UHRF1 ubiquitin ligase activity supports the maintenance of low-density CpG methylation.

The RING E3 ubiquitin ligase UHRF1 is an established cofactor for DNA methylation inheritance. Nucleosomal engagement through histone and DNA interactions directs UHRF1 ubiquitin ligase activity toward lysines on histone H3 tails, creating binding sites for DNMT1 through ubiquitin interacting motifs (UIM1 and UIM2). Here, we profile contributions of UHRF1 and DNMT1 to genome-wide DNA methylation inheritance and dissect specific roles for ubiquitin signaling in this process. We reveal DNA methylation maintenance at low-density CpGs is vulnerable to disruption of UHRF1 ubiquitin ligase activity and DNMT1 ubiquitin reading activity through UIM1. Hypomethylation of low-density CpGs in this manner induces formation of partially methylated domains (PMD), a methylation signature observed across human cancers. Furthermore, disrupting DNMT1 UIM2 function abolishes DNA methylation maintenance. Collectively, we show DNMT1-dependent DNA methylation inheritance is a ubiquitin-regulated process and suggest a disrupted UHRF1-DNMT1 ubiquitin signaling axis contributes to the development of PMDs in human cancers.

Update on Thrombosis Risk in Patients with Cancer: Focus on Novel Anticancer Immunotherapies.

Thromboembolic complications, including venous thromboembolism (VTE) and arterial thromboembolism (ATE), increase mortality and morbidity, and delay treatment in patients with cancer. Therefore, an increased understanding of underlying risk profiles, the identification of risk factors and predictive biomarkers, and ultimately the development of specific cardiovascular prevention strategies in patients with cancer is needed. Medical anticancer therapies have undergone a remarkable development in recent years with the advent of targeted and immunotherapeutic treatment options, including immune checkpoint inhibitors (ICI), chimeric antigen receptor (CAR) T-cell therapies and bispecific T-cell engagers (BiTEs). These developments have important implications for the accompanied risk of thromboembolic events in patients with cancer. First, the increased use of these highly effective therapies renders a growing proportion of patients with cancer at risk of thromboembolic events for a prolonged risk period due to an increase in patient survival despite advanced cancer stages. Second, potential direct cardiovascular toxicity and prothrombotic effect of novel anticancer immunotherapies are a matter of ongoing debate, with emerging reports suggesting a relevant risk of VTE and ATE associated with ICI, and relevant dysregulations of hemostasis in the frequently observed cytokine-release syndrome associated with BiTEs and CAR T-cell therapy. The aim of the present narrative review is to summarize the implications of the emerging use of anticancer immunotherapy for thromboembolic events in patients with cancer, and to provide an overview of available data on the rates and risk factors for VTE and ATE associated with ICI, CAR T-cell therapy, and BiTEs.

Molecular diagnostics tailoring personalized cancer therapy-an oncologist's view.

Medical oncology is rapidly evolving with the implementation of personalized, targeted therapies. Advances in molecular diagnostics and the biologic understanding of cancer pathophysiology led to the identification of specific genetic alterations as drivers of cancer progression. Further, improvements in drug development enable the direct interference with these pathways, which allow tailoring personalized treatments based on a distinct molecular characterization of tumors. Thereby, we are currently experiencing a paradigm-shift in the treatment of cancers towards cancer-type agnostic, molecularly targeted, personalized therapies. However, this concept has several important hurdles and limitations to overcome to ultimately increase the proportion of patients benefitting from the precision oncology approach. These include the assessment of clinical relevancy of identified alterations, capturing and interpreting levels of heterogeneity based on intra-tumoral or time-dependent molecular evolution, and challenges in the practical implementation of precision oncology in routine clinical care. In the present review, we summarize the current state of cancer-agnostic precision oncology, discuss the concept of molecular tumor boards, and consider current limitations of personalized cancer therapy. Further, we provide an outlook towards potential future developments including the implementation of functionality assessments of identified genetic alterations and the broader use of liquid biopsies in order to obtain more comprehensive and longitudinal genetic information that might guide personalized cancer therapy in the future.

Incidence of Diabetes Mellitus and Its Impact on Outcomes in Patients Undergoing Surgical Pancreatectomy for Non-Malignant and Malignant Pancreatobiliary Diseases-A Retrospective Analysis.

Diabetes mellitus (DM) is a prominent risk factor for malignant and non-malignant pancreatic diseases. Furthermore, the presence of DM predicts an unfavourable outcome in people with pancreatic cancer. This retrospective observational study investigated 370 patients who underwent pancreatic resection surgery for various indications (84.3% in malignant indication) in a single surgery centre in Graz, Austria. The preoperative and postoperative diabetes statuses were evaluated according to surgery method and disease entity and predictors for diabetes development after surgery, as well as outcomes (survival and cancer recurrence) according to diabetes status, were analysed. In the entire cohort, the postoperative diabetes (postopDM) incidence was 29%. PostopDM occurred significantly more frequently in malignoma patients than in those with benign diseases (31.3% vs. 16.7%; p = 0.040, OR = 2.28). In the malignoma population, BMI, longer surgery duration, and prolonged ICU and hospital stay were significant predictors of diabetes development. The 1- and 2-year follow-ups showed a significantly increased mortality of people with postopDM in comparison to people without diabetes (HR 1-year = 2.02, p = 0.014 and HR 2-years = 1.56, p = 0.034). Local cancer recurrence was not influenced by the diabetes status. Postoperative new-onset diabetes seems to be associated with higher mortality of patients with pancreatic malignoma undergoing pancreatobiliary surgery.

A promoterless AAV6.2FF-based lung gene editing platform for the correction of surfactant protein B deficiency.

Surfactant protein B (SP-B) deficiency is a rare genetic disease that causes fatal respiratory failure within the first year of life. Currently, the only corrective treatment is lung transplantation. Here, we co-transduced the murine lung with adeno-associated virus 6.2FF (AAV6.2FF) vectors encoding a SaCas9-guide RNA nuclease or donor template to mediate insertion of promoterless reporter genes or the (murine) Sftpb gene in frame with the endogenous surfactant protein C (SP-C) gene, without disrupting SP-C expression. Intranasal administration of 3 × 1011 vg donor template and 1 × 1011 vg nuclease consistently edited approximately 6% of lung epithelial cells. Frequency of gene insertion increased in a dose-dependent manner, reaching 20%-25% editing efficiency with the highest donor template and nuclease doses tested. We next evaluated whether this promoterless gene editing platform could extend survival in the conditional SP-B knockout mouse model. Administration of 1 × 1012 vg SP-B-donor template and 5 × 1011 vg nuclease significantly extended median survival (p = 0.0034) from 5 days in the untreated off doxycycline group to 16 days in the donor AAV and nuclease group, with one gene-edited mouse living 243 days off doxycycline. This AAV6.2FF-based gene editing platform has the potential to correct SP-B deficiency, as well as other disorders of alveolar type II cells.

Importance of different electronic medical record components for chronic disease identification in a Swiss primary care database: a cross-sectional study.

BACKGROUND: Primary care databases collect electronic medical records with routine data from primary care patients. The identification of chronic diseases in primary care databases often integrates information from various electronic medical record components (EMR-Cs) used by primary care providers. This study aimed to estimate the prevalence of selected chronic conditions using a large Swiss primary care database and to examine the importance of different EMR-Cs for case identification. METHODS: Cross-sectional study with 120,608 patients of 128 general practitioners in the Swiss FIRE ("Family Medicine Research using Electronic Medical Records") primary care database in 2019. Sufficient criteria on three individual EMR-Cs, namely medication, clinical or laboratory parameters and reasons for encounters, were combined by logical disjunction into definitions of 49 chronic conditions; then prevalence estimates and measures of importance of the individual EMR-Cs for case identification were calculated. RESULTS: A total of 185,535 cases (i.e. patients with a specific chronic condition) were identified. Prevalence estimates were 27.5% (95% CI: 27.3-27.8%) for hypertension, 13.5% (13.3-13.7%) for dyslipidaemia and 6.6% (6.4-6.7%) for diabetes mellitus. Of all cases, 87.1% (87.0-87.3%) were identified via medication, 22.1% (21.9-22.3%) via clinical or laboratory parameters and 19.3% (19.1-19.5%) via reasons for encounters. The majority (65.4%) of cases were identifiable solely through medication. Of the two other EMR-Cs, clinical or laboratory parameters was most important for identifying cases of chronic kidney disease, anorexia/bulimia nervosa and obesity whereas reasons for encounters was crucial for identifying many low-prevalence diseases as well as cancer, heart disease and osteoarthritis. CONCLUSIONS: The EMR-C medication was most important for chronic disease identification overall, but identification varied strongly by disease. The analysis of the importance of different EMR-Cs for estimating prevalence revealed strengths and weaknesses of the disease definitions used within the FIRE primary care database. Although prioritising specificity over sensitivity in the EMR-C criteria may have led to underestimation of most prevalences, their sex- and age-specific patterns were consistent with published figures for Swiss general practice.

Malignant Proliferating Pilar Tumor: Clinicopathologic, Immunohistochemical, and Molecular Study of 17 Cases.

Proliferating pilar tumors are rare neoplasms that differentiate toward the outer sheath near the isthmus and can rarely undergo malignant transformation. We performed histopathologic evaluation on 26 benign proliferating pilar tumor (BPPT) and 17 malignant proliferating pilar tumor (MPPT). Ki-67 and p53 immunostains were performed on 13 BPPT and 10 MPPT. Six MPPT cases were successfully analyzed by a next-generation sequencing platform which surveyed exonic DNA sequences of 447 cancer genes and 191 regions across 60 genes for rearrangement detection. Patient demographics and clinical characteristics were similar between the BPPT and MPPT groups. Follow-up data of 16 of 17 MPPT (median, 25 mo) showed metastasis in 1 MPPT. The histologic features associated with MPPT include size >2.5 cm, adjacent desmoplastic stroma, small nests or cords of atypical epithelium in surrounding stroma, irregular infiltration or borders, abnormal keratinization, large hyperchromatic nuclei, prominent nucleoli, severe cytologic atypia, nuclear pleomorphism, necrosis, and increased mitotic figures. MPPT harbors copy number gains of 15q and losses of 6p and 6q, findings previously reported in BPPT. However, MPPT harbors frequent TP53 mutations as molecular markers of progression. Different from cutaneous squamous cell carcinoma, MPPT more frequently demonstrates low tumor mutational burden and typically lacks a UV signature, suggestive of a different etiologic pathway than squamous cell carcinoma. In summary, with a median follow-up of 25 months, this study shows that MPPT is a biologically indolent carcinoma with rare metastasis. Molecular analyses suggest a non-UV-related pathogenesis with frequent TP53 aberration.

Quantification of cross-vendor variation in ADC measurements in vendor-specific prostate MRI-protocols.

PURPOSE: The purpose of this study was to quantify the variability of Apparent Diffusion Coefficient (ADC) and test if there were statistically significant differences in ADC between MRI systems and sequences. METHOD: With a two-chamber cylindrical ADC phantom with fixed ADC values (1,000 and 1,600x10-6 mm2/s) a single-shot (ss) Echo Planar Imaging (EPI), a multi-shot EPI, a reduced field of view DWI (zoom) and a Turbo Spin Echo DWI sequence were tested in six MRI systems from three vendors at 1.5 T and 3 T. Technical parameters were according to Prostate Imaging Reporting and Data System Version 2.1. ADC maps were calculated by vendor specific algorithms. Absolute and relative differences in ADC from the phantom-ADC were calculated and differences between sequences were tested. RESULTS: At 3 T absolute differences from phantom given ADC (∼1,000 and âˆ¼ 1,600x10-6 mm2/s) were -83 - 42x10-6 mm2/s (-8.3%-4.2%) and -48 - 15x10-6 mm2/s (-3%-0.9%), respectively and at 1.5 T absolute differences were -81 - 26x10-6 mm2/s (-2.6%-8.1%) and -74 - 67x10-6 mm2/s (-4.6%-4.2%), respectively. Significant statistical differences in ADC measurements were identified between vendors in all sequences except for ssEPI and zoom at 3 T in the 1,600x10-6 mm2/s phantom chamber. Significant differences were also identified between ADC measurements at 1.5 T and 3 T in some of the sequences and vendors, but not all. CONCLUSION: The variation of ADC between different MRI systems and prostate specific DWI sequences is limited in this phantom study and without apparent clinical relevance. However, prospective multicenter studies of prostate cancer patients are needed for further investigation.

Discovery and properties of a monoclonal antibody targeting 8-oxoA, an oxidized adenine lesion in DNA and RNA.

8-oxoA, a major oxidation product of adenosine, is a mispairing, mutagenic lesion that arises in DNA and RNA when •OH radicals or one-electron oxidants attack the C8 adenine atom or polymerases misincorporate 8-oxo(d)ATP. The danger of 8-oxoA is underscored by the existence of dedicated cellular repair machinery that explicitly excise it from DNA, the attenuation of translation induced by 8-oxoA-mRNA or damaged ribosomes, and its potency as a TLR7 agonist. Here we present the discovery, purification, and biochemical characterization of a new mouse IgGk1 monoclonal antibody (6E4) that specifically targets 8-oxoA. Utilizing an AchE-based competitive ELISA assay, we demonstrate the selectivity of 6E4 for 8-oxoA over a plethora of canonical and chemically modified nucleosides including 8-oxoG, A, m6A, 2-oxoA, and 5-hoU. We further show the ability of 6E4 to exclusively recognize 8-oxoA in nucleoside triphosphates (8-oxoATP) and DNA/RNA oligonucleotides containing a single 8-oxoA. 6E4 also binds 8-oxoA in duplex DNA/RNA antigens where the lesion is either paired correctly or base mismatched. Our findings define the 8-oxoAde nucleobase as the critical epitope and indicate mAb 6E4 is ideally suited for a broad range of immunological applications in nucleic acid detection and quality control.

Comparison of a Thiolated Demineralized Bone Matrix Hydrogel to a Clinical Product Control for Regeneration of Large Sheep Cranial Defects.

Regeneration of calvarial bone remains a major challenge in the clinic as available options do not sufficiently regenerate bone in larger defect sizes. Calvarial bone regeneration cases involving secondary medical conditions, such as brain herniation during traumatic brain injury (TBI) treatment, further exacerbate treatment options. Hydrogels are well-positioned for severe TBI treatment, given their innate flexibility and potential for bone regeneration to treat TBI in a single-stage surgery. The current study evaluated a photocrosslinking pentenoate-modified hyaluronic acid polymer with thiolated demineralized bone matrix (i.e., TDBM hydrogel) capable of forming a completely interconnected hydrogel matrix for calvarial bone regeneration. The TDBM hydrogel demonstrated a setting time of 120 s, working time of 3 to 7 days, negligible change in setting temperature, physiological setting pH, and negligible cytotoxicity, illustrating suitable performance for in vivo application. Side-by-side ovine calvarial bone defects (19 mm diameter) were employed to compare the TDBM hydrogel to the standard-of-care control material DBX®. After 16 weeks, the TDBM hydrogel had comparable healing to DBX® as demonstrated by mechanical push-out testing (~800 N) and histology. Although DBX® had 59% greater new bone volume compared to the TDBM hydrogel via micro-computed tomography, both demonstrated minimal bone regeneration overall (15 to 25% of defect volume). The current work presents a method for comparing the regenerative potential of new materials to clinical products using a side-by-side cranial bone defect model. Comparison of novel biomaterials to a clinical product control (i.e., standard-of-care) provides an important baseline for successful regeneration and potential for clinical translation.

Inhibited KdpFABC transitions into an E1 off-cycle state.

KdpFABC is a high-affinity prokaryotic K+ uptake system that forms a functional chimera between a channel-like subunit (KdpA) and a P-type ATPase (KdpB). At high K+ levels, KdpFABC needs to be inhibited to prevent excessive K+ accumulation to the point of toxicity. This is achieved by a phosphorylation of the serine residue in the TGES162 motif in the A domain of the pump subunit KdpB (KdpBS162-P). Here, we explore the structural basis of inhibition by KdpBS162 phosphorylation by determining the conformational landscape of KdpFABC under inhibiting and non-inhibiting conditions. Under turnover conditions, we identified a new inhibited KdpFABC state that we termed E1P tight, which is not part of the canonical Post-Albers transport cycle of P-type ATPases. It likely represents the biochemically described stalled E1P state adopted by KdpFABC upon KdpBS162 phosphorylation. The E1P tight state exhibits a compact fold of the three cytoplasmic domains and is likely adopted when the transition from high-energy E1P states to E2P states is unsuccessful. This study represents a structural characterization of a biologically relevant off-cycle state in the P-type ATPase family and supports the emerging discussion of P-type ATPase regulation by such states.

Identification of fusions with potential clinical significance in melanoma.

Though uncommon in melanoma, gene fusions may have therapeutic implications. Next generation sequencing-based clinical assays, designed to detect relevant gene fusions, mutations, and copy number changes, were performed on 750 melanomas (375 primary and 375 metastases) at our institution from 2014-2021. These included 599 (80%) cutaneous, 38 (5%) acral, 11 (1.5%) anorectal, 23 (3%) sinonasal, 27 (3.6%) eye (uveal/ conjunctiva), 11 (1.5%) genital (vulva/penile), and 41 (5.5%) melanomas of unknown primary. Sixteen fusions (2%) were detected in samples from 16 patients: 12/599 (2%) cutaneous, 2/38 (5%) acral, 1/9 (11%) vulva, 1/23(4.3%) sinonasal; and 12/16 (75%) fusions were potentially targetable. We identified two novel rearrangements: NAGS::MAST2 and NOTCH1::GNB1; and two fusions that have been reported in other malignancies but not in melanoma: CANT1::ETV4 (prostate cancer) and CCDC6::RET (thyroid cancer). Additional fusions, previously reported in melanoma, included: EML4::ALK, MLPH::ALK, AGAP3::BRAF, AGK::BRAF, CDH3::BRAF, CCT8::BRAF, DIP2B::BRAF, EFNB1::RAF1, LRCH3::RAF1, MAP4::RAF1, RUFY1::RAF1, and ADCY2::TERT. Fusion positive melanomas harbored recurrent alterations in TERT and CDKN2A, among others. Gene fusions were exceedingly rare (0.2%) in BRAF/RAS/NF1-mutant tumors and were detected in 5.6% of triple wild-type melanomas. Interestingly, gene rearrangements were significantly enriched within the subset of triple wild-type melanomas that harbor TERT promoter mutations (18% versus 2%, p < 0.0001). Thirteen (81%) patients were treated with immunotherapy for metastatic disease or in the adjuvant setting. Six of 12 (50%) patients with potentially actionable fusions progressed on immunotherapy, and 3/6 (50%) were treated with targeted agents (ALK and MEK inhibitors), 2 off-label and 1 as part of a clinical trial. One patient with an AGAP3::BRAF fusion positive melanoma experienced a 30-month long response to trametinib. We show that, detecting fusions, especially in triple wild-type melanomas with TERT promoter mutations, may have a clinically significant impact in patients with advanced disease who have failed front-line immunotherapy.

Incidence of Revision Surgery After Decompression With vs Without Fusion Among Patients With Degenerative Lumbar Spinal Stenosis.

Importance: Only limited data derived from large prospective cohort studies exist on the incidence of revision surgery among patients who undergo operations for degenerative lumbar spinal stenosis (DLSS). Objective: To assess the cumulative incidence of revision surgery after 2 types of index operations-decompression alone or decompression with fusion-among patients with DLSS. Design, Setting, and Participants: This cohort study analyzed data from a multicenter, prospective cohort study, the Lumbar Stenosis Outcome Study, which included patients aged 50 years or older with DLSS at 8 spine surgery and rheumatology units in Switzerland between December 2010 and December 2015. The follow-up period was 3 years. Data for this study were analyzed between October and November 2021. Exposures: All patients underwent either decompression surgery alone or decompression with fusion surgery for DLSS. Main Outcomes and Measures: The primary outcome was the cumulative incidence of revision operations. Secondary outcomes included changes in the following patient-reported outcome measures: Spinal Stenosis Measure (SSM) symptom severity (higher scores indicate more pain) and physical function (higher scores indicate more disability) subscale scores and the EuroQol Health-Related Quality of Life 5-Dimension 3-Level questionnaire (EQ-5D-3L) summary index score (lower scores indicate worse quality of life). Results: A total of 328 patients (165 [50.3%] men; median age, 73.0 years [IQR, 66.0-78.0 years]) were included in the analysis. Of these, 256 (78.0%) underwent decompression alone and 72 (22.0%) underwent decompression with fusion. The cumulative incidence of revisions after 3 years of follow-up was 11.3% (95% CI, 7.4%-15.1%) for the decompression alone group and 13.9% (95% CI, 5.5%-21.5%) for the fusion group (log-rank P = .60). There was no significant difference in the need for revision between the 2 groups over time (unadjusted absolute risk difference, 2.6% [95% CI, -6.3% to 11.4%]; adjusted absolute risk difference, 3.9% [95% CI, -5.2% to 17.0%]; adjusted hazard ratio, 1.40 [95% CI, 0.63-3.13]). The number of revisions was significantly associated with higher SSM symptom severity scores (ß, 0.171; 95% CI, 0.047-0.295; P = .007) and lower EQ-5D-3L summary index scores (ß, -0.061; 95% CI, -0.105 to -0.017; P = .007) but not with higher SSM physical function scores (ß, 0.068; 95% CI, -0.036 to 0.172; P = .20). The type of index operation was not significantly associated with the corresponding outcomes. Conclusions and Relevance: This cohort study showed no significant association between the type of index operation for DLSS-decompression alone or fusion-and the need for revision surgery or the outcomes of pain, disability, and quality of life among patients after 3 years. Number of revision operations was associated with more pain and worse quality of life.

Patterns of Peripheral Blood B-Cell Subtypes Are Associated With Treatment Response in Patients Treated With Immune Checkpoint Inhibitors: A Prospective Longitudinal Pan-Cancer Study.

Background: Immune checkpoint inhibitors (ICIs) have revolutionized systemic anti-tumor treatments across different types of cancer. Nevertheless, predictive biomarkers regarding treatment response are not routinely established yet. Apart from T-lymphocytes, the humoral immunity of B-lymphocytes is studied to a substantially lesser extent in the respective setting. Thus, the aim of this study was to evaluate peripheral blood B-cell subtypes as potential predictors of ICI treatment response. Methods: Thirty-nine cancer patients receiving ICI therapy were included into this prospective single-center cohort study. All had a first blood draw at the date before treatment initiation and a second at the time of first response evaluation (after 8-12 weeks). Seven different B-cell subtypes were quantified by fluorescence-activated cell sorting (FACS). Disease control- (DCR) and objective response rate (ORR) were co-primary study endpoints. Results: Overall, DCR was 48.7% and ORR was 25.6%, respectively. At baseline, there was no significant association of any B-cell subtype with neither DCR nor ORR. At the first response evaluation, an increase in the frequency of CD21- B-cells was a statistically significant negative predictor of response, both regarding DCR (OR=0.05, 95%CI=0.00-0.67, p=0.024) and ORR (OR=0.09, 95%CI=0.01-0.96, p=0.046). An increase of the frequency of switched memory B-cells was significantly associated with reduced odds for DCR (OR=0.06, 95%CI=0.01-0.70, p=0.025). Patients with an increased frequency of naïve B-cells were more likely to benefit from ICI therapy as indicated by an improved DCR (OR=12.31, 95%CI=1.13-134.22, p=0.039). Conclusion: In this study, certain B-cell subpopulations were associated with ICI treatment response in various human cancer types.

Benefit of Metastasectomy in Renal Cell Carcinoma: A Propensity Score Analysis.

INTRODUCTION: To quantify the magnitude of benefit of metastasectomy as compared to medical treatment alone in patients with metastatic renal cell carcinoma (mRCC). PATIENTS AND METHODS: We therefore conducted a propensity score analysis of overall survival (OS) in 106 mRCC patients with metachronous metastasis, of whom 36 (34%) were treated with metastasectomy, and 70 (66%) with medical therapy alone. RESULTS: The most frequent metastasectomy procedures were lung resections (n = 13) and craniotomies (n = 6). Median time-to-progression after metastasectomy was 0.7 years (25th-75th percentile: 0.3-2.7). After a median follow-up of 6.2 years and 63 deaths, 5-year OS estimates were 41% and 22% in the metastasectomy and medical therapy group, respectively (log-rank P = .00007; Hazard ratio (HR) = 0.38, 95%CI: 0.21-0.68). Patients undergoing metastasectomy had a significantly higher prevalence of favorable prognostic factors, such as fewer bilateral lung metastases and longer disease-free intervals between nephrectomy and metastasis diagnosis. After propensity score weighting for these differences and adjusting for immortal time bias, the favorable association between metastasectomy and OS became much weaker (HR = 0.62, 95%CI: 0.39-1.00, P = .050). Propensity-score-weighted 5-year OS estimates were 24% and 20% in the metastasectomy and medical therapy group, respectively (log-rank P = .001). In exploratory analyses, the benefit of metastasectomy was confined to patients who achieved complete resection of all known metastases. CONCLUSION: Within the limitations of an observational study, these findings support the concept of metastasectomy being associated with an OS benefit in mRCC patients. Metastasectomies not achieving complete resection of all known lesions are likely without OS benefit.

Prescription Rates, Polypharmacy and Prescriber Variability in Swiss General Practice-A Cross-Sectional Database Study.

Purpose: The frequency of medication prescribing and polypharmacy has increased in recent years in different settings, including Swiss general practice. We aimed to describe patient age- and sex-specific rates of polypharmacy and of prescriptions of the most frequent medication classes, and to explore practitioner variability in prescribing. Methods: Retrospective cross-sectional study based on anonymized electronic medical records data of 111 811 adult patients presenting to 116 Swiss general practitioners in 2019. We used mixed-effects regression analyses to assess the association of patient age and sex with polypharmacy (≥5 medications) and with the prescription of specific medication classes (second level of the Anatomical Therapeutic Chemical Classification System). Practitioner variability was quantified in terms of the random effects distributions. Results: The prevalence of polypharmacy increased with age from 6.4% among patients aged 18-40 years to 19.7% (41-64 years), 45.3% (65-80 years), and 64.6% (81-92 years), and was higher in women than in men, particularly at younger ages. The most frequently prescribed medication classes were antiinflammatory and antirheumatic products (21.6% of patients), agents acting on the renin-angiotensin system (19.9%), analgesics (18.7%), and drugs for acid related disorders (18.3%). Men were more often prescribed agents targeting the cardiovascular system, whereas most other medications were more often prescribed to women. The highest practitioner variabilities were observed for vitamins, for antiinflammatory and antirheumatic products, and for mineral supplements. Conclusion: Based on practitioner variability, prevalence, and risk potential, antiinflammatory drugs and polypharmacy in older patients appear to be the most pressing issues in current drug prescribing routines.

Patterns of Thromboembolism in Patients with Advanced Pancreatic Cancer Undergoing First-Line Chemotherapy with FOLFIRINOX or Gemcitabine/nab-Paclitaxel.

INTRODUCTION: Recent advances in prophylactic anticoagulation and antineoplastic treatment for advanced pancreatic cancer (aPC) warrant an updated reassessment of thromboembolic risk in this population. This multicenter retrospective cohort study aims to comprehensively characterize incidence, risk factors, and outcomes of venous (VTE) and arterial thromboembolism (ATE) in homogenously treated patients with aPC. METHODS: Four hundred and fifty-five patients with aPC undergoing palliative first-line chemotherapy (Gemcitabine/nab-Paclitaxel (GN) or FOLIRINOX) were included. Primary outcomes were objectively confirmed VTE and/or ATE. RESULTS: Over a median follow-up of 26 months, 86 VTE (cumulative incidence: 20.0%; 95% confidence interval [CI]: 16.3-24.0) and 11 ATE events (cumulative incidence: 2.8%; 95% CI: 1.5-4.9) were observed. VTE diagnosis was associated with increased mortality (transition hazard ratio [THR]: 1.59 [95% CI: 1.21-2.09]) and increased risk of cancer progression (THR: 1.47 [95% CI: 1.08-2.01]), while the impact of ATE on mortality was numerically but not statistically significant (THR: 1.85 [95% CI: 0.87-3.94]). The strongest predictor of increased VTE risk was history of cancer-associated VTE (subdistribution hazard ratio [SHR]: 3.29 [95% CI: 2.09-5.18]), while the Khorana score (SHR: 0.78 [0.57-1.06]) failed to predict VTE risk. A history of cerebrovascular disease was associated with markedly increased ATE risk (SHR: 22.05 [95% CI: 6.83-71.22], p < 0.001), especially ischemic stroke. Risk of VTE/ATE did not significantly differ according to type of first-line chemotherapy. CONCLUSION: Patients with aPC undergoing palliative first-line chemotherapy with FOLFIRINOX or GN face a high risk for VTE/ATE and its diagnosis is linked to worse clinical outcomes. VTE-risk prediction models have limited ability to sub-stratify thrombotic events in this high-risk scenario.

Cutaneous Findings of Sporadic, Adult-Onset Neuronal Intranuclear Inclusion Disease.

ABSTRACT: Neuronal intranuclear inclusion disease is a rare, progressive neurodegenerative disease whose hallmark histopathologic finding is the presence of ubiquitin-positive hyaline intranuclear inclusions in neuronal and non-neuronal cells. We present a case of neuronal intranuclear inclusion disease in a 61-year-old Asian man with a history of repeated episodes of altered mental status, long-standing bladder dysfunction, and cerebrovascular accidents. The patient had characteristic magnetic imaging findings of high signal along the cortico-medullary junction on diffusion-weighted sequences and symmetric T2 hyperintensity in the paravermal area of the cerebellum. Skin biopsies showed characteristic histopathologic findings of ubiquitin-positive intranuclear inclusions that ultrastructurally composed of filamentous material without limiting membrane within eccrine epithelium and dermal fibroblasts. Our case highlights the utility of readily accessible skin biopsy in the diagnosis of this rare neurodegenerative disease.