Publication update in urology - November 22

Βιβλιογραφικη ενημερωση αττικο για τον Νοέμβριο του 22

1. Βιβλιογραφικη ενημερωση Γ’ πανεπιστημιακη ουρολογικη κλινικη

2. - Neoadjuvant 177Lu-PSMA-I&T Radionuclide Treatment in Patients with High-risk Prostate Cancer Before Radical Prostatectomy: A Single-arm Phase 1 Trial - genitourinary lesions due to monkeypox - First-in-human Intravesical Delivery of Pembrolizumab Identifies Immune Activation in Bladder Cancer Unresponsive to Bacillus Calmette-Guérin

3. LU-PSMA-617 Τι θέση έχει ως τώρα στα guidelines ;

4. HIGH-RISK PROSTATE CANCER Προβλέπεται Νέο- adjuvant θεραπεία ;

5. OBJECTIVE To evaluate whether a lutetium-177 prostate-specific membrane antigen radioligand ( LuPSMA ) can be safely administered to patients with HRLPC before robot assisted radical prostatectomy (RARP) and to describe immediate oncological outcomes

6. METHODS 14 high-risk prostate cancer patients with high uptake in ⁶⁸Ga-PSMA/PET between 2019-2021 (HRLPC or pelvic N+) Fluorine-18- fluorodeoxyglucose (FDG) PET/CT was performed to exclude patients with low PSMA expression and discordant positive FDG PET/CT Diagnosis only via MRI plus Targeted biopsy 2 or 3 Lu-PSMA doses in 2-weeks intervals (7.4 GBq /dose) Blood count, PSA, and complete metabolic profile, including liver and thyroid function, were evaluated before treatment initiation and every 2 wk after treatment until surgery. At 4–6 wk after the last LuPSMA dose, RARP with PLND was performed by two experienced surgeons 13 patients RARP+PLND (3 T3a, 2 N1) Endpoints: Safety (perioperative complications, functional toxicity) IPSS; IIEF; EQ-5D-3L; KHQ

7. Results - safety Six patients received two LuPSMA doses and eight received three doses. SPECT images revealed that all patients had elevated focal uptake in the prostate after the first dose, concordant with the elevated uptake demonstrated on PSMA PET/CT Of 14 patients who received LuPSMA , 13 underwent RARP with PLND with no intraoperative complications. One patient did not undergo surgery because of S-T depressions observed during routine preoperative electrocardiography.

8. Functional results No changes in urinary function, sexual function, or general QoL during the Lu-PSMA treatment period were reported. Continence: 12 patients used one pad or less at 3 months Erectile function: 8 patients underwent NVB preservation. 4 could achieve an erection suitable for intercourse None of the patient developed anastomotic stricture

9. Immediate Oncological outcomes After Lu-PSMA: Median decrease in PSA was 3.45 (17%) ng/ml after two Lu-PSMA doses and 4.3 (34%) ng/ml after three doses ISUP group downgrading in three patients (from ISUP 4 to 3 in two patients and from 5 to 3 in one patient) and upgrading in one patient (from ISUP 4 to 5). Overall, Positive Surgical Margins were observed in seven patients (53 %) During median follow-up of 12 mo , three patients (23%) experienced biochemical recurrence (PSA >0.2 ng/ml)

10. Discussion keys The goal of neoadjuvant therapy is to improve survival in patients at risk of disease progression after local treatment Neoadjuvant therapy given before radical prostatectomy may have a local impact or systemic effect by suppressing metastatic foci. A large phase 3 trial evaluated ADT with docetaxel in the neoadjuvant setting . There was no improvement in 3-yr biochemical progression-free survival and the authors concluded that use of chemohormonal therapy before radical prostatectomy in HRLPC was not supported. Several randomized trials have compared standard hormonal therapy and newer agents such as abiraterone , enzalutamide , and their combination. Although more favorable pathological responses were observed in some patients, longterm results are pending. Previous LuPSMA trials included patients with metastatic PC with extensive skeletal involvement. The higher tumor burden and greater number of LuPSMA treatments (up to six) may explain the systemic toxicity observed, which included bone marrow injury in up to 10% of patients with metastatic PC

11. Discussion keys The study is limited mainly by the small number of patients. The study was conducted at a single tertiary center and only two surgeons performed the surgeries. Nevertheless, we were able to show that RARP after neoadjuvant treatment with two or three LuPSMA doses is safe, thereby laying the foundation for larger trials.

12. CONCLUSION Treatment with neoadjuvant LuPSMA followed by RARP appears to be safe in patients with HRLPC. While longer oncological outcomes are pending, continence recovery seems to be unaffected by LuPSMA treatment.

13. Introduction Monkeypox is a zoonosis caused by monkeypox virus (MPXV), an orthopoxvirus . MPXV was first isolated from humans in 1970, and was previously isolated in 1958 from macaques used in research. Since May 2022, more than 40 000 cases have been reported in 87 countries not previously considered MPXV endemic areas. In the current situation, transmission is mainly human-to-human.

14. Transmission Close contact with skin lesions, droplets, or fomites . The virus has also been isolated from blood, urine, seminal fluid, and the nasopharynx . The typical clinical picture includes fever, headache, palpable lymphadenopathy , and worsening general condition associated with a macular skin rash progressing to vesiculopustular lesions. The most recent series describes genital area involvement showing vesiculopustular lesions and associated penile oedema

15. Methods This was a prospective observational descriptive study of male patients with confirmed MPXV infection and genital area involvement All the patients with confirmed MPXV disease at our hospital and genitourinary symptoms between May and August 2022 were invited to participate in the study. Genital area involvement was defined as any skin lesions, skin changes, or oedema in the penile and scrotal areas. All patients were diagnosed using polymerase chain reaction (PCR). Screening for sexually transmitted diseases (STDs) was carried out systematically for human immunodeficiency virus (HIV), chlamydia , syphilis, Neisseria gonorrhoeae , Epstein-Barr virus, and cytomegalovirus 14 cases of males with genitourinary involvement due to MPXV infection, with no history of travel to endemic areas.

16. RESULTS - TRANSMISSION The median time between exposure (when known) and symptom onset was 13 days (range 3–30). 71% (n = 10) were men who had sex with other men and 14.2% (n = 2) had heterosexual intercourse. Two patients (14.5%) maintained that they had had no sexual intercourse in the weeks before symptom onset. 57% of the patients (n = 8) were HIV-positive; one patient was diagnosed at an STD screening clinic

17. RESULTS – CLINICAL FINDINGS In six patients (43%) the initial symptom was related to the genitourinary area. All patients presented with cutaneous or mucosal involvement with vesicles and pustules. Penile oedema was present in 43% of cases (n = 6) and 57% (n = 8) had palpable lymphadenopathy in the groin area. All the patients had systemic symptoms such as malaise (n = 4, 28.5%), fever (n = 5, 35.7%), and different skin lesions such as papules, vesicles, pustules, and scabs (n = 14, 100%)

18. RESULT – ATYPICAL PRESENTATION Patient 1 had an atypical presentation. Attended for consultation because of symptoms compatible with sepsis. Fever (42 C), hypotension (blood pressure 94/54 mm Hg), and tachycardia (140 beats/min) accompanied by headache and poor general condition. Oedema of the penis with inflammatory changes on the surface Bilateral inguinal lymph nodes were palpable and a purulent discharge from the anus was observed. Penile ultrasound and a computed tomography scan showed inflammatory changes in the skin and subcutaneous cellular tissue, proctitis without collections or abscesses, and prominent bilateral mesorectal and inguin The patient had negative urine and blood cultures. Serology was positive for HIV-1 (viral load 7820 copies/ml and 265/mm3 CD4 T-lymphocytes) and Chlamydia trachomatis ( serovar L1–L3) lymphadenopathies

19. DISCUSSION In this series, 43% of patients (n = 6) presented for consultation because of a lesion in the genitourinary area as the initial symptom. Hence, urologists have a fundamental role in the differential diagnosis of MPXV disease, as it can be confused with other STDs such as secondary syphilis and lymphogranuloma venereum Urologists should know that MPXV infection may present as penile oedema and they should therefore maintain a high level of suspicion for such cases, making an early diagnosis of the infection and screening for other STDs. The urologist should also know that the normal incubation period is between 4.2 and 17.3 d (5th–95th percentile) and recommend isolation for case contacts is for 21 d

20. MPXV disease is currently being transmitted between humans. Penile oedema and involvement of the genitourinary tract are common, and in many cases is the main symptom prompting medical consultation. It is vital for urologists and surgeons to be aware of this disease for a correct differential diagnosis with regards other STDs, with which it can be confused or coincide

21. introduction Treatment for non–muscle-invasive bladder cancer (NMIBC) is endoscopic resection followed by intravesical adjuvant chemotherapy or bacillus Calmette-Guérin (BCG) In 2021, the first intravenous anti-PD1 checkpoint immunotherapy (CPI) was approved for patients with BCG-unresponsive NMIBC with carcinoma in situ While pembrolizumab was well tolerated, 66% of patients reported an adverse event (AE), with a total of 11 serious AEs (SAEs) in eight patients Target to check Safety , toxicity, and clinical response from the first-in-human clinical trial of intravesical administration of an immune checkpoint inhibitor

22. methods NCT02808143 was a phase 1 dose-escalation trial using increasing doses of intravesical pembrolizumab with BCG in patients unresponsive to BCG Patients had a history of high-grade bladder cancer (Ta, T1, or Tis ) and were treated with at least seven doses of BCG (five during induction and two during maintenance). Patients were also eligible if they were BCG unresponsive and had been treated with at least three doses of a salvage regimen (such as gemcitabine and/or docetaxel ).

23. methods After enrollment, 9 patients received a single intravesical dose of pembrolizumab at the specified dose level (1 or 2 mg/kg) at week –2 prior to induction. Participants were then treated with BCG (TICE; 50 mg, weeks 0–5) and intravesical pembrolizumab (weeks 0, 2, and 4). After induction, participants received only intravesical pembrolizumab during maintenance, first every 2 weeks until week 17 and then every 4 weeks for the remainder of the year.

24. methods At each visit, patients underwent an evaluation and physical examination to identify any AEs with endoscopic evaluation at week 17 and every 8 weeks until the completion of the trial at week 52 (last cystoscopy on week 49). Urine was analyzed for cytopathology and any concerning lesion was biopsied. Any high-grade recurrence, whether in the bladder or throughout the urinary tract, was considered a recurrence and treatment was halted. After the last dose of trial therapy, patients were followed clinically for disease recurrence and survival every 3 mo (±30 d) during years 1 and 2.

25. Clinical evolution The response to pembrolizumab and BCG was evaluated by cystoscopy , urine cytology, and bladder biopsy when indicated The median follow-up time among five patients who were alive at the end of the study was 35 months All patients recurred with Reccurence -Free-Survival rates of 100%, 67% (95% CI: 42–100%), and 22% (95% CI: 7– 75%) at 3, 6, and 12 months, respectively The median RFS was 6.2 months. No differences in RFS rates was observed between the two cohorts. Progression occurred in five patients with median Progression-FS of 36 months. The PFS rates at 6 and 12 months were 100% and 56%, respectively. Progression to locally advanced cancer (T2+Nany, TxN +, or M+) occurred in four of nine patients, with recurrence in six of nine patients outside of the treated bladder—upper tract urothelial (two), lung (one), prostate (two), and pelvis (one)

26. Response evaluation To determine whether pembrolizumab was confined to the bladder, they evaluated plasma and urine levels of pembrolizumab for cohort 1. No detectable levels of pembrolizumab in the blood (serum or plasma) in any patient. Most of the pretreatment urine collected at baseline had a large concentration of granulocytes Treatment resulted to significant decrease in granulocytes Relative to early recurrences, late recurring populations had significantly lower fractions of granulocytes and a higher fraction of lymphocytes, in particular higher CD4+ and CD8+ T cells, at weeks 0 and 2 Increased levels of BCG-regulated inflammatory cytokines (tumor necrosis factor [TNF]-alpha and interleukin [IL]-8) . Chemokines such as MIP-1 beta and monocyte chemoattractant (MCP1) increased from week –2 to 5 during induction treatment.

27. Tumor dna analysis Using DNA, pan- cytokeratin , and CD68 and CD3 as protein markers for the tumor and tumor microenvironment (TME), 151 areas of interest (AOIs) collectively from eight patients, were evaluated. Comparison of the transcriptomic profile of pre- and post-treatment tumor epithelium ( PanCK +) found significant enrichment of inflammatory pathways in PanCK + post-treatment tumor AOIs Post-treatment tumors depicted an inflamed phenotype with enrichment of pathways involved in immune regulation (inflammation and antigen presentation , and TGF-b signaling) and cytokine signaling (IL-6, IL-2, IFNA, CXCR4, TLR, and IL signaling).

28. Urine analysis

29. Tumor microenvironment analysis

30. Differences in transcriptional programs in tumor and tumor microenvironment from early and late responders

31. Conclusions Intravesical pembrolizumab is a safe and feasible alternative in patients with BCGunresponsive NMIBC. broad range of immune responses observed in the urine collected during trial and in the tumor tissue at the end of the trial. Changes in the immune niche are detectable in the urine as early as after one dose of pembrolizumab . Nevertheless, as evident by analysis of recurrences observed in the trial, duration of antitumor immunity is dependent on pretreatment tumor composition, and future trials should explore combination therapies and careful patient selection to improve efficacy

32. FINALLY IT’S OVER