Restricted access and advanced disease in post-pandemic testicular cancer.

INTRODUCTION: Urologists observed reduced cancer consultations and surgeries during the SARS-CoV-2 pandemic, raising concern about treatment delays. Testicular cancer serves as a particularly sensitive marker of this phenomenon, as the clinical stage of testicular cancer at presentation is predictive of cancer-specific survival. We aimed to investigate whether COVID-related restrictions to primary care access resulted in increased incidence of metastatic germ cell testis cancer. METHODS: A retrospective chart review was conducted on all cases of testicular cancer managed surgically at our center from March 1, 2018, to February 28, 2023. Patients were categorized into temporal cohorts, representing before, during, and following the implementation of COVID-19 public health restrictions in the province of Newfoundland and Labrador. RESULTS: Forty-one cases of testicular germ cell tumors were identified during the study period. The mean age at diagnosis was 40.8 years (standard deviation ±13.7). Demographics did not vary across the cohorts. Clinical stage 3 disease remained stable before and during the pandemic at 10.5% and 9.1% of cases, respectively. In the post-pandemic period, there was an increase to 27.3% (p=0.617). Surgical wait times remained stable across the pandemic (p=0.151). CONCLUSIONS: There was a 16.8% rise in clinical stage III disease from the pre-pandemic to post-pandemic period. Our study failed to identify a statistically significant increase in metastatic testis cancer incidence upon lifting of pandemic restrictions. Further study is necessary to confirm suspicions that pandemic restrictions contributed to increased incidence of metastatic testis cancer.

A General Approach to Optically Pure, α-Methyl Non-Natural Amino Acids: Enabling Unique Peptides as Drug Candidates.

An α-methyl, non-natural amino acid (NNAA) building block equipped with an alkyl halide tail that could be readily transformed into an organozinc was prepared. This single organometallic was cross-coupled to an array of heterocyclic electrophiles using the Pd-PEPPSI-IHeptCl catalyst to produce a wide selection of optically pure α-methyl NNAAs. With these in hand, non-natural peptides are being produced for evaluation in a variety of therapeutic areas in drug discovery.

Impact of the COVID-19 pandemic on diagnosis of renal cell carcinoma and disease stage at presentation.

INTRODUCTION: Renal cell carcinoma (RCC) is often associated with significant morbidity and mortality, with overall survival contingent on multiple factors - most importantly, disease stage at diagnosis. Disruptions in healthcare delivery during the COVID-19 pandemic have resulted in various reported diagnostic and treatment delays, which have had detrimental impacts on malignancies such as RCC. METHODS: Surgically managed cases of RCC at our center were identified using a retrospective chart review of all nephrectomies conducted from March 1, 2018, to February 28, 2023. Examination of disease characteristics in three time period cohorts (before, during, and following the COVID-19 pandemic) was undertaken. Timeframes were consistent with implementation and abolition of public health restrictions in the province of Newfoundland and Labrador. RESULTS: A total of 483 surgically managed RCC cases were identified during the study period. The median age was 65 years (interquartile range [IQR] 56-71), and 62.3% of patients were male. Demographics did not vary across timeframes. Before and during the pandemic, pathologic stage 3 (pT3) disease was reported in 38.9% and 35.4% of cases, respectively, whereas the post-pandemic period saw this presentation in 50.0% of patients. Surgical wait times increased significantly across study timeframes (p=0.003). CONCLUSIONS: The first year following the COVID-19 pandemic saw an 11.1% increase in patients presenting with pT3 RCC. These findings are suggestive of a clinically significant stage migration, which paired with prolonged wait times for surgery, provide critical consideration in the urgency of diagnostic and treatment decisions for RCC in the immediate future.

The Utility of Salvage Radiotherapy for an Inoperable Inguinal Recurrence of Squamous Cell Carcinoma of the Penis.

Penile cancer is a rare genitourinary malignancy for which limited treatment options exist beyond primary surgical resection. Metastatic lymphadenopathy represents a particularly poor prognosis with a lack of literature to suggest the effectiveness of radiation or systemic therapies. Our case documents an inguinal recurrence of penile squamous cell carcinoma not amenable to surgical intervention demonstrating complete response to salvage radiotherapy in the palliative setting. These observations propose the need for further research around the utility of radiotherapy in the management of metastatic penile malignancies.

A quality assurance review of penile cancer diagnostic delays and stage at presentation during the COVID-19 pandemic.

INTRODUCTION: Penile carcinomas represent a rare malignancy associated with significant psychosocial impacts that deter afflicted individuals from seeking medical attention, thus, worsening prognosis. Following the dramatic shift in healthcare delivery to virtual platforms, it is suspected that prevalent psychosocial impacts have been further compounded by the COVID-19 pandemic, resulting in several late-stage presentations and engendering poorer outcomes. METHODS: A retrospective chart review of surgically managed cases of penile cancer was conducted from January 2020 to June 2022 to identify patients that may have been unduly impacted by the COVID-19 pandemic. Included cases were analyzed in quantifying diagnostic and treatment delays, along with patient outcomes. Relevant epidemiological and pathological markers were also examined. RESULTS: Ten patients met the inclusion criteria. Average time delay from first complaint of a penile lesion to surgical management was 75 days, with 60% of patients experiencing a time delay of two months or more. The average delay from first complaint to diagnosis was 62 days in 2020 and 18 days in 2021. Advanced-stage disease was present in six (60%) individuals at presentation, while four (40%) patients perished during the study period. CONCLUSIONS: In cases of concern for penile malignancy, virtual care cannot replace the necessity of physical exams in preventing diagnostic and treatment delays. The present study further highlights the necessity of initial physical examination of penile abnormalities in preventing fatal outcomes for those afflicted. Such consideration warrants urgent examination of referred males with genital abnormalities to prevent further exacerbation of delays.

Structural Insights into the Inhibition of Undecaprenyl Pyrophosphate Synthase from Gram-Positive Bacteria.

The polyprenyl lipid undecaprenyl phosphate (C55P) is the universal carrier lipid for the biosynthesis of bacterial cell wall polymers. C55P is synthesized in its pyrophosphate form by undecaprenyl pyrophosphate synthase (UppS), an essential cis-prenyltransferase that is an attractive target for antibiotic development. We previously identified a compound (MAC-0547630) that showed promise as a novel class of inhibitor and an ability to potentiate ß-lactam antibiotics. Here, we provide a structural model for MAC-0547630's inhibition of UppS and a structural rationale for its enhanced effect on UppS from Bacillus subtilis versus Staphylococcus aureus. We also describe the synthesis of a MAC-0547630 derivative (JPD447), show that it too can potentiate ß-lactam antibiotics, and provide a structural rationale for its improved potentiation. Finally, we present an improved structural model of clomiphene's inhibition of UppS. Taken together, our data provide a foundation for structure-guided drug design of more potent UppS inhibitors in the future.

Functional Adrenocortical Carcinoma: A Rare Case With Thrombus Extension Into the Inferior Vena Cava and a Presentation of Cushing Syndrome.

Adrenocortical carcinoma (ACC) is a rare, highly malignant endocrine tumor, often associated with a poor prognosis. Most patients who develop ACC are either children of ages 1-6, or adults in their fourth to fifth decade of life. Individuals with a functional cortisol-secreting ACC frequently present with Cushing syndrome. We report a case of an 18-year-old male who was found to have a large ACC tumor, with thrombus extension into the inferior vena cava (IVC), after presenting with Cushing syndrome. ACC presents a challenging scenario for physicians as surgical resection remains the only form of curative therapy, however, despite such treatment many patients quickly develop metastases.

Development of a 3D-printed testicular cancer model for testicular examination education.

INTRODUCTION: Testicular cancer is the most commonly diagnosed malignancy in young males. Testicular examination is a non-invasive and inexpensive means of detecting testicular cancer at an early stage. In this project, a set of 3D-printed models was developed to facilitate teaching testicular examination and improving understanding of testicular malignancies among patients and medical learners. METHODS: Five scrotum models were designed: a control model with healthy testes, and four models containing a healthy testicle and a testicle with an endophytic mass of varying size. The anatomy, texture, and composition of the 3D-printed models were refined using an iterative process between the design team and urologists. The completed models were assessed by six urologists, two urology nurse practitioners, and 32 medical learners. Participants were asked to inspect and palpate each model, and to provide feedback using a five-point Likert scale. RESULTS: Clinicians reported that the models enabled accurate simulation of a testicular examination involving both healthy and pathologic testes (χ̄=4.3±1.0). They agreed that the models would be useful teaching tools for both medical learners (χ̄=4.8±0.5) and patients (χ̄=4.8±0.7). Following an educational session with the models, medical learners reported improvements in confidence and skill in performing a testicular examination. CONCLUSIONS: 3D-printed models can effectively simulate palpation of both healthy and pathologic testes. The developed models have the potential to be a useful adjunct in teaching testicular examination and in demonstrating abnormal findings that require further investigation.

Nephroureterectomy of Right-to-Left Crossed Fused Renal Ectopia with Urothelial Carcinoma.

Urothelial carcinoma in a crossed fused renal ectopia (CFRE) is an exceedingly rare clinical finding. We describe the surgical management used to treat upper tract urothelial carcinoma in a 64-year-old man with a right-to-left CFRE. Nephroureterectomy with bladder cuff excision was the treatment of choice. The fused kidney was carefully dissected until an area of demarcation emerged between the vasculature supplying the left and right moieties. Pressure was applied to the isthmus separating the two moieties, and a sharp incision was made to release the left moiety. The operation was completed with limited blood loss. Pathology revealed a high-grade T3 papillary urothelial carcinoma with negative margins. To our knowledge, the case is the first to report urothelial carcinoma in a right-to-left CFRE.

Identification of tumor size as the only factor associated with nondiagnostic biopsies in patients with small renal masses.

INTRODUCTION: As greater numbers of small renal masses (SRMs) are discovered incidentally, renal tumor biopsy (RTB) is an increasingly recognized step for the management of these lesions, ideally for the prevention of surgical overtreatment for benign disease. While the diagnosis can often be obtained preoperatively by RTB, indeterminate results create greater difficulty for patients and clinicians. This study examines a series of RTBs, identifying the portion of these that were able to yield a diagnosis, and correlates patient factors, including RENAL and PADUA scoring, with the outcome of a non-diagnostic result. METHODS: Patients were identified as having undergone RTB at the Princess Margaret Cancer Centre in Ontario, Canada, between January 2000 and December 2009. Data was compiled from these 423 patients and analyzed using CART methodology to determine the level of association between various patient and tumor factors and the outcome of a non-diagnostic biopsy. Tumor size was further used to develop a classification tree to describe the prediction of a non-diagnostic biopsy. RESULTS: Of these 423 patients undergoing RTB, 66 (16%) resulted in a non-diagnostic biopsy. The only patient or tumor factor that was found to be associated with a non-diagnostic outcome was mass size, where small masses (<1.28 cm diameter) were found to have a 38% chance of being non-diagnostic, compared with a 13% chance in those tumors >1.28 cm diameter (86% accuracy, 95% confidence interval [CI] 0.82-0.89). CONCLUSIONS: When evaluating SRMs for diagnostic workup, mass size is the only tumor or patient characteristic associated with a non-diagnostic RTB.

Classification tree for the prediction of malignant disease and the prediction of non-diagnostic biopsies in patients with small renal masses.

INTRODUCTION: Preoperative prediction of benign vs. malignant small renal masses (SRMs) remains a challenge. This study: 1) validates our previously published classification tree (CT) with an external cohort; 2) creates a new CT with the combined cohort; and 3) evaluates the RENAL and PADUA scoring systems for prediction of malignancy. METHODS: This study includes a total of 818 patients with renal masses; 395 underwent surgical resection and 423 underwent biopsy. A CT to predict benign disease was developed using patient and tumour characteristics from the 709 eligible participants. Our CT is based on four parameters: tumour volume, symptoms, gender, and symptomatology. CART modelling was also used to determine if RENAL and PADUA scoring could predict malignancy. RESULTS: When externally validated with the surgical cohort, the predictive accuracy of the old CT dropped. However, by combining the cohorts and creating a new CT, the predictive accuracy increased from 74% to 87% (95% confidence interval 0.84-0.89). RENAL and PADUA score alone were not predictive of malignancy. One limitation was the lack of available histological data from the biopsy series. CONCLUSIONS: The validated old CT and new combined-cohort CT have a predictive value greater than currently published nomograms and single-biopsy cohorts. Overall, RENAL and PADUA scores were not able to predict malignancy.

Renal cell carcinoma after neuroblastoma: A case study and review of the literature.

We present a case of renal cell carcinoma (RCC) arising in a 26-year-old patient with a history of neuroblastoma. RCC after a previous diagnosis of neuroblastoma is very uncommon, and there have only been 23 reported cases. Using the results of our patient workup, we hoped to determine whether there was a genetic predisposition or iatrogenic cause for the RCC. There is no clear explanation why neuroblastoma survivors are prone to developing RCC. However, genetic predisposition and previous treatment likely play a role. Since there have been few cases described, and few investigations into the genetics of this subtype of RCC, it remains important for individual cases to be added to the literature of this recently described and rare entity.

Growth kinetics of small renal masses: A prospective analysis from the Renal Cell Carcinoma Consortium of Canada.

INTRODUCTION: Most small renal masses (SRMs) are diagnosed incidentally and have a low malignant potential. As more elderly patients and infirm patients are diagnosed with SRMs, there is an increased interest in active surveillance (AS) with delayed intervention. Patient and tumour characteristics relating to aggressive disease have not been well-studied. The objective was to determine predictors of growth of SRMs treated with AS. METHODS: A multicentre prospective phase 2 clinical trial was conducted on 207 SRMs in 169 patients in 8 institutions in Canada from 2004 to 2009; in these patients treatment was delayed until disease progression. Patient and tumour characteristics were evaluated to determine predictors of growth of SRMs by measuring rates of change in growth (on imaging) over time. All patients underwent AS for presumed renal cell carcinoma (RCC) based on diagnostic imaging. We used the following factors to develop a predictive model of tumour growth with binary recursive partitioning analysis: patient characteristics (age, symptoms at diagnosis) and tumour characteristics (consistency [solid vs. cystic] and maximum diameter at diagnosis. RESULTS: With a median follow-up of 603 days, 169 patients (with 207 SRMs) were followed prospectively. Age, symptoms at diagnosis, tumour consistency and maximum diameter of the renal mass were not predictors of growth. This cohort was limited by lack of availability of patient and tumour characteristics, such as sex, degree of endophytic component and tumour location. CONCLUSION: Slow growth rates and the low malignant potential of SRMs have led to AS as a treatment option in the elderly and infirm population. In a large prospective cohort, we have shown that age, symptoms, tumour consistency and maximum diameter of the mass at diagnosis are not predictors of growth of T1a lesions. More knowledge on predictors of growth of SRMs is needed.

Intermittent LHRH therapy in the management of castrate-resistant prostate cancer (CRPCa): results of a multi-institutional randomized prospective clinical trial.

BACKGROUND: Patients who develop castration-resistant prostate cancer (CRPCa) typically continue on androgen deprivation therapy (ADT). Whether these patients need to remain on ADT has not been well studied. We conducted a multicenter randomized trial to compare an intermittent versus continuous approach to ADT in CRPCa patients. Overall survival, health-related quality of life (QOL), and cost were the main endpoints. METHODS: CRPCa patients were randomized 2:1 to intermittent or continuous luteinizing hormone-releasing hormone agonists (LHRHa). Patients were followed with clinical assessments, laboratory investigations, and QOL questionnaires (EORTC QLQ-C30 or PROSQOLI) every 2 months. If the serum testosterone rose above castrate levels (1.75 nmol/L), LHRHa were reinitiated. The study was designed to close if >50% of patients needed to restart ADT in the intermittent arm. RESULTS: Thirty-one patients were followed with a median follow-up of 26.8 months-18 in the intermittent arm and 13 in the continuous. Twelve of 18 patients on the intermittent arm were reinitiated on LHRHa at a median time of 17.9 months. There was no difference in overall or cancer-specific survival between the 2 arms. There was no statistically significant difference in QOL between the 2 arms at 0 and 12 months. The total mean costs at 24 months were significantly lower in the intermittent arm ($3135 vs. $8253 Canadian dollars, P=0.0167) compared with the continuous. The main limitation of this study is the small sample size. CONCLUSIONS: We have observed that intermittent ADT in patients with CRPCa, using a testosterone of >1.75 ngmol/L as a trigger to reinitiate LHRHa, results in a substantial cost savings with no negative impact on oncologic and QOL outcomes.

Acute reversible kidney injury secondary to bilateral ureteric obstruction.

BACKGROUND: Acute reversible kidney injury (ARKI) secondary to bilateral ureteric obstruction (BUO) is a common urological problem. Our goals were to describe the etiology, management and outcomes of such patients identified between 2006 and 2009 and to compare them with a similar historical study published in 1982. METHODS: Chart review was performed on 49 patients with AKRI secondary to BUO. ARKI was defined as ≥33% decrease in serum creatinine after intervention. Those with malignant and benign causes of obstruction were identified and management and outcome data were collected. RESULTS: Of these 49 patients, 83% had BUO secondary to malignancy, 28% of these presenting for the first time. Prevalence of bladder cancer was increased (p = 0.04) and cervix trended lower (p = 0.07) compared with the earlier study; prostate cancer was unchanged (p = 0.51). The average survival was 239 days; 90% of patients died within a year after presenting with BUO from a malignant etiology. Compared with the 1982 group, there were trends towards a decrease in the frequency of retroperitoneal fibrosis (p = 0.08) and an increase in bilateral ureteric calculi (p = 0.16) in the benign group. CONCLUSIONS: Patients with ARKI secondary to BUO most likely have an underlying malignancy, with almost a third of them being diagnosed for the first time. Prevalence of bladder cancer increased while cervical cancer trended lower. The cause for the former is unclear; the latter may be due to aggressive screening. Prostate cancer remained unchanged despite the widespread implementation of prostate-specific antigen testing. Patients with an underlying malignancy do poorly and those with a newly diagnosed malignancy do worst. Those with ARKI secondary to benign causes did well.

Burkholderia cepacia infection of the prostate caused by inoculation of contaminated ultrasound gel during transrectal biopsy of the prostate.

Burkholderia cepacia infection of the prostate is very rare. We report 6 cases of prostatic infection secondary to inoculation of contaminated ultrasound gel during transrectal biopsy of the prostate. All of these patients required hospitalization and were treated with intravenous antibiotics. One of these cases is the first description of chronic prostatitis with B. cepacia.

Synthesis of 4-(5-iodo-3-methylpyrazolyl) phenylsulfonamide and its elaboration to a COX II inhibitor library by solution-phase suzuki coupling using Pd/C as a solid-supported catalyst.

An effective synthesis of 4-(5-iodo-3-methylpyrazolyl) phenylsulfonamide has been developed. This aromatic iodide template served as an efficient oxidative addition partner for the preparation of a solution-phase library of Celecoxib analogues via Suzuki coupling using Pd/C, a readily filterable catalyst.