Gastrointestinal Polyps and Polyposis in Individuals Harboring Germline CHEK2 Mutations.

BACKGROUND: Checkpoint kinase 2 is a tumor suppressor gene in the deoxyribonucleic acid damage checkpoint system that may be mutated in several cancers. Patients with germline checkpoint kinase 2 mutations and multiple colon polyps were noted during routine care, and genetic testing is recommended for patients with as few as 10 lifetime polyps. OBJECTIVE: This study assessed whether checkpoint kinase 2 is associated with attenuated or oligopolyposis and characterized the gastrointestinal clinicopathologic profile. DESIGN: Retrospective observational study. SETTINGS: Records from patients harboring germline checkpoint kinase 2 mutations from 1999-2020 were reviewed. PATIENTS: A total of 45 patients with germline checkpoint kinase 2 mutations with endoscopic examinations. MAIN OUTCOME MEASURES: Description of clinicopathologic variables. RESULTS: Twenty-five of 45 patients had polyps: 3 with only upper gastrointestinal polyps, 17 with only lower gastrointestinal polyps and 5 with both upper and lower gastrointestinal polyps. The most common germline checkpoint kinase 2 mutations in patients with polyps were p.S428F (n = 10), p.I157T (n = 4) and p.T476M (n = 2), with other mutations present in 1 patient each. Among patients with lower gastrointestinal polyps, 9 had adenomas, 6 had serrated polyps, 1 had an inflammatory polyp and 6 had both adenomatous and serrated polyps. Three patients (p.I157T, n = 2; p.R117G, n = 1) had >10 adenomas, and 1 (p.G259fs) had 18 serrated polyps. Five patients (11.1%) developed colorectal adenocarcinoma, including 2 with >10 adenomas. Five patients with p.S428F (50%) exclusively had right- sided adenomas. LIMITATIONS: Single-center descriptive study. CONCLUSIONS: Germline checkpoint kinase 2 mutations should be considered in patients with polyposis. The preponderance of right- sided adenomas in patients with p.S428F mutations suggests the importance of right-sided colonoscopy in these patients. See Video Abstract.

Teaching Hospitals and Textbook Outcomes After Major Urologic Cancer Surgery.

OBJECTIVE: To assess textbook outcomes by hospital teaching status following major surgery for urologic cancers. METHODS: We used 100% national Medicare Provider Analysis and Review files from 2017-2020 to assess rates of textbook outcomes in patients undergoing bladder (ie, radical cystectomy), kidney (ie, radical or partial nephrectomy), and prostate (ie, radical prostatectomy) surgery for genitourinary malignancies. The extent of integration of learners into each hospital's workforce-defined as major, minor, and non teaching hospitals-was the primary exposure. A textbook outcome, measured at the patient level, was defined as the absence of in-hospital mortality and mortality within 30days of surgery, no readmission 30days following discharge, no postoperative complication, and no prolonged length of stay. RESULTS: Textbook outcomes were achieved in 51% (8564/16,786) of patients after bladder cancer surgery, 70% (39,938/57,300) of patients after kidney cancer surgery, and 82% (50,408/61,385) of patients after prostate cancer surgery. After adjusting for patient- and hospital-level characteristics, teaching hospitals had higher rates of textbook outcomes in those undergoing bladder (50.7% vs 44.0%; P = .001), kidney (72.0% vs 69.7%; P = .02), and prostate (85.3% vs 81.0%; P <.001) surgery. This effect was attenuated, but not eliminated, by surgical volume in additional sensitivity analyses for bladder (OR: 1.20, 95% CI: 1.00-1.42; P = .04) and prostate (OR: 1.15, 95% CI: 1.00-1.32; P = .04) surgery. There were no significant differences in kidney cancer surgery outcomes after adjusting for hospital volume (OR: 1.03, 95% CI: 0.93-1.14; P = .6). CONCLUSION: Undergoing major cancer surgery at a teaching hospital was associated with an increased likelihood of achieving a textbook outcome. This effect was attenuated by volume but persisted for bladder and prostate surgery.

Addressing financial toxicity in cancer treatment-An opportunity for the 340B drug pricing program.

Cancer treatment has become increasingly expensive, partially due to the use of specialty drugs. The costs of these drugs are often passed down to patients, who may face the consequences of paying for more than they can afford, leading to financial toxicity. The 340B drug pricing program is a health care policy that may provide an opportunity to mitigate the financial consequences of cancer care. The 340B program requires manufacturers to sell outpatient drugs at a discount to hospitals caring for a significant number of socioeconomically disadvantaged individuals. The program intended for hospitals to use savings from discounted purchases to expand their safety net to vulnerable patients. Some studies have shown that participating hospitals do this by offering more charity and discounted care, whereas others have demonstrated that hospitals fail to sufficiently expand their safety net. A potential flaw of the program is the lack of guidance from governing bodies on how hospitals should use savings from discounted purchases. There has been growing discussion among stakeholders to reform the 340B program given the mixed findings of its effectiveness. With the rising costs of specialty drugs and associated prevalence of financial toxicity in patients with cancer, there is an opportunity to address these issues through reform that improves the program. Directing hospitals to offer specific safety net opportunities, such as passing along discounted drug prices to vulnerable populations, could help the growing number of patients who are financially burdened by medications at the core of the 340B program.

Millimeter-wave and high-resolution infrared spectroscopy of the low-lying vibrational states of pyridazine isotopologues.

The gas-phase rotational spectrum from 8 to 750 GHz and the high-resolution infrared (IR) spectrum of pyridazine (o-C4H4N2) have been analyzed for the ground and four lowest-energy vibrationally excited states. A combined global fit of the rotational and IR data has been obtained using a sextic, centrifugally distorted-rotor Hamiltonian with Coriolis coupling between appropriate states. Coriolis coupling has been addressed in the two lowest-energy coupled dyads (ν16, ν13 and ν24, ν9). Utilizing the Coriolis coupling between the vibrational states of each dyad and the analysis of the IR spectrum for ν16 and ν9, we have determined precise band origins for each of these fundamental states: ν16 (B1) = 361.213 292 7 (17) cm-1, ν13 (A2) = 361.284 082 4 (17) cm-1, ν24 (B2) = 618.969 096 (26) cm-1, and ν9 (A1) = 664.723 378 4 (27) cm-1. Notably, the energy separation in the ν16-ν13 Coriolis-coupled dyad is one of the smallest spectroscopically measured energy separations between vibrational states: 2122.222 (72) MHz or 0.070 789 7 (24) cm-1. Despite ν13 being IR inactive and ν24 having an impractically low-intensity IR intensity, the band origins of all four vibrational states were measured, showcasing the power of combining the data provided by millimeter-wave and high-resolution IR spectra. Additionally, the spectra of pyridazine-dx isotopologues generated for a previous semi-experimental equilibrium structure (reSE) determination allowed us to analyze the two lowest-energy vibrational states of pyridazine for all nine pyridazine-dx isotopologues. Coriolis-coupling terms have been measured for analogous vibrational states across seven isotopologues, both enabling their comparison and providing a new benchmark for computational chemistry.

Unpacking overuse of androgen deprivation therapy for prostate cancer to inform de-implementation strategies.

BACKGROUND: Many men with prostate cancer will be exposed to androgen deprivation therapy (ADT). While evidence-based ADT use is common, ADT is also used in cases with no or limited evidence resulting in more harm than benefit, i.e., overuse. Since there are risks of ADT (e.g., diabetes, osteoporosis), it is important to understand the behaviors facilitating overuse to inform de-implementation strategies. For these reasons, we conducted a theory-informed survey study, including a discrete choice experiment (DCE), to better understand ADT overuse and provider preferences for mitigating overuse. METHODS: Our survey used the Action, Actor, Context, Target, Time (AACTT) framework, the Theoretical Domains Framework (TDF), the Capability, Opportunity, Motivation-Behavior (COM-B) Model, and a DCE to elicit provider de-implementation strategy preferences. We surveyed the Society of Government Service Urologists listserv in December 2020. We stratified respondents based on the likelihood of stopping overuse as ADT monotherapy for localized prostate cancer ("yes"/"probably yes," "probably no"/"no"), and characterized corresponding Likert scale responses to seven COM-B statements. We used multivariable regression to identify associations between stopping ADT overuse and COM-B responses. RESULTS: Our survey was completed by 84 respondents (13% response rate), with 27% indicating "probably no"/"no" to stopping ADT overuse. We found differences across respondents who said they would and would not stop ADT overuse in demographics and COM-B statements. Our model identified 2 COM-B domains (Opportunity-Social, Motivation-Reflective) significantly associated with a lower likelihood of stopping ADT overuse. Our DCE demonstrated in-person communication, multidisciplinary review, and medical record documentation may be effective in reducing ADT overuse. CONCLUSIONS: Our study used a behavioral theory-informed survey, including a DCE, to identify behaviors and context underpinning ADT overuse. Specifying behaviors supporting and gathering provider preferences in addressing ADT overuse requires a stepwise, stakeholder-engaged approach to support evidence-based cancer care. From this work, we are pursuing targeted improvement strategies. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03579680.

Keratin 17 is a prognostic and predictive biomarker in pancreatic ductal adenocarcinoma.

OBJECTIVES: To determine the role of keratin 17 (K17) as a predictive biomarker for response to chemotherapy by defining thresholds of K17 expression based on immunohistochemical tests that could be used to optimize therapeutic intervention for patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: We profiled K17 expression, a hallmark of the basal molecular subtype of PDAC, by immunohistochemistry in 2 cohorts of formalin-fixed, paraffin-embedded PDACs (n = 305). We determined a K17 threshold of expression to optimize prognostic stratification according to the lowest Akaike information criterion and explored the potential relationship between K17 and chemoresistance by multivariate predictive analyses. RESULTS: Patients with advanced-stage, low K17 PDACs treated using 5-fluorouracil (5-FU)-based chemotherapeutic regimens had 3-fold longer survival than corresponding cases treated with gemcitabine-based chemotherapy. By contrast, PDACs with high K17 did not respond to either regimen. The predictive value of K17 was independent of tumor mutation status and other clinicopathologic variables. CONCLUSIONS: The detection of K17 in 10% or greater of PDAC cells identified patients with shortest survival. Among patients with low K17 PDACs, 5-FU-based treatment was more likely than gemcitabine-based therapies to extend survival.

Measures of Ethics and Social Responsibility Among Undergraduate Engineering Students: Findings from a Longitudinal Study.

Prior research on engineering students' understandings of ethics and social responsibility has produced mixed and sometimes conflicting results. Seeking greater clarity in this area of investigation, we conducted an exploratory, longitudinal study at four universities in the United States to better understand how engineering undergraduate students perceive ethics and social responsibility and how those perceptions change over time. Undergraduate engineering students at four U.S. universities were surveyed three times: during their 1st (Fall 2015), 5th (Fall 2017), and 8th semesters (Spring 2019). The students who completed all three surveys (n = 226) comprise the sample that was analyzed in this paper for changes in their scores on five instruments: Fundamentals of Engineering/Situational Judgment, Moral Disengagement, ABET Engineering Work and Practice Considerations, Macroethics, and Political and Social Involvement Scale. We found that students modestly increased their knowledge of ethics and ability to apply that knowledge in situations calling for them to exercise judgment. In addition, they consistently indicated that health and safety considerations in engineering were of highest importance. They also showed steady levels of social consciousness over time, in contrast to other studies which detected a culture of increasing disengagement in engineering students throughout the four years of their undergraduate studies.

Factors affecting Accountable Care Organizations' decisions to remain in or exit the Medicare Shared Savings Program following Pathways to Success.

The Medicare Shared Savings Program (MSSP) is an alternative payment model launched in 2012, creating Accountable Care Organizations (ACOs) to improve quality and lower costs for Traditional Medicare patients. Most MSSP participants were expected to shift from bearing no financial risk to a 2-sided risk model (ie, bonus if spending reduced below historical benchmarks, penalty if not), yet fewer than 20% did. Therefore, in 2019, the Centers for Medicare and Medicaid Services launched the Pathways to Success program, which required shifting to a 2-sided model within 12 months. For the first time, more ACOs exited than entered the MSSP. To understand these participation decisions, we conducted qualitative interviews with ACO leaders. Pathways caused ACOs to reassess their potential shared savings vs losses, particularly in light of benchmarking methodology changes; reconsider perceived nonrevenue benefits; and reassess participation in the MSSP vs other programs. As ACOs, particularly those assuming downside risk, have contained costs and enhanced care quality, policymakers should strive to improve MSSP enrollment rates in downside-risk models through strategies that allow ACOs to achieve shared savings and deliver accountable care.

5-Hydroxymethylcytosine (5-hmC) loss is a marker of malignancy in biliary neoplasms.

OBJECTIVES: Adenocarcinomas of the biliary tract frequently present diagnostic challenges because of their histologic overlap with benign and preinvasive lesions. The molecular profiles of biliary adenocarcinomas vary by anatomical location. Variations in IDH1/2, common in intrahepatic cholangiocarcinoma, can lead to defective production of 5-hydroxymethylcytosine (5-hmC). Limited ancillary studies are available for biliary adenocarcinomas, and loss of 5-hmC staining could serve as a helpful ancillary diagnostic tool for biliary tract malignancies. METHODS: We evaluated 93 cases-20 benign biliary lesions, 15 preinvasive biliary neoplasms, 46 invasive biliary carcinomas, and 12 pancreatic adenocarcinomas-for 5-hmC staining. Preoperative biopsies from 16 cases of biliary carcinoma were also stained. Sixteen nonneoplastic/reactive bile duct biopsies served as controls. RESULTS: Loss of 5-hmC was seen in 41 of 46 (89.1%) biliary malignancies vs 0 of 20 benign tumors (P < .001), for a sensitivity and specificity of 89.1% and 100%, respectively. Intrahepatic cholangiocarcinoma showed loss of 5-hmC in 11 of 13 (84.6%) cases, similar to the 30 of 33 (90.9%) cases in other biliary adenocarcinomas (P = .61). Similarly, 5-hmC loss was more frequent in distal bile duct adenocarcinomas than in pancreatic ductal adenocarcinomas, at 15 of 17 (88.2%) vs 4 of 12 (33.3%), respectively (P = .0045). There was no difference in the frequency of 5-hmC loss in patients that received neoadjuvant therapy vs those who did not (90.9% vs 88.6%, P > .99). 5-hmC immunohistochemistry in preoperative biopsies was concordant with the resection specimen in 81.3% (13/16) of cases. CONCLUSIONS: Loss of 5-hmC is not unique to intrahepatic cholangiocarcinoma among biliary carcinomas, but is a useful diagnostic marker differentiating malignancies of the biliary tree from benign mimics.

The 340B Program and oral specialty drugs for advanced prostate cancer.

INTRODUCTION: Expensive oral specialty drugs for advanced prostate cancer can be associated with treatment disparities. The 340B program allows hospitals to purchase medications at discounts, generating savings that can improve care of the socioeconomically disadvantaged. This study assessed the effect of hospital 340B participation on advanced prostate cancer. METHODS: The authors performed a retrospective cohort study of Medicare beneficiaries with advanced prostate cancer from 2012 to 2019. The primary outcome was use of an oral specialty drug. Secondary outcomes included monthly out-of-pocket costs and treatment adherence. We evaluated the effects of 1) hospital 340B participation, 2) a regional measure vulnerability, the social vulnerability index (SVI), and 3) the interaction between hospital 340B participation and SVI on outcomes. RESULTS: There were 2237 and 1100 men who received care at 340B and non-340B hospitals. There was no difference in specialty drug use between 340B and non-340B hospitals, whereas specialty drug use decreased with increased SVI (odds ratio, 0.95, p = .038). However, the interaction between hospital 340B participation and SVI on specialty drug use was not significant. Neither 340B participation, SVI, or their interaction were associated with out-of-pocket costs. Although hospital 340B participation and SVI were not associated with treatment adherence, their interaction was significant (p = .020). This demonstrated that 340B was associated with better adherence among socially vulnerable men. CONCLUSIONS: The 340B program was not associated with specialty drug use in men with advanced prostate cancer. However, among those who were started on therapy, 340B was associated with increased treatment adherence in more socially vulnerable men.

Markedly increased duodenal villous surface apoptosis in patients taking pre-exposure prophylaxis (PrEP) against human immunodeficiency virus.

AIMS: Pre-exposure prophylaxis (PrEP) consists of combination antiretroviral therapy and is increasingly utilized to prevent human immunodeficiency virus (HIV) in high-risk populations. Two index cases noted during routine care showed markedly increased duodenal villous surface apoptosis in patients on PrEP. We sought to examine the prevalence of this finding and identify any clinicopathologic correlations. METHODS: Gastrointestinal biopsy specimens from 23 male patients aged 18-40 years taking PrEP and 23 control patients were reviewed. Patients with HIV, inflammatory gastrointestinal diseases, and celiac disease were excluded. Apoptoses were counted on surface epithelium and deep crypts. The highest apoptotic body count per tissue fragment was recorded. Clusters were defined as groups of ≥5 apoptoses. Apoptotic counts between patients taking PrEP and controls were compared using t-tests. RESULTS: In PrEP patients, the median age was 35 years (range 25-40) and 83% (19/23) were white. The control patients were demographically similar (median age: 32 years [range 23-40]; 70% [16/23] white). Duodenal apoptosis in villous surface epithelium was increased in PrEP patients, with 14/23 (60.9%) patients having ≥10 surface apoptoses compared to 2/23 (8.7%) controls (P = 2.1 × 10-3 ) and 14/23 (61%) having clusters compared to 3/23 (13%) controls (P = 2.0 × 10-3 ). There was no significant association between increased surface apoptosis or clusters and clinical symptoms or duration of PrEP use. CONCLUSION: Markedly increased villous surface apoptosis, particularly in clusters, is often seen in the duodenum of patients taking PrEP. Although the mechanism and significance are unknown, knowledge of this peculiar finding may prevent unnecessary additional testing.

BDNF and cAMP are neuroprotective in a porcine model of traumatic optic neuropathy.

Traumatic optic neuropathy (TON) is a devastating condition that can occur after blunt or penetrating trauma to the head, leading to visual impairment or blindness. Despite these debilitating effects, no clinically available therapeutic targets neuroprotection or promotes axon regeneration in this or any optic neuropathy. Limited data in large-animal models are a major obstacle to advancing treatments toward clinical therapeutics. To address this issue, we refined a surgical model of TON in Yucatan minipigs. First, we validated the model by demonstrating visual impairment by flash visual-evoked potential and retinal ganglion cell degeneration and death. Next, we developed and optimized a delivery method and nontoxic dosing of intravitreal brain-derived neurotrophic factor (BDNF) and cAMP. Finally, we showed that intravitreal injection of BDNF and cAMP rescued visual function and protected against retinal ganglion cell death and optic nerve axon degeneration. Together these data in a preclinical large-animal model advance our understanding of and ability to model TON and further identify and develop candidate clinical therapeutics.

National Trends in Management of Newly Diagnosed Prostate Cancer.

BACKGROUND: Deciding whether to treat or conservatively manage patients with prostate cancer is challenging. Recent changes in guidelines, advances in treatment technologies, and policy can influence decision making surrounding management, particularly for those for whom the decision to treat is discretionary. Contemporary trends in management of newly diagnosed prostate cancer are unclear. METHODS: Using national Medicare data, men with newly diagnosed prostate cancer were identified between 2014 and 2019. Patients were classified by 5- and 10-year noncancer mortality risk. Multinomial logistic regression models were fit to assess adjusted trends in management over time. The primary outcome was management of prostate cancer: local treatment (inclusive of surgery, radiation, brachytherapy, or cryotherapy), hormone therapy, or observation. RESULTS: Local treatment was the most common form of management and stable across years (68%). Use of observation increased (21%-23%, P < .001) and use of hormone therapy decreased (11%-8%, P < 0.001). After stratifying by 10-year non-cancer mortality risk, observation increased among men with low (22.3%-26.1%, P < .001) and moderate (19.9%-23.5%, P < .001) mortality risk. Conversely, use of treatment increased among those with high (62.8%-68.0%, P = .004) and very high (45.5%-54.1%, P < .001) risk of noncancer mortality. These trends were similar across groups when stratified by 5-year noncancer mortality risk. CONCLUSION: Nationally, use of local treatment remains common and was stable throughout the study period. However, while local treatment declined among men with a lower risk of noncancer mortality, it increased among men with a higher risk of non-cancer mortality.

Hospital-physician integration and clinical volume in traditional Medicare.

OBJECTIVE: To test the effect of hospital-physician integration on primary care physicians' (PCP) clinical volume in traditional Medicare. DATA SOURCES AND STUDY SETTING: Nationwide retrospective longitudinal study using Medicare claims and other data sources from 2010 to 2016. STUDY DESIGN: We identified 70,000 PCPs, some of whom remained non-integrated and some who became hospital-integrated during this study period. We used an event study design to identify the effect of integration on key measures of physicians' clinical volume, including the number of claims, work-relative value units (RVUs), professional revenue generated, number of patients treated, and facility fee revenue generated. PRINCIPAL FINDINGS: Per-physician clinical volume declined by statistically and economically significant margins. Relative to the comparison group who remained non-integrated, work RVUs fell by 7% (95% confidence interval [CI]: -8.6% to -5.5%); the number of patients treated fell by 4% (95% CI: -5.8% to -2.6%); and claims volume among PCPs who became hospital-integrated fell by over 15% (95% CI: -16.8% to -13.5%). Though professional revenue declined by $29,165 (95% CI: -$32,286 to -$26,044), this loss was almost entirely offset by increased facility fee revenue of $28,556 (95% CI: 26,909 to 30,203). CONCLUSIONS: Hospital-physician integration may affect the quantity of clinical services delivered by PCPs to traditional Medicare beneficiaries. Reductions in clinical volume associated with integration may have long-term consequences for the supply of physician services and patient access to primary care. Future research on physician time use and patient access following hospital integration would further add to the evidence base.

National Long-term Survival Estimates After Radical Prostatectomy for Prostate Cancer.

OBJECTIVE: To examine survival and disease control outcomes, including metastasis-related survival outcomes, in a large contemporary cohort of patients undergoing radical prostatectomy for localized prostate cancer. METHODS: We conducted a retrospective study of men with localized prostate cancer treated with radical prostatectomy from 2005 to 2015 with follow-up through 2019 in the Veterans Health Administration. We defined biochemical recurrence (BCR) as a prostate-specific antigen ≥0.2 ng/mL. We used a validated natural language processing encoded dataset to identify incident metastatic prostate cancer. We estimated overall survival from time of surgery, time of BCR, and time of first metastasis using the Kaplan-Meier method. We then estimated time from surgery to BCR, BCR to metastatic disease, and prostate-cancer-specific survival from various time points using cumulative incidence considering competing risk of death. RESULTS: Of 21,992 men undergoing radical prostatectomy, we identified 5951 (27%) who developed BCR. Of men with BCR, 677 (11%) developed metastases. We estimated the 10-year cumulative incidence of BCR and metastases after BCR were 28% and 20%, respectively. Median overall survival after BCR was 14years, with 10-year survival of 70%. From the time of metastasis, median overall survival approached 7years, with 10-year overall survival of 34%. Prostate cancer-specific survival for the entire cohort at 10years was 94%. CONCLUSION: In this large contemporary national cohort, survival for men with biochemically recurrent prostate cancer is longer than historical cohorts. When counseling patients and designing clinical studies, these updated estimates may serve as more reliable reflections of current outcomes.

Association Between Urologist Merit-Based Incentive Payment System Performance and Quality of Prostate Cancer Care.

INTRODUCTION: We performed a study to evaluate the association between urologist performance in the Merit-Based Incentive Payment System (MIPS), and quality and spending for prostate cancer care. METHODS: Medicare beneficiaries with prostate cancer diagnosed between 2017 and 2019 were assigned to their primary urologist. Associated MIPS scores were identified and categorized based on thresholds for payment adjustment as low (worst), moderate, and high (best). Multivariable mixed effects models were used to measure the association between MIPS performance and adherence to quality measures and price standardized spending for prostate cancer. RESULTS: Adherence to quality measures did not vary across MIPS performance groups for pretreatment counselling by both a urologist and radiation oncologist (low-76%, [95% CI 73%-80%], moderate-77% [95% CI 74%-79%], and high-75% [95% CI 74%-76%]) and avoiding treatment in men with a high risk of noncancer mortality within 10 years of diagnosis (low-40% [95% CI 35%-45%], moderate-39% [95% CI 36%-43%], high-38% [95% CI 36%-39%]). Men on active surveillance managed by high performers more likely received a confirmatory test (44% [95% CI 43%-46%]) compared to those managed by moderate (38% [95% CI 33%-42%]) performers, but not low performers (36% [95% CI 29%-44%]). There was no difference in adjusted spending across MIPS performance groups. CONCLUSIONS: Better performance in MIPS is associated with a higher rate of confirmatory testing in men initiating active surveillance for prostate cancer. However, performance was not associated with other dimensions of quality nor spending.

Arginase-1 is More Specific Than Hepatocyte Paraffin 1 for Differentiating Hepatocellular Carcinomas With Cytoplasmic Clearing from Nonhepatocellular Clear Cell Tumors in Liver Biopsies.

Arginase-1 (Arg1) and hepatocyte paraffin antigen 1 (HepPar1) are specific and sensitive markers of hepatocellular differentiation. HepPar1 is a granular cytoplasmic immunostain that may be negative in hepatocellular carcinoma (HCC) with cytoplasmic clearing. Arg1 shows uniform cytoplasmic positivity and frequent nuclear positivity. This study was undertaken to determine the staining pattern of Arg1 in HCC with cytoplasmic clearing and compare its use to HepPar1. Fifteen resected HCCs with cytoplasmic clearing and 31 biopsies of clear cell liver tumors (14 HCCs and 17 nonhepatocellular tumors) were identified. Resections were stained with Arg1 to characterize the pattern, intensity, and extent of Arg1 positivity. Biopsies were stained with Arg1 (n=31) and HepPar1 (n=28). In all, 13/15 resected and 11/14 biopsied HCCs with cytoplasmic clearing showed nuclear positivity for Arg1. Both Arg1 and HepPar1 stained significantly more HCCs than nonhepatocellular tumors (13/14 and 11/12, respectively, with P <0.0001 and P =0.0018, respectively). However, HepPar1 stained significantly more nonhepatocellular tumors (5/12) than Arg1 (0/17, P =0.0445). Arg1 frequently displayed nuclear positivity, and interobserver agreement was better for Arg1 ( K =0.93 vs. 0.79). Overall, Arg1 is more specific than HepPar1 for differentiating HCC with cytoplasmic clearing from nonhepatocellular clear cell tumors in the liver. Its staining characteristics, including nuclear positivity, make it easier to interpret in combination with morphology, improving interobserver variability, and it stains significantly fewer mimics than HepPar1.

The Cousa objective: a long-working distance air objective for multiphoton imaging in vivo.

Multiphoton microscopy can resolve fluorescent structures and dynamics deep in scattering tissue and has transformed neural imaging, but applying this technique in vivo can be limited by the mechanical and optical constraints of conventional objectives. Short working distance objectives can collide with compact surgical windows or other instrumentation and preclude imaging. Here we present an ultra-long working distance (20 mm) air objective called the Cousa objective. It is optimized for performance across multiphoton imaging wavelengths, offers a more than 4 mm2 field of view with submicrometer lateral resolution and is compatible with commonly used multiphoton imaging systems. A novel mechanical design, wider than typical microscope objectives, enabled this combination of specifications. We share the full optical prescription, and report performance including in vivo two-photon and three-photon imaging in an array of species and preparations, including nonhuman primates. The Cousa objective can enable a range of experiments in neuroscience and beyond.

Urologist practice divestment from radiation vault ownership and treatment patterns for prostate cancer.

BACKGROUND: Urologists practicing in single-specialty groups with ownership in radiation vaults are more likely to treat men with prostate cancer. The effect of divestment of vault ownership on treatment patterns is unclear. METHODS: A 20% sample of national Medicare claims was used to perform a retrospective cohort study of men with prostate cancer diagnosed between 2010 and 2019. Urology practices were categorized by radiation vault ownership as nonowners, continuous owners, and divested owners. The primary outcome was use of local treatment, and the secondary outcome was use of intensity-modulated radiation therapy (IMRT). A difference-in-differences framework was used to measure the effect of divestment on outcomes compared to continuous owners. Subgroup analyses assessed outcomes by noncancer mortality risk (high [>50%] vs. low [≤50%]). RESULTS: Among 72 urology practices that owned radiation vaults, six divested during the study. Divestment led to a decrease in treatment compared with those managed at continuously owning practices (difference-in-differences estimate, -13%; p = .03). The use of IMRT decreased, but this was not statistically significant (difference-in-differences estimate, -10%; p = .13). In men with a high noncancer mortality risk, treatment (difference-in-differences estimate, -28%; p < .001) and use of IMRT (difference-in-differences estimate, -27%; p < .001) decreased after divestment. CONCLUSIONS: Urology group divestment from radiation vault ownership led to a decrease in prostate cancer treatment. This decrease was most pronounced in men who had a high noncancer mortality risk. This has important implications for health care reform by suggesting that payment programs that encourage constraints on utilization, when appropriate, may be effective in reducing overtreatment.

Sustained versus repetitive standing trunk extension results in greater spinal growth and pain improvement in back pain:A randomized clinical trial.

BACKGROUND: McKenzie standing trunk extension exercises have been used for the management of low back pain (LBP). However, no study to date has investigated the effect of standing trunk extension postures on spinal height and clinical outcomes. OBJECTIVE: To evaluate in subjects with LBP following a period of trunk loading how spinal height, pain, symptoms' centralization and function outcome measures respond to two standing postures interventions: (1) repetitive trunk extension (RTE) and (2) sustained trunk extension (STE). METHODS: A consecutive sample of convenience of people with LBP were recruited to participate in 2-session physical therapy using either RTE or STE in standing. RESULTS: Thirty participants (18 women) with a mean age of 53 ± 17.5 years completed the study. The first session resulted in spinal height increase (spinal growth) of 2.07 ± 1.32 mm for the RTE intervention and 4.54 ± 1.61 mm for the STE group (p< 0.001; ES = 1.67), while the second session (2-week following the first session) resulted in spinal growth of 2.39 ± 1.46 mm for the RTE group and 3.91 ± 2.06 mm for the STE group (p= 0.027; ES = 0.85). The STE group presented with the larger reduction in most pain from 6 to 2 as compared to the RTE group from 6 to 4 between Session 1 and Session 2 (p< 0.001). There was no difference between the groups in Modified Oswestry score and symptoms centralization (p= 0.88 and p= 0.77, respectively). CONCLUSION: People with LBP experienced greater spine growth and improvements of pain during standing STE as compared to RTE. People with LBP could use such postures and movements to alleviate their LBP and improve spine height while in a weight bearing position.