Impact of HLA class I functional divergence on HIV control.

Heterozygosity of Human leukocyte antigen (HLA) class I genes is linked to beneficial outcomes after HIV infection, presumably through greater breadth of HIV epitope presentation and cytotoxic T cell response. Distinct allotype pairs, however, differ in the extent to which they bind shared sets of peptides. We developed a functional divergence metric that measures pairwise complementarity of allotype-associated peptide binding profiles. Greater functional divergence for pairs of HLA-A and/or HLA-B allotypes was associated with slower AIDS progression and independently with enhanced viral load control. The metric predicts immune breadth at the peptide level rather than gene level and redefines HLA heterozygosity as a continuum differentially affecting disease outcome. Functional divergence may affect response to additional infections, vaccination, immunotherapy, and other diseases where HLA heterozygote advantage occurs.

The Wrong Fight-Prior Authorization.

This essay describes the author's experience with denial of prior authorization for imaging to complete cancer staging.

Risk of secondary malignancy following radiation therapy for prostate cancer.

We investigated whether prostate cancer patients treated with external beam radiation therapy (EBRT) have a higher cumulative incidence of secondary cancer compared with patients treated with radical prostatectomy (RP). We used state-wide linked data from South Australia to follow men with prostate cancer diagnosed from 2002 to 2019. The cumulative incidence of overall and site-specific secondary cancers between 5 and 15 years after treatment was estimated. Fine-Gray competing risk analyses were performed with additional sensitivity analyses to test different scenarios. A total of 7625 patients were included (54% underwent RP and 46% EBRT). Characteristics of the two groups differed significantly, with the EBRT group being older (71 vs. 64 years), having higher comorbidity burden and being more likely to die during follow-up than the RP group. Fifteen-year cumulative incidence for all secondary cancers was 27.4% and 22.3% in EBRT and RP groups, respectively. In the adjusted models, patients in the EBRT group had a significantly higher risk of genitourinary (adjusted subhazard ratio (aSHR), 2.29; 95%CI 1.16-4.51) and lung (aSHR, 1.93; 95%CI 1.05-3.56) cancers compared with patients in the RP group. However, there was no statistically significant difference between the two groups for risk of any secondary cancer, gastro-intestinal, skin or haematologic cancers. No statistically significant differences in overall risk of secondary cancer were observed in any of the sensitivity analyses and patterns for risk at specific cancer sites were relatively consistent across different age restriction and latency/time-lag scenarios. In conclusion, the increased risk of genitourinary and lung cancers among men undergoing EBRT may relate partly to treatment effects and partly to unmeasured residual confounding.

Long term genitourinary toxicity following curative intent intensity-modulated radiotherapy for prostate cancer: a systematic review and meta-analysis.

BACKGROUND: Recent studies have shown that radiation-induced pelvic toxicity often requires urological consultation. However, the 10-year incidence of genitourinary toxicity following intensity-modulated radiotherapy (IMRT) amongst patients with localised prostate cancer remains unclear. Hence, we conducted a systematic review and meta-analysis to determine the incidence of late genitourinary toxicity relying on Radiation Therapy Oncology Group (RTOG) and Common Terminology Criteria for Adverse Events (CTCAE) grade as well as the incidence of specific genitourinary toxicity. Secondary objectives involved quantifing the number of studies reporting 120-month follow-up endpoints, time to event analysis, predictive factors or economic evaluation. METHODS: Articles published from January 2008 to December 2021 describing prospective studies were systematically searched in MEDLINE, EMBASE and Cochrane (PROSPERO protocol CRD42019133320). Quality assessment was performed by use of the Cochrane Risk of Bias 2 Tool for RCTs and the Newcastle Ottowa Scale for non-RCTs. Meta-analysis was performed on the 60-month incidence of RTOG and CTCAE Grade ≥2 genitourinary toxicity, haematuria, urinary retention and urinary incontinence. RESULTS: We screened 4721 studies and six studies met our inclusion criteria. All included studies involved normofractionation, three included a hypofractionation comparator arm and none involved nodal irradiation. The pooled 60-month cumulative incidence of RTOG and CTCAE Grade ≥2 genitourinary toxicity were 17% (95% CI: 5-20%, n = 678) and 33% (95% CI: 27-38%, n = 153), respectively. The pooled 60-month cumulative incidence of Haematuria was 5% (95% CI: -4-14%, n = 48), Urinary incontinence 12% (95% CI: 6-18%, n = 194), Urinary retention 24% (95% CI: 9-40%, n = 10). One study reported time to event analyses, one reported predictive factors, no studies reported economic analysis or 120-month toxicity. There was considerable heterogeneity amongst the studies. CONCLUSION: There are few high-quality studies reporting 60-month toxicity rates after IMRT. Conservative estimates of 60-month toxicity rates are high and there is need for longer follow-up and consistent toxicity reporting standards.

Predicting post-radiation genitourinary hospital admissions in patients with localised prostate cancer.

PURPOSE: The risk of treatment-related toxicity is important for patients with localised prostate cancer to consider when deciding between treatment options. We developed a model to predict hospitalisation for radiation-induced genitourinary toxicity based on patient characteristics. METHODS: The prospective South Australian Prostate Cancer Clinical Outcomes registry was used to identify men with localised prostate cancer who underwent curative intent external beam radiotherapy (EBRT) between 1998 and 2019. Multivariable Cox proportional regression was performed. Model discrimination, calibration, internal validation and utility were assessed using C-statistics and area under ROC, calibration plots, bootstrapping, and decision curve analysis, respectively. RESULTS: There were 3,243 patients treated with EBRT included, of which 644 (20%) patients had a treated-related admission. In multivariable analysis, diabetes (HR 1.35, 95% CI 1.13-1.60, p < 0.001), smoking (HR 1.78, 95% CI 1.40-2.12, p < 0.001), and bladder outlet obstruction (BOO) without transurethral resection of prostate (TURP) (HR 7.49, 95% CI 6.18-9.08 p < 0.001) followed by BOO with TURP (HR 4.96, 95% CI 4.10-5.99 p < 0.001) were strong independent predictors of hospitalisation (censor-adjusted c-statistic = 0.80). The model was well-calibrated (AUC = 0.76). The global proportional hazards were met. In internal validation through bootstrapping, the model was reasonably discriminate at five (AUC 0.75) years after radiotherapy. CONCLUSIONS: This is the first study to develop a predictive model for genitourinary toxicity requiring hospitalisation amongst men with prostate cancer treated with EBRT. Patients with localised prostate cancer and concurrent BOO may benefit from TURP before EBRT.

Pelvic Radiation Disease.

Pelvic radiation is increasingly being used for the neoadjuvant and definitive treatment of pelvic organ malignancy. While this treatment can be highly effective, and may assist in organ sparing, it is also associated with significant toxicity and devastating adverse events that need to be considered. In broad terms, pelvic radiation disease affects both the primary target organ as well as adjacent organs and soft tissue structures, with complications that can be classified and graded according to consensus criteria. The complication grade is often modality, dose, and area dependent. The most common manifestations are proctitis, cystitis, recto-urethral fistula, ureteric stricture, and bone involvement. Toxicity can be misdiagnosed for many years, resulting in significant management delays. Complications can be difficult to prevent and challenging to treat, requiring specialized multi-disciplinary input to achieve the best possible strategy to minimize impact and improve patient quality of life.

Effects of metastatic CRC predictors on treatment outcomes.

BACKGROUND: Colorectal cancer (CRC) is the third most commonly diagnosed malignant tumor. The problem of mCRC is urgent due to both an increase in the number of metastatic tumors and the implementation of high-tech treatment methods that have significantly improved the results of a 5-year survival. METHODS: The research used the method of experiment and observation. Current study included data of 332 patients with CRC who received comprehensive treatment from 2014 to 2018 in oncology centers of the Republic of Kazakhstan. The patients were treated according to the clinical protocols for the treatment of oncological diseases approved in the Republic of Kazakhstan, including surgical treatment, as well as chemotherapy and radiation therapy, depending on the stage and localization of the process. A comprehensive treatment also included surgical treatment, chemotherapy, targeted chemotherapy and, in some cases, radiation therapy for rectal cancer. The diagnosis was confirmed morphologically in all patients; process dissemination was recorded using standard examination methods. Among the patients, women prevailed - 182 (54.8%) women and 150 men (45.2%) were included; the Caucasian race prevailed - 170 (51.2%) patients and 162 (48.8%) patients were of the Asian race. The mean age of the patients at the time of treatment was 56.4 ± 0.6 years (from 25 to 79 years). Histologically, adenocarcinoma prevailed represented by glandular - in 95.6%, mucous - in 2.9% and trabecular - in 1.5% of cases. A comprehensive treatment was used in 209 (63.0%) patients and other types of treatment were used in 123 (37.0%) patients (PCT, stoma + PCT). Radiation therapy was administered to 13 (3.9%) patients diagnosed with rectal cancer. RESULTS: A comparative analysis of the results of pharmacotherapy in the patients with mCRC showed that of 332 patients, 263 (79.2%) received targeted chemotherapy and 69 (20.8%) received standard polychemotherapy. At the time of the study, 85 (32.3%) patients in the targeted chemotherapy group were still alive, with a median survival of 42.0 ± 1.7 months, 95% CI (38.6-45.4). In the polychemotherapy group, 7 (10.1%) patients were alive, while the median survival rate was 20.0 ± 1.7 months, 95% CI (16.6-23.4). CONCLUSION: Based on the results, it was concluded that targeted chemotherapy schemes increased progression-free survival, compared to standard polychemotherapy schemes.

Incidence of genitourinary complications following radiation therapy for localised prostate cancer.

PURPOSE: Studies of genitourinary toxicity following radiotherapy for prostate cancer are mainly from high volume single institutions and the incidence and burden of treatment remain uncertain. Hence we determine the cumulative incidence of treatment-related genitourinary toxicity in patients with localised prostate cancer treated with primary external beam radiotherapy (EBRT) at a state population level. METHODS: We analysed data from a prospective population-based cohort, including hospital admission and cancer registry data, for men with localised prostate cancer who underwent primary EBRT without nodal irradiation between 1998 and 2019 in South Australia. The 10-year cumulative incidence of genitourinary toxicity requiring hospitalisation or procedures was determined. Clinical predictors of toxicity and the volume of admissions, non-operative, minor operative and major operative procedures were determined. RESULTS: All the included patients (n = 3350) had EBRT, with a median (IQR) of 74 Gy (70-78) in 37 fractions (35-39). The 10-year cumulative incidence of was 28.4% (95% CI 26.3-30.6) with a total of 2545 hospital admissions, including 1040 (41%) emergency and 1893 (74%) readmissions. The 10-year cumulative incidence of patients in this cohort requiring a urological operative procedure was 18% (95% CI 16.1-19.9), with a total of 106 (4.2%) non-operative, 1044 (41%) minor operative and 57 (2.2%) major operative urological procedures. CONCLUSIONS: Genitourinary toxicity after radiotherapy for prostate cancer is common. Although there continue to be advancements in radiotherapy techniques, patients and physicians should be aware of the risk of late toxicity when considering EBRT.

Valsalva leak point pressure (VLPP) greater than 70 cm H2O is an indicator for sling success: a success prediction model for the male transobturator sling.

INTRODUCTION AND OBJECTIVES: Urodynamic studies are often performed in the evaluation of post-prostatectomy urinary incontinence (PPUI). The male transobturator sling (TOS) is a minimally invasive treatment for PPUI. Others have reported their results with a specific Valsalva leak point pressure (VLPP) that predicts a good outcome with the male TOS. Our objective was to determine the relationship of the pre-operative VLPP on the success rate of the male TOS in a high-volume, single center. We hypothesized that a higher pre-operative VLPP better predicts successful outcomes. METHODS: We reviewed patients undergoing a male TOS placement from 2006 to 2012 at our institution. Patients who underwent TOS placement were identified using our patient data portal (DEDUCE). Demographic, urodynamic, and follow-up data were extracted by chart review. Post-operative success was defined by the use of 0 or 1 security pad, a negative stress test on exam, or pad weight of less than 8 g per 24 h. Cox and linear regression models were performed. RESULTS: 290 patients were included. All patients underwent a radical prostatectomy for prostate cancer and presented with PPUI. Mean age at surgery was 66.3 (± 7.4) years and 84% were Caucasian. Median time to follow-up was 5 months (IQR 1-15). A linear regression model shows an inverse prediction curve for sling failure versus VLPP (p = 0.02). The hazard ratio for failure with a VLPP of ≤ 70 cm H2O compared with a VLPP of > 70 cm H2O, adjusted for pelvic radiation and 24-h pad weight was 0.5 (95% CI 0.2-0.98). CONCLUSION: Patient selection is imperative in the success of the male TOS for patients with PPUI. In our cohort of patients with PPUI, those with a pre-procedural VLPP of > 70 cm H2O were 50% less likely to fail after TOS placement versus those with a VLPP ≤ 70 cm H2O. In our practice, we use these data to support the use of VLPP cut off of 70 cm H2O as an indicator for success to help in the evaluation and counseling of patients.

The impact of the coronavirus disease 2019 pandemic on elective urological procedures in Australia.

OBJECTIVE: To investigate the changes in elective private urological procedures in Australia during the coronavirus disease 2019 pandemic. METHODS: Data were extracted from publicly available datasets from Medicare Benefits Schedule using item numbers assigned to each commonly performed urological intervention. These procedures were divided into three groups: Oncological therapeutic, diagnostic, and non-oncological therapeutic procedures. A smoothing model, based on the historic procedure numbers from 2017 to 2019, was used to forecast monthly number of procedures performed in each category between January 2020 and June 2020. These forecasted models were compared with reported figures. RESULTS: A total of 108 169 procedures were performed between January 2020 and June 2020 based on the Medicare Benefits Schedule item numbers listed. There was a significant reduction (percentage change) in total procedures performed in April 2020 (-22.6%, 95% confidence interval [CI]: -28.7% to -15.4%) and May 2020 (-33.2%, 95% CI: -37.5% to -28.3%). There was a significant reduction in oncological therapeutic, non-oncological therapeutic, and diagnostic procedures performed in April 2020 and May 2020 (p<0.05). These numbers did not include procedures performed in public sector. CONCLUSION: There was a significant reduction in total urological procedures (including diagnostic, oncological, and non-oncological) performed in months of April 2020 and May 2020 during time of federal restrictions. Both public and private healthcare sectors need to be supported in the upcoming months to prevent further delays in treatment and poorer clinical outcomes.

Identification and Characterization of Antigen-Specific CD8+ T Cells Using Surface-Trapped TNF-α and Single-Cell Sequencing.

CD8+ T cells are key mediators of antiviral and antitumor immunity. The isolation and study of Ag-specific CD8+ T cells, as well as mapping of their MHC restriction, has practical importance to the study of disease and the development of therapeutics. Unfortunately, most experimental approaches are cumbersome, owing to the highly variable and donor-specific nature of MHC-bound peptide/TCR interactions. Here we present a novel system for rapid identification and characterization of Ag-specific CD8+ T cells, particularly well suited for samples with limited primary cells. Cells are stimulated ex vivo with Ag of interest, followed by live cell sorting based on surface-trapped TNF-α. We take advantage of major advances in single-cell sequencing to generate full-length sequence data from the paired TCR α- and ß-chains from these Ag-specific cells. The paired TCR chains are cloned into retroviral vectors and used to transduce donor CD8+ T cells. These TCR transductants provide a virtually unlimited experimental reagent, which can be used for further characterization, such as minimal epitope mapping or identification of MHC restriction, without depleting primary cells. We validated this system using CMV-specific CD8+ T cells from rhesus macaques, characterizing an immunodominant Mamu-A1*002:01-restricted epitope. We further demonstrated the utility of this system by mapping a novel HLA-A*68:02-restricted HIV Gag epitope from an HIV-infected donor. Collectively, these data validate a new strategy to rapidly identify novel Ags and characterize Ag-specific CD8+ T cells, with applications ranging from the study of infectious disease to immunotherapeutics and precision medicine.

Cancer survivors exercise at higher intensity in outdoor settings: The GECCOS trial.

PURPOSE: This randomized cross-over group pilot trial assessed feasibility of recruiting survivors from a long-term follow-up clinic to an exercise group and measured whether outdoor or indoor exercise sessions better supported exercise motivation and behaviors in survivors of cancer. METHODS: Sixteen adolescent and young adult survivors of any cancer completed indoor and outdoor exercise sessions in this randomized cross-over pilot trial. Measures of physical activity, motivation, and fatigue were taken 2 weeks before and 2 weeks after indoor sessions and 2 weeks before and 2 weeks after outdoor sessions. Measures of physical activity and fatigue were also taken during each exercise session. RESULTS: Initial recruiting of 19 participants met recruiting goals. Survivors who attended the most sessions lived an average of 8.7 km closer to the clinic. Objectively measured physical activity intensity was 0.63 metabolic equivalents of a task (METs) per minute greater during outdoor exercise sessions as compared to indoor exercise sessions. There were no meaningful differences in long term, habitual physical activity behavior, motivation, or fatigue in the weeks following the outdoor exercise sessions as compared to the indoor exercise sessions. CONCLUSIONS: This study shows the feasibility of recruiting survivors from a long-term follow-up clinic to community-based exercise groups. Although this brief pilot intervention did not show significant effects on habitual physical activity behavior or motivation in adolescent and young adult survivors of cancer, the greater exercise intensity during the outdoor exercise sessions indicate that holding group exercise sessions for survivors outdoors may promote greater intensity during exercise.

Classification systems for anterior urethral stricture disease in men: a systematic review.

OBJECTIVE: To identify and explore the various classification systems that have been proposed for anterior urethral stricture disease (AUSD) and to identify the advantages and disadvantages of each. METHODS: A comprehensive systematic review was conducted in MEDLINE, EMBASE, SCOPUS and COCHRANE databases with a search strategy created appropriately. Titles and abstracts of search results were screened by two authors and selected for full-text review. Studies exploring urethral stricture classification, clinical scoring or staging systems used in men over the age of 18 with benign anterior urethral stricture disease were included. RESULTS: The search identified 3113 articles, of which 10 were selected for inclusion after scrutiny. Four classification systems were identified. These include ULTRA score, urethral stricture score, cystoscopy-based staging system and Gombe Urethrographic score. These were based on various modalities, including cystoscopy, retrograde urethrogram (RUG) and sonourethrogram (SUG). From the scoring systems identified, the urethral stricture scoring system has multiple external validation studies and is predictive of operative complexity, operative time, recurrence and postoperative complications. CONCLUSIONS: Several classification systems have been proposed for AUSD. Each has its advantages and disadvantages. The urethral stricture score has been externally validated and shown to been predictive of surgical outcomes and recurrence. There are no scores that incorporate patient-related outcome measures (PROMs). Many classification systems have yet to provide sufficient external validation. Further external validation studies are needed before the general adoption of a particular system.

Urinary Pubic Symphysis Fistula Leads to Histopathologic Osteomyelitis in Prostate Cancer Survivors.

OBJECTIVE: To assess the histologic findings in the pubic bone resected during extirpative surgery for urinary pubic symphysis fistula (UPF). The concurrent presence of osteomyelitis and the need for bone resection at time of extirpative surgery for UPF has been debated. We hypothesized that UPF results in histopathologically confirmed osteomyelitis, underscoring the importance of bone resection at the time of surgery. METHODS: An IRB-approved retrospective review of all patients undergoing surgery for UPF from 2012 to 2019 was performed. Demographic data were recorded. A single pathologist performed histopathologic examination of bone tissue in each case. Logistic regression and Fisher exact test were used to assess association of osteomyelitis with clinical factors. RESULTS: We identified 36 patients who underwent major extirpative surgery for UPF with bone pathology available for review. Bone histopathology findings confirmed presence of osteomyelitis in the majority (n = 32, 88.9%). This was characterized as chronic osteomyelitis in 15 (41.7%), acute osteomyelitis only in 1 (2.8%) and combined chronic, and acute osteomyelitis in 16 (44.4%). Osteonecrosis was seen in 11 cases (33.6%). There was no correlation between presence of osteomyelitis and age, timing from radiotherapy to diagnosis of UPF, type of radiotherapy, or history of endoscopic bladder outlet procedures. CONCLUSION: Osteomyelitis is present on histology of the pubic bone resected during surgery for UPF in the majority of cases (88.9%). Osteonecrosis is also common. These findings underscore the critical importance of pubic bone resection at time of UPF surgery to adequately treat the diseased bone.

Structure-Based Virtual Screening of Ultra-Large Library Yields Potent Antagonists for a Lipid GPCR.

Cysteinyl leukotriene G protein-coupled receptors, CysLT1R and CysLT2R, regulate bronchoconstrictive and pro-inflammatory effects and play a key role in allergic disorders, cardiovascular diseases, and cancer. CysLT1R antagonists have been widely used to treat asthma disorders, while CysLT2R is a potential target against uveal melanoma. However, very few selective antagonist chemotypes for CysLT receptors are available, and the design of such ligands has proved to be challenging. To overcome this obstacle, we took advantage of recently solved crystal structures of CysLT receptors and an ultra-large Enamine REAL library, representing a chemical space of 680 M readily available compounds. Virtual ligand screening employed 4D docking models comprising crystal structures of CysLT1R and CysLT2R and their corresponding ligand-optimized models. Functional assessment of the candidate hits yielded discovery of five novel antagonist chemotypes with sub-micromolar potencies and the best Ki = 220 nM at CysLT1R. One of the hits showed inverse agonism at the L129Q constitutively active mutant of CysLT2R, with potential utility against uveal melanoma.

HLA tapasin independence: broader peptide repertoire and HIV control.

Human leukocyte antigen (HLA) class I allotypes vary in their ability to present peptides in the absence of tapasin, an essential component of the peptide loading complex. We quantified tapasin dependence of all allotypes that are common in European and African Americans (n = 97), which revealed a broad continuum of values. Ex vivo examination of cytotoxic T cell responses to the entire HIV-1 proteome from infected subjects indicates that tapasin-dependent allotypes present a more limited set of distinct peptides than do tapasin-independent allotypes, data supported by computational predictions. This suggests that variation in tapasin dependence may impact the strength of the immune responses by altering peptide repertoire size. In support of this model, we observed that individuals carrying HLA class I genotypes characterized by greater tapasin independence progress more slowly to AIDS and maintain lower viral loads, presumably due to increased breadth of peptide presentation. Thus, tapasin dependence level, like HLA zygosity, may serve as a means to restrict or expand breadth of the HLA-I peptide repertoire across humans, ultimately influencing immune responses to pathogens and vaccines.

Characteristics and Price Increases Among Sole-Source, Off-Patent Drugs in the United States, 2008 to 2018.

Importance: Some sole-source, off-patent drugs in the United States have undergone substantial price hikes in recent years. Despite increased attention by lawmakers, there are limited data to guide policy. Objectives: To describe key attributes of sole-source, off-patent, off-exclusivity drugs; to characterize the prevalence of price increases; and to identify attributes associated with price increases. Design, Setting, and Participants: In this cross-sectional study, 300 sole-source, off-patent, off-exclusivity drug products met inclusion criteria and were selected for analysis from January 1, 2008, to December 31, 2018. Attributes were identified from multiple sources, and yearly wholesale acquisition cost prices were determined from First Databank. Main Outcomes and Measures: The association of drug attributes with the following 2 price change thresholds was measured after adjusting for inflation: 25% or more price increase in a calendar year (wholesale acquisition cost) and 50% or more price increase in a calendar year. The rate of annual price increase over time was also measured. Results: Of the 300 drug products and 2242 observations analyzed, the overall inflation-adjusted mean increase in drug prices was 8.8% (95% CI, 7.8%-9.8%) per year. Ninety-five drugs (31.7%) increased by 25% or more during any calendar year, and 66 drugs (22.0%) increased by 50% or more during any calendar year. An initial price of less than $2 per unit (adjusted odds ratio [aOR], 2.36; 95% CI, 1.69-3.29), antineoplastic and immunomodulatory class (aOR, 2.72; 95% CI, 1.31-5.65), dermatologic class (aOR, 2.95; 95% CI, 1.80-4.84), oral route (aOR, 2.01; 95% CI, 1.45-2.79), and US Food and Drug Administration (FDA) approval before 1990 (aOR, 1.52; 95% CI, 1.14-2.03) were attributes of drugs that were more likely to be associated with a 25% or more price increase in a calendar year after adjusting for by initial price. Similarly, an initial price of less than $2 per unit (aOR, 2.68; 95% CI, 1.76-4.09), antineoplastic and immunomodulatory class (aOR, 3.07; 95% CI, 1.54-6.12), oral route of administration (aOR, 1.70; 95% CI, 1.11-2.60), and FDA approval before 1990 (aOR, 2.02; 95% CI, 1.40-2.94) were attributes of drugs that were more likely to be associated with a 50% or more price increase in a calendar year after adjusting for by initial price. Price increases of 25% or more were most common in 2014, and price increases of 50% or more were most common in 2013. Conclusions and Relevance: Price increases among sole-source, off-patent drugs are common, and policy interest in this practice is warranted. These findings should inform state drug pricing legislation.

Extirpative Cultures Reveal Infectious Pubic Bone Osteomyelitis in Prostate Cancer Survivors With Urinary-Pubic Symphysis Fistulae (UPF).

OBJECTIVE: To examine the infectious features of patients with urinary pubic symphysis fistula (UPF) and their association with osteomyelitis. METHODS: We conducted a review of our quality improvement database for 36 patients with UPF undergoing bone resection and extirpative surgery from October 2012 to January 2019. An assessment of bone and urine cultures was carried out along with surgical, radiologic, and demographic data. We analyzed descriptive statistics and used Fisher Exact Tests and unpaired Welch t tests to assess for associations with positive bone cultures. RESULTS: In our cohort, 33 patients (91.7%) had positive bone cultures with the 3 most common organisms being candida (22.0%), enterococcus (18.0%), and pseudomonas (10.0%). There was a correlation between positive preoperative urine culture and positive bone culture (P <.01), with 63.0% of those with positive urine cultures growing the same organism on bone culture. CONCLUSION: In this series, 91.7% of patients undergoing extirpative surgery for UPF at our institution have positive bone cultures at time of pubic bone debridement. Additionally, we demonstrate a statistically significant correlation between positive urine cultures and positive bone cultures in these patients. This supports the need for a multidisciplinary approach including infectious disease, orthopedic surgery and reconstructive urology in order to address this complex clinical condition.

Association between perioperative intraperitoneal local anaesthetic infusion and long-term survival and cancer recurrence after colectomy: follow-up analysis of a previous randomized controlled trial.

BACKGROUND: High concentrations of local anaesthetic have an anti-proliferative effect on colonic cancer in vitro. Intraperitoneal local anaesthetic (IPLA) has shown analgesic benefit and improved recovery in the perioperative setting. The long-term effects of IPLA in colon cancer resection have not been examined. This study aims to review the survival and oncological outcomes of a previously conducted trial that compared perioperative IPLA with placebo. METHODS: Sixty patients underwent colonic resection for benign and malignant disease as part of a double-blinded, randomized, placebo-controlled study between September 2008 and November 2009. The IPLA group received instillation of intraperitoneal ropivacaine before dissection followed by a 3-day infusion. The placebo group was treated identically but with 0.9% saline solution. A follow-up analysis was conducted to evaluate overall survival, disease-free survival and recurrence specifically for patients undergoing resection for stages I-III colon cancer. Kaplan-Meier analysis was performed, and the log-rank test was used to evaluate difference in survival between groups. RESULTS: Thirty-seven of the 60 patients had stages I-III colon cancer and were included in this analysis. Nineteen patients were in the placebo group. There was no significant difference in overall survival or all-cause mortality. There was a higher incidence of cancer-specific mortality in the local anaesthetic group (P < 0.046). CONCLUSION: It does not appear that IPLA is associated with a significant survival benefit in patients with colonic malignancy undergoing colectomy. Other studies are needed to analyse the long-term outcomes.

Posterior urethral stenosis after prostate cancer treatment: contemporary options for definitive management.

Posterior urethral stenosis (PUS) is an uncommon but challenging problem following prostate cancer therapy. A review of the recent literature on the prevalence of PUS and treatment modalities used in the last decade was performed. A summative narrative of current accepted techniques in management of PUS is presented, and supplement with our own experience and algorithms.