Discrimination of low- and high-grade appendiceal mucinous neoplasms by targeted sequencing of cancer-related variants.

DNA was obtained from matching micro-dissected, primary tumor cells, paired metastases, and peripheral blood mononuclear cells (germline) from patients with appendiceal mucinous neoplasms. We compared specimens from patient cohorts comprising low-grade adenomucinous neoplasm versus high-grade mucinous adenocarcinoma using a targeted, amplicon sequencing panel of 409 cancer related genes (Ion Torrent Comprehensive Cancer Panel, Thermo-Fisher, Waltham, MA). Copy number variants, single nucleotide variants and small insertions/deletions were identified using a multiplex algorithm pipeline (GATK, VarScan2, MuTect2, SIFT, SIFT-INDEL, PolyPhen-2, Provean). There were significantly more damaging variants in high-grade versus low-grade tumor cohorts. Both cohorts contained damaging, heterozygous germline variants (catenin ß1; notch receptor 1 and 4) in pathways associated with cell-lineage specification (WNT, NOTCH). Damaging, somatic KRAS proto-oncogene, GTPase mutations were present in both cohorts, while somatic GNAS complex locus mutations were confined to low-grade neoplasms. Variants predominantly affected transcription factors, kinases, and stem cell signaling molecules in canonical pathways including epithelial to mesenchymal transition, stem cell pluripotency, p53, PTEN, and NF-қB signaling pathways. High-grade tumors demonstrated MYC proto-oncogene, bHLH transcription factor (MYC) and death domain associated protein (DAXX) amplification and damaging somatic variants in tumor protein p53 (TP53), likely to amplify an aggressive phenotype. Damaging APC, WNT signaling pathway regulator (APC) deletions were identified in metastatic tissue of both cohorts suggesting a role in invasive disease. Our data suggest that germline dysregulation of WNT and/or NOTCH pathways predisposes patients toward a secretory cell phenotype (i.e., goblet-like cells) upon acquisition of somatic KRAS mutations. Additional somatically acquired variants activating oncogenes MYC and DAXX and inhibiting the critical tumor suppressor, tumor protein TP53, were consistent with manifestation of a high-grade phenotype. These additional changes within the epithelial to mesenchymal transition signaling network (WNT, NOTCH, RAS/ERK/PI3K, PTEN, NF-қB), produce aggressive high-grade tumor characteristics by actively driving cells towards dedifferentiation, proliferation, and migration.

Variation in Guideline Concordant Active Surveillance Followup in Diverse Urology Practices.

PURPOSE: We examined the frequency of followup prostate specific antigen testing and prostate biopsy among men treated with active surveillance in the academic and community urology practices comprising MUSIC (Michigan Urological Surgery Improvement Collaborative). MATERIALS AND METHODS: MUSIC is a consortium of 42 practices that maintains a prospective clinical registry with validated clinical data on all patients diagnosed with prostate cancer at participating sites. We identified all patients in MUSIC practices who entered active surveillance and had at least 2 years of continuous followup. After determining the frequency of repeat prostate specific antigen testing and prostate biopsy, we calculated rates of concordance with NCCN Guidelines® recommendations (ie at least 3 prostate specific antigen tests and 1 surveillance biopsy) collaborative-wide and across individual practices. RESULTS: We identified 513 patients who entered active surveillance from January 2012 through September 2013 and had at least 2 years of followup. Among the 431 men (84%) who remained on active surveillance for 2 years 132 (30.6%) underwent followup surveillance testing at a frequency that was concordant with NCCN® (National Comprehensive Cancer Network®) recommendations. At the practice level, the median rate of guideline concordant followup was 26.5% (range 10% to 67.5%, p <0.001). Among patients with discordant followup, the absence of followup biopsy was common and not significantly different across practices (median rate 82.0%, p = 0.35). CONCLUSIONS: Among diverse community and academic practices in Michigan, there is wide variation in the proportion of men on active surveillance who meet guideline recommendations for followup prostate specific antigen testing and repeat biopsy. These data highlight the need for standardized active surveillance pathways that emphasize the role of repeat surveillance biopsies.

A Statewide Intervention Improves Appropriate Imaging in Localized Prostate Cancer.

PURPOSE: We implemented a statewide intervention to improve imaging utilization for the staging of patients with newly diagnosed prostate cancer. MATERIALS AND METHODS: MUSIC (Michigan Urological Surgery Improvement Collaborative) is a quality improvement collaborative comprising 42 diverse practices representing approximately 85% of the urologists in Michigan. MUSIC has developed imaging appropriateness criteria (prostate specific antigen greater than 20 ng/ml, Gleason score 7 or higher and clinical stage T3 or higher) which minimize unnecessary imaging with bone scan and computerized tomography. After baseline rates of radiographic staging were established in 2012 and 2013, we used multidimensional interventions to deploy these criteria in 2014. Imaging utilization was then remeasured in 2015 to evaluate for changes in practice patterns. RESULTS: A total of 10,554 newly diagnosed patients with prostate cancer were entered into the MUSIC registry from January 1, 2012 through December 31, 2013 and January 1, 2015 through December 31, 2015. Of these patients 7,442 (79%) and 7,312 (78%) met our criteria to avoid bone scan and computerized tomography imaging, respectively. The use of bone scan imaging when not indicated decreased from 11.0% at baseline to 6.5% after interventions (p <0.0001). The use of computerized tomography when not indicated decreased from 14.7% at baseline to 7.7% after interventions (p <0.0001). Variability among practices decreased substantially after the interventions as well. The use of recommended imaging remained stable during these periods. CONCLUSIONS: An intervention aimed at appropriate use of imaging was associated with decreased use of bone scans and computerized tomography among men at low risk for metastases.

Appropriateness Criteria for Active Surveillance of Prostate Cancer.

PURPOSE: The adoption of active surveillance varies widely across urological communities, which suggests a need for more consistency in the counseling of patients. To address this need we used the RAND/UCLA Appropriateness Method to develop appropriateness criteria and counseling statements for active surveillance. MATERIALS AND METHODS: Panelists were recruited from MUSIC urology practices. Combinations of parameters thought to influence decision making were used to create and score 160 theoretical clinical scenarios for appropriateness of active surveillance. Recent rates of active surveillance among real patients across the state were assessed using the MUSIC registry. RESULTS: Low volume Gleason 6 was deemed highly appropriate for active surveillance whereas high volume Gleason 6 and low volume Gleason 3+4 were deemed appropriate to uncertain. No scenario was deemed inappropriate or highly inappropriate. Prostate specific antigen density, race and life expectancy impacted scores for intermediate and high volume Gleason 6 and low volume Gleason 3+4. The greatest degree of score dispersion (disagreement) occurred in scenarios with long life expectancy, high volume Gleason 6 and low volume Gleason 3+4. Recent rates of active surveillance use among real patients ranged from 0% to 100% at the provider level for low or intermediate biopsy volume Gleason 6, demonstrating a clear opportunity for quality improvement. CONCLUSIONS: By virtue of this work urologists have the opportunity to present specific recommendations from the panel to their individual patients. Community-wide efforts aimed at increasing rates of active surveillance and reducing practice and physician level variation in the choice of active surveillance vs treatment are warranted.

What is the impact of a clinically related readmission measure on the assessment of hospital performance?

BACKGROUND: The Hospital Readmission Reduction Program (HRRP) penalizes hospitals for high all-cause unplanned readmission rates. Many have expressed concern that hospitals serving patient populations with more comorbidities, lower incomes, and worse self-reported health status may be disproportionately penalized by readmissions that are not clinically related to the index admission. The impact of including clinically unrelated readmissions on hospital performance is largely unknown. We sought to determine if a clinically related readmission measure would significantly alter the assessment of hospital performance. METHODS: We analyzed Medicare claims for beneficiaries in Michigan admitted for pneumonia and joint replacement from 2011 to 2013. We compared each hospital's 30-day readmission rate using specifications from the HRRP's all-cause unplanned readmission measure to values calculated using a clinically related readmission measure. RESULTS: We found that the mean 30-day readmission rates were lower when calculated using the clinically related readmission measure (joint replacement: all-cause 5.8%, clinically related 4.9%, p < 0.001; pneumonia: all cause 12.5%, clinically related 11.3%, p < 0.001)). The correlation of hospital ranks using both methods was strong (joint replacement: 0.95 (p < 0.001), pneumonia: 0.90 (p < 0.001)). CONCLUSIONS: Our findings suggest that, while greater specificity may be achieved with a clinically related measure, clinically unrelated readmissions may not impact hospital performance in the HRRP.

Comparison of Pathological Outcomes for Men with Low Risk Prostate Cancer from Diverse Practice Settings: Similar Results from Immediate Prostatectomy or Initial Surveillance with Delayed Prostatectomy.

PURPOSE: We compared pathological outcomes after radical prostatectomy for a population based sample of men with low risk prostate cancer initially on active surveillance and undergoing delayed prostatectomy vs those treated with immediate surgery in order to better understand this expectant management approach outside of the context of academic cohorts. We hypothesized that delays in surgery due to initial surveillance would not impact surgical pathological outcomes. MATERIALS AND METHODS: We performed a prospective cohort study of 2 groups of patients with NCCN low risk prostate cancer from practices in the Michigan Urological Surgery Improvement Collaborative, that is 1) men who chose initial active surveillance and went on to delayed prostatectomy and 2) men who chose immediate prostatectomy. Diagnoses occurred from January 2011 through August 2015. For these 2 groups we compared radical prostatectomy Gleason scores, and rates of extraprostatic disease, positive surgical margins, seminal vesicle invasion and lymph node metastases. RESULTS: During a median followup of 506 days 79 (6%) of 1,359 low risk men choosing initial surveillance transitioned to prostatectomy. Compared to those treated with immediate prostatectomy (778), men undergoing delayed surgery were more likely to have Gleason score 7 or greater disease (69.2% vs 48.8%, respectively, p=0.004), but were no more likely to have positive margins, extraprostatic extension, seminal vesicle invasion or lymph node metastases. CONCLUSIONS: Patients with low risk prostate cancer who enter active surveillance have higher grade disease at prostatectomy compared to those undergoing immediate surgery. However, the lack of difference in other adverse pathological outcomes suggests preservation of the window of curability.

Everything or Nothing: Supervised High-intensity Exercise is the Only Way to Achieve Meaningful Results.

Prehabilitation exercise should be performed via supervised, high-intensity exercise training regimens. This type of training is preferred by patients, increases exercise accountability, leads to emotional and social benefits, and ensures that exercises are performed in a safe and efficient manner.

Recovery of Social Continence and Sexual Function in Men With High-risk Prostate Cancer After Radical Prostatectomy: Results From a Statewide Collaborative.

OBJECTIVES: To examine post-operative urinary and sexual functional outcomes for men with high-risk prostate cancer (HRPCa) who underwent radical prostatectomy (RP) within the Michigan Urological Surgery Improvement Collaborative (MUSIC). METHODS: We identified patients who underwent RP for HRPCa in MUSIC between 2014 and 2023. HRPCa was defined according to American Urological Association criteria. Patients completed Expanded Prostate Cancer Index Composite (EPIC-26) pre-RP and 3-, 6-, 12-, and 24-months postoperatively. Primary outcomes included social continence, defined as 0-1 pads used daily; and recovery of sexual function, defined as the ability to achieve erections firm enough for intercourse. Multivariable and bivariate analyses were performed to identify factors associated with recovery of social continence and sexual function. RESULTS: Around 1323 patients were included in the post-RP urinary continence analysis and 422 men in the sexual function analysis. Fifty-eight percent and 86% of patients achieved social continence at 3- and 12-months post-RP, respectively. Continence recovery was associated with higher baseline EPIC-26 urinary continence scores (OR 1.10, per 5 points, 95% CI 1.06-1.15, P <.001), and negatively associated with increasing age (OR 0.78 per 5-year increase, 95% CI 0.71-0.85 P <.001). Fifteen percent of patients had recovery of sexual function at 12-month post-RP. On bivariate analysis, recovery of sexual function was associated with nerve-sparing at time of RP, lower pre-operative PSA, and not receiving post-RP ADT/RT. CONCLUSION: RP for HRPCa has acceptable rates of postoperative social continence. However, post-RP recovery of sexual function remains a challenge. This information has important implications for pre-operative counseling and post-operative follow-up for patients with HRPCa.

Intra-practice Urologist-level Variation in Targeted Fusion Biopsy Outcomes.

OBJECTIVE: To examine the extent to which the urologist performing biopsy contributes to variation in prostate cancer detection during fusion-guided prostate biopsy. METHODS: All men in the Michigan Urological Surgery Improvement Collaborative (MUSIC) clinical registry who underwent fusion biopsy at Michigan Medicine from August 2017 to March 2019 were included. The primary outcomes were clinically significant cancer detection rate (defined as Gleason Grade ≥2) in targeted cores and clinically significant cancer detection on targeted cores stratified by PI-RADS score. Bivariate and multivariable logistic regression analyses were performed. RESULTS: A total of 1133 fusion biopsies performed by 5 providers were included. When adjusting for patient age, PSA, race, family history, prostate volume, clinical stage, and PI-RADS score, there was no significant difference in targeted clinically significant cancer detection rates across providers (range = 38.5%-46.9%, adjusted P-value = .575). Clinically significant cancer detection rates ranged from 11.1% to 16.7% in PI-RADS 3 (unadjusted P = .838), from 24.6% to 43.4% in PI-RADS 4 (adjusted P = .003), and from 69.4% to 78.8% in PI-RADS 5 (adjusted P = .766) lesions. CONCLUSION: There was a statistically significant difference in clinically significant prostate cancer detection in PI-RADS 4 lesions across providers. These findings suggest that even among experienced providers, variation at the urologist level may contribute to differences in clinically significant cancer detection rates within PI-RADS 4 lesions. However, the relative impact of biopsy technique, radiologist interpretation, and MR acquisition protocol requires further study.

Intraoperative parathyroid hormone levels ≤40 pg/mL are associated with the lowest persistence rates after parathyroidectomy for primary hyperparathyroidism.

BACKGROUND: Intraoperative parathyroid hormone (IOPTH) monitoring is used to predict biochemical cure during parathyroidectomy for primary hyperparathyroidism; however, there is variability in the intraoperative parathyroid hormone criteria used by surgeons to predict normocalcemia after parathyroidectomy. This study sought to determine the intraoperative parathyroid hormone criteria correlated with the lowest rates of persistent hyperparathyroidism after parathyroidectomy for primary hyperparathyroidism. MATERIALS AND METHODS: This is a retrospective cohort study of 2,654 patients with primary hyperparathyroidism who underwent parathyroidectomy with intraoperative parathyroid hormone monitoring at a single institution from 1999 to 2014. Multivariate logistic regression analysis was used to measure the association between the lowest intraoperative parathyroid hormone level and the persistence of primary hyperparathyroidism after parathyroidectomy. RESULTS: A total of 66 patients (2.5%) had persistent hyperparathyroidism after parathyroidectomy. Using the traditional intraoperative parathyroid hormone criteria of a ≥50% decrease from the baseline level, the rate of persistent primary hyperparathyroidism was greater when intraoperative parathyroid hormone did not decrease to ≥50% from the baseline level (17 of 180 patients [9.4%] vs 49 of 2,474 [2.0%], [OR 5.9, 95% CI 3.2-10.5, P < .001]). Regardless of whether intraoperative parathyroid hormone decreased ≥50%, patients with a lowest intraoperative parathyroid hormone above the normal range (10-65 pg/mL) had greater persistence rates compared with patients with an intraoperative parathyroid hormone <65 pg/mL (30 of 350 [8.6%] vs 36 of 2,304 [1.6%], [OR 6.6, 95% CI 3.4-12.7, P < .001]). Furthermore, patients with a lowest intraoperative parathyroid hormone 40 to 65 pg/mL had increased rates of adjusted persistence compared with patients with lowest intraoperative parathyroid hormone ≤40 pg/mL (13 of 385 [3.4%] vs 23 of 1,919 [1.2%], [OR 4.2, 95% CI 2.0-8.7, P < .001]). Patients with lowest intraoperative parathyroid hormone <5 to 20 pg/mL did not have decreased rates of persistence compared with patients with lowest intraoperative parathyroid hormone 20 to 40 pg/mL (9 of 996 [0.9%] vs 14 of 923 [1.5%], [OR 0.5, 95% CI 0.2-1.2, P = .14]). CONCLUSION: Patients with a lowest intraoperative parathyroid hormone ≤40 pg/mL compared with the traditional criteria of a ≥50% decrease from baseline and a final parathyroid hormone in the normal range (<65 pg/mL) had the lowest rates of persistent primary hyperparathyroidism after parathyroidectomy for primary hyperparathyroidism. The single criteria of a lowest intraoperative parathyroid hormone level ≤40 pg/mL may best predict the lowest persistent disease rates after parathyroidectomy for primary hyperparathyroidism.

An Opportunity to Improve Medicare's Planned Readmissions Measure.

In the Hospital Readmission Reduction Program (HRRP), the Centers for Medicare & Medicaid Services (CMS) utilizes a planned/unplanned algorithm to prevent hospitals from being penalized for scheduled rehospitalizations. We evaluated version 3.0 of the CMS planned readmission algorithm and hypothesized that some readmissions categorized as planned by the HRRP algorithm may actually be unplanned. We identified 143,054 index admissions and 16,116 thirty- day readmissions for 131 hospitals. Only 1252 readmissions were considered planned according to Medicare's readmission algorithm. The majority of these planned readmissions (723 [57.8%]) had an "emergent" or "urgent" admission type listed on the readmission claim, and many (513 [41.0%]) had emergency department charges, suggesting unanticipated returns to the hospital. HRRP should consider using the admission type variable and/or the presence of emergency department charges as a source of information when determining whether a readmission is planned or unplanned.