A switch from GnRH agonist to GnRH antagonist in castration-resistant prostate cancer patients leads to a low response rate on PSA

Purpose

At the time of castration resistance, it is recommended to realize hormonal manipulations before chemotherapy. We evaluated the impact of a switch from GnRH agonist to antagonist in patients with castration-resistant prostate cancer on PSA and testosterone levels at 3 months.

Methods

Retrospectively, 17 patients from 5 different centers undergoing androgen deprivation therapy and presenting rising PSA confirmed on 3 blood samples 2 weeks apart and despite a castrate testosterone level (<0.5 ng/ml) were reviewed. Antiandrogen withdrawal syndrome had been tested before the switch. Degarelix was administered as followed: 240 mg for the first injection and then 80 mg every month, subcutaneously. We evaluated the PSA and testosterone level variation 3 months after the switch. Patients who experienced a variation in PSA of less than 10% compared to the baseline or who had a more than 10% PSA decrease were defined as responders.

Results

Mean PSA level at the switch was 34.3 ± 50.3 ng/ml, with a mean testosterone level of 0.21 ± 0.13 ng/ml. Three months after the switch, mean PSA level was 59.9 ± 81.6 ng/ml (P = 0.061), with a mean testosterone level of 0.19 ± 0.08 ng/ml (P = 0.086). At 3 months, 4 patients (23%) responded to therapy. Thirteen patients (77%) experienced a rise in PSA of more than 10% compared to baseline; 41% of patients decreased their testosterone level. The limitations of this study are its retrospective nature and the limited number of patients.

Conclusion

Switch from an agonist to an antagonist of GnRH has a limited impact on PSA at 3 months in castration-resistant prostate cancer patients.     

Altered thermogenesis and impaired bone remodeling in Misty mice

Fat mass may be modulated by the number of brown‐like adipocytes in white adipose tissue (WAT) in humans and rodents. Bone remodeling is dependent on systemic energy metabolism and, with age, bone remodeling becomes uncoupled and brown adipose tissue (BAT) function declines. To test the interaction between BAT and bone, we employed Misty (m/m) mice, which were reported be deficient in BAT. We found that Misty mice have accelerated age‐related trabecular bone loss and impaired brown fat function (including reduced temperature, lower expression of Pgc1a, and less sympathetic innervation compared to wild‐type (+/ +)). Despite reduced BAT function, Misty mice had normal core body temperature, suggesting heat is produced from other sources. Indeed, upon acute cold exposure (4°C for 6 hours), inguinal WAT from Misty mice compensated for BAT dysfunction by increasing expression of Acadl, Pgc1a, Dio2, and other thermogenic genes. Interestingly, acute cold exposure also decreased Runx2 and increased Rankl expression in Misty bone, but only Runx2 was decreased in wild‐type. Browning of WAT is under the control of the sympathetic nervous system (SNS) and, if present at room temperature, could impact bone metabolism. To test whether SNS activity could be responsible for accelerated trabecular bone loss, we treated wild‐type and Misty mice with the β‐blocker, propranolol. As predicted, propranolol slowed trabecular bone volume/total volume (BV/TV) loss in the distal femur of Misty mice without affecting wild‐type. Finally, the Misty mutation (a truncation of DOCK7) also has a significant cell‐autonomous role. We found DOCK7 expression in whole bone and osteoblasts. Primary osteoblast differentiation from Misty calvaria was impaired, demonstrating a novel role for DOCK7 in bone remodeling. Despite the multifaceted effects of the Misty mutation, we have shown that impaired brown fat function leads to altered SNS activity and bone loss, and for the first time that cold exposure negatively affects bone remodeling.     

Laparoscopic ampullectomy for an ampullarian adenoma

Lesions involving the ampulla of Vater are rare entities (0.1–0.2 %) with high malignant potential (90 %) [1]. As a treatment, the surgical procedure known as duodenopancreatectomy was the main option, whatever the tumor’s stage or nature. Yet with improvements of endoscopic diagnostic and therapeutic techniques, management of these lesions has been modified, enabling endoscopic removal of adenoma and adenocarcinoma-in situ. Thus, when endoscopic treatment is not possible, surgical ampullectomy is still an alternative option to duodenopancreatectomy [1, 2]. The continuous improvements in surgical techniques and instruments now allow the safe realization of laparoscopic ampullectomy, despite the few cases described in the literature [3, 4]. Here we present a surgical technique in a 52-year-old patient with an ampulloma. The ampulloma was discovered during a gastroscopy for abdominal pain. The endoscopic ultrasound with biopsy revealed a 15-mm adenoma with moderate-grade dysplasia. The thoracoabdominal CT scan was normal. The procedure was performed as shown. The tumor histology showed a R0 resection (5-mm surgical margin) of an adenoma with focal high-grade dysplasia. At 3-year follow-up, outcomes were unremarkable, without any complications.     

Urinary protein patterns in patients with Balkan endemic nephropathy

Purpose

Urinary excretion of beta2-microglobulin (beta2-MG), albumin, immunoglobulin G (IgG) and protein was examined in patients with Balkan endemic nephropathy (BEN), glomerulonephritis (GN) and healthy controls.

Methods

The proteins were measured in morning urine samples from 74 patients with BEN, 50 healthy persons and 22 patients with GN.

Results

In BEN patients, median values for albumin, beta2-MG and protein were above upper normal limits, but median IgG was inside normal range. All patients with GN had microalbuminuria (MAU) and half of them had increased urinary beta2-MG, which was also found in eleven patients with increased urinary IgG. In BEN patients, there were significant negative correlations between eGFR and all measured urinary proteins, the composition of which changed during the course of BEN. In patients with eGFR > 60 ml/min/1.73 m² isolated beta2-MG was the most frequent finding (10/12 patients), but MAU was present in 4/12 patients. In BEN patients with eGFR between 30 and 59 ml/min/1.73 m², beta2-MG appeared as often as the combination of beta2-MG and albumin and isolated MAU. Out of 49 BEN patients with eGFR > 30 ml/min/1.73 m² 15 had increased urinary IgG either alone (1) or together with beta2-MG (3) or albumin (3) or beta2-MG and albumin (8). In BEN patients with GFR < 30 ml/min/1.73 m² only 1/25 had isolated beta2-MG but increased urinary IgG with increased beta2-MG, and albumin was the most frequent.

Conclusion

Although low-molecular weight proteinuria was the most frequent urinary finding in BEN patients, MAU was frequently detected in advanced stages of BEN but also in some patients with eGFR > 60 ml/min/1.73 m². IgG was increasingly found as eGFR decreased.     

Serum Isoform [−2]proPSA Derivatives Significantly Improve Prediction of Prostate Cancer at Initial Biopsy in a Total PSA Range of 2–10 ng/ml: A Multicentric European Study

Background

Strategies to reduce prostate-specific antigen (PSA)–driven prostate cancer (PCa) overdiagnosis and overtreatment seem to be necessary.

Objective

To test the accuracy of serum isoform [−2]proPSA (p2PSA) and its derivatives, percentage of p2PSA to free PSA (fPSA; %p2PSA) and the Prostate Health Index (PHI)—called index tests—in discriminating between patients with and without PCa.

Design, setting, and participants

This was an observational, prospective cohort study of patients from five European urologic centers with a total PSA (tPSA) range of 2–10 ng/ml who were subjected to initial prostate biopsy for suspected PCa.

Outcome measurements and statistical analysis

The primary end point was to evaluate the specificity, sensitivity, and diagnostic accuracy of index tests in determining the presence of PCa at prostate biopsy in comparison to tPSA, fPSA, and percentage of fPSA to tPSA (%fPSA) (standard tests) and the number of prostate biopsies that could be spared using these tests. Multivariable logistic regression models were complemented by predictive accuracy analysis and decision curve analysis.

Results and limitations

Of >646 patients, PCa was diagnosed in 264 (40.1%). Median tPSA (5.7 vs 5.8 ng/ml; p = 0.942) and p2PSA (15.0 vs 14.7 pg/ml) did not differ between groups; conversely, median fPSA (0.7 vs 1 ng/ml; p < 0.001), %fPSA (0.14 vs 0.17; p < 0.001), %p2PSA (2.1 vs 1.6; p < 0.001), and PHI (48.2 vs 38; p < 0.001) did differ significantly between men with and without PCa. In multivariable logistic regression models, p2PSA, %p2PSA, and PHI significantly increased the accuracy of the base multivariable model by 6.4%, 5.6%, and 6.4%, respectively (all p < 0.001). At a PHI cut-off of 27.6, a total of 100 (15.5%) biopsies could have been avoided. The main limitation is that cases were selected on the basis of their initial tPSA values.

Conclusions

In patients with a tPSA range of 2–10 ng/ml, %p2PSA and PHI are the strongest predictors of PCa at initial biopsy and are significantly more accurate than tPSA and %fPSA.

Trial registration

The study is registered at http://www.controlled-trials.com, ref. ISRCTN04707454.