Longitudinal assessment of plasma androgen receptor copy number predicts overall survival in subsequent treatment lines in castration-resistant prostate cancer: analysis from a prospective trial.

BACKGROUND: Baseline plasma androgen-receptor copy number (AR-CN) is a promising biomarker for metastatic castration-resistant prostate cancer (mCRPC) outcome and treatment response; however, the role of its longitudinal testing is unproven. We aimed to evaluate the prognostic role of AR-CN assessed before subsequent treatment lines in mCRPC patients. METHODS: A subgroup analysis of a prospective multicenter biomarker trial (IRSTB030) was carried out. Plasma AR-CN status (classified as normal or gain, cut-off value = 2) was assessed with digital PCR before each treatment line. RESULTS: Forty mCRPC patients receiving sequentially docetaxel, cabazitaxel and an AR signaling inhibitor (abiraterone or enzalutamide) were analyzed. At multivariate analysis, at each assessment overall survival (OS) was independently correlated with AR-CN status [first line: hazard ratio (HR) 4.1 [95% confidence interval (CI) 1.6-10.5]; second line: HR 2.4 (95% CI 1.1-5.3); third line: HR 2.1 (95% CI 1.0-4.3)] and median prostate-specific antigen [first line: HR 4.4 (95% CI 1.8-10.9); second line: HR 3.4 (95% CI 1.6-7.2); third line: HR 2.5 (95% CI 1.2-5.6)]. In the three subsequent assessments, AR-CN status changed from normal to gain in 15 (38%) patients. These patients had longer OS (47 months) compared with patients presenting AR-CN gain from first assessment (36 months), but shorter than those maintaining normal AR-CN (69 months) (P = 0.003). CONCLUSIONS: Plasma AR-CN correlates with survival not only at baseline (before first treatment), but also in the assessments before the following lines. Interestingly, AR-CN status may change from normal to gain across subsequent treatments in a significant number of cases, identifying a group of patients with intermediate outcomes. Longitudinal assessment of AR-CN status could represent a promising method to capture mCRPC intrinsic heterogeneity and to improve clinical management.

Serial transverse enteroplasty (STEP) in case of short bowel syndrome: did we achieve our goal? A systematic review.

Surveys on Serial Transverse Enteroplasty (STEP) published in international literature (1 January 2003- 31 May 2021) were searched. Articles were included from 17 countries: 1/23 comparative and 22/23 cohort studies. STEP was performed on 308 patients: pediatrics, adults, and mixed ages. Pediatric group included 16 studies and the adult 6. Pre-STEP residual small bowell (SB) length for pediatrics and adults ranged from 18 to 26 cm and from 30 to 70 cm, respectively. Post-STEP increased SB length for pediatrics and adults ranged between 42 and 100% and 50% and 176%, respectively. For pediatrics, enteral autonomy was reached in 32.22% of cases, parenteral nutrition (PN) dependence was 36.11%, a repeated STEP procedure (Re-STEP) was needed in 17.22%, and a bowel transplant was performed in 6.11%. In adults, enteral autonomy was achieved in 52.38%, while PN dependence was 37.1%, and no Re-STEP or transplantation were required. For the mixed group, post-STEP bowel length increased from 2 to 50 cm, enteral autonomy was obtained in 43%, PN dependence was 57%, without reported Re-STEP or transplantation. Mortality rates were between 5.55% (pediatric) and 7.14% (adults). Preoperative length with preservation of ileocecal valve represented the main predictive factors to achieve enteral autonomy.

Grade group system and plasma androgen receptor status in the first line treatment for metastatic castration resistant prostate cancer.

In localized prostate cancer (PCa), Grade Group (GG) and Gleason Score (GS) have a well-established prognostic role. In metastatic castration resistant prostate cancer (mCRPC), the prognostic role of GS and GG is less defined. In first-line treatment of mCRPC, androgen receptor (AR)-directed drugs (abiraterone acetate, enzalutamide) and docetaxel represent the referring options. There is no evidence that the GS/GG systems can add information to guide the choice between AR-directed drugs and docetaxel in the first-line setting of mCRPC. Nowadays there are no validated biomarkers, which define patients who may benefit or not from hormonal treatments or chemotherapy. Androgen receptor (AR) copy number variations (CNV) are predictive factors of poor response to abiraterone and enzalutamide. There are no available data about the association between AR CNV and GG. In this retrospective study, we analysed the association of the highest GG score with AR CNV and their impact on the clinical outcome of AR-directed drugs and docetaxel as first-line therapy for mCRPC patients. Patients benefit from docetaxel, abiraterone or enzalutamide regardless the GG. However, the presence of GG5 and AR CNV gain identifies a subgroup of patients with poor prognosis, which could benefit from front-line docetaxel instead of AR-directed drugs.

Androgen receptor gain in circulating free DNA and splicing variant 7 in exosomes predict clinical outcome in CRPC patients treated with abiraterone and enzalutamide.

BACKGROUND: Androgen receptor (AR) signaling inhibitors represent the standard treatment in metastatic castration resistance prostate cancer (mCRPC) patients. However, some patients display a primary resistance, and several studies investigated the role of the AR as a predictive biomarker of response to treatment. This study is aimed to evaluate the role of AR in liquid biopsy to predict clinical outcome to AR signaling inhibitors in mCRPC patients. METHODS: Six milliliters of plasma samples were collected before first-line treatment with abiraterone or enzalutamide. Circulating free DNA (cfDNA) and exosome-RNA were isolated for analysis of AR gain and AR splice variant 7 (AR-V7), respectively, by digital droplet PCR. RESULTS: Eighty-four mCRPC patients received abiraterone (n = 40) or enzalutamide (n = 44) as first-line therapy. Twelve patients (14.3%) presented AR gain and 30 (35.7%) AR-V7+ at baseline. Median progression-free survival (PFS) and overall survival (OS) were significantly longer in AR-V7- vs AR-V7+ patients (24.3 vs 5.4 months, p < 0.0001; not reached vs 16.2 months, p = 0.0001, respectively). Patients carrying the AR gain had a median PFS of 4.8 vs 24.3 months for AR normal patients (p < 0.0001). Median OS was significantly longer in AR normal vs patients with AR gain (not reached vs 8.17 months, p < 0.0001). A significant correlation between AR-V7 and AR gain was observed (r = 0.28; p = 0.01). The AR gain/AR-V7 combined analysis confirmed a strong predictive effect for biomarkers combination vs patients without any AR aberration (PFS 3.8 vs 28 month, respectively; OS 6.1 vs not reached, respectively; p < 0.0001). CONCLUSIONS: The present study demonstrates that cfDNA and exosome-RNA are both a reliable source of AR variants and their combined detection in liquid biopsy predicts resistance to AR signaling inhibitors.

Combination radium-223 therapies in patients with bone metastases from castration-resistant prostate cancer: A review.

Chemotherapeutic agents (docetaxel, cabazitaxel), hormonal therapies (abiraterone, enzalutamide) and radium-223 improve survival in patients with bone metastatic castration-resistant prostate cancer (mCRPC). Combinations of radium-223 with these agents or novel drugs have been investigated in order to improve survival and decrease bone-related morbidity. In mCRPC, clinical and preclinical data indicate that radium-223, abiraterone and enzalutamide have a direct effect on prostate cancer cells and bone microenvironment when administered as single agents. Initial results from studies of radium-223 and abiraterone, enzalutamide or docetaxel demonstrated efficacy without any safety concern in pre-treated mCRPC; however, this safety profile changed when radium-based combination therapies were administered in un-pretreated mCRPC. This review underline the biological rationale for combining radium strategies, investigating their effects on bone in terms of control of skeletal-related events and bone disease progression. The aim is to understand the possible reasons why different radium-based combination treatments can led to different clinical outcomes.

Treatment of squamous cell carcinoma of the anal canal: A new strategies with anti-EGFR therapy and immunotherapy.

The incidence of squamous cell carcinoma of the anal canal (SCAC) is increasing in both sexes but the standard treatment remains that of 20 years ago. However, interesting data have recently emerged on the use of anti-epidermal growth factor receptor (EGFR) agents and immunotherapy in advanced disease. Thus, new avenues of research are opening up that will hopefully lead to more effective therapeutic strategies. We provide an overview of the latest studies published on this tumor and discuss the possible future therapeutic options for combination therapy, anti-EGFR treatment and radiotherapy.

Magnetic properties and hyperfine interactions in Cr8, Cr7Cd, and Cr7Ni molecular rings from ¹9F-NMR.

A detailed experimental investigation of the (19)F nuclear magnetic resonance is made on single crystals of the homometallic Cr8 antiferromagnetic molecular ring and heterometallic Cr7Cd and Cr7Ni rings in the low temperature ground state. Since the F(-) ion is located midway between neighboring magnetic metal ions in the ring, the (19)F-NMR spectra yield information about the local electronic spin density and (19)F hyperfine interactions. In Cr8, where the ground state is a singlet with total spin S(T) = 0, the (19)F-NMR spectra at 1.7 K and low external magnetic field display a single narrow line, while when the magnetic field is increased towards the first level crossing field, satellite lines appear in the (19)F-NMR spectrum, indicating a progressive increase in the Boltzmann population of the first excited state S(T) = 1. In the heterometallic rings, Cr7Cd and Cr7Ni, whose ground state is magnetic with S(T) = 3/2 and S(T) = 1/2, respectively, the (19)F-NMR spectrum has a complicated structure which depends on the strength and orientation of the magnetic field, due to both isotropic and anisotropic transferred hyperfine interactions and classical dipolar interactions. From the (19)F-NMR spectra in single crystals we estimated the transferred hyperfine constants for both the F(-)-Ni(2+) and the F(-)-Cd(2+) bonds. The values of the hyperfine constants compare well to the ones known for F(-)-Ni(2+) in KNiF3 and NiF2 and for F(-)-Cr(3+) in K2NaCrF6. The results are discussed in terms of hybridization of the 2s, 2p orbitals of the F(-) ion and the d orbitals of the magnetic ion. Finally, we discuss the implications of our results for the electron-spin decoherence.

Local spin density in the Cr7Ni antiferromagnetic molecular ring and 53Cr-NMR.

We present (53)Cr-NMR spectra collected at low temperature in a single crystal of the heterometallic antiferromagnetic (AF) ring Cr(7)Ni in the S = 1/2 ground state with the aim of establishing the distribution of the local electronic moment in the ring. Due to the poor S/N we observed only one signal which is ascribed to three almost equivalent (53)Cr nuclei in the ring. The calculated spin density in Cr(7)Ni in the ground state, with the applied magnetic field both parallel and perpendicular to the plane of the ring, turns out to be AF staggered with the greatest component of the local spin for the Cr(3+) ions next to the Ni(2+) ion. The (53)Cr-NMR frequency was found to be in good agreement with the local spin density calculated theoretically by assuming a core polarization field of H(cp) = - 11 T/µ(B) for both orientations, close to the value found previously in Cr(7)Cd. The observed orientation dependence of the local spin moments is well reproduced by the theoretical calculation and evidences the importance of single-ion and dipolar anisotropies.

[Acute cocaine poisoning in a body packer. Clinical case]. / Intossicazione acuta da cocaina in "body packer". Caso clinico.

This report takes into consideration the complications due to "body packers" cocaine absorption. In particular we report a clinical case in which severe dysrhythmias occurred. We think an early insertion of a pacemaker able to rid ectopic focus by overdriving is essential by comparison with an effective anti-dysrhythmic therapy. We also examine the cocaine metabolites values in the patient's serum and urine.

Prevention of pulmonary complications by 6-methylprednisolone in major abdominal surgery.

Methylprednisolone sodium succinate (MPSS) was compared in a randomized, double blind study to placebo in the prevention of respiratory complications in patients submitted to abdominal (vascular, pancreatic or hepatic) surgery. Two out of 42 (4.8%) patients treated with MPSS and 9 patients out of 40 (22.5%) who received placebo experienced a pulmonary complication (p less than 0.05) The results indicate that methylprednisolone could prevent the onset of respiratory complications in patients undergoing major abdominal surgery.