Impact of pathologic features on local recurrence in penile squamous cell carcinoma after penectomy.

BACKGROUND: Penile squamous cell carcinoma (PSCC) is a rare malignancy that may be cured in cases of local disease by resection of the primary tumor. Risk factors and patterns of local recurrence (LR) have not been well described in cases requiring partial or radical penectomy. In this study, we evaluated risk factors for LR and the impact of frozen and final margin assessment. MATERIALS AND METHODS: We evaluated 119 patients with PSCC who had undergone partial or radical penectomy from 2007 to 2023. Data regarding clinical and pathologic features were collected by retrospective chart review. The primary outcome of interest was LR. Determinants of LR were analyzed by Student's t, Fisher's exact, chi-square and logistic regression analysis. Predictive statistics of frozen margin status on final margin were assessed and LR rates for subsets of frozen and final margin interaction were defined. Finally, all cases of positive margins and LR were described to highlight patterns of LR and the importance of margin status in these cases. RESULTS: There were 8 (6.7%) cases of local recurrence. There were no significant predictors of LR, although a trend toward increased LR risk was observed among those with a positive final margin. Positive final margins were found in 15 (13%) cases. Frozen margin analysis was utilized in 79 cases, of which 10 (13%) were positive. The sensitivity, specificity, positive predictive value, and negative predictive value of frozen margin status for final margins were 44%, 92%, 40%, and 93%, respectively. There were no LR among cases in which frozen margin was not sent. Analysis of all cases with positive margin and/or LR identified three subsets of patients: CIS or focally positive margin resulting in either no LR or LR managed with minimal local intervention, bulky disease in which survival is determined by response to subsequent therapy rather than local recurrence, and clinically significant local recurrence requiring continued surveillance and intervention despite negative margins. CONCLUSIONS: LR is rare, even in cases of larger, proximal tumors requiring partial or radical penectomy. In this study, no statistically significant risk factors for local recurrence were identified; however, analysis of frozen and final margins provided insight into the importance of margin status and patterns of local recurrence. When feasible, visibly intra-operative negative margins are an excellent predictor of low risk for LR, and, in cases of CIS or focally positive margins, further resection to achieve negative margins is unlikely to reduce the risk of clinically significant LR. Additionally, in cases of bulky disease, the goals of resection should be focused toward palliation and next line therapy.

A Targeted, Personalized Management Strategy in Advanced Penile Squamous Cell Carcinoma.

Penile squamous cell carcinoma (PSCC) is a rare malignancy with poor outcomes in advanced stages, with dismal response and survival rates using conventional surgical and systemic options. Additionally, the ability to detect and monitor residual disease with current imaging modalities remains difficult. Therefore, advances in multimodal management and disease monitoring are desperately needed. We present a case of advanced PSCC utilizing multimodal management informed by next-generation sequencing and circulating tumor DNA monitoring. These genomic techniques were valuable in guiding management and deserve further evaluation in the management of PSCC and other rare malignancies.

Refining the serum miR-371a-3p test for viable germ cell tumor detection.

Circulating miR-371a-3p has excellent performance in the detection of viable (non-teratoma) germ cell tumor (GCT) pre-orchiectomy; however, its ability to detect occult disease is understudied. To refine the serum miR-371a-3p assay in the minimal residual disease setting we compared performance of raw (Cq) and normalized (∆Cq, RQ) values from prior assays, and validated interlaboratory concordance by aliquot swapping. Revised assay performance was determined in a cohort of 32 patients suspected of occult retroperitoneal disease. Assay superiority was determined by comparing resulting receiver-operator characteristic (ROC) curves using the Delong method. Pairwise t-tests were used to test for interlaboratory concordance. Performance was comparable when thresholding based on raw Cq vs. normalized values. Interlaboratory concordance of miR-371a-3p was high, but reference genes miR-30b-5p and cel-miR-39-3p were discordant. Introduction of an indeterminate range of Cq 28-35 with a repeat run for any indeterminate improved assay accuracy from 0.84 to 0.92 in a group of patients suspected of occult GCT. We recommend that serum miR-371a-3p test protocols are updated to (a) utilize threshold-based approaches using raw Cq values, (b) continue to include an endogenous (e.g., miR-30b-5p) and exogenous non-human spike-in (e.g., cel-miR-39-3p) microRNA for quality control, and (c) to re-run any sample with an indeterminate result.

Perioperative Complications and Oncologic Outcomes of Nephrectomy Following Immune Checkpoint Inhibitor Therapy: A Multicenter Collaborative Study.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are now a mainstay of metastatic renal cell carcinoma (RCC) management with five current Food and Drug Administration-approved regimens. However, data regarding nephrectomy outcomes following an ICI are limited. OBJECTIVE: To evaluate the safety and outcomes of nephrectomy following an ICI. DESIGN, SETTING, AND PARTICIPANTS: A retrospective review was performed of patients with primary locally advanced or metastatic RCC undergoing nephrectomy following an ICI in five US academic centers between January 2011 and September 2021. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Clinical data, perioperative outcomes, and 90-d complications/readmissions were recorded and evaluated by univariate and logistic regression models. Recurrence-free and overall survival probabilities were estimated by the Kaplan-Meier method. RESULTS AND LIMITATIONS: A total of 113 patients with a median (interquartile range) age of 63 (56-69) yr were included. The main ICI regimens were nivolumab ± ipilimumab (n = 85) and pembrolizumab ± axitinib (n = 24). Risk groups included 95% intermediate- and 5% poor-risk patients. Surgical procedures were 109 radical and four partial nephrectomies, including 60 open, 38 robotic, and 14 laparoscopic with five (10%) conversions. Two intraoperative complications were reported (bowel and pancreatic injury). The median operative time, estimated blood loss, and hospital stay were 3 h, 250 ml, and 3 d, respectively. A complete pathologic response (ypT0N0) was noted in six (5%) patients. The 90-d complication rate was 24%, with 12 (11%) patients requiring readmission. On a multivariable analysis, two or more risk factors (odds ratio [OR] 2.91, 95% confidence interval [CI]: 1.09, 7.42) and pathologic T stage ≥T3 (OR 4.21, 95% CI: 1.13-15.8) were independently associated with a higher 90-d complication rate. The 3-yr estimated overall survival and recurrence-free survival rates were 82% and 47%, respectively. Limitations include the retrospective nature and heterogeneous cohort in terms of clinicopathologic characteristics and ICI regimens received. CONCLUSIONS: Nephrectomy following ICI therapy is feasible and a potential consolidative therapy option in select patients. Further research in the neoadjuvant setting is also warranted. PATIENT SUMMARY: This study evaluates the outcomes of kidney surgery following immune checkpoint inhibitor therapy (mainly nivolumab and ipilimumab or pembrolizumab and axitinib) for patients with advanced kidney cancer. We utilized data from five academic centers across the USA and found that surgery in this setting did not have more complications or returns to the hospital than similar surgeries, indicating that it is a safe and feasible procedure at this time.

Refining the serum miR-371a-3p test for viable germ cell tumor detection: identification and definition of an indeterminate range.

Circulating miR-371a-3p has excellent performance in the detection of viable (non-teratoma) GCT pre-orchiectomy; however, its ability to detect occult disease is understudied. To refine the serum miR-371a-3p assay in the minimal residual disease setting we compared performance of raw (Cq) and normalized (∆Cq, RQ) values from prior assays, and validated interlaboratory concordance by aliquot swapping. Revised assay performance was determined in a cohort of 32 patients suspected of occult retroperitoneal disease. Assay superiority was determined by comparing resulting receiver-operator characteristic (ROC) curves using the Delong method. Pairwise t-tests were used to test for interlaboratory concordance. Performance was comparable when thresholding based on raw Cq vs. normalized values. Interlaboratory concordance of miR-371a-3p was high, but reference genes miR-30b-5p and cel-miR-39-3p were discordant. Introduction of an indeterminate range of Cq 28-35 with a repeat run for any indeterminate improved assay accuracy from 0.84 to 0.92 in a group of patients suspected of occult GCT. We recommend that serum miR-371a-3p test protocols are updated to a) utilize threshold-based approaches using raw Cq values, b) continue to include an endogenous (e.g., miR-30b-5p) and exogenous non-human spike-in (e.g., cel-miR-39-3p) microRNA for quality control, and c) to re-run any sample with an indeterminate result.

11C, 12C and 13C-Cyanation of Electron-Rich Arenes via Organic Photoredox Catalysis.

As a non-invasive imaging technology, positron emission tomography (PET) plays a crucial role in personalized medicine, including early diagnosis, patient screening, and treatment monitoring. The advancement of PET research depends on the discovery of new PET agents, which requires the development of simple and efficient radiolabeling methods in many cases. As bioisosteres for halogen and carbonyl moieties, nitriles are important functional groups in pharmaceutical and agrochemical compounds. Here, we disclose a mild organophotoredox-catalyzed method for efficient cyanation of a broad spectrum of electron-rich arenes, including abundant and readily available veratroles and pyrogallol trimethyl ethers. Notably, the transformations not only are compatible with various affordable 12C and 13C-cyanide sources, but also could be applied to carbon-11 synthons to incorporate [11C]nitriles into arenes. The aryl [11C]nitriles can be further derivatized to [11C]carboxylic acids, [11C]amides, and [11C]alkyl amines. The newly developed reaction can serve as a powerful tool for generating new PET agents.

Actionable genomic landscapes from a real-world cohort of urothelial carcinoma patients.

BACKGROUND: Recent targeted therapies for advanced and metastatic urothelial cancer have generated enthusiasm, but the actionable genomic landscape of early-stage disease remains largely unknown. Here, we utilized a large, real-world cohort to comprehensively investigate the incidence of genetic alterations with potential therapeutic implications at all stages of bladder cancer. MATERIALS AND METHODS: We retrospectively analyzed next-generation sequencing (NGS) data from 1,562 bladder cancer patients (stages I-IV) with formalin-fixed, paraffin-embedded tumor biopsies sequenced using the Tempus xT solid tumor assay. Incidence of genetic alterations, tumor mutational burden (TMB), microsatellite instability (MSI), and PD-L1 status were assessed and stratified by bladder cancer stage. For patients with tumor-normal match sequencing (n=966), incidental germline alterations in 50 genes were assessed. RESULTS: The cohort was composed of 165 stage I-II, 211 stage III, and 1,186 stage IV tumors. TMB-high, PD-L1 positive, and MSI-high status were noted in 14%, 33%, and 0.7% of tumors, respectively, and were similar across stages. Alterations in fibroblast growth factor receptor (FGFR)2/3, homologous recombination repair genes, additional DNA repair gene mutations (ERCC2, RB1, FANCC), and NTRK fusions were detected at similar frequencies across disease stages. We identified a low rate of incidental germline mutations in all tumors (5.2%) and in specific genes: MUTYH (1.9%), BRCA2 (0.5%), and ATM (0.8%). CONCLUSIONS: Important subsets of patients demonstrate genetic alterations in potentially actionable molecular pathways at all stages. This analysis found minimal variability in these alterations across stages, providing rationale for early identification of genetic alterations and personalization of therapies at all stages for patients with bladder cancer.

Monitoring the Calibration of In-Office 3D Printers.

Most desktop 3D printers lack features that allow manual calibration of printer parameters. It is crucial to assess the accuracy of printing to minimize the margin of error and variance between each print. Therefore, this study aimed to develop a method for monitoring the calibration of in-office 3D printers. A calibration coupon was designed to have a tolerance and dimensions that define nominal geometry and allow the measurement of variances occurring in X−Y axes and curvature. Ten printing cycles were run on two stereolithography (SLA) 3D printers with two different resins. Additionally, the coupons were positioned in five positions on the build platform to assess errors caused by differences in positioning. Measurements were made on the X and Y axes. No statistical difference was noted between the coupons being printed in different positions on the build platform and between the two resins at both X and Y axes of measurement (p > 0.05). Desktop 3D printers currently lack a standardized calibration protocol, which provides a closed loop for design and manufacturing of printed parts. The coupon in this study will allow monitoring the calibration of desktop 3D printers to ensure high-quality printing.

Entero-Urachal Fistula: An Unusual Initial Presentation of Penetrating and Stricturing Crohn's Disease.

Crohn's disease (CD) has a wide variety of clinical presentations, ranging from abdominal pain to stricture and fistula. Fistulas involving the genitourinary tract can be severe and often require surgical intervention. Given the array of presenting symptoms, a delay in diagnosis can occur. We present the case of a healthy active duty soldier, with no previous medical history, found to have CD through an initial presentation of isolated umbilical drainage. Imaging workup identified an entero-uracho-cutaneous fistula with involvement of the transverse colon. Urachal anomalies are uncommon, and entero-urachal fistula as an initial presentation of CD is exceedingly rare. This case highlights the need to consider CD in the differential for patients with umbilical drainage despite a lack of concurrent more frequent presenting symptoms (abdominal pain, bloody diarrhea, and perianal fistula). Maintaining awareness of uncommon initial presentations of CD can minimize delay in diagnosis and thereby mitigate the risk of severe complications.

Evaluation of miR-371a-3p to predict viable germ cell tumor in patients with pure seminoma receiving retroperitoneal lymph node dissection.

INTRODUCTION AND OBJECTIVE: Conventional serum tumor markers (STMs) for testicular germ cell tumors (GCTs) offer limited performance with particularly poor sensitivity in cases of minimal residual disease and pure seminoma. While growing evidence has indicated miR-371a-3p to be a superior biomarker, its utility in detecting pure seminoma at recurrence has not been extensively explored. This study's objective was to explore miR-371a-3p's utility in detecting metastatic pure seminoma at retroperitoneal lymph node dissection (RPLND). METHODS: RNA was isolated from patient serum samples collected pre-RPLND. Fifteen patients were assigned to our 'benign' (n = 6) or 'seminoma' (n = 9) group based on pathological confirmation of viable seminoma. Five of the patients received chemotherapy before RPLND (PC-RPLND), and 10 were chemotherapy naïve. MiR-371a-3p expression was quantified via RT-quantitative polymerase chain reaction. The Cq values were statistically evaluated to obtain performance measurements. RESULTS: Median relative expression of miR-371a-3p was higher in the Seminoma group than the Benign, but this difference was not statistically significant (Rq = 3705 and 241, respectively, p = 0.2844). Of the 10 chemotherapy naïve patients, nine had viable seminoma at RPLND, and seven had elevated miR-371a-3p expression. Among the five postchemotherapy (PC) patients, zero had viable GCT at RPLND, and two had elevated miR-371a-3p expression. The primary RPLND group presented 78% sensitivity and 100% specificity. Specificity in the PC-RPLND group was 60%. An optimal Rq threshold of 28.62 was determined by Youden's J statistic, yielding 78% sensitivity and 67% specificity. Receiver operating characteristic analysis provided an AUC of 0.704 (95% CI: 0.43-0.98, p = 0.1949). Despite modest performance, miR-371a-3p exhibited improved sensitivity and specificity compared with conventional STMs. CONCLUSIONS: MiR-371a-3p outperformed STMs in the primary RPLND settings. However, miR-371a-3p was not a robust predictor of pathology in the PC setting. These results suggest that pure seminoma at RPLND is a clinical context, wherein the miRNA assay may require further refinement.

Testosterone and the Androgen Receptor.

Testosterone is a steroid hormone that is responsible for the development of normal male sexual characteristics and function as well as the maintenance of homeostasis among multiple organ systems throughout life. Testosterone production is regulated by the hypothalamic-pituitary axis under the direction of gonadotropin-releasing hormone and luteinizing hormone. The testosterone-bound androgen receptor (AR) is a potent regulator of gene expression and may regulate a significant proportion of genes in prostate cells. Therapeutic modulation of testosterone levels and AR signaling activity can be achieved by several different approaches, with distinct consequences and side effects.

Rare congenital abnormality resulting in spontaneous bilateral deep venous thrombosis and pulmonary emboli in a young healthy man.

This report describes a unique case of a healthy man in his 30s, who presented with progressive unilateral leg swelling with no common risk factors identified. Two days prior to the swelling he had developed significant abdominal pain following a treadmill exercise session. Ultrasound imaging revealed extensive deep vein thrombosis involving bilateral ileo-femoral venous systems, extending up the inferior vena cava (IVC). Further investigation using a CT venogram revealed the rare congenital anomaly of hypoplasia of the renal IVC. Successful treatment involved 48 hours of an intravenous unfractionated heparin infusion, followed by lifelong anticoagulation.

Routine Overnight Vital Signs Are Rarely Associated with Major Clinical Events in Patients Undergoing Radical Cystectomy: A Retrospective Cohort Study.

INTRODUCTION: Evidence has associated patient sleep disruption with adverse clinical outcomes. Overnight vital sign checks are a frequent source of patient sleep disruption. We sought to determine the utility of routine overnight vital sign checks in stable postoperative patients following radical cystectomy for bladder cancer. METHODS: We assembled a database containing all routine vital sign checks from postoperative days 0 through 6 for all patients who underwent radical cystectomy at our institution during a 5-year period (2016-2020). Sets of overnight vital signs were flagged as "abnormal" based on specified criteria and then reviewed by 2 blinded reviewers to determine whether they were associated with significant clinical interventions. RESULTS: A total of 546 patients representing 2,589 patient-nights in the hospital were included. Abnormal vital signs resulting in "moderate" or "major" clinical interventions (corresponding to concern for Clavien-Dindo grade ≥II complications) occurred during 17/2,589 (0.65%) patient-nights. Thus, 152 patient-nights of routine vital sign checks were required to identify a single moderate or major clinical event. Reviewing all overnight-onset complications, we noted that a majority (15/23, 65%) of Clavien-Dindo grade II complications were manifested only by symptoms or laboratory abnormalities without vital sign derangements, whereas all grade ≥III complications had associated vital sign abnormalities. CONCLUSIONS: Routine overnight vital signs were associated with a low frequency of clinically significant events. Reduced intensity of overnight vital sign checks may be a safe addition to enhanced-recovery packages in carefully selected patients.

Investigation of Patient-Specific Maxillofacial Implant Prototype Development by Metal Fused Filament Fabrication (MF3) of Ti-6Al-4V.

Additive manufacturing (AM) and related digital technologies have enabled several advanced solutions in medicine and dentistry, in particular, the design and fabrication of patient-specific implants. In this study, the feasibility of metal fused filament fabrication (MF3) to manufacture patient-specific maxillofacial implants is investigated. Here, the design and fabrication of a maxillofacial implant prototype in Ti-6Al-4V using MF3 is reported for the first time. The cone-beam computed tomography (CBCT) image data of the patient's oral anatomy was digitally processed to design a 3D CAD model of the hard tissue and fabricate a physical model by stereolithography (SLA). Using the digital and physical models, bone loss condition was analyzed, and a maxillofacial implant initial design was identified. Three-dimensional (3D) CAD models of the implant prototypes were designed that match the patient's anatomy and dental implant requirement. In this preliminary stage, the CAD models of the prototypes were designed in a simplified form. MF3 printing of the prototypes was simulated to investigate potential deformation and residual stresses. The patient-specific implant prototypes were fabricated by MF3 printing followed by debinding and sintering using a support structure for the first time. MF3 printed green part dimensions fairly matched with simulation prediction. Sintered parts were characterized for surface integrity after cutting the support structures off. An overall 18 ± 2% shrinkage was observed in the sintered parts relative to the green parts. A relative density of 81 ± 4% indicated 19% total porosity including 11% open interconnected porosity in the sintered parts, which would favor bone healing and high osteointegration in the metallic implants. The surface roughness of Ra: 18 ± 5 µm and a Rockwell hardness of 6.5 ± 0.8 HRC were observed. The outcome of the work can be leveraged to further investigate the potential of MF3 to manufacture patient-specific custom implants out of Ti-6Al-4V.

Native Ureter Ventriculo-Ureteral Shunt Placement for Management of Refractory Hydrocephalus in a Child With a History of Renal Transplant: Case Report and Technical Note.

This report describes the case of a 5-year-old male with intractable hydrocephalus secondary to neonatal intraventricular hemorrhage who was ultimately managed with the placement of a ventriculo-ureteral (VU) shunt. He had previously failed numerous attempts at cerebrospinal fluid shunting, choroid plexus cauterization, and endoscopic third ventriculostomy. The patient had a history of end stage renal disease, and had previously undergone renal transplant. In an operation that involved Neurosurgeons, Pediatric Urologists, and Transplant surgeons, a Gibson incision was used to avoid the patient's multiple intra-abdominal adhesions, and his nonfunctioning renal unit was used to implant a VU shunt without early or late complications.

Custom Anatomical 3D Spacer for Temporomandibular Joint Resection and Reconstruction.

Two cases are presented using a two-stage approach and a custom antibiotic spacer placement. Temporomandibular reconstruction can be very demanding and accomplished with a variety of methods in preparation of a total joint and ramus reconstruction with total joint prostheses (TMJ Concepts, Ventura, CA). Three-dimensional reconstructions from diagnostic computed tomography were used to establish a virtually planned resection which included the entire condyle-ramus complex. From these data, digital designs were used to manufacture molds to facilitate intraoperative fabrication of precise custom anatomic spacers from rapidly setting antibiotic-impregnated polymethyl methacrylate. Molds were manufactured using vat polymerization (stereolithography) with a photopolymer in the first case and powder bed fusion (electron beam melting) with Ti6AL4V for the second. Surgical methodology and the use of molds for intraoperative spacer fabrication for each case are discussed.

Massive carotid artery aneurysm presenting as an oropharyngeal swelling in a young woman.

A 28-year-old woman presented to the emergency department with a 5-day history of a sore throat and a pharyngeal swelling that increased in size. The patient was previously investigated for Marfan's syndrome after episodes of bilateral spontaneous pneumothoraces but did not meet the criteria for diagnosis. Examination revealed a large pulsatile lesion in the oropharynx. CT angiography revealed an internal carotid artery aneurysm. The patient underwent a successful urgent open repair of the aneurysm with a primary arterio-arterial anastomosis without a patch. Histopathology of the aneurysmal sac revealed cystic medial degeneration.

Tularemia outbreak at a metropolitan airport, Texas.

A jackrabbit die-off near a metropolitan airport was observed by an airport contractor. Further investigation determined that this die-off was probably due to epizootic tularemia. Because of proximity to areas of heavy human traffic and fears of transmission of tularemia to humans, the local health district and department of emergency management organized a multiagency response involving local animal control, environmental health, public health, law enforcement, and airport personnel, in addition to state and federal agencies. The tularemia epizootic subsequently ended, and no cases of human tularemia occurred. In our after-action analysis, we identified several lessons learned: the importance of animal illness surveillance, which can serve as a warning for potential human illness and epidemic; the usefulness of pre-event planning, training, and exercises in facilitating a coordinated response; the usefulness of an effective communication system with the healthcare community; the importance of responders being familiar with Centers for Disease Control and Prevention (CDC) Category A bioterrorism agents when considering a rapid response; and the fact that attempts at environmental control may result in perturbations in animal populations with unintended consequences.