[BREAST CANCER-RELATED LYMPHEDEMA: INCIDENCE AND RISK FACTORS, PREVENTIVE MEASURES AND TREATMENTS].

INTRODUCTION: Lymphedema is a pathological condition in which intercellular protein-rich fluid accumulates and leads over time to inflammation, adipose tissue hypertrophy and fibrosis. Secondary lymphedema is caused by injury or blockage of the lymphatic system and the main cause in the Western world is the treatment of a variety of cancers, the main one being breast cancer. Chronic arm edema after breast cancer surgery is a common problem with an estimated incidence of 1 in 5 patients after breast cancer treatment. In this article we review the main risk factors, approaches to reducing the risk of developing lymphedema after treatment for breast cancer and existing treatment protocols for lymphedema including the surgical innovations in this field and our experience in these innovative surgical approaches. To date, 26 physiological surgeries have been performed at the Tel Aviv Medical Center using the microsurgical approach for treating lymphedema. These surgeries had no significant complications and the improvement was observed to be greater in the group of patients with secondary lymphedema. Lymphovenous anastomosis and vascularized lymph node transfer offer promising solutions for the treatment of breast cancer related lymphedema. The introduction of additional techniques and the refinement of these procedures will probably continue to improve the results in the future.

Cardiovascular Proteomics: A Post Hoc Analysis from a Phase II Randomized Clinical Trial Comparing GnRH Antagonist vs GnRH Agonist among Men with Advanced Prostate Cancer.

PURPOSE: Recent studies demonstrated reduced cardiovascular (CV) risk with gonadotropin-releasing hormone (GnRH) antagonist, yet the underlying mechanism remains undetermined. The objective of this study was to examine longitudinal changes over time in established CV related proteins among men treated with GnRH agonists vs GnRH antagonist. MATERIALS AND METHODS: We performed a proteomics analysis of serum samples collected during a phase II randomized study among 80 men with advanced prostate cancer and preexisting CV disease who were randomized to receive a GnRH agonist (39) or GnRH antagonist (41) for 1 year. Serum samples were collected at baseline and at 3, 6 and 12 months following treatment, and analyzed levels of 188 proteins using the CV panel II and III of the Olink Multiplex platform (Olink Proteomics AB, Uppsala, Sweden). We fitted a linear mixed effects model to assess evidence of a treatment effect across CV related protein values. This included terms for treatment arm, protein levels and time-by-treatment interaction. Results were corrected for multiple testing using the Benjamini-Hochberg method. RESULTS: The CV proteomics analysis included 283 samples from 78 subjects. We identified 5 proteins with distinct patterns over time depending on study arm: human chitotriosidase, macrophage receptor with collagenous structure, cathepsin D, superoxide dismutase 2 and hydroxyacid oxidase 1. All 5 are associated with plaque stability and demonstrated an increased level among subjects in the GnRH antagonist arm compared to agonist. CONCLUSIONS: We compared longitudinal changes in CV proteins among men using androgen deprivation therapy. Our results support a direct protective effect of GnRH antagonist on plaque stability rather than a hazardous consequence of GnRH agonists on plaque rupture. This is a hypothesis generating study, and requires further confirmation.

Trends in urological emergencies in the Era of COVID-19.

PURPOSE: To evaluate trends in emergency room (ER) urological conditions during COVID-19 pandemic lockdown. MATERIALS AND METHODS: Retrospective analyses of renal colic, hematuria, and urinary retention in ER's admissions of a tertiary hospital during the lockdown period (March 19 to May 4, 2020) in Israel. Patient's demographics and clinical characteristics were compared to those in corresponding periods during 2017-2019, with estimated changes in ER arrival and waiting times, utilization of imaging tests, numbers of hospitalizations, and urgent procedure rates. RESULTS: The number of ER visits for renal colic, hematuria, and urinary retention decreased by 37%, from an average of 451 (2017-2019) to 261 patients (2020). Clinical severity was similar between groups, with no major differences in patient's age, vital signs, or laboratory results. The proportion of ER visits during night hours increased significantly during lockdown (44.8% vs. 34.2%, p=0.002). There was a decrease in renal colic admission rate from 19.8% to 8.4% (p=0.001) without differences in urgent procedures rates, while the 30-day revisit rate decreased from 15.8% to 10.3% during lockdown (p=0.02). CONCLUSIONS: General lockdown was accompanied by a significant decrease in common urological presentations to the ER. This change occurred across the clinical severity spectrum of renal colic, hematuria, and urinary retention. In the short term, it appears that patients who sought treatment did not suffer from complications that could be attributed to late arrival or delay in treatment. The long-term implications of abstinence from seeking emergent care are not known and require further investigation.

Short-Term Outcomes of Active Surveillance for Low Risk Prostate Cancer among Men with Germline DNA Repair Gene Mutations.

PURPOSE: Men with germline mutations in DNA repair genes have a higher risk of prostate cancer. Active surveillance is the preferred treatment modality for low risk prostate cancer. However, many fear offering this alternative to men with germline mutations. We describe the short-term oncologic outcomes of active surveillance in a population of men with a high genetic predisposition for prostate cancer. MATERIALS AND METHODS: A prospective cohort of men with germline DNA repair gene mutations were diagnosed with Grade Group 1 prostate cancer. All men were offered active surveillance. Followup consisted of prostate specific antigen every 3 months, multiparametric magnetic resonance imaging and a magnetic resonance imaging-ultrasound fusion confirmatory biopsy within 1 year of diagnosis. The primary end points included treatment and progression-free survival. RESULTS: Eighteen carriers of DNA repair gene mutations were diagnosed with low risk prostate cancer (BRCA1 [8], BRCA2 [6], CHEK2 [2], Lynch syndrome [2]). Of these patients 15 (83%) initiated active surveillance and 3 (17%) declined. All but 1 were fully compliant with the active surveillance protocol (93%). Overall 20% (3) had upgrading at confirmatory biopsy and were treated. At a median followup of 28 months (IQR 8.5-42) 80% of patients (12) on active surveillance are free from upgrading or radical treatment. CONCLUSIONS: Active surveillance may be feasible among carriers diagnosed with low risk prostate cancer. If embarking on active surveillance, carriers should be very carefully monitored at a specialized clinic, optimizing patient compliance and minimizing risk. Until larger scale studies with long-term followup become available, this option should be cautiously discussed with the patient.

[FACIAL NERVE PARALYSIS - THERAPEUTIC APPROACH, FACIAL REANIMATION AND ADJUNCTIVE TREATMENT].

INTRODUCTION: Paralysis of the facial mimetic muscles causes loss of voluntary and non-voluntary muscle function, as well as facial tone. This is a devastating condition with profound functional, aesthetic and psychological consequences. Etiologies include congenital paralysis and acquired paralysis following viral infection, trauma, head and neck tumors, iatrogenic damage and more. Clinical presentation includes ocular symptoms (dry eye, epiphora, corneal irritation), nasal symptoms (nasal obstruction) and oral symptoms (drooling and speech disturbances). Reconstruction of facial nerve function is based on renewing the neural input to the paralyzed face in parallel with transferring a functioning muscle. The gold standard in long term facial paralysis reanimation includes a two-stage procedure that involves cross-face nerve grafting and later on a free gracilis muscle transfer. This method allows reconstruction of a symmetric, spontaneous and voluntary smile. In cases when cross-face nerve grafting is impossible, a free-gracilis muscle transfer is performed with neural coaptation to another cranial nerve, most commonly the motor nerve to the masseter muscle (of the trigeminal nerve). Non-microsurgical methods for facial reanimation exist, however, nowadays they are rarely performed. In addition to the surgical reconstruction, other surgical and non-surgical procedures are performed for functional and aesthetic symmetrization purposes. These include fat injection to the face, botulinum toxin injection, oculoplastic procedures and more. In this article we describe our patient population with facial nerve paralysis, common facial reanimation procedures, considerations in choosing the appropriate reconstruction procedure and the general approach for treatment of facial paralysis in our multidisciplinary facial paralysis clinic.

Cardiovascular Morbidity in a Randomized Trial Comparing GnRH Agonist and GnRH Antagonist among Patients with Advanced Prostate Cancer and Preexisting Cardiovascular Disease.

PURPOSE: Androgen deprivation therapy may increase the risk of cardiovascular disease. Limited data suggest that GnRH (gonadotropin-releasing hormone) antagonist may be associated with a lower risk of cardiovascular disease than GnRH agonist. MATERIALS AND METHODS: We performed a phase II, randomized, open label study in men with prostate cancer and preexisting cardiovascular disease who were randomized to receive GnRH agonists or antagonists for 1 year. The primary outcome was endothelial function measured by the EndoPAT 2000 device (Itamar Medical, Caesarea, Israel). The predefined secondary outcome was a new cardiovascular event. Patients were followed for the development of cardiovascular disease, defined as death, myocardial infarction, a cerebrovascular event, percutaneous angioplasty with coronary stent insertion or hospitalizations due to cardiac events. RESULTS: A total of 80 patients were enrolled in study, including 41 and 39 who received GnRH antagonist and agonist, respectively. Patients in each arm had similar baseline characteristics. We did not detect a difference in the primary end point (endothelial function) between the groups (mean ± SD reactive hyperemia index 2.07 ± 0.15 vs 1.92 ± 0.11, p=0.42). However, during the trial period a new cardiovascular event (the secondary end point) developed in 15 patients. Of cases new major cardiovascular and cerebrovascular events developed in 9, including death in 2, myocardial infarction in 1, a cerebrovascular event in 2 and percutaneous angioplasty with coronary stent insertion in 4. Of the patients 20% randomized to GnRH agonist experienced a major cardiovascular and cerebrovascular event compared to 3% of those on GnRH antagonist (p=0.013). The absolute risk reduction in major cardiovascular and cerebrovascular events at 12 months using GnRH antagonist was 18.1% (95% CI 4.6-31.2, p=0.032). CONCLUSIONS: To our knowledge this is the first prospective study to test cardiovascular outcomes among patients with prostate cancer who received androgen deprivation therapy. No differences in the primary end point were noted between the study arms. However, the secondary end point revealed that patients treated with GnRH agonist experienced significantly more major cardiovascular and cerebrovascular events than those treated with GnRH antagonist. These phase II results suggest that in patients with prostate cancer who have preexisting cardiovascular disease selecting the androgen deprivation therapy modality may differentially affect cardiac outcomes.

Predictors of surgical site infection after radical cystectomy: should we enhance surgical antibiotic prophylaxis?

PURPOSE: To compare surgical site infections (SSI) rate after radical cystectomy (RC) over time and ascertain whether antibiotic prophylaxis should be enhanced. METHODS: All medical records of RC patients in a single tertiary uro-oncology center between 2007 and 2017 were analyzed. SSI was defined using the criteria of the US Centers for Disease Control and Prevention. All bacterial culture results and antimicrobial resistance rates were recorded. Lastly, multivariable logistic regression analysis was performed to ascertain SSI predictors. RESULTS: RC was performed in 405 patients, of which 96 (23.7%) developed SSI. No differences were demonstrated in the mean age, gender, NIDDM prevalence, neoadjuvant chemotherapy, positive preoperative urine culture, bowel preparation, and surgery time between both groups. However, statistically significant higher median BMI, age-adjusted Charlson Comorbidity score, usage of ceftriaxone preoperatively, and intensive care unit (ICU) hospitalization were noted in SSI patients. Overall, 62/96 (63.5%) SSI patients had a positive wound culture, with only 16.7% of the pathogens being sensitive to their perioperative antibiotics. Lastly, on multivariable analysis rising BMI, preoperative ceftriaxone and ICU hospitalization were associated with a higher SSI rate. CONCLUSIONS: Preoperative BMI reduction, and maximal preoperative medical optimization in an attempt to lower ICU admittance rates, should be part of the ideal strategy for lowering SSI rates. Additionally, preoperative antibiotics should be enhanced to harbor-wide spectrum coverage, based on local resistance rates.

A novel urine cytology stain for the detection and monitoring of bladder cancer.

PURPOSE: CellDetect® is a unique platform technology comprising a proprietary plant extract and 3 dyes that enables color discrimination between malignant (red) and benign (green) cells based on specific metabolic alterations exclusive to the former. Preclinical studies and clinical trials demonstrated the applicability of the new technology in many cell culture lines and various cancers. We explored its performance characteristics in bladder cancer. MATERIALS AND METHODS: We performed an open label, 2-step study at tertiary medical centers. The study enrolled patients with newly diagnosed or a history of urothelial carcinoma. Step 1 involved staining archived biopsies. Slides were evaluated by 2 independent pathologists, who determined the concordance of the new staining technology with the hematoxylin and eosin based diagnosis. Step 2 included staining urine specimens with the new method and comparing findings to the patient final diagnosis and the results of standard urine cytology. RESULTS: A total of 58 archived biopsies were collected. The concordance of staining using the new platform technology with the hematoxylin and eosin based diagnosis was 100%. The new method applied to 44 urine smears showed 94% sensitivity and 89% specificity to detect urothelial carcinoma. Compared to standard urine cytology the new technology had overall superior sensitivity (94% vs 46%), particularly for low grade tumors (88% vs 17%, each p <0.005). There was no significant difference in specificity between the 2 staining techniques. CONCLUSIONS: Findings show the capability of CellDetect to accurately identify urothelial carcinoma. This indicates that the technology can be further developed to provide an alternative urine cytology test with diagnostic value that may have significant clinical benefits.

Personalized prostate cancer screening among men with high risk genetic predisposition- study protocol for a prospective cohort study.

BACKGROUND: Prostate cancer screening among the general population is highly debatable. Nevertheless, screening among high-risk groups is appealing. Prior data suggests that men carrying mutations in the BRCA1& 2 genes may be at increased risk of developing prostate cancer. Additionally, they appear to develop prostate cancer at a younger age and with a more aggressive course. However, prior studies did not systematically perform prostate biopsies and thus cannot determine the true prevalence of prostate cancer in this population. METHODS: This will be a prospective diagnostic trial of screening for prostate cancer among men with genetic predisposition. The target population is males (40-70 year old) carrying a BRCA1 and/or BRCA2 germ line mutation. They will be identified via our Genetic counseling unit. All men after signing an informed consent will undergo the following tests: PSA, free to total PSA, MRI of prostate and prostate biopsy. The primary endpoint will be to estimate the prevalence, stage and grade of prostate cancer in this population. Additionally, the study aims to estimate the impact of these germ line mutations on benign prostatic hyperplasia. Furthermore, this study aims to create a bio-bank of tissue, urine and serum of this unique cohort for future investigations. Finally, this study will identify an inception cohort for future interventional studies of primary and secondary prevention. DISCUSSION: The proposed research is highly translational and focuses not only on the clinical results, but on the future specimens that will be used to advance our understanding of prostate cancer patho-physiology. Most importantly, these high-risk germ-line mutation carriers are ideal candidates for primary and secondary prevention initiatives. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02053805.

Low-dose oral desmopressin for treatment of nocturia and nocturnal enuresis in patients after radical cystectomy and orthotopic urinary diversion.

OBJECTIVES: To assess the effect of oral desmopressin on nocturia and nocturnal enuresis in patients after orthotopic neobladder reconstruction. PATIENTS AND METHODS: Of 55 patients who underwent radical cystectomy and orthotopic neobladder reconstruction at our medical centre in the period 2004-2011, 34 patients were deemed eligible for the present study. Inclusion criteria were estimated glomerular filtration rate >50 mL/min/1.73 m(2) , normal baseline sodium serum level, intact daytime urinary continence, and any degree of nocturia or nocturnal enuresis. Patients were treated daily with oral desmopressin 0.1 mg at bedtime for 30 days and completed the Nocturia, Nocturnal Enuresis and Sleep Interruption Questionnaire at trial enrollment and closure. Sodium serum levels were monitored throughout. RESULTS: Three patients withdrew from the trial because of headaches or anxiety. The mean (sd) number of nocturnal voids decreased from 2.5 (1.4)/night at baseline to 1.5 (1.3)/night at trial closure (P = 0.015). The number of patients with one or no episodes of nocturnal enuresis per week increased from six to 12 (19 to 39%; P = 0.065). Thirteen patients (42%) reported an increase of a minimum 1-2 h of sleep until the first nocturnal void; all of them asked to continue the drug. No significant adverse events or changes in sodium level were observed. CONCLUSIONS: Bedtime treatment with low-dose oral desmopressin appears to decrease episodes of nocturia and nocturnal enuresis effectively and safely in ∼50% of the patients with neobladder, allowing longer undisrupted sleep time and improved quality of life. Further investigation is warranted to determine if higher doses would result in a more meaningful clinical response.

Soft Tissue Reconstruction After Revascularization.

Diabetic foot ulcer represents the primary cause of hospital admissions, amputations, and mortality in diabetic patients. The development of diabetic foot ulcers is influenced by peripheral neuropathy, infection, and ischemia, with diabetes contributing to peripheral artery disease. Free tissue transfer combined with revascularisation of the lower extremity provides the potential opportunity for limb salvage in individuals with lower extremity defects due to critical limb ischemia and diabetic foot.

Need for episiotomy in a subsequent delivery following previous delivery with episiotomy.

PURPOSE: To assess the need of episiotomy in a subsequent delivery in women with previous primiparous vaginal delivery with episiotomy. METHODS: In this historical prospective study, we followed primiparous women who had an episiotomy at a normal vaginal delivery. The study group included parturient women (n = 201) who underwent an episiotomy at a vaginal delivery during a 2-year period (2001-2002). Inclusion criteria were: primiparity, term singleton vaginal delivery, episiotomy, and a subsequent vaginal delivery in Edith Wolfson Medical Center. Exclusion criteria were instrumental delivery at the index delivery, preterm delivery or twins at the subsequent delivery. Episiotomy in the enrolled parturient women was done when it is thought that failure to perform episiotomy would result in perineal tears. The control group (n = 201) was formed from the same time period and included women who had a spontaneous vaginal delivery without episiotomy. RESULTS: Of the 201 women with episiotomy at the index delivery, 48 (23.9 %) had episiotomy at the subsequent delivery compared to only 20 women (10.0 %) out of the 201 women without an episiotomy at index delivery (p < 0.05). Having an episiotomy at the index delivery significantly increased odds of a subsequent episiotomy (OR 2.84, 95 % CI 1.62-4.99, p < 0.05) and the risk of spontaneous perineal tears (59.2 vs. 23.4 %, p < 0.05) at the subsequent delivery. CONCLUSION: Episiotomy at first vaginal delivery significantly and independently increased the risk of repeated episiotomy and spontaneous perineal tears in a subsequent delivery.

Prostate-specific antigen level association with COVID-19 infection and vaccination.

INTRODUCTION: The associations among SARS-CoV-2 infection, vaccination and total serum prostate serum antigen (PSA) levels in men undergoing screening for prostate cancer are unknown. METHODS: A retrospective analysis of data from a large health maintenance organization. Records of individuals aged 50 to 75 years with two serum PSA tests taken between March 2018 and November 2021 were included. Individuals with prostate cancer were excluded. Changes in PSA levels were compared between individuals who had at least 1 SARS-CoV-2 vaccination and/or infection between the two PSA tests and individuals who did not have an infection and were not vaccinated between the two PSA tests. Subgroup analyses were performed to assess the impact of the elapsed time between the event and the second PSA test on the results. RESULTS: The study and control groups included 6,733 (29%) and 16 286 (71%) individuals, respectively. Although the median time between PSA tests was shorter in the study vs. the control group (440 vs. 469 days, P<.001), PSA elevation between the tests was higher in the study group (0.04 vs. 0.02, P<.001). The relative risk for PSA elevation ≥1 ng/dL was 1.22 (95% CI 1.1, 1.35). Among individuals who were vaccinated, PSA increased by 0.03 ng/dL (IQR -0.12, 0.28) and 0.09 ng/dL (IQR -0.05, 0.34) after 1 and 3 doses, respectively (P<.001). Multivariate linear regression showed that SARS-CoV-2 events (ß 0.043; 95% CI 0.026-0.06) were associated with a greater risk for PSA elevation, after adjusting for age, baseline PSA and days between PSA tests. CONCLUSION: SARS-CoV-2 infection and vaccinations are associated with a slight increase in PSA, with the third anti-COVID vaccine dose having a more prominent impact, but its clinical significance is unknown yet. Any significant increase in PSA must be investigated and cannot be dismissed as secondary to SARS-CoV-2 infection or vaccination.

Single-Dose Post-Office Fulguration Mitomycin C Instillation Appears to Improve Recurrence-Free Survival in Patients With Low-Grade Noninvasive Bladder Cancer.

INTRODUCTION: Perioperative instillation of mitomycin-C (MMC) has shown effectiveness in reducing the recurrence of low-grade non-muscle invasive bladder cancer (NMIBC). Data is lacking about the impact of single-dose MMC following office fulguration of low-grade urothelial carcinoma. We compared the outcomes of small-volume low-grade recurrent NMIBC in patients treated with office-fulguration - with and without an immediate single-dose instillation of MMC. PATIENTS AND METHODS: A retrospective analysis of medical records of patients with recurrent small-volume (≤1 cm) low-grade papillary urothelial cancer who underwent fulguration in a single institution between January 2017 and April 2021 either with or without instillation of post-fulguration MMC (40mg/50 mL). The primary outcome was recurrence-free survival (RFS). RESULTS: Of 108 patients (27% women) who underwent fulguration, 41% received intravesical MMC. The treatment and control groups had similar sex ratio, mean age, mass size, tumor multifocality and or tumor grade. Median RFS was 20 months (95% CI 4-36) in the MMC group and 9 months (95% CI 5-13) in the control group (P = .038). Multivariate Cox regression analysis showed that MMC instillation was associated with longer RFS (OR = 0.552, 95% CI 0.320-0.955, P = .034) and multifocality was associated with shorter RFS (OR = 1.866, 1.078-3.229, P = .026). A higher rate of grade 1-2 adverse events was observed in the MMC group (18.2%) vs. the control (6.8%, P = .048). No complications grade 3 or higher were observed. CONCLUSION: A single dose of MMC instilled after office fulguration is associated with longer RFS compared to patients who did not receive MMC after the procedure, with no associated high-grade complications.

Use of Recanalized Vessels for Diabetic Foot Reconstruction: Pushing the Boundaries of Reconstruction in a Vasculopathic Lower Extremity.

BACKGROUND: Free flap after lower extremity revascularization may enable limb salvage in defects after critical limb ischemia. This study examined the outcomes of reconstruction of ischemic diabetic foot according to the severity of the vessel occlusion and assessed whether recanalized vessels may serve as a reliable recipient vessel. METHODS: A total of 62 patients who underwent diabetic foot reconstruction with free flaps after successful percutaneous transluminal angioplasty (PTA) from February of 2010 to February of 2016 were identified and divided into three groups: group 1, nonoccluded vessels as recipient ( n = 11); group 2, recanalized artery after PTA for partially occluded artery ( n = 30); and group 3, recanalized artery after PTA for completely occluded artery ( n = 21). RESULTS: Flap survival was statistically higher in group 2 (90%) compared with group 3 (67%) ( P < 0.05). Subsequent major amputation was significantly lower in groups 1 and 2 [0/7 and 1/30 (3.3%)] compared with group 3 [5/21 (23.8%)] ( P < 0.05). The patient survival and limb salvage rate was 90.9% at 1 and 3 years in group 1, 89.8% at 1 year and 86.3% at 3 and 5 years in group 2, and 76.2% at 1, 3, and 5 years in group 3. This difference was not statistically significant ( P = 0.485). CONCLUSIONS: The use of recanalized vessels after PTA can be safe for partially occluded arteries but requires caution for completely occluded arteries. Using completely occluded vessels after PTA can be attempted when other options are not available and achieves a 76% chance of limb salvage. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Long-Term Survival and Functional Recovery of Cryopreserved Vascularized Groin Flap and Below-the-Knee Rat Limb Transplants.

Effective cryopreservation of large tissues, limbs, and organs has the potential to revolutionize medical post-trauma reconstruction options and organ preservation and transplantation procedures. To date, vitrification and directional freezing are the only viable methods for long-term organ or tissue preservation, but are of limited clinical relevance. This work aimed to develop a vitrification-based approach that will enable the long-term survival and functional recovery of large tissues and limbs following transplantation. The presented novel two-stage cooling process involves rapid specimen cooling to subzero temperatures, followed by gradual cooling to the vitrification solution (VS) and tissue glass transition temperature. Flap cooling and storage were only feasible at temperatures equal to or slightly lower than the VS Tg (i.e., -135°C). Vascularized rat groin flaps and below-the-knee (BTK) hind limb transplants cryopreserved using this approach exhibited long-term survival (>30 days) following transplantation to rats. BTK-limb recovery included hair regrowth, normal peripheral blood flow, and normal skin, fat, and muscle histology. Above all, BTK limbs were reinnervated, enabling rats to sense pain in the cryopreserved limb. These findings provide a strong foundation for the development of a long-term large-tissue, limb and organ preservation protocol for clinical use.

Neoadjuvant 177Lu-PSMA-I&T Radionuclide Treatment in Patients with High-risk Prostate Cancer Before Radical Prostatectomy: A Single-arm Phase 1 Trial.

BACKGROUND: High-risk localized prostate cancer (HRLPC) has a substantial risk of disease progression despite local treatment. Neoadjuvant systemic therapy before definitive local therapy may improve oncological outcomes by targeting the primary tumor and micrometastatic disease. 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. DESIGN, SETTING, AND PARTICIPANTS: This was an open-label, single-arm clinical trial. Patients with HRLPC and elevated radioligand uptake on PSMA positron emission tomography/computed tomography were enrolled. Two or three LuPSMA radioligand doses (7.4 GBq) were given at 2-wk intervals. RARP with lymph node dissection was performed 4 wk after the last LuPSMA dose. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The rate of surgical complications, operative parameters, changes in functional and quality-of-life measures, and immediate oncological outcomes (histological findings and biochemical response) were measured. Data were analyzed descriptively. RESULTS AND LIMITATIONS: Fourteen patients participated (median age 67 yr). Prostate-specific antigen decreased by 17% (interquartile range [IQR] 9-50%) after two LuPSMA doses and 34% (IQR 11-60%) after three doses. Thirteen patients underwent RARP with no identifiable anatomical changes or intraoperative complications. Four patients (30%) had postoperative complications (pneumonia, pulmonary embolism, urinary leak with urinary tract infection). At 3 mo postoperatively, 12 patients (92%) required one pad or less. Final whole-mount pathology showed positive surgical margins (PSMs) in seven patients (53%) and downgrading to International Society of Urological Pathology grade group 3 in three patients (23%). Treatment-related effects included a clear vacuolated cytoplasm and pyknotic nuclei. CONCLUSIONS: LuPSMA followed by RARP appears to be surgically safe. While oncological outcomes are pending, continence recovery seems to be unaffected by LuPSMA treatment. PATIENT SUMMARY: We evaluated outcomes for patients with aggressive localized prostate cancer who received treatment with a radioactive agent before surgical removal of their prostate. This approach appears to be safe and feasible, but its therapeutic efficacy is still unknown.