverse pathology and biochemical progression, respectively.

Results

No inflammation was found in 49 men (17 %), while 153 (53 %) and 85 (30 %) had mild and marked inflammation. During a median follow-up of 77 months, biochemical recurrence occurred among 126 (44 %) men. On multivariate analysis, more inflammation was associated with greater risk of positive margins, capsular penetration, and seminal vesicle invasion (all p < 0.05). Marked inflammation was associated with increased PSA recurrence risk when adjusting for preoperative features only (HR 2.08, 95 % CI 1.02–4.24), but not after adjusting for pathologic features.

Conclusions

Inflammation within prostate cancer was associated with more advanced disease, although it is unclear whether aggressive disease caused increased inflammation or inflammation caused aggressive disease.     

Cyclin D1 is required for proliferation of olig2‐expressing progenitor cells in the injured cerebral cortex

Little is known about the molecular mechanisms driving proliferation of glial cells after an insult to the central nervous system (CNS). To test the hypothesis that the G1 regulator cyclin D1 is critical for injury‐induced cell division of glial cells, we applied an injury model that causes brain damage within a well‐defined region. For this, we injected the neurotoxin ibotenic acid into the prefrontal cortex of adult mice, which leads to a local nerve cell loss but does not affect the survival of glial cells. Here, we show that cyclin D1 immunoreativity increases drastically after neurotoxin injection. We find that the cyclin D1‐immunopositive (cyclin D1+) cell population within the lesioned area consists to a large extent of Olig2+ oligodendrocyte progenitor cells. Analysis of cyclin D1‐deficient mice demonstrates that the proliferation rate of Olig2+ cells diminishes upon loss of cyclin D1. Further, we show that cyclin‐dependent kinase (cdk) 4, but not cdk6 or cdk2, is essential for driving cell division of Olig2‐expressing cells in our injury model. These data suggest that distinct cell cycle proteins regulate proliferation of Olig2+ progenitor cells following a CNS insult.     

LCPT once‐daily extended‐release tacrolimus tablets versus twice‐daily capsules: a pooled analysis of two phase 3 trials in important de novo and stable kidney transplant recipient subgroups

African‐American and elderly kidney transplant recipients (KTR) have increased risk for poor clinical outcomes post‐transplant. Management of immunosuppression may be challenging in these patients and contribute to worse outcomes. A novel once‐daily formulation of tacrolimus (LCPT) has demonstrated noninferiority, similar safety, improved bioavailability, a consistent concentration time profile, and less peak and peak‐trough fluctuations vs. tacrolimus twice‐daily (Tac BID). This pooled analysis of two phase 3 randomized, controlled trials, including 861 (LCPT N = 428; Tac BID N = 433; 38% of patients were stable KTR, and 62% were de novo KTR) patients, examined the efficacy of LCPT in KTR subgroups (blacks, females, and age ≥65). Overall, treatment failure [death, graft failure, centrally read biopsy‐proven acute rejection (BPAR), or lost to follow‐up] at 12 months was as follows: LCPT: 11.9%, BID Tac: 13.4% [?1.48% (?5.95%, 2.99%)]. BPAR rates were as follows: LCPT: 8.2%, Tac BID: 9.5% [?1.29% (?5.14%, 2.55%)]. Numerically, fewer treatment failure events with LCPT were found in the majority of subgroups, with significantly less treatment failure associated with LCPT among black KTR [?13.82% (?27.22%, ?0.31%)] and KTR ≥65 [?13.46% (?25.27%, ?0.78%)]. This pooled analysis suggests numerically lower efficacy failure rates associated with LCPT among high‐risk subgroups, in particular black KTR and KTR ≥65 years old.     

Gastric Stenosis After Laparoscopic Sleeve Gastrectomy: Diagnosis and Management

Purpose

The use of laparoscopic sleeve gastrectomy (LSG) is increasing worldwide. Although post-LSG gastric stenosis (GS) is less frequent, it has not been well defined and lacks standardized management procedures. The objective of the present study was to describe a series of patients with GS symptoms after LSG and to develop a standardized management procedure for this complication.

Methods

We performed a retrospective analysis of a prospective database of patients presenting with GS after LSG procedures performed between January 2008 and March 2014. The primary efficacy criterion was the frequency of post-LSG GS. GS was classified as functional (i.e. a gastric twist) or organic. The secondary efficacy criteria included the time interval between LSG and diagnosis of GS, the type of stenosis, the type of management, and the follow-up data.

Results

During the study period, 1210 patients underwent primary or secondary LSG. Seventeen patients had post-operative symptoms of GS (1.4 %); one patient had achalasia that had not been diagnosed preoperatively and thus was excluded from our analysis. The median time interval between LSG and diagnosis of GS was 47.2 days (1–114). Eleven patients had organic GS and six had functional GS. Seven patients required nutritional support. Endoscopic treatment was successful in 15 patients (88.2 %) after balloon dilatation (n?=?13) or insertion of a covered stent (n?=?2). Two of the 15 patients required conversion to Roux-en-Y gastric bypass (11.8 %).

Conclusion

GS after LSG is a rare complication but requires standardized management. Most cases can be treated successfully with endoscopic balloon dilatation.

     

Learning and memory performance following acute intranasal insulin administration in abstinent smokers

The highest incidence of relapse to smoking occurs within the first 2 weeks of a cessation attempt. In addition to enhanced nicotine craving, this phase of smoking cessation is also marked by learning and memory dysfunction. Many smokers are not able to overcome these symptoms, and they relapse to smoking shortly after trying to quit. In two clinical studies, we evaluated intranasal insulin for efficacy in improving learning and memory function during nicotine withdrawal. Our first study was a crossover evaluation (N = 19) following 20 hr of smoking abstinence. Study 2 was a parallel design study (N = 50) following 16 hr of abstinence. Intranasal insulin (60 IU) dose was administered in both studies and cognitive function was measured using California Verbal Learning Test‐II. Intranasal insulin did not improve learning over the 5 verbal learning trials. In addition, intranasal insulin did not improve either short‐ or long‐delay recall in either study. In summary, the one‐time administration of intranasal insulin does not improve verbal learning and memory in smokers. Whether longer administration schedules may be of benefit should be evaluated in future studies.     

Effects of hemodynamic conditions and valve sizing on leaflet bending stress in self-expanding transcatheter aortic valve: An in vitro study

Transcatheter aortic valve (TAV) replacement has become a viable alternative to surgery for high and intermediate risk patients with severe aortic stenosis. This technology may extend to the younger and lower risk patients. In this population, long-term durability of the TAV is key. Increased leaflet mechanical stress is one of the main determinants of valve structural deterioration. This in vitro study aims at evaluating leaflet bending stress (LBS) in the self-expanding TAV for different valve sizes, stroke volumes (SV), and degrees of valve oversizing (OS). Three different sizes (23, 26, and 29 mm) of CoreValve (CV) were tested on a pulse duplicator in annulus size ranging from 17 to 26 mm. Leaflet bending stress and bending of the leaflet coaptation line in diastole pinwheeling index (PI) were measured using high-speed camera imaging (1000 images/s). For each given CV and annulus size, geometric orifice area (GOA) increased significantly with OS (P < .001) and SV (P = .001). LBS decreased with increasing prosthesis size and aortic annulus (AA) size while increasing with SV (P < .03). The largest value of peak LBS (3.79 MPa) was obtained with the CV 23 mm in AA of 17 mm (%OS = 35%), SV 90 mL and the smallest value (0.99 MPa) for the CV 29 mm in AA of 26 mm (%OS = 12%), SV 30 mL. On multivariable analysis, LBS increased independently with larger OS, smaller AA size and higher SV. The PI increased with decreasing AA size and increasing OS. Moderate valve OS, such as generally used for transcatheter aortic valve implantation, is associated with increased LBS during valve opening and closing, especially in small annuli. Hence, TAV OS may negatively impact long-term valve durability.