Ongoing evolution of the Mycobacterium tuberculosis lactate dehydrogenase reveals the pleiotropic effects of bacterial adaption to host pressure.

The bacterial determinants that facilitate Mycobacterium tuberculosis (Mtb) adaptation to the human host environment are poorly characterized. We have sought to decipher the pressures facing the bacterium in vivo by assessing Mtb genes that are under positive selection in clinical isolates. One of the strongest targets of selection in the Mtb genome is lldD2, which encodes a quinone-dependent L-lactate dehydrogenase (LldD2) that catalyzes the oxidation of lactate to pyruvate. Lactate accumulation is a salient feature of the intracellular environment during infection and lldD2 is essential for Mtb growth in macrophages. We determined the extent of lldD2 variation across a set of global clinical isolates and defined how prevalent mutations modulate Mtb fitness. We show the stepwise nature of lldD2 evolution that occurs as a result of ongoing lldD2 selection in the background of ancestral lineage-defining mutations and demonstrate that the genetic evolution of lldD2 additively augments Mtb growth in lactate. Using quinone-dependent antibiotic susceptibility as a functional reporter, we also find that the evolved lldD2 mutations functionally increase the quinone-dependent activity of LldD2. Using 13C-lactate metabolic flux tracing, we find that lldD2 is necessary for robust incorporation of lactate into central carbon metabolism. In the absence of lldD2, label preferentially accumulates in dihydroxyacetone phosphate (DHAP) and glyceraldehyde-3-phosphate (G3P) and is associated with a discernible growth defect, providing experimental evidence for accrued lactate toxicity via the deleterious buildup of sugar phosphates. The evolved lldD2 variants increase lactate incorporation to pyruvate while altering triose phosphate flux, suggesting both an anaplerotic and detoxification benefit to lldD2 evolution. We further show that the mycobacterial cell is transcriptionally sensitive to the changes associated with altered lldD2 activity which affect the expression of genes involved in cell wall lipid metabolism and the ESX- 1 virulence system. Together, these data illustrate a multifunctional role of LldD2 that provides context for the selective advantage of lldD2 mutations in adapting to host stress.

Adding a Coefficient for Race to the 4Kscore Improves Calibration for Black Men.

PURPOSE: Black men face a higher incidence of high-risk prostate cancer (PCa) compared with non-Black men. While the 4Kscore is a widely utilized commercial test for PCa risk assessment, it does not currently account for racial differences. The aim of this study is to describe and validate a prespecified race coefficient for the 4Kscore with the goal of improving the accuracy of this test for Black men. MATERIALS AND METHODS: Using data from 85 Black men from the initial US prospective validation study, a race coefficient of 0.6 on the log-odds scale was prespecified. We calculated discrimination, calibration, and clinical utility of the 4Kscore with and without this coefficient for Black race in our primary analysis cohort of 205 Black men undergoing biopsy for PCa in a Veterans Affairs (VA) institution. We performed a sensitivity analysis using a combined cohort from the US prospective validation and the VA studies. RESULTS: The mean probability of high-grade PCa from the 4Kscore in the primary cohort increased from 25% to 37% with race coefficient addition. Incorporating the race coefficient improved 4Kscore's calibration in Black men, with consequent improvements in clinical utility based on decision curve analysis. Model discrimination was maintained (AUC 0.825 vs 0.828, P = .14) in the combined cohort of Black and non-Black men from the US prospective and VA studies and the calibration remained largely unchanged. CONCLUSIONS: Incorporating a prespecified coefficient for Black race improved calibration and clinical utility of the 4Kscore among Black men and should be added to the 4Kscore.

Testosterone Therapy in Men After Radical Prostatectomy for Organ-Confined, Low-Intermediate Prostate Cancer.

PURPOSE: Testosterone therapy (TTh) in men with T deficiency who have undergone radical prostatectomy (RP) for prostate cancer remains controversial. We aimed to assess the impact of TTh on biochemical recurrence (BCR) rates after RP in men with low-intermediate organ-confined disease. MATERIALS AND METHODS: This study included men who underwent an RP at our institution for organ-confined prostate cancer and had grade groups 1 to 3 on RP pathology. A Cox model was created for time to BCR with T use included as a time-dependent covariate, adjusted for age, preoperative PSA, grade group at RP, and the presence of comorbidities. A landmark analysis was used: Patients were included in the analysis if their last PSA in the 18 weeks postoperatively was undetectable and they had not had BCR or been lost to follow-up by that point, and follow-up for BCR began at 18 weeks. BCR was defined as a PSA ≥ 0.1 ng/mL after RP with a second confirmatory rise ≥ 0.1 ng/mL. RESULTS: The study population included 5199 men after RP, with 198 patients receiving T at any point after RP and 5001 not receiving T. The median age was 59 (IQR, 55-65) and 61 (IQR, 56-66) years, respectively. Men in the T group tended to present with more vascular comorbidities. For those receiving T, clomiphene citrate was prescribed in 49% of men, 32% received transdermal T, and 19% intramuscular T. We found a nonsignificantly decreased risk of BCR associated with the use of T after RP (HR, 0.84; 95% CI, 0.48-1.46; P = .5), and overall rates of BCR were low, with probability of BCR at 5 years less than 2% in both groups. CONCLUSIONS: TTh can be given to select men after RP. We found no evidence that administration of TTh after RP causes BCR.

Do Phosphodiesterase Type 5 Inhibitors Increase the Risk of Biochemical Recurrence After Radical Prostatectomy?

PURPOSE: There have been conflicting studies on the association between phosphodiesterase type 5 inhibitor (PDE5i) use and biochemical recurrence (BCR) following radical prostatectomy (RP). Our aim was to determine whether PDE5i drug exposure after RP increases the risk of BCR in patients undergoing RP. MATERIALS AND METHODS: An institutional database of prostate cancer patients treated between January 2009 and December 2020 was reviewed. BCR was defined as 2 PSA measurements greater than 0.1 ng/mL. PDE5i exposure was defined using a 0 to 3 scale, with 0 representing never use, 1 sometimes use, 2 regularly use, and 3 routinely use. The risk of BCR with any PDE5i exposure, the quantity of exposure, and the duration of PDE5i exposure were assessed by multivariable Cox proportional hazards models. RESULTS: The sample size included 4630 patients to be analyzed, with 776 patients having BCR. The median follow-up for patients without BCR was 27 (IQR 12, 49) months. Eighty-nine percent reported taking a PDE5i at any time during the first 12 months after RP, and 60% reported doing so for 6 or more months during the year after RP. There was no evidence of an increase in the risk of BCR associated with any PDE5i use (HR 1.05, 95% CI 0.84, 1.31, P = .7) or duration of PDE5i use in the first year (HR 0.98 per 1 month duration, 95% CI 0.96, 1.00, P = .055). Baseline oncologic risk was lower in patients using PDE5i, but differences between groups were small, suggesting that residual confounding is unlikely to obscure any causal association with BCR. CONCLUSIONS: Prescription of PDE5i to men after RP can be based exclusively on quality of life considerations. Patients receiving PDE5is can be reassured that their use does not increase the risk of BCR.

Randomized Trial of Transverse vs Vertical Extraction Site Incision After Robotic Radical Prostatectomy.

PURPOSE: Incisional hernias are a frequent complication following robotic radical prostatectomy. Observational data in men undergoing robotic prostatectomy suggest that transverse closure resulted in lower hernia rates than vertical closure. We sought to compare the incidence of incisional hernia after robotic radical prostatectomy after vertical and transverse extraction site closure. MATERIALS AND METHODS: We conducted a clinically integrated, crossover, cluster randomized trial at a single tertiary referral center (January 2016-September 2021) comparing the rate of hernia after transverse vs vertical extraction site excision in 1356 patients treated with minimally invasive radical prostatectomy. The primary outcome was between-group incidence of incisional hernia within 15 months of prostatectomy defined by physical examination and self-reported patient surveys. RESULTS: Overall, 197 (20%) patients developed an incisional hernia within 15 months, 797 did not have an incisional hernia within this period, and 362 had missing outcome data regarding incisional hernia. We found no significant difference in hernia rates between the 2 incision types (absolute between-group difference 1.8%; 95% CI -3.4%, 6.6%; P = .5) in the primary analysis or in the 3 sensitivity analyses. Notably, because of the inclusive definition of hernia used, these data cannot be used as an estimate of the true prevalence of incisional hernia. CONCLUSIONS: Surgeons should choose the incision and closure approach they are most comfortable with when extracting specimens. Studies of modifications to the surgical technique are best conducted as randomized comparisons, and the clinically integrated, crossover, cluster randomized trial allows large trials to be completed at a single center and at low cost. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01407263.

Remote Symptom Monitoring with Clinical Alerts Following Mastectomy: Do Early Symptoms Predict 30-Day Surgical Complications.

BACKGROUND: Electronic patient-reported outcome measures (ePROMs) for real-time remote symptom monitoring facilitate early recognition of postoperative complications. We sought to determine whether remote, electronic, patient-reported symptom-monitoring with Recovery Tracker predicts 30-day readmission or reoperation in outpatient mastectomy patients. METHODS: We conducted a retrospective review of breast cancer patients who underwent outpatient (< 24-h stay) mastectomy with or without reconstruction from April 2017 to January 2022 and who received the Recovery Tracker on Days 1-10 postoperatively. Of 5,130 patients, 3,888 met the inclusion criteria (2,880 mastectomy with immediate reconstruction and 1,008 mastectomy only). We focused on symptoms concerning for surgical complications and assessed if symptoms reaching prespecified alert levels-prompting a nursing call-predicted risk of 30-day readmission or reoperation. RESULTS: Daily Recovery Tracker response rates ranged from 45% to 70%. Overall, 1,461 of 3,888 patients (38%) triggered at least one alert. Most red (urgent) alerts were triggered by pain and fever; most yellow (less urgent) alerts were triggered by wound redness and pain severity. The 30-day readmission and reoperation rates were low at 3.8% and 2.4%, respectively. There was no statistically significant association between symptom alerts and 30-day reoperation or readmission, and a clinically relevant increase in risk can be excluded (odds ratio 1.08; 95% confidence interval 0.8-1.46; p = 0.6). CONCLUSIONS: Breast cancer patients undergoing mastectomy with or without reconstruction in the ambulatory setting have a low burden of concerning symptoms, even in the first few days after surgery. Patients can be reassured that symptoms that do present resolve quickly thereafter.

Transfers and anesthesia-related postoperative outcomes after 3361 same-day cancer surgeries at a freestanding surgery center: An observational retrospective study.

BACKGROUND AND OBJECTIVES: Expanding outpatient surgery to the increasing number of procedures and patient populations warrants continuous evaluation of postoperative outcomes to ensure the best care and safety. We describe adverse postoperative outcomes and transfer rates related to anesthesia in a large sample of patients who underwent same-day cancer surgery at a freestanding ambulatory surgery center. METHODS: Between January 2017 and June 2021, 3361 cancer surgeries, including breast and plastic, head and neck, gynecology, and urology, were performed. The surgeries were indicated for diagnosis, staging, and/or treatment. We report the incidence of transfers and adverse postoperative outcomes related to anesthesia. RESULTS: Breast and plastic surgeries were the most common (1771, 53%), followed by urology (1052, 31%), gynecology (410, 12%), and head and neck surgeries (128, 4%). Based on patients' first procedure, comorbidity levels were highest for urology (75% American Society of Anesthesiologists physical status score 3, 1.7% score 4) and lowest for breast surgeries (31% score 3, 0.2% score 4). Most gynecology surgeries used general anesthesia (97.6%), whereas breast surgeries used the least (38%). A total of seven patients (0.2%; 95% CI: 0.08%-0.4%) were immediately transferred to an outside hospital; four due to anesthesia-related reasons. Only 7 (0.2%) patients needed additional postoperative care related to anesthesia-related adverse events, specifically cardiac events (4), difficult intubations (2), desaturation (1), and agitation, nausea, and headache (1). CONCLUSIONS: The incidence of anesthesia-related adverse postoperative outcomes is low in cancer patients undergoing outpatient surgeries at our freestanding ambulatory surgery center. This suggests that carefully selected cancer patients, including patients with metastatic cancer, can undergo anesthesia for same-day surgery, making cancer care accessible locally and reducing stress associated with travel for treatment. More research investigating complication rates related to surgery and to cancer disease trajectory are needed to establish a complete evaluation of safety for outpatient cancer surgery.

Successful completion of large, low-cost randomized cancer trials at an academic cancer center.

BACKGROUND: Concerns about low accrual have long been a standard part of the discourse on cancer clinical trials, reaching even as far as the news media. Indeed, so many trials are closed before completing accrual that a cottage industry has recently developed creating statistical models to predict trial failure. We previously proposed four methodologic fixes for the current crisis in clinical trials: (1) dramatically reducing the number of eligibility criteria, (2) using data routinely collected in clinical practice for trial endpoints; then lowering barriers to accrual by (3) cluster randomization or (4) staged consent. METHODS: We report our practical experience of applying these fixes to randomized trials at Memorial Sloan Kettering Cancer Center. RESULTS: We have completed seven single-center randomized trials, with several more underway and accruing rapidly, with a total accrual approaching 10,000. Many of the trials have compared surgical interventions, an area where trials have traditionally been hard to complete. Only one of these trials was externally funded. While low costs were possible due to the existing research infrastructure at our institution, such infrastructure is common at major cancer centers. CONCLUSIONS: Further research on innovative clinical trial designs is warranted, particularly in higher-stakes settings, and in trials of medical and radiotherapy interventions.

Optimizing accrual to a large-scale, clinically integrated randomized trial in anesthesiology: A 2-year analysis of recruitment.

BACKGROUND: Performing large randomized trials in anesthesiology is often challenging and costly. The clinically integrated randomized trial is characterized by simplified logistics embedded into routine clinical practice, enabling ease and efficiency of recruitment, offering an opportunity for clinicians to conduct large, high-quality randomized trials under low cost. Our aims were to (1) demonstrate the feasibility of the clinically integrated trial design in a high-volume anesthesiology practice and (2) assess whether trial quality improvement interventions led to more balanced accrual among study arms and improved trial compliance over time. METHODS: This is an interim analysis of recruitment to a cluster-randomized trial investigating three nerve block approaches for mastectomy with immediate implant-based reconstruction: paravertebral block (arm 1), paravertebral plus interpectoral plane blocks (arm 2), and serratus anterior plane plus interpectoral plane blocks (arm 3). We monitored accrual and consent rates, clinician compliance with the randomized treatment, and availability of outcome data. Assessment after the initial year of implementation showed a slight imbalance in study arms suggesting areas for improvement in trial compliance. Specific improvement interventions included increasing the frequency of communication with the consenting staff and providing direct feedback to clinician investigators about their individual recruitment patterns. We assessed overall accrual rates and tested for differences in accrual, consent, and compliance rates pre- and post-improvement interventions. RESULTS: Overall recruitment was extremely high, accruing close to 90% of the eligible population. In the pre-intervention period, there was evidence of bias in the proportion of patients being accrued and receiving the monthly block, with higher rates in arm 3 (90%) compared to arms 1 (81%) and 2 (79%, p = 0.021). In contrast, in the post-intervention period, there was no statistically significant difference between groups (p = 0.8). Eligible for randomization rate increased from 89% in the pre-intervention period to 95% in the post-intervention period (difference 5.7%; 95% confidence interval = 2.2%-9.4%, p = 0.002). Consent rate increased from 95% to 98% (difference of 3.7%; 95% confidence interval = 1.1%-6.3%; p = 0.004). Compliance with the randomized nerve block approach was maintained at close to 100% and availability of primary outcome data was 100%. CONCLUSION: The clinically integrated randomized trial design enables rapid trial accrual with a high participant compliance rate in a high-volume anesthesiology practice. Continuous monitoring of accrual, consent, and compliance rates is necessary to maintain and improve trial conduct and reduce potential biases. This trial methodology serves as a template for the implementation of other large, low-cost randomized trials in anesthesiology.

The oncologic risk of magnetic resonance imaging-targeted and systematic cores in patients treated with radical prostatectomy.

BACKGROUND: Magnetic resonance imaging (MRI)-targeted prostate biopsy (MRI-biopsy) detects high-Grade Group (GG) prostate cancers not identified by systematic biopsy (S-biopsy). However, questions have been raised whether cancers detected by MRI-biopsy and S-biopsy, grade-for-grade, are of equivalent oncologic risk. The authors evaluated the relative oncologic risk of GG diagnosed by S-biopsy and MRI-biopsy. METHODS: This was a retrospective analysis of all patients who had both MRI-biopsy and S-biopsy and underwent with prostatectomy (2014-2022) at Memorial Sloan Kettering Cancer Center. Three logistic regression models were used with adverse pathology as the primary outcome (primary pattern 4, any pattern 5, seminal vesicle invasion, or lymph node involvement). The first model included the presurgery prostate-specific antigen level, the number of positive and negative S-biopsy cores, S-biopsy GG, and MRI-biopsy GG. The second model excluded MRI-biopsy GG to obtain the average risk based on S-biopsy GG. The third model excluded S-biopsy GG to obtain the risk based on MRI-biopsy GG. A secondary analysis using Cox regression evaluated the 12-month risk of biochemical recurrence. RESULTS: In total, 991 patients were identified, including 359 (36%) who had adverse pathology. MRI-biopsy GG influenced oncologic risk compared with S-biopsy GG alone (p < .001). However, if grade was discordant between biopsies, then the risk was intermediate between grades. For example, the average risk of advanced pathology for patients who had GG2 and GG3 on S-biopsy was 19% and 66%, respectively, but the average risk was 47% for patients who had GG2 on S-biopsy and patients who had GG3 on MRI-biopsy. The equivalent estimates for 12-month biochemical recurrence were 5.8%, 15%, and 10%, respectively. CONCLUSIONS: The current findings cast doubt on the practice of defining risk group based on the highest GG. Because treatment algorithms depend fundamentally on GG, further research is urgently required to assess the oncologic risk of prostate tumors depending on detection technique. PLAIN LANGUAGE SUMMARY: Using magnetic resonance imaging (MRI) to help diagnose prostate cancer can help identify more high-grade cancers than using a systematic template biopsy alone. However, we do not know if high-grade cancers diagnosed with the help of an MRI are as dangerous to the patient as high-grade cancers diagnosed with a systematic biopsy. We examined all of our patients who had an MRI biopsy and a systematic biopsy and then had their prostates removed to find out if these patients had risk factors and signs of aggressive cancer (cancer that spread outside the prostate or was very high grade). We found that, if there was a difference in grade between the systematic biopsy and the MRI-targeted biopsy, the risk of aggressive cancer was between the two grades.

Same-Day Discharge vs Inpatient Robotic-Assisted Radical Prostatectomy: Complications, Time-Driven Activity-Based Costing, and Patient Satisfaction.

PURPOSE: Historically, robotic-assisted radical prostatectomy is accompanied by an inpatient hospital admission. The COVID-19 pandemic necessitated a transition to same-day discharge robotic-assisted radical prostatectomy in some centers to free up critically needed inpatient beds. This study aims to compare complications, total health care costs, and patient satisfaction for same-day discharge vs inpatient robotic-assisted radical prostatectomy. MATERIALS AND METHODS: We compared 392 consecutive robotic-assisted radical prostatectomies performed as same-day discharge (n = 206) vs inpatient (n = 186) from February 2020 to November 2022 at 2 academic medical centers. We utilized propensity score analysis to assess the impact of same-day discharge vs inpatient robotic-assisted radical prostatectomy on 30-day complications (primary outcome). Time-driven activity-based costing analysis was applied to compare total costs of robotic-assisted radical prostatectomy care, and we administered a validated Patient Satisfaction Outcome Questionnaire to compare satisfaction scores. RESULTS: Inpatient robotic-assisted radical prostatectomy patients were more likely to be older, self-reported Black race or Hispanic ethnicity, and have higher American Society of Anesthesiologists classification. Complication rates were nonsignificantly lower for same-day discharge vs inpatient robotic-assisted radical prostatectomy (OR 0.87, 95% CI 0.35 to 2.21; P = .8). Same-day discharge vs inpatient robotic-assisted radical prostatectomy demonstrated a $2106 (19%) overall cost reduction. Median satisfaction survey scores were similar, and a clinically significant difference can be excluded. CONCLUSIONS: Same-day discharge robotic-assisted radical prostatectomy is cost-effective and should be the preferred approach in appropriately selected patients.

Health-related Quality of Life After Robotic-assisted vs Open Radical Cystectomy: Analysis of a Randomized Trial.

PURPOSE: We compare health-related quality of life using a broad range of validated measures in patients randomized to robotic-assisted radical cystectomy vs open radical cystectomy. METHODS: We retrospectively analyzed patients that had enrolled in both a randomized controlled trial comparing robotic-assisted laparoscopic radical cystectomy vs open radical cystectomy and a separate prospective study of health-related quality of life. The prospective health-related quality of life study collected 14 patient-reported outcomes measures preoperatively and at 3, 6, 12, 18, and 24 months postoperatively. Linear mixed-effects models with an interaction term (study arm×time) were used to test for differences in mean domain scores and differing effects of approach over time, adjusting for baseline scores. RESULTS: A total of 72 patients were analyzed (n=32 robotic-assisted radical cystectomy, n=40 open radical cystectomy). From 3-24 months post-radical cystectomy, no significant differences in mean scores were detected. Mean differences were small in the following European Organization for Research and Treatment of Cancer QLQ-C30 (Core Quality of Life Questionnaire) domains: Global Quality of Life (-1.1; 95% CI -8.4, 6.2), Physical Functioning (-0.4; 95% CI -5.8, 5.0), Role Functioning (0.7; 95% CI -8.6, 10.0). Mean differences were also small in bladder cancer-specific domains (European Organization for Research and Treatment of Cancer QLQ-BLM30 [Muscle Invasive Bladder Cancer Quality of Life Questionnaire]): Body Image (2.9; 95% CI -7.2, 13.1), Urinary Symptoms (8.0; 95% CI -3.0, 19.0). In Urostomy Symptoms, there was a significant interaction term (P < .001) due to lower open radical cystectomy scores at 3 and 24 months. Other domains evaluating urinary, bowel, sexual, and psychosocial health-related quality of life were similar. CONCLUSIONS: Over a broad range of health-related quality of life domains comparing robotic-assisted radical cystectomy and open radical cystectomy, there are unlikely to be clinically relevant differences in the medium to long term, and therefore health-related quality of life over this time period should not be a consideration in choosing between approaches.

Standardized prostate cancer incidence and mortality rates following initial non-malignant biopsy result.

OBJECTIVES: To compare the incidence of subsequent prostate cancer diagnosis and death following an initial non-malignant systematic transrectal ultrasonography (TRUS) biopsy with that in an age- and calendar-year matched population over a 20-year period. SUBJECTS AND METHODS: This population-based analysis compared a cohort of all men with initial non-malignant TRUS biopsy in Denmark between 1995 and 2016 (N = 37 231) with the Danish population matched by age and calendar year, obtained from the NORDCAN 9.1 database. Age- and calendar year-corrected standardized prostate cancer incidence (SIR) and prostate cancer-specific mortality ratios (SMRs) were calculated and heterogeneity among age groups was assessed with the Cochran's Q test. RESULTS: The median time to censoring was 11 years, and 4434 men were followed for more than 15 years. The corrected SIR was 5.2 (95% confidence interval [CI] 5.1-5.4) and the corrected SMR was 0.74 (95% CI 0.67-0.81). Estimates differed among age groups (P < 0.001 for both), with a higher SIR and SMR among younger men. CONCLUSION: Men with non-malignant TRUS biopsy have a much higher incidence of prostate cancer but a risk of prostate cancer death below the population average. This underlines that the oncological risk of cancers missed in the initial TRUS biopsy is low. Accordingly, attempts to increase the sensitivity of initial biopsy are unjustified. Moreover, current follow-up after non-malignant biopsy is likely to be overaggressive, particularly in men over the age of 60 years.

Predictive value of kallikrein forms and ß-microseminoprotein in blood from patients with evidence of detectable levels of PSA after radical prostatectomy.

PURPOSE: To determine whether ß-microseminoprotein or any of the kallikrein forms in blood-free, total or intact PSA or total hK2-predict metastasis in patients with evidence of detectable levels of PSA in blood after radical prostatectomy. METHOD: We determined marker concentrations in blood from 173 men treated with radical prostatectomy and evidence of detectable levels of PSA in the blood (PSA ≥ 0.05) after surgery between 2014 and 2015 and at least 1 year after any adjuvant therapy. We used Cox regression to determine whether any marker was associated with metastasis using both univariate and multivariable models that included standard clinical predictors. RESULTS: Overall, 42 patients had metastasis, with a median follow-up of 67 months among patients without an event. The levels of intact and free PSA and free-to-total PSA ratio were significantly associated with metastasis. Discrimination was highest for free PSA (c-index: 0.645) and free-to-total PSA ratio (0.625). Only free-to-total PSA ratio remained associated with overall metastasis (either regional or distant) after including standard clinical predictors (p = 0.025) and increased discrimination from 0.686 to 0.697. Similar results were found using distant metastasis as an outcome (p = 0.011; c-index increased from 0.658 to 0.723). CONCLUSION: Our results provide evidence that free-to-total PSA ratio can risk stratifying patients with evidence of detectable levels of PSA in blood after RP. Further research is warranted on the biology of prostate cancer markers in patients with evidence of detectable levels of PSA in blood after radical prostatectomy. Our findings on the free-to-total ratio for predicting adverse oncologic outcomes need to be validated in other cohorts.

Preoperative glucose in surgical oncology patient is not associated with postoperative outcomes after adjustment for frailty.

BACKGROUND: Observational studies have shown associations between even small elevations in preoperative glucose and poorer outcomes, including increased length of stay (LOS) and higher mortality. This has led to calls for aggressive glycemic control in the preoperative period, including delay of treatment until glucose is reduced. However, it is not known whether there is a direct causal effect of blood glucose or whether adverse outcomes result from overall poorer health in patients with higher glucose. METHODS: Analysis was performed using a retrospective database of patients aged 65 and older who underwent cancer surgery. The last measured preoperative glucose was the exposure variable. The primary outcome was extended LOS (>4 days). Secondary outcomes included mortality, acute kidney injury (AKI), major postoperative complications during the admission period, and readmission within 30 days. The primary analysis was a logistic regression with prespecified covariates: age, sex, surgical service, and the Memorial Sloan Kettering-Frailty Index. In an exploratory analysis, lasso regression was used to select covariates from a list of 4160 candidate variables. RESULTS: This study included 3796 patients with a median preoperative glucose of 104 mg/dL (interquartile range: 93-125). Higher preoperative glucose was univariately associated with increased odds of LOS > 4 days (odds ratio [OR]: 1.45, 95% confidence interval [CI]: 1.22-1.73), with similar results for AKI, readmission, and mortality. Adjustment for confounders eliminated these associations for LOS (OR: 0.97 [95% CI: 0.80-1.18]) and attenuated all other glucose-outcome associations. Lasso regression gave comparable results to the primary analysis. Using the upper bound of the respective 95% confidence interval, we estimated that, at best, successful reduction of elevated preoperative glucose would reduce the risk of LOS > 4 days, 30-day major complication, and 30-day mortality by 4%, 0.5%, and 1.3%, respectively. CONCLUSIONS: Poor outcomes following cancer surgery in older adults with elevated glucose are most likely related to poorer overall health in these patients rather than a direct causal effect of glucose. Aggressive glycemic management in the preoperative period has very limited potential benefits and is therefore unwarranted.

Patient and procedure characteristics associated with postoperative pain after prophylactic versus therapeutic ambulatory bilateral breast surgery.

BACKGROUND AND OBJECTIVES: We investigated whether age, body mass index (BMI), and tissue expander placement were related to postoperative opioid requirement for patients undergoing therapeutic versus prophylactic breast surgery. METHODS: Postoperative opioid consumption was evaluated for patients who underwent bilateral mastectomy with immediate implant-based reconstruction at a freestanding ambulatory cancer surgery center between 2016 and 2021. Ordinal regression tested whether surgical indication was associated with increased postoperative opioid requirements after adjusting for age, BMI, and tissue expander placement. RESULTS: Of 2447 patients, 6% underwent prophylactic surgeries. Therapeutic mastectomy patients had lower postoperative opioid requirement (OR = 0.67; 95% CI: 0.50-0.91; p = 0.030), but this was not significant after adjusting for covariates (OR = 0.75; 95% CI: 0.53-1.07; p = 0.2). Opioid use increased with higher BMI (OR = 1.06; 95% CI: 1.05-1.08; p < 0.001) and decreased with age (OR = 0.97; 95% CI: 0.96-0.98; p < 0.001) with therapeutic mastectomy patients being older (median 46 vs. 39). The subpectoral tissue expander group had nearly double the postoperative opioid requirement compared to prepectoral placement (OR = 1.86; 95% CI: 1.55-2.23; p < 0.001). CONCLUSIONS: Increased postoperative opioid requirement in women undergoing prophylactic procedures is best explained by age. Mastectomy patients should be counseled similarly about postoperative pain irrespective of indication. A larger prophylactic mastectomy sample is required to provide more precise estimates.

Impact of previous depression on the risk of suicide among prostate cancer patients.

BACKGROUND: Prior studies of suicide risk among prostate cancer patients are conflicting. We compared the risk of suicide in prostate cancer patients to cancer-free men including adjustment for clinical stage, socioeconomic position, somatic comorbidity, and previous depression. MATERIALS AND METHODS: A cohort of 37,527 men diagnosed with prostate cancer in Denmark during 1998-2011 was identified in the Danish Prostate Cancer Registry (DaPCaR) and compared with 357,384 cancer-free men matched by age at the time of diagnosis. The primary outcome was death from suicide. Data were analyzed using cumulative incidence functions and multivariable Cox regression models. RESULTS: Among prostate cancer patients, 3813 had a previous depression, defined as filed antidepressant prescription within three years before diagnosis. In the study period, 108 prostate cancer patients were registered with suicide as the cause of death, hereof 26 with previous depression. There was no difference in the cumulative incidence of suicide between prostate cancer patients and cancer-free men. There was no effect modification of previous depression on the risk of suicide (p = .12). The hazard ratio (HR) for suicide varied with time since diagnosis. A sensitivity analysis showed that the risk of suicide was highest within the first year of diagnosis where prostate cancer patients had a 1.70-fold increased hazard compared with cancer-free men (95% CI, 1.11-2.59). Men with prostate cancer and previous depression had a three-fold increased hazard for suicide compared with prostate cancer patients without a history of depression (HR 2.84, 95% CI, 1.82-4.45). CONCLUSION: The absolute risk of suicide is low following a prostate cancer diagnosis. Time since diagnosis and a history of depression was associated with the highest risk of suicide. Healthcare professionals should be aware of an increased risk of suicide among men with previous depression, especially in the immediate aftermath of the diagnosis.

A comparison of brief versus explicit descriptors for verbal rating scales: interrupted time series design.

BACKGROUND: Verbal rating scales (VRS) are widely used in patient-reported outcome (PRO) measures. At our institution, patients complete an online instrument using VRSs with a five-point brief response scale to assess symptoms as part of routine follow-up after ambulatory cancer surgery. We received feedback from patients that the brief VRS descriptors such as "mild" or "somewhat" were vague. We added explicit descriptors to our VRSs, for instance, "Mild: I can generally ignore my pain" for pain severity or "Somewhat: I can do some things okay, but most of my daily activities are harder because of fatigue" for fatigue interference. We then compared responses before and after this change was made. METHODS: The symptoms investigated were pain, fatigue and nausea. Our hypothesis was that the explicit descriptors would reduce overall variance. We therefore compared the coefficient of variation of scores and tested the association between symptoms scores and known predictors thereof. We also compared time to completion between questionnaires with and without the additional descriptors. RESULTS: A total of 17,500 patients undergoing 21,497 operations were assigned questionnaires in the period before the descriptors were added; allowing for a short transition period, 1,417 patients having 1436 operations were assigned questionnaires with the additional descriptors. Symptom scores were about 10% lower with the additional descriptors but the coefficient of variation was slightly higher. Moreover, the only statistically significant difference between groups for association with a known predictor favored the item without the additional language for nausea severity (p = 0.004). Total completion time was longer when the instrument included the additional descriptors, particularly the first and second time that the questionnaire was completed. CONCLUSIONS: Adding descriptors to a VRS of post-operative symptoms did not improve scale properties in patients undergoing ambulatory cancer surgery. We have removed the additional descriptors from our tool. We recommend further comparative psychometric research using data from PROs collected as part of routine clinical care.

A randomized comparison of two-stage versus traditional one-stage consent for a low-stakes randomized trial.

BACKGROUND/AIMS: It has been proposed that informed consent for randomized trials should be split into two stages, with the purported advantage of decreased information overload and patient anxiety. We compared patient understanding, anxiety and decisional quality between two-stage and traditional one-stage consent. METHODS: We approached patients at an academic cancer center for a low-stakes trial of a mind-body intervention for procedural distress during prostate biopsy. Patients were randomized to hear about the trial by either one- or two-stage consent (n = 66 vs n = 59). Patient-reported outcomes included Quality of Informed Consent (0-100); general and consent-specific anxiety and decisional conflict, burden, and regret. RESULTS: Quality of Informed Consent scores were non-significantly superior for two-stage consent, by 0.9 points (95% confidence interval = -2.3, 4.2, p = 0.6) for objective and 1.1 points (95% CI = -4.8, 7.0, p = 0.7) for subjective understanding. Differences between groups for anxiety and decisional outcomes were similarly small. In a post hoc analysis, consent-related anxiety was lower among two-stage control patients, likely because scores were measured close to the time of biopsy in the two-stage patients receiving the experimental intervention. CONCLUSION: Two-stage consent maintains patient understanding of randomized trials, with some evidence of lowered patient anxiety. Further research is warranted on two-stage consent in higher-stakes settings.

MRI-guided focused ultrasound focal therapy for patients with intermediate-risk prostate cancer: a phase 2b, multicentre study.

BACKGROUND: Men with grade group 2 or 3 prostate cancer are often considered ineligible for active surveillance; some patients with grade group 2 prostate cancer who are managed with active surveillance will have early disease progression requiring radical therapy. This study aimed to investigate whether MRI-guided focused ultrasound focal therapy can safely reduce treatment burden for patients with localised grade group 2 or 3 intermediate-risk prostate cancer. METHODS: In this single-arm, multicentre, phase 2b study conducted at eight health-care centres in the USA, we recruited men aged 50 years and older with unilateral, MRI-visible, primary, intermediate-risk, previously untreated prostate adenocarcinoma (prostate-specific antigen ≤20 ng/mL, grade group 2 or 3; tumour classification ≤T2) confirmed on combined biopsy (combining MRI-targeted and systematic biopsies). MRI-guided focused ultrasound energy, sequentially titrated to temperatures sufficient for tissue ablation (about 60-70°C), was delivered to the index lesion and a planned margin of 5 mm or more of normal tissue, using real-time magnetic resonance thermometry for intraoperative monitoring. Co-primary outcomes were oncological outcomes (absence of grade group 2 and higher cancer in the treated area at 6-month and 24-month combined biopsy; when 24-month biopsy data were not available and grade group 2 or higher cancer had occurred in the treated area at 6 months, the 6-month biopsy results were included in the final analysis) and safety (adverse events up to 24 months) in all patients enrolled in the study. This study is registered with ClinicalTrials.gov, NCT01657942, and is no longer recruiting. FINDINGS: Between May 4, 2017, and Dec 21, 2018, we assessed 194 patients for eligibility and treated 101 patients with MRI-guided focused ultrasound. Median age was 63 years (IQR 58-67) and median concentration of prostate-specific antigen was 5·7 ng/mL (IQR 4·2-7·5). Most cancers were grade group 2 (79 [78%] of 101). At 24 months, 78 (88% [95% CI 79-94]) of 89 men had no evidence of grade group 2 or higher prostate cancer in the treated area. No grade 4 or grade 5 treatment-related adverse events were reported, and only one grade 3 adverse event (urinary tract infection) was reported. There were no treatment-related deaths. INTERPRETATION: 24-month biopsy outcomes show that MRI-guided focused ultrasound focal therapy is safe and effectively treats grade group 2 or 3 prostate cancer. These results support focal therapy for select patients and its use in comparative trials to determine if a tissue-preserving approach is effective in delaying or eliminating the need for radical whole-gland treatment in the long term. FUNDING: Insightec and the National Cancer Institute.