Biochemical recurrence rate in patients with positive surgical margins at radical prostatectomy with further negative resected tissue

OBJECTIVE

To determine the biochemical recurrence (BCR) rate in patients with positive surgical margins (PSMs) on the prostate specimen who have additional negative tissue resected from that site (M+ ?), compared to patients with negative margins (M?) and those with persistent PSM (M+), as those with PSM at radical prostatectomy (RP) are at greater risk of BCR, and in some instances where suspicious tissue is noted in the prostate bed or when frozen‐section analysis shows PSM, additional tissue is resected from the suspect site of the PSM.

PATIENTS AND METHODS

Between January 1999 and June 2007, 4217 consecutive patients underwent open or laparoscopic RP with no previous radiotherapy or hormonal therapy. The median (interquartile range) follow‐up was 37.4 (21.1–60.7) months.

RESULTS

Pathological organ‐confined (OC) cancer was present in 2901 men, of whom 2659 had M?, 216 had M+, and 26 had M+ ?. Extracapsular extension (ECE) alone with no seminal vesicle or lymph node involvement was present in 843 men, of whom 657 had M?, 174 had M+ and 12 had M+ ?. For patients with OC cancer, the 36‐month actuarial BCR‐free probability was 97.9% (95% confidence interval 97.3–98.5) for M?, vs 89.0 (84.1–93.9)% for M+ vs 100% for M+ ?. For patients with ECE, the 36‐month actuarial BCR‐free probability was 83.7 (80.0–87.4)% for M? vs 73.7 (66.1–81.3)% for M+ vs 90.0 (71.4–100)% for M+ ?. The main limitation of the study was its retrospective nature, with the reason for resection of additional tissue not always well documented.

CONCLUSIONS

While the few patients with PSMs and further negative resected tissue limited the statistical analysis, it would appear that in these patients the disease behaves as in those with negative margins.     

Prognostic Significance of Carbonic Anhydrase IX (CA-IX), Endoglin (CD105) and 8-hydroxy-2′-deoxyguanosine (8-OHdG) in Breast Cancer Patients

The aim of this study was to examine the prognostic significance of carbonic anhydrase IX (CA-IX), an endogenous marker for tumor hypoxia; endoglin (CD105), a proliferation-associated and hypoxia-inducible glycoprotein and 8-hydroxy-2′-deoxyguanosine (8-OHdG), an oxidative DNA lesion, in breast cancer patients. Immunohistochemical expressions of CA-IX, CD105 and 8-OHdG, analyzed on paraffin-embedded tumor tissues from forty female breast cancer patients, were used to assess their prognostic implication on overall survival (OS) and relapse-free survival (RFS). Patients with high CA-IX expression (above cut-off value) had a higher occurrence of relapse (P = 0.002). High CA-IX expression was significantly associated with shorter RFS (P < 0.001, hazard ratio (HR) 0.21) and shorter OS (P < 0.001, HR 0.19). Lymph node negative patients with high CA-IX expression had worse RFS (P = 0.031, HR 0.14) and OS (P = 0.005, HR 0.05). Patients with grade I&II tumors and high CA-IX expression showed shorter RFS (P = 0.028, HR 0.28) and OS (P = 0.008, HR 0.20). Worse OS (P = 0.046, HR 0.28) was found in subgroup of patients with grade II tumors and high CA-IX expression. Among all three markers, only high CA-IX expression was strong independent prognostic indicator for shorter OS (HR 4.14, 95% CI 1.28–13.35, P = 0.018) and shorter RFS (HR 3.99, 95% CI 1.38–11.59, P = 0.011). Elevated expression of CA-IX was an independent prognostic factor for decreased RFS and OS and a significant marker for tumor aggressiveness. CD105 had week prognostic value; whereas, 8-OHdG, in this study, did not provide sufficient evidence as a prognostic indicator in breast cancer patients.     

Alleviation of acute and chronic graft-versus-host disease in a murine model is associated with glucocerebroside-enhanced natural killer T lymphocyte plasticity

BACKGROUND: Natural killer T (NKT) lymphocytes play a role in graft-versus-host disease GVHD (GVHD). Glucocerebroside (GC) is a naturally occurring glycolipid that plays a role in the immune modulation of NKT lymphocytes. This study aims to determine the effect of GC in murine models of semiallogeneic/acute and chronic GVHD. METHODS: Acute and chronic GVHD were generated by fusion of splenocytes from C57BL/6 to (C57BL/6xBalb/c) F1 mice, and from B10.D2 donor mice into Balb/c, respectively. Recipients were treated daily with GC. Histological and immunological parameters of GVHD were assessed. RESULTS: Treatment with GC significantly alleviated GVHD in both models The beneficial effect of GC was associated with an increase in the intrahepatic/peripheral NKT lymphocyte ratio in the semiallogeneic/acute model. This ratio was decreased in the chronic GVHD model. A significant increase in intrahepatic CD8+ lymphocyte trapping was noted in the semiallogeneic/acute model, whereas the opposite effect was observed in the chronic GVHD model. Administration of GC led to decreased serum interferon-gamma and increased serum interleukin-4 levels in the Th1-mediated model, whereas the opposite effect was observed in the Th2-mediated models. CONCLUSIONS: GC ameliorates GVHD in both Th1- and Th2-mediated murine models, suggesting it is able to differentially affect the immune system. GC may alleviate immunologically incongruous disorders, and may be associated with "fine tuning" of immune responses.     

Bilateral cavernous nerve interposition grafting during radical retropubic prostatectomy: Memorial Sloan-Kettering Cancer Center experience

PURPOSE: Cavernous nerve graft is an option for men requiring bilateral cavernous nerve resection for cancer control during radical prostatectomy. We determined the success rate and identified determinants of success of bilateral cavernous nerve grafting following resection of the 2 nerves during radical prostatectomy in patients who were potent preoperatively. MATERIALS AND METHODS: We retrospectively reviewed the records of 44 consecutive patients who underwent bilateral nerve grafting from 1999 to 2004. Postoperative erectile function was defined as the achievement of erections satisfactory for intercourse with or without oral medication. We calculated cumulative erectile function recovery rates using Kaplan-Meier curves. The log rank test was used to compare variables affecting erectile function recovery with p <0.0083 considered significant after adjusting for the number of variables evaluated using the Bonferroni correction. RESULTS: The overall 5-year cumulative recovery of erectile function permitting penetration was 34% and the rate of consistent penetration was 11%. None of the analyzed variables were significantly associated with recovery of postoperative erectile function, including patient age (p = 0.3), incomplete bilateral cavernous nerve resection (p = 0.045), sural nerve grafts compared to genitofemoral or ilioinguinal nerves as donor sites (p = 0.067), post-radiation salvage radical prostatectomy (p = 0.15), neoadjuvant hormone therapy (p = 0.7) and comorbidities (p = 0.15) or medications (p = 0.4) affecting EF. CONCLUSIONS: Bilateral cavernous nerve grafts might be beneficial in select patients. A definitive answer awaits the performance of a multi-institutional, randomized, controlled trial.     

Pelvimetric Dimensions do not Impact upon Nerve Sparing or Erectile Function Recovery in Patients Undergoing Radical Retropubic Prostatectomy

IntroductionThe impact of unfavorable pelvic anatomy on the likelihood of having a nerve sparing radical retropubic prostatectomy (RRP) and the potential correlation between pelvic dimensions and recovery of erectile function (EF) after RRP have not been previously evaluated.AimTo determine the impact of different pelvic bony and soft tissue dimensions as well as apical prostate depth on the likelihood of performing bilateral nerve sparing and on recovery of EF after RP.MethodsBetween November 2001 and June 2007, 644 potent men undergoing RRP had preoperative MRI where pelvimetry was performed with bilateral nerve sparing in 504 men. Outcomes including varying degrees of recovery of EF (level 1: normal; level 2: partial erections routinely sufficient for intercourse; level 3: partial erections occasionally sufficient for intercourse) were assessed. Median follow‐up was 44.1 (interquartile range: 29.2, 65.3) months. We evaluated independent predictors of performing a bilateral nerve sparing procedure and of recovery of EF using multivariable Cox proportional hazards methods.Main Outcome MeasuresLikelihood of performing bilateral nerve sparing as well as recovery of EF after RRP.ResultsPatients with higher clinical stage and biopsy Gleason score are less likely to undergo bilateral nerve sparing. Surgeon is also a factor in the likelihood of having bilateral nerve sparing RRP. On multivariate Cox regression analysis, factors predictive of recovery of EF were age, pretreatment erectile function, surgeon, and modified Charlson score. None of the pelvimetric dimensions were significant predictors of any degree of recovery of EF. However, the study is limited by its retrospective nature and by being based on MRI evaluations useful for cancer staging rather than anatomical evaluation of pelvimetric dimensions.ConclusionsWe did not find unfavorable pelvic anatomy to impact the likelihood of performing a nerve sparing procedure or to be predictive of any degree of recovery of EF after RRP. von Bodman C, Matikainen MP, Favaretto RL, Matsushita K, Mulhall JP, Eastham JA, Scardino PT, Akin O, and Rabban F. Pelvimetric dimensions do not impact upon nerve sparing or erectile function recovery in patients undergoing radical retropubic prostatectomy.     

A Src/Abl kinase inhibitor, SKI-606, blocks breast cancer invasion, growth, and metastasis in vitro and in vivo

The central role of Src in the development of several malignancies, including breast cancer, and the accumulating evidence of its interaction with receptor tyrosine kinases, integrins, and steroid receptors have identified it as an attractive therapeutic target. In the current study, we have evaluated the effect of a Src/Abl kinase inhibitor, SKI-606, on breast cancer growth, migration, invasion, and metastasis. Treatment of human breast cancer cells MDA-MB-231 with SKI-606 caused a marked inhibition of cell proliferation, invasion, and migration by inhibiting mitogen-activated protein kinase and Akt phosphorylation. For in vivo studies, MDA-MB-231 cells transfected with the plasmid encoding green fluorescent protein (GFP; MDA-MB-231-GFP) were inoculated into the mammary fat pads of female BALB/c nu/nu mice. Once tumor volume reached 30 to 50 mm(3), animals were randomized and treated with vehicle alone or 150 mg/kg SKI-606 by daily oral gavage. Experimental animals receiving SKI-606 developed tumors of significantly smaller volume (45-54%) compared with control animals receiving vehicle alone. Analysis of lungs, liver, and spleen of these animals showed a significant decrease in GFP-positive tumor metastasis in animals receiving SKI-606 at a dose that was well tolerated. Western blot analysis and immunohistochemical analysis of primary tumors showed that these effects were due to the ability of SKI-606 to block tumor cell proliferation, angiogenesis, growth factor expression, and inhibition of Src-mediated signaling pathways in vivo. Together, the results from these studies provide compelling evidence for the role of Src inhibitors as therapeutic agents for blocking breast cancer growth and metastasis.     

Immunomodulation of experimental colitis: the role of NK1.1 liver lymphocytes and surrogate antigens--bystander effect.

The imbalance between Th1 pro-inflammatory and Th2 anti-inflammatory cytokine-producing cells plays a major role in the pathogenesis of inflammatory bowel disease (IBD). Induction of oral tolerance to colitis-extracted proteins was previously shown to down-regulate the anti-colon immune response, thereby alleviating experimental colitis. Immune bystander effect and liver-associated lymphocytes expressing the NK1.1 marker (NK1.1(+) LAL) have been suggested as being important in tolerance induction. The aims of the present study were to determine whether oral administration of inflammatory and non-inflammatory colon-extracted proteins of different species can induce peripheral immune tolerance and alleviate experimental colitis; and to examine the role of NK1.1(+) LAL in oral tolerance induction. Colitis was induced in C57/B6 mice by intracolonic instillation of trinitrobenzene sulphonic acid (TNBS). Mice received six oral doses of colonic proteins extracted from TNBS-colitis colonic wall, or normal colonic wall, from four different species. Standard clinical, macroscopic, and microscopic scores were used for colitis assessment. Serum interferon gamma (IFNgamma) and interleukin 10 (IL10) levels were measured by ELISA. To evaluate the role of NK1.1(+) LAL in maintaining the balance between immunogenic and tolerogenic subsets of cells, their cytotoxicity functions were tested in tolerized and non-tolerized-mice. The administration of mouse-derived colitis-extracted proteins, or of surrogate proteins extracted from normal mouse colon, or from rat or human inflammatory colons, was found to alleviate experimental colitis. Tolerized mice had less diarrhoea; showed a marked reduction of colonic ulceration, intestinal and peritoneal adhesions, wall thickness, and oedema; and demonstrated a significant improvement of all microscopic parameters for colitis. Induction of tolerance led to an increase in IL10 and a decrease in IFNgamma serum levels. NK1.1(+) LAL cytotoxicity function increased markedly in tolerized mice. In contrast, mice fed with proteins extracted from normal rat, rabbit, and human colon, or from rabbit inflammatory colon, developed severe colitis, with a marked increase in IFNgamma and a decrease in IL10 serum levels, and down-regulation of NK1.1(+) LAL function. This study has shown that oral tolerance can be induced in experimental colitis by means of the feeding of surrogate antigens; this alleviates experimental colitis. NK1.1(+) LAL cytotoxicity function is associated with peripheral tolerance induction and may help to maintain the Th1/Th2 immune balance.     

Evaluation of thyroglobulin expression in murine reproductive organs during pregnancy

Citation Moravej A, Jeddi‐Tehrani M, Salek‐Moghaddam AR, Dokouhaki P, Ghods R, Rabbani H, Kazemi‐Sefat GE, Shahbazi M, Zarnani AH. Evaluation of thyroglobulin expression in murine reproductive organs during pregnancy. Am J Reprod Immunol 2010; 64: 97–103 Problem In pregnant women with antithyroglobulin antibody, prevalence of abortion is 2–4 fold higher compared to normal controls. Direct effect of such harmful autoantibodies on female reproductive organs may serve a role in pregnancy loss. Method of study Expression of thyroglobulin in decidua, placenta, and ovary of pregnant Balb/c mice ((Balb/c×Balb/c and Balb/c×C57BL/6) during early, middle, and late stages of pregnancy was evaluated. Expression of thyroglobulin was investigated in these tissues by semi‐quantitative RT‐PCR. In addition, polyclonal antithyroglobulin antibody was produced, and expression of thyroglobulin protein in aforesaid tissues was evaluated by immunohistochemistry and dot‐blot analysis. Results The results showed that thyroglobulin message is not expressed in placenta, decidua, or ovary in any stages of pregnancy. The same results were obtained at the protein level. Conclusion It is likely that antithyroglobulin antibodies have no direct detrimental effect on such organs in patients with thyroid autoimmunity suffering from recurrent abortion.