Identifying patients at risk for significant versus clinically insignificant postoperative prostate-specific antigen failure.

PURPOSE: We evaluated whether men at risk for significant versus clinically insignificant prostate-specific antigen (PSA) failure after radical prostatectomy could be identified using information available at diagnosis. PATIENTS AND METHODS: A prospective prostate cancer screening study that enrolled, diagnosed, and treated 1,011 men with radical prostatectomy at Barnes-Jewish Hospital (St Louis, MO) from January 1, 1989, to June 1, 2002, for localized prostate cancer formed the study cohort. Preoperative predictors of a postoperative PSA doubling time (DT) of less than 3 months and more than 12 months or no PSA failure were identified using logistic regression. RESULTS: A preoperative PSA velocity more than 2.0 ng/mL/yr (P = .001) and biopsy Gleason score 7 (P = .006) or 8 to 10 (P = .003) were significantly associated with having a postoperative PSA DT less than 3 months. A PSA level less than 10 ng/mL (P = .005), a nonpalpable cancer (P = .001) with a Gleason score < or = 6 (P = .0002), and a preoperative PSA increase that did not exceed 0.5 ng/mL/yr (P = .03) were significantly associated with a postoperative PSA DT of at least 12 months or no PSA failure. Most men with these preoperative characteristics and a postoperative PSA DT of 12 months or more had a persistent postoperative PSA level of at least 0.2 ng/mL that did not exceed 0.25 ng/mL after a median follow-up of 3.6 years. CONCLUSION: A postoperative PSA DT less than 3 months is associated with a preoperative PSA velocity more than 2.0 ng/mL/yr and high-grade disease. Select men with a postoperative PSA DT more than 12 months may not require salvage radiation therapy.     

Outcomes in patients with Gleason score 8-10 prostate cancer: relation to preoperative PSA level

Study Type – Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? High‐grade prostate cancers are associated with poor disease‐specific outcomes. A proportion of these tumours produce little PSA. This study demonstrates that among Gleason 8–10 prostate cancers, some of the worst survival outcomes are associated with the lowest PSA levels.

OBJECTIVE

• ? To assess outcomes of patients with Gleason score 8–10 prostate cancer (CaP) with a low (≤2.5 ng/mL) vs higher preoperative serum PSA levels.

PATIENTS AND METHODS

• ? From 1983 to 2003, 5544 patients underwent open radical prostatectomy, of whom 354 had a Gleason 8–10 tumour in the prostatectomy specimen.
• ? Patients were stratified according to preoperative PSA level into four strata: ≤2.5 ng/mL (n= 31), 2.6–4 ng/mL (n= 31), 4.1–10 ng/mL (n= 174), and >10 ng/mL (n= 118).
• ? We compared biochemical progression‐free survival (PFS), metastasis‐free survival (MFS), and cancer‐specific survival (CSS) as a function of preoperative PSA level.

RESULTS

• ? Patients with PSA level ≤2.5 ng/mL were more likely to have seminal vesicle invasion (P= 0.003).
• ? On Kaplan–Meier survival analysis, patients with a PSA level ≤2.5 ng/mL had proportionately worse outcomes than their counterparts with higher PSA levels.
• ? The 7‐year PFS in the PSA ≤2.5 ng/mL stratum was lower than those of the PSA 2.6–4 ng/mL and 4–10 ng/mL strata (36% vs 50 and 42%, respectively); however, the lowest 7‐year PFS was found in those with a PSA level >10 ng/mL (32%, P= 0.02).
• ? Gleason score 8–10 tumours with a PSA level ≤2.5 ng/mL also tended to have the lowest 7‐year MFS (75, 93, 89 and 92% for PSA level ≤2.5, 2.6–4, 4.1–10 and >10 ng/mL, respectively, P= 0.2) and CSS (81, 100, 94 and 90% for PSA level ≤2.5, 2.6–4, 4.1–10 and >10 ng/mL, respectively, P= 0.3), although these differences were not statistically significant.
• ? In the subset with palpable disease, Gleason grade 8–10 disease with PSA level ≤2.5 ng/mL also was associated with a worse prognosis.

CONCLUSIONS

• ? In patients with Gleason grade 8–10 disease, a proportion of these tumours are so poorly differentiated that they produce relatively little PSA.
• ? Patients with high‐grade, low‐PSA tumours had less favourable outcomes than many of those with higher PSA levels.

     

Predictors of subsequent prostate cancer in men with a prostate specific antigen of 2.6 to 4.0 ng/ml and an initially negative biopsy

PURPOSE: Almost 75% of men with a prostate specific antigen (PSA) of 2.6 to 4.0 ng/ml have no evidence of prostate cancer on biopsy. Deciding whether and when to repeat the biopsy is challenging. We determined if patient specific variables might identify men at increased risk for the subsequent detection of prostate cancer. MATERIALS AND METHODS: We analyzed the records of 24,893 men from a community based prostate cancer screening study. Our study group consisted of 1,202 men with PSA 2.6 to 4.0 ng/ml and a previously negative prostate biopsy. Patient specific variables were analyzed for their value in predicting a future diagnosis of prostate cancer. RESULTS: Of 1,011 men with adequate followup 136 (13.5%) were subsequently diagnosed with prostate cancer. Mean followup +/- SD in men without prostate cancer was 72 +/- 36 months. Prostate cancer was subsequently diagnosed in 35% of men with high grade prostatic intraepithelial neoplasia (HGPIN) on initial biopsy (p <0.0001), in 18% with abnormal or suspicious digital rectal examination (DRE) (p = 0.02) and 16% with an annual PSA velocity of 0 ng/ml (p = 0.002). Multivariate analysis identified HGPIN, initial PSA 3.6 to 4.0 ng/ml, abnormal DRE, family history of prostate cancer and annual PSA velocity 0 ng/ml as predictors of prostate cancer. CONCLUSIONS: Men with a PSA of 2.6 to 4.0 ng/ml and negative biopsy should be advised to undergo repeat biopsy if they have HGPIN, initial PSA 3.6 to 4.0 ng/ml, abnormal DRE, a family history of prostate cancer or a PSA velocity of 0 ng/ml or greater.     

Is the utility of prostate‐specific antigen velocity for prostate cancer detection affected by age?

OBJECTIVE

To determine whether prostate‐specific antigen velocity (PSAV) is useful for prostate cancer detection in men from different age groups, and whether the same PSAV thresholds can reasonably be applied to all men aged ≥40 years.

PATIENTS AND METHODS

From a large prostate cancer screening study, 13 615 men had data on age and a calculable PSAV. We used statistical analysis to examine the ability of PSAV to predict prostate cancer risk in each age decade.

RESULTS

For men of all ages, the median PSAV was 0.6–0.7 ng/mL/year in men with prostate cancer, and 0–0.1 ng/mL/year in men with no prostate cancer (P < 0.005 for all). On receiver operating characteristic (ROC) analysis, the area under the curve was 0.800, 0.697, 0.693, and 0.668 for predicting prostate cancer risk using PSAV for men aged 40–49, 50–59, 60–69 and ≥70 years, respectively. In the multivariate model controlling for race, family history, and the total PSA level, both PSA and PSAV were significant independent predictors of prostate cancer risk in men of all ages.

CONCLUSIONS

The PSAV is significantly higher in men of all ages with prostate cancer compared with men with no prostate cancer; although on ROC analysis it performed the best in young men. Interestingly, the median PSAV in men with prostate cancer was <0.75 ng/mL/year regardless of age, suggesting that this threshold may be too high. Overall, this data confirms that PSAV is a useful tool for prostate cancer detection for men aged ≥40 years.     

Preclinical to Clinical Translation of CNS Transporter Occupancy of TD-9855, a Novel Norepinephrine and Serotonin Reuptake Inhibitor

Background:

Monoamine reuptake inhibitors exhibit unique clinical profiles that reflect distinct engagement of the central nervous system (CNS) transporters.

Methods:

We used a translational strategy, including rodent pharmacokinetic/pharmacodynamic modeling and positron emission tomography (PET) imaging in humans, to establish the transporter profile of TD-9855, a novel norepinephrine and serotonin reuptake inhibitor.

Results:

TD-9855 was a potent inhibitor of norepinephrine (NE) and serotonin 5-HT uptake in vitro with an inhibitory selectivity of 4- to 10-fold for NE at human and rat transporters. TD-9855 engaged norepinephrine transporters (NET) and serotonin transporters (SERT) in rat spinal cord, with a plasma EC₅₀ of 11.7ng/mL and 50.8ng/mL, respectively, consistent with modest selectivity for NET in vivo.Accounting for species differences in protein binding, the projected human NET and SERT plasma EC₅₀ values were 5.5ng/mL and 23.9ng/mL, respectively. A single-dose, open-label PET study (4–20mg TD-9855, oral) was conducted in eight healthy males using the radiotracers [¹¹C]-3-amino-4- [2-[(di(methyl)amino)methyl]phenyl]sulfanylbenzonitrile for SERT and [¹¹C]-(S,S)-methylreboxetine for NET. The long pharmacokinetic half-life (30–40h) of TD-9855 allowed for sequential assessment of SERT and NET occupancy in the same subject. The plasma EC₅₀ for NET was estimated to be 1.21ng/mL, and at doses of greater than 4mg the projected steady-state NET occupancy is high (>75%). After a single oral dose of 20mg, SERT occupancy was 25 (±8)% at a plasma level of 6.35ng/mL.

Conclusions:

These data establish the CNS penetration and transporter profile of TD-9855 and inform the selection of potential doses for future clinical evaluation.     

p64 flow diverter: Results in 108 patients from a single center

Background and purposeFlow diverters are increasingly used to treat intracranial aneurysms. We report the safety and efficacy of the p64 flow diverter, a resheathable and detachable device for intracranial aneurysms.Materials and methodsWe retrospectively reviewed 108 patients with 109 aneurysms treated with the p64 between March 2014 and July 2019. There were 87 women and 21 men, mean age 57 years. Of 109 aneurysms, 74 were discovered incidentally, 12 were symptomatic, 18 were previously treated, and five were ruptured dissection aneurysms. A total of 10 aneurysms were located in the posterior circulation. The mean aneurysm or remnant size was 8.1 mm.ResultsHemorrhage by perforation with the distal guidewire occurred in two patients with permanent neurological deficits in one. In one patient, acute in-stent occlusion caused infarction with a permanent deficit. Permanent morbidity was 1.9% (2 of 108, 95%CI 0.1–6.9%); there was no mortality. During follow-up, three in-stent occlusions occurred, all asymptomatic. There were no delayed hemorrhagic complications. At six months, 77 of 96 aneurysms (80.2%) were completely occluded, and at last follow-up, this increased to 93 of 96 aneurysms (96.9%). In-stent stenosis at any degree occurred in 11 patients, progressing to asymptomatic complete occlusion in one. In the other patients, stenosis resolved or improved at further follow-up.ConclusionThe p64 offers an effective and safe treatment option. Aneurysm occlusion rate was 97% at last follow-up, mostly achieved with a single device. There were no delayed hemorrhagic complications. Delayed in-stent stenosis infrequently progresses to occlusion but remains a matter of concern.     

Lung tumor-associated derepressed alloantigen coded for by the K region of the H-2 major histocompatibility complex

Transplacental induction of lung tumors in C3HfeB/HeN (C3Hf) strain mice can be readily achieved with the carcinogen 1-ethyl-1-nitrosourea. Several of these tumors express, as a tumor-associated transplantation antigen (TATA), a normal tissue alloantigen present in strain A and C3H/HeN (C3H) mice. In the present study it was shown that the tumor-associated alloantigen on the C3Hf-derived lung tumor 85 was present in all mice of H-2(a) and H-2(k) haplotypes tested and in CBA (532) strain mice (H-2(ka) haplotype). Studies using congenic-resistant and recombinant strains of mice indicated that the genetic locus controlling the expression of this antigen was either within or to the left of the H-2K region of the major histocompatibility complex (MHC). Thus the antigen was expressed in B10.A (4R) mice (kkbbbb MHC haplotype) but not in B10 (bbbbbb) or B10.AQR mice (qkkddd). The antigen was expressed in all tissues tested of C3H and A strain mice. It was not detected on any tissue tested including embryo tissue of C3Hf mice or mice of MHC haplotype other than H-2(k) or H-2(a). Because C3Hf strain mice were originally derived from C3H strain mice (H-2(k)), the MHC haplotype of C3Hf mice has been provisionally designated H-2(kb). The finding of a tumor-associated change in the expression of a H-2K region-coded antigen is consistent with the concept that MHC-coded antigens may act as targets for immunological surveillance of tumors.