Predicting Postoperative Satisfaction with Breasts: How Important is the Preoperative BREAST-Q Score?

BACKGROUND: The role that preoperative Satisfaction with Breast plays in a patient's postoperative course after postmastectomy breast reconstruction (PMBR) is not understood. The aim of this study is to understand the impact of the preoperative score on postoperative outcome as an independent variable. METHODS: We examined patients who underwent PMBR between 2017 and 2021 and who completed the BREAST-Q Satisfaction with Breasts at 1 year postoperatively. Two multiple linear regression models (Model 1 with the preoperative Satisfaction with Breasts score and Model 2 without the preoperative score), likelihood ratio tests, simple t-statistics, and sample patient dataset to predict the 1 year score were performed. Multiple imputation was used to account for missing preoperative scores. RESULTS: Overall, 2324 patients were included. Model 1 showed that the preoperative score is significantly associated with the postoperative score (ß = 0.09, 95% confidence interval 0.04-0.14; p < 0.001). Comparing Model 1 and Model 2 demonstrated that including preoperative Satisfaction with Breasts in a regression significantly improves model fit (test statistic = 10.04; p = 0.0021). Using the absolute value of the t-statistics as a measure of variable importance in linear regression, the importance of the preoperative score was quantified as 3.39-more important than neoadjuvant radiation, mastectomy weight, body mass index, bilateral prophylactic mastectomy, and race, but less than adjuvant radiation, reconstruction type, and psychiatric diagnoses. CONCLUSION: Preoperative Satisfaction with Breasts scores are an important independent predictor of postoperative satisfaction after PMBR. Just as vital sign and work-up are carefully documented before surgery, preoperative scores should be collected to pre-emptively gauge patients' satisfaction and optimize postoperative outcomes.

Application of the updated International IgA Nephropathy Prediction Tool in children one- or two-years post-biopsy.

The pediatric International IgA Nephropathy (IgAN) Prediction Tool comprises two models with and without ethnicity and is the first method to predict the risk of a 30% decline in estimated glomerular filtration rate (eGFR) or kidney failure in children at the time of biopsy using clinical risk factors and Oxford MEST histology scores. However, it is unknown if the Prediction Tool can be applied after a period of observation post-biopsy. Using an international multi-ethnic cohort of 947 children with IgAN, 38% of whom were followed into adulthood, the Prediction Tool was updated for use one-year after biopsy. Compared to the original pediatric Prediction Tool, the updated post-biopsy Prediction Tool had a better model fit with higher R2D (51%/50% vs 20%), significant increase in 4-year C-statistics (0.83 vs 0.73/0.69, ΔC 0.09 [95% confidence interval 0.07-0.10] and ΔC 0.14 [0.12-0.15]) and better 4-year calibration with lower integrated calibration indices (0.74/0.54 vs 2.45/1.01). Results were similar after internal validation and when the models were applied two-years after biopsy. Trajectories of eGFR after a baseline one-year post-biopsy were non-linear and those at higher predicted risk started with a lower eGFR and experienced a more rapid decline over time. In children, eGFR had a variable rate of increase until 15-18 years old then decreased linearly with a more rapid decline in higher risk groups that was similar to young adults of comparable risk. Thus, the original pediatric Prediction Tool should be used in children at the time of biopsy, and the updated pediatric Prediction Tool should be used to revaluate risk one- or two-years after biopsy.

Alternative reproductive tactics and evolutionary rescue.

Almost all life on earth is facing environmental change, and understanding how populations will respond to these changes is of urgent importance. One factor that is known to affect the speed by which a population can evolve when faced with changes in the environment is strong sexual selection. This increases the adaptive capacity of a population by increasing reproductive skew toward well-adapted (usually) males who will, on average, be best able to compete for matings. This effect could potentially be disrupted when males pursue alternative reproductive tactics (ARTs), whereby males within a species exhibit qualitatively different behaviors in their pursuit of matings. ARTs are diverse, but one common class is those expressed through condition-dependent polyphenism such that high-quality, well-adapted males compete aggressively for mates and low-quality, poorly adapted males attempt to acquire matings via other, nonaggressive behaviors. Here, using an individual-based modeling approach, we consider the possible impacts of ARTs on adaptation and evolutionary rescue. When the ART is simultaneous, meaning that low-quality males not only engage in contests but also pursue other tactics, adaptive capacity is reduced and evolutionary rescue, where a population avoids extinction by adapting to a changing environment, becomes less likely. This is because the use of the ART allows low-quality males to contribute more maladaptive genes to the population than would happen otherwise. When the ART is fixed, however, such that low-quality males will only use the alternative tactic and do not engage in contests, we find the opposite: adaptation happens more quickly and evolutionary rescue when the environment changes is more likely. This surprising effect is caused by an increase in the mating success of the highest quality males who face many fewer competitors in this scenario-counterintuitively, the presence of males pursuing the ART increases reproductive skew toward those males in the best condition.

Interrogating the Role of Endocytosis Pathway and Organelle Trafficking for Doxorubicin-Based Combination Ionic Nanomedicines.

We have studied the endocytic mechanisms that determine subcellular localization for three carrier-free chemotherapeutic-photothermal (chemo-PTT) combination ionic nanomedicines (INMs) composed of doxorubicin (DOX) and an near-infrared (NIR) dye (ICG, IR820, or IR783). This study aims to understand the cellular basis for previously published enhanced toxicity results of these combination nanomedicines toward MCF-7 breast cancer cells. The active transport mechanism of INMs, unlike free DOX, which is known to employ passive transport, was validated by conducting temperature-dependent cellular uptake of the drug in MCF-7 cells using confocal microscopy. The internalization pathway of these INMs was further probed in the presence and absence of different endocytosis inhibitors. Detailed examination of the mode of entry of the carrier-free INMs in MCF-7 cells revealed that they are primarily internalized through clathrin-mediated endocytosis. In addition, time-dependent subcellular localization studies were also investigated. Examination of time-dependent confocal images indicated that the INMs targeted multiple organelles, in contrast to free DOX that primarily targets the nucleus. Collectively, the high cellular endocytic uptake in cancerous cells (EPR effect) and the multimode targeting ability demonstrated the main reason for the low half-maxima inhibitory concentration (IC50) value (the high cytotoxicity) of these carrier-free INMs as compared to their respective parent chemo and PTT drugs.

Soft tissue aneurysmal bone cyst presenting as an enlarging neck mass: Case report and review of the head and neck literature.

Soft tissue aneurysmal bone cysts (STABCs) are rare neoplasms histopathologically identical to aneurysmal bone cysts. These benign lesions are characterized by thin, peripheral ossification and no skeletal continuity. STABC may be difficult to distinguish from myositis ossificans (MO) and malignant entities from imaging and fine needle aspiration, due to rarity and overlapping features. We present a case of a STABC occurring in the paraspinal cervical muscles. The imaging, histopathology, molecular analysis, and treatment are discussed. Four other published cases of STABC of the head and neck are reviewed.

Age-specific colorectal cancer incidence trends in Canada, 1971-2021.

INTRODUCTION: Colorectal cancer (CRC) incidence among adults younger than 50 years has increased in recent decades, leading to some advocating for lowering the age to start CRC screening. Here, we estimate age-specific trends in CRC incidence in Canada and changes in risk by birth cohort. METHODS: CRC incidence data from 1971 to 2021 by province, sex, and five-year age group (35-64) were obtained from the National Cancer Incidence Reporting System and the Canadian Cancer Registry. Annual percent changes in age-specific or age-adjusted incidence rates were analyzed with joinpoint regression. Birth cohort effect was estimated with age-period-cohort models and reported as cohort incidence rate ratios (IRRs) with respect to the 1947-51 cohort. RESULTS: CRC incidence has increased among all age groups under 50 years, with the largest relative increases occurring in the youngest age group (35-39 years). Males and females had similar incidence trends, though males under age 50 had larger increases than females. The birth cohort analysis showed that males born since 1966 have a significantly higher risk than those born at any other time. CONCLUSIONS: These results up to 2021 confirm and update reports that CRC incidence is increasing among adults under age 50 in Canada and that the youngest birth cohorts carry the highest risk. Future studies should assess the effectiveness of CRC screening in younger populations.

Novel inhibition of central carbon metabolism pathways by Rac and Cdc42 inhibitor MBQ-167 and paclitaxel.

Triple negative breast cancer (TNBC) represents a therapeutic challenge where standard chemotherapy is limited to paclitaxel. MBQ-167, a clinical stage small molecule inhibitor that targets Rac and Cdc42, inhibits tumor growth and metastasis in mouse models of TNBC. Herein, we investigated the efficacy of MBQ-167 in combination with paclitaxel in TNBC pre-clinical models, as a prelude to safety trials of this combination in advanced breast cancer patients. Individual MBQ-167 or combination therapy with paclitaxel was more effective at reducing TNBC cell viability and increasing apoptosis compared to paclitaxel alone. In orthotopic mouse models of human TNBC (MDA-MB-231 and MDA-MB-468), individual MBQ-167, paclitaxel, or the combination reduced mammary tumor growth with similar efficacy, with no apparent liver toxicity. However, paclitaxel single agent treatment significantly increased lung metastasis, while MBQ-167, single or combined, reduced lung metastasis. In the syngeneic 4T1/BALB/c model, combined MBQ-167 and paclitaxel decreased established lung metastases by ~80%. To determine the molecular basis for the improved efficacy of the combined treatment on metastasis, 4T1 tumor extracts from BALB/c mice treated with MBQ-167, paclitaxel, or the combination were subjected to transcriptomic analysis. Gene set enrichment identified specific downregulation of central carbon metabolic pathways by the combination of MBQ-167 and Paclitaxel but not individual compounds. Biochemical validation, by immunoblotting and metabolic Seahorse analysis, shows that combined MBQ-167 and paclitaxel reduces glycolysis. This study provides a strong rationale for the clinical testing of MBQ-167 in combination with paclitaxel as a potential therapeutic for TNBC and identifies a unique mechanism of action.

Clinical Outcomes and Targeted Genomic Analysis of Renal Cell Carcinoma Brain Metastases Treated with Stereotactic Radiosurgery.

BACKGROUND: Molecular profiles of renal cell carcinoma (RCC) brain metastases (BMs) are not well characterized. Effective management with locoregional therapies, including stereotactic radiosurgery (SRS), is critical as systemic therapy advancements have improved overall survival (OS). OBJECTIVE: To identify clinicogenomic features of RCC BMs treated with SRS in a large patient cohort. DESIGN, SETTING, AND PARTICIPANTS: A single-institution retrospective analysis was conducted of all RCC BM patients treated with SRS from January 1, 2010 to March 31, 2021. INTERVENTION: SRS for RCC BMs. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Next-generation sequencing was performed to identify gene alterations more prevalent in BM patients. Clinical factors and genes altered in ≥10% of samples were assessed per patient using Cox proportional hazards models and per individual BM using clustered competing risks regression with competing risk of death. RESULTS AND LIMITATIONS: Ninety-one RCC BM patients underwent SRS to 212 BMs, with a median follow-up of 38.8 mo for patients who survived. The median intracranial progression-free survival and OS were 7.8 (interquartile range [IQR] 5.7-11) and 21 (IQR 16-32) mo, respectively. Durable local control of 83% was achieved at 12 mo after SRS, and 59% of lesions initially meeting the radiographic criteria for progression at 3-mo evaluation would be considered to represent pseudoprogression at 6-mo evaluation. A comparison of genomic alterations at both the gene and the pathway level for BM+ patients compared with BM- patients revealed phosphoinositide 3-kinase (PI3K) pathway alterations to be more prevalent in BM+ patients (43% vs 16%, p = 0.001, q = 0.01), with the majority being PTEN alterations (17% vs 2.7%, p = 0.003, q = 0.041). CONCLUSIONS: To our knowledge, this is the largest study investigating genomic profiles of RCC BMs and the only such study with annotated intracranial outcomes. SRS provides durable in-field local control of BMs. Recognizing post-SRS pseudoprogression is crucial to ensure appropriate management. The incidence of PI3K pathway alterations is more prevalent in BM+ patients than in BM- patients and warrants further investigation in a prospective setting. PATIENT SUMMARY: We examined the outcomes of radiotherapy for the treatment of brain metastases in kidney cancer patients at a single large referral center. We found that radiation provides good control of brain tumors, and certain genetic mutations may be found more commonly in patients with brain metastasis.

Understanding the physical literacy development of 8- to 12-year-old children living with chronic medical conditions: A comprehensive, mixed methods inquiry.

BACKGROUND: Physical literacy is a concept used to describe the combined physical, affective and cognitive capacities facilitating an active lifestyle. Physical activity participation is essential for children living with chronic medical conditions, but knowledge of physical literacy among this group is scarce. METHODS: An explanatory, sequential mixed methods design was used to comprehensively describe the physical literacies of children with chronic medical conditions (CMCs). Participants were recruited from paediatric cardiology, respirology/cystic fibrosis, neurology, haematology and endocrinology outpatient clinics. All participants completed the Canadian Assessment of Physical Literacy (2nd Edition), and those with higher and lower scores were invited to a semi-structured interview. A deductive-inductive thematic analysis was applied using Margaret Whitehead's conceptualization of physical literacy. RESULTS: Using normative strata, 80.0% of the 99 children assessed (mean age = 9.97 ± 1.3 years, 48% girls) were considered beginning or progressing in their overall physical literacy (mean score = 56.5 ± 13.8/100). Meanwhile, physical literacy informed participants' approach to new, active experiences and may have contributed to a strong sense of self. There was a significant difference between endocrinology and haematology patients on total physical literacy score (p = 0.03) but not domain scores. Participants scored high on motivation/confidence (mean = 22.9 ± 5.0/30) but obtained low physical competence (mean = 11.8 ± 5.6/30) and daily behaviour scores (n = 72, mean = 15.5 ± 7.1/30). Main themes represent salient experiences of children with CMCs within the domains of physical literacy, including their need to evaluate active contexts, self-regulate activity intensity and manage physical limitations. CONCLUSIONS: Children with CMCs can achieve recommended levels of physical literacy without meeting normative standards for physical competence. Participants would benefit from a physical literacy intervention that targets the development of bodily self-regulation skills and risk evaluation in active settings.

Extracellular RNA in oncogenesis, metastasis and drug resistance.

Extracellular vesicles and nanoparticles (EVPs) are now recognized as a novel form of cell-cell communication. All cells release a wide array of heterogeneous EVPs with distinct protein, lipid, and RNA content, dependent on the pathophysiological state of the donor cell. The overall cargo content in EVPs is not equivalent to cellular levels, implying a regulated pathway for selection and export. In cancer, release and uptake of EVPs within the tumour microenvironment can influence growth, proliferation, invasiveness, and immune evasion. Secreted EVPs can also have distant, systemic effects that can promote metastasis. Here, we review current knowledge of EVP biogenesis and cargo selection with a focus on the role that extracellular RNA plays in oncogenesis and metastasis. Almost all subtypes of RNA have been identified in EVPs, with miRNAs being the best characterized. We review the roles of specific miRNAs that have been detected in EVPs and that play a role in oncogenesis and metastasis.

Comparison of EV characterization by commercial high-sensitivity flow cytometers and a custom single-molecule flow cytometer.

High-sensitivity flow cytometers have been developed for multi-parameter characterization of single extracellular vesicles (EVs), but performance varies among instruments and calibration methods. Here we compare the characterization of identical (split) EV samples derived from human colorectal cancer (DiFi) cells by three high-sensitivity flow cytometers, two commercial instruments, CytoFLEX/CellStream, and a custom single-molecule flow cytometer (SMFC). DiFi EVs were stained with the membrane dye di-8-ANEPPS and with PE-conjugated anti-EGFR or anti-tetraspanin (CD9/CD63/CD81) antibodies for estimation of EV size and surface protein copy numbers. The limits of detection (LODs) for immunofluorescence and vesicle size based on calibration using cross-calibrated, hard-dyed beads were ∼10 PE/∼80 nm EV diameter for CytoFLEX and ∼10 PEs/∼67 nm for CellStream. For the SMFC, the LOD for immunofluorescence was 1 PE and ≤ 35 nm for size. The population of EVs detected by each system (di-8-ANEPPS+/PE+ particles) differed widely depending on the LOD of the system; for example, CellStream/CytoFLEX detected only 5.7% and 1.5% of the tetraspanin-labelled EVs detected by SMFC, respectively, and median EV diameter and antibody copy numbers were much larger for CellStream/CytoFLEX than for SMFC as measured and validated using super-resolution/single-molecule TIRF microscopy. To obtain a dataset representing a common EV population analysed by all three platforms, we filtered out SMFC and CellStream measurements for EVs below the CytoFLEX LODs as determined by bead calibration (10 PE/80 nm). The inter-platform agreement using this filtered dataset was significantly better than for the unfiltered dataset, but even better concordance between results was obtained by applying higher cutoffs (21 PE/120 nm) determined by threshold analysis using the SMFC data. The results demonstrate the impact of specifying LODs to define the EV population analysed on inter-instrument reproducibility in EV flow cytometry studies, and the utility of threshold analysis of SMFC data for providing semi-quantitative LOD values for other flow cytometers.

Dynamic Anthropometrics in Pancreatic Cancer: Associations Between Body Composition Changes During Neoadjuvant Therapy and Survival Outcomes After Resection.

BACKGROUND: Assessment of individual tumor biology and response to systemic therapy in pancreatic ductal adenocarcinoma (PDAC) remains a clinical challenge. The significance of anthropometric (body composition) changes during chemotherapy as a surrogate for tumor biology in the setting of localized PDAC is unknown. METHODS: A retrospective, single-institution analysis of patients with PDAC who received neoadjuvant therapy (NAT) and pancreatectomy from 2017 to 2021 was performed. Radiologic anthropometric analysis used artificial intelligence-driven software to segment and compute total and sub-compartment muscle area, adipose tissue area, and attenuation values at the level of the L3 vertebra. Kaplan-Meier survival estimates, log-rank tests, and multivariable Cox regression models were used in survival analyses. RESULTS: The inclusion criteria were met by 138 patients. Although decreases in muscle and adipose tissue areas during NAT were predominant, a subset of patients experienced an increase in these compartments. Increases in muscle greater than 5% (hazard ratio [HR], 0.352; 95% confidence interval [CI] 0.135-0.918; p = 0.033) and increases in adipose tissue greater than 15% (HR, 0.375; 95% CI 0.144-0.978; p = 0.045), were significantly associated with improved survival, whereas loss of visceral fat greater than 15% was detrimental (HR 1.853; CI 1.099-3.124; p = 0.021). No significant associations with single time-point anthropometrics were observed. Gains in total muscle and adipose mass were associated with improved pathologic response to systemic therapy and less advanced pathologic tumor stage. CONCLUSIONS: Dynamic anthropometric analysis during NAT for PDAC is a stronger prognostic indicator than measurements taken at a single point in time. Repeated anthropometric analysis during preoperative chemotherapy may serve as a biomarker for individual tumor biology and response to therapy.

Hirayama Disease: Surgical Restoration of Hand Function.

PURPOSE: Hirayama disease (HD) is a rare, nonfamilial, self-limiting, progressive lower cervical myelopathy, resulting in debilitating distal upper-extremity motor deficits, mimicking high ulnar neuropathy, lower trunk brachial plexopathy, or C8-T1 radiculopathy. Although most literature focuses on pathophysiology and prevention of disease progression, there remains limited discussion regarding treatment to improve upper-extremity function in patients with stable disease. The upper-extremity manifestations of HD are reviewed along with surgical options for restoring hand function. METHODS: A retrospective review of patients with HD who underwent reconstruction to improve hand function was undertaken. Demographic data, preoperative electrodiagnostic and electromyographic, and physical examination findings were collected. Outcome data involved postoperative grip, pinch, and functional assessment documented on clinical visits. Qualitative descriptions of the surgical techniques are described. RESULTS: Among six patients identified, four met the inclusion criteria and underwent tendon transfers and selected joint arthrodeses. All patients were diagnosed as teenagers, were right hand-dominant, and three were male. Unilateral symptoms were present in one patient and were bilateral in the rest. All patients were treated with tendon transfers for thumb opposition, grasp, anticlaw, and thumb interphalangeal joint arthrodesis. All patients had postoperative grip strength improvement. The average follow-up was 3.2 years. CONCLUSIONS: Hirayama disease is a rare disease often managed by spine surgeons and neurologists who may be unaware of options for restoring hand function deficits. Technical strategies and outcomes of improving hand function in HD have not been adequately described. Surgical options to improve hand function are tailored to the deficits and include tendon transfers, select joint arthrodeses, and/or tenodeses. Risk of disease progression and expectations following hand reconstruction must be managed carefully. TYPE OF STUDY LEVEL OF EVIDENCE: Therapeutic V.

Revisiting the Posterior Approach for Cervical Radiculopathy Utilizing Endoscopic Techniques: A Favorable Short-Term Outcome and Cost Comparison With Anterior Cervical Discectomy and Fusion.

BACKGROUND: Cervical radiculopathy is a spine ailment frequently requiring surgical decompression via anterior cervical discectomy and fusion (ACDF) or posterior foraminotomy/discectomy. While endoscopic posterior foraminotomy/discectomy is gaining popularity, its financial impact remains understudied despite equivalent randomized long-term outcomes to ACDF. In a cohort of patients undergoing ACDF vs endoscopic posterior cervical foraminotomy/discectomy, we sought to compare the total cost of the surgical episode while confirming an equivalent safety profile and perioperative outcomes. METHODS: A single-center retrospective cohort study of patients with unilateral cervical radiculopathy undergoing ACDF or endoscopic cervical foraminotomy between 2018 and 2023 was undertaken. Primary outcomes included the total cost of care for the initial surgical episode (not charges or reimbursement). Perioperative variables and neurological recovery were recorded. Multivariable analysis tested age, body mass index, race, gender, insurance type, operative time, and length of stay. RESULTS: A total of 38 ACDF and 17 endoscopic foraminotomy/discectomy operations were performed. All patients underwent single-level surgery except for 2 two-level endoscopic decompressions. No differences were found in baseline characteristics and symptom length except for younger age (46.8 ± 9.4 vs 57.6 ± 10.3, P = 0.002) and more smokers (18.4% vs 11.8%, P = 0.043) in the ACDF group. Actual hospital costs for the episode of surgical care were markedly higher in the ACDF cohort (mean ±95% CI; $27,782 ± $2011 vs $10,103 ± $720, P < 0.001) driven by the ACDF approach (ß = $17,723, P < 0.001) on multivariable analysis. On sensitivity analysis, ACDF was never cost-efficient compared with endoscopic foraminotomy, and endoscopic failure rates of 64% were required for break-even cost. ACDF was associated with significantly longer operative time (167.7 ± 22.0 vs 142.7 ± 27.4 minutes, P < 0.001) and length of stay (1.1 ± 0.5 vs 0.1 ± 0.2 days, P < 0.001). No significant difference was found regarding 90-day neurological improvement, readmission, reoperation, or complications. CONCLUSION: Compared with patients treated with a single-level ACDF for unilateral cervical radiculopathy, endoscopic posterior cervical foraminotomy/discectomy can achieve a similar safety profile, pain relief, and neurological recovery at considerably less cost. These findings may help patients and surgeons revisit offering the posterior cervical foraminotomy/discectomy utilizing endoscopic techniques. CLINICAL RELEVANCE: Endoscopic posterior cervical foraminotomy/discectomy offers comparable safety, pain relief, and neurological recovery to traditional methods but at a significantly lower cost.

Testicular Germ Cell Tumors with Venous Tumor Thrombus: Prevalence, Presentation, and Management.

BACKGROUND AND OBJECTIVE: There are limited data on the prevalence and management of testicular germ cell tumor (TGCT) cases presenting with venous tumor thrombus (VTT). Our objectives were to describe the prevalence of TGCT with VTT, to identify a multicenter retrospective cohort, and to ascertain expert opinion regarding optimal management of this entity. METHODS: Using the IBM Marketscan database, we identified men with testicular cancer who underwent retroperitoneal lymph node dissection (RPLND) with concurrent VTT or inferior vena cava (IVC) tumor thrombectomy to estimate the prevalence of VTT in TGCT. To identify a multicenter retrospective cohort of patients, we surveyed surgeons and described the presentation, management, and outcomes for the cohort. KEY FINDINGS AND LIMITATIONS: The prevalence of TGCT with VTT in the IBM Marketscan database was 0.3% (n = 7/2517) when using stringent criteria and 3.1% (n = 79/2517) when using broad criteria. In response to our survey, 16 surgeons from ten centers contributed data for 34 patients. Most patients (n = 29, 85%) presented with nonseminomatous germ cell tumor. Surgical management was used for 93.9% (n = 31), including postchemotherapy tumor thrombectomy with primary cavorrhaphy in 63%. The Marketscan analysis was limited to insured individuals and did not include clinicopathological details, and use of billing codes may have included patients with stromal tumors. In addition, lack of responses to the anonymous survey limited data capture, and the RedCap survey did not address symptoms specific to IVC obstruction or allow central review of the imaging leading to VTT diagnosis. CONCLUSIONS AND CLINICAL IMPLICATIONS: VTT among males with TGCT is rare and requires complex multidisciplinary management, including venous tumor thrombectomy at the time of postchemotherapy RPLND. PATIENT SUMMARY: Using a medical database, we estimated that the frequency of testicular cancer cases in which the tumor extends into a blood vessel (called venous tumor thrombus, VTT) is just 0.3-3.1%. We carried out a survey of surgeons with experience of this condition. Our results indicate that although testicular cancers respond well to chemotherapy, VTT is less responsive and complex surgery is necessary for this rare condition.

Beta-arrestin 1 mediated Src activation via Src SH3 domain revealed by cryo-electron microscopy.

Beta-arrestins (ßarrs) are key regulators and transducers of G-protein coupled receptor signaling; however, little is known of how ßarrs communicate with their downstream effectors. Here, we use cryo-electron microscopy to elucidate how ßarr1 recruits and activates non-receptor tyrosine kinase Src. ßarr1 binds Src SH3 domain via two distinct sites: a polyproline site in the N-domain and a non-proline site in the central crest region. At both sites ßarr1 interacts with the aromatic surface of SH3 which is critical for Src autoinhibition, suggesting that ßarr1 activates Src by SH3 domain displacement. Binding of SH3 to the central crest region induces structural rearrangements in the ß-strand V, finger, and middle loops of ßarr1 and interferes with ßarr1 coupling to the receptor core potentially impacting receptor desensitization and downstream signaling.

Pembrolizumab plus enzalutamide for metastatic castration-resistant prostate cancer progressing on enzalutamide: cohorts 4 and 5 of the phase 2 KEYNOTE-199 study.

BACKGROUND: KEYNOTE-199 (NCT02787005) is a multicohort phase 2 study evaluating pembrolizumab in patients with metastatic castration-resistant prostate cancer (mCRPC). Results from cohorts 4 (C4) and 5 (C5) are presented. METHODS: Eligible patients had not received chemotherapy for mCRPC and had responded to enzalutamide prior to developing resistance as defined by Prostate Cancer Clinical Trials Working Group 3 guidelines. Patients with RECIST-measurable disease were enrolled in C4, and patients with bone-only or bone-predominant disease were enrolled in C5. All patients received pembrolizumab 200 mg every 3 weeks for ≤35 cycles with ongoing enzalutamide until progression, unacceptable toxicity, or withdrawal. The primary end point was objective response rate (ORR) per RECIST v1.1 by blinded independent central review in C4. Secondary end points included disease control rate (DCR), overall survival, and safety in each cohort and both cohorts combined. RESULTS: A total of 126 patients were treated (C4, n = 81; C5, n = 45). Median age was 72 years (range 43-92), and 87.3% had received ≥6 months of enzalutamide prior to study entry. Confirmed ORR was 12.3% (95% CI 6.1-21.5%) for C4. Median duration of response in C4 was 8.1 months (range, 2.5+ to 15.2), and 5 of these patients experienced an objective response lasting ≥6 months. DCR was 53.1% (95% CI 41.7-64.3%) in C4 and 51.1% (95% CI 35.8-66.3%) in C5. Median overall survival was 17.6 months (95% CI 14.0-22.6) in C4 and 20.8 months (95% CI 14.1-28.9) in C5. Grade ≥3 treatment-related adverse events occurred in 35 patients (27.8%); 2 patients in C4 died from immune-related adverse events (myasthenic syndrome and Guillain-Barré syndrome). CONCLUSIONS: The addition of pembrolizumab to ongoing enzalutamide treatment in patients with mCRPC that progressed on enzalutamide after initial response demonstrated modest antitumor activity with a manageable safety profile. CLINICAL TRIAL REGISTRY AND ID: ClinicalTrials.gov, NCT02787005.

Comparison of sampling techniques and diagnostic tests for Cryptosporidium serpentis in eastern indigo snakes (Drymarchon couperi).

OBJECTIVE: The purpose of this study was to compare various sampling techniques and commercially available diagnostic tests for Cryptosporidium serpentis. METHODS: A colony of 80 eastern indigo snakes (Drymarchon couperi) in human care was screened for the presence of C serpentis using endoscopic gastric mucosal biopsies for histologic and molecular analyses. At the time of endoscopic examination and biopsy, a cloacal swab, gastric swab, and gastric lavage sample were also collected. A C serpentis-specific probe hybridization quantitative PCR (qPCR) was performed on each sample. The gastric lavage sample was divided equally for direct microscopy, acid-fast stain, rapid qualitative immunochromatographic assay, direct fluorescent antibody, and 5 different PCR analyses. If a fecal sample was available at the time of endoscopic evaluation, it was also evaluated for Cryptosporidium oocysts by direct microscopy and acid-fast staining. RESULTS: When comparing test results to histologic analyses, the sensitivity of the probe hybridization qPCR of gastric biopsy, gastric lavage, and gastric swab was 100% while the cloacal swab was 72%. When gastric lavage tests were compared, qPCRs outperformed the other tests. CONCLUSIONS: Endoscopic biopsy for histologic and qPCR analyses is recommended for disease diagnosis, while gastric lavage or gastric swab samples for qPCR analysis are as sensitive as endoscopic biopsy for screening for the pathogen but cannot diagnose disease. CLINICAL RELEVANCE: The results from this study allow the veterinary practitioner to select the most appropriate sample and testing methodology when evaluating an ophidian patient for gastric cryptosporidiosis.

Characterization of atrial arrhythmias following mitral valve repair: Incidence and risk factors.

OBJECTIVES: This study aims to investigate the occurrence, type and correlation of early and late atrial arrhythmias following mitral valve repair in patients with no preoperative history of atrial arrhythmias. METHODS: Patients undergoing mitral valve (MV) repair for degenerative disease were included. Early and late postoperative electrocardiograms were evaluated for the incidence and type of atrial arrhythmia (atrial fibrillation [AF] or atrial tachycardia [AT]). RESULTS: The 192 patients were included. Early atrial arrhythmias occurred in 100/192 (52.1%) patients; AF in 61 (31.8%) patients, early AT in 15 (7.8%) and both in 24 (12.5%). In total 89% of patients were discharged in sinus rhythm. During a follow-up time of 7.3 years, 14 patients (7.3%) died and 49 (25.5%) patients developed late atrial arrhythmias. At 10 years, the cumulative incidence of any late atrial arrhythmia, with death as competing risk, was 64% (95% confidence interval [CI] = 55%-72%). On Fine-Gray model analysis, only early postoperative AF lasting >24 h was related to the development of late AF (hazard ratio 5.99, 95% CI = 1.78%-20.10%, p = .004). Early postoperative ATs were related to the development of late tachycardias, independent of their duration (<24 h hazard ratio 4.25, 95% CI = 1.89-9.57, p = .001 and >24 h hazard ratio 3.51, 95% CI = 1.65-7.46, p = .001). CONCLUSIONS: Early and late atrial arrhythmias were common after MV repair surgery. Only early postoperative AF lasting >24 h was a risk factor for the occurrence of late AF. Conversely, any postoperative AT was correlated to the development of late ATs.