A Systematic Review of Loco-Sedative Anesthesia for Urologic Surgery.

OBJECTIVE: To perform a systematic review of the characteristics and outcomes of conscious sedation and local anesthesia for various urologic procedures. Urologic care has much to gain from the routine integration of ambulatory surgery via loco-sedative anesthetic techniques for both surgeon and patient. METHODS: A comprehensive systematic literature search was conducted on PubMed, and Scopus databases following PRISMA criteria from June to August 2021. Articles were included if they were English, prospective, randomized, or non-randomized controlled trials that used local anesthetic or conscious sedation for urologic interventions in adult patients. Additionally, included studies provided primary data on the use loco-sedative anesthesia and the efficacy and complications. All studies included were further reviewed to assess the biases and conflicts of interests. RESULTS: 32 studies with 6897 patients were included in the review. Mean patient age was 46.4 years. The most common anesthetic and analgesic relief was the use of local anesthetic with 1% lidocaine. The majority used lidocaine as an injection, whereas the second most common route of administration was a topical cream. However, there was significant heterogeneity in the type of local or conscious sedation method and whether a combination was used. 44.4% of the studies used the visual analog scale as their primary endpoint. All the studies reported an 83% to 100% successful procedure rate without note of significant sedation-related complications. CONCLUSIONS: Given the high efficacy rates, loco-sedative anesthesia is a promising technique for urologic interventions and should be further investigated to determine whether it may become be the standard of care.

Characterization of the Relative Change in Objective and Subjective Metrics by Baselining Patients Who Have Wearable Technology Before Total Knee Arthroplasty.

BACKGROUND: Wearable sensors and associated supporting technologies (ie, patient applications) can provide both objective (joint position, step counts, etc.) and subjective data (ie, pain scores and patient-reported outcome measures) to track a patient's episode of care. Establishing a subjective and objective baseline of a patient's experience may arguably be beneficial for multiple reasons, including setting recovery expectations for the patient and demonstrating the effectiveness or success of the intervention. METHODS: In this pilot study, we characterized a subset of patients (n = 82 from 7 surgeons) using a wearable sensor system at least 6 days before total knee arthroplasty and provided postsurgical data up to 50 days postintervention. The 5-day average before surgery for total step counts (activity), achieved flexion and extension on a progress test (functional limit) and visual analog scale daily pain score were calculated. The difference from baseline was then calculated for each patient for each day postsurgery and reported as averages. RESULTS: On average, a patient will experience a relative deficit of 4,000 steps immediately following surgery that will return to near-baseline levels 50 days postintervention. A 30° deficit in flexion and a 10° deficit in extension will return at a similar rate as steps. Relative pain scores will worsen with an increase of approximately 3 points immediately following surgery. However, pain will decrease by 2 points relative to baseline between 40 and 50 days. CONCLUSIONS: The results of this pilot study demonstrate a method to baseline a patient's presurgical subjective and objective data and to provide a reference for postsurgical recovery expectations. Applications for these data include benchmarking for evaluating intervention success as well as setting patient expectations.

CB307: A Dual Targeting Costimulatory Humabody VH Therapeutic for Treating PSMA-Positive Tumors.

PURPOSE: CD137 is a T- and NK-cell costimulatory receptor involved in consolidating immunologic responses. The potent CD137 agonist urelumab has shown clinical promise as a cancer immunotherapeutic but development has been hampered by on-target off-tumor toxicities. A CD137 agonist targeted to the prostate-specific membrane antigen (PSMA), frequently and highly expressed on castration-resistant metastatic prostate cancer (mCRPC) tumor cells, could bring effective immunotherapy to this immunologically challenging to address disease. EXPERIMENTAL DESIGN: We designed and manufactured CB307, a novel half-life extended bispecific costimulatory Humabody VH therapeutic to elicit CD137 agonism exclusively in a PSMA-high tumor microenvironment (TME). The functional activity of CB307 was assessed in cell-based assays and in syngeneic mouse antitumor pharmacology studies. Nonclinical toxicology and toxicokinetic properties of CB307 were assessed in a good laboratory practice (GLP) compliant study in cynomolgus macaques. RESULTS: CB307 provides effective CD137 agonism in a PSMA-dependent manner, with antitumor activity both in vitro and in vivo, and additional activity when combined with checkpoint inhibitors. A validated novel PSMA/CD137 IHC assay demonstrated a higher prevalence of CD137-positive cells in the PSMA-expressing human mCRPC TME with respect to primary lesions. CB307 did not show substantial toxicity in nonhuman primates and exhibited a plasma half-life supporting weekly clinical administration. CONCLUSIONS: CB307 is a first-in-class immunotherapeutic that triggers potent PSMA-dependent T-cell activation, thereby alleviating toxicologic concerns against unrestricted CD137 agonism.

Detection of endometrial cancer in cervico-vaginal fluid and blood plasma: leveraging proteomics and machine learning for biomarker discovery.

BACKGROUND: The anatomical continuity between the uterine cavity and the lower genital tract allows for the exploitation of uterine-derived biomaterial in cervico-vaginal fluid for endometrial cancer detection based on non-invasive sampling methodologies. Plasma is an attractive biofluid for cancer detection due to its simplicity and ease of collection. In this biomarker discovery study, we aimed to identify proteomic signatures that accurately discriminate endometrial cancer from controls in cervico-vaginal fluid and blood plasma. METHODS: Blood plasma and Delphi Screener-collected cervico-vaginal fluid samples were acquired from symptomatic post-menopausal women with (n = 53) and without (n = 65) endometrial cancer. Digitised proteomic maps were derived for each sample using sequential window acquisition of all theoretical mass spectra (SWATH-MS). Machine learning was employed to identify the most discriminatory proteins. The best diagnostic model was determined based on accuracy and model parsimony. FINDINGS: A protein signature derived from cervico-vaginal fluid more accurately discriminated cancer from control samples than one derived from plasma. A 5-biomarker panel of cervico-vaginal fluid derived proteins (HPT, LG3BP, FGA, LY6D and IGHM) predicted endometrial cancer with an AUC of 0.95 (0.91-0.98), sensitivity of 91% (83%-98%), and specificity of 86% (78%-95%). By contrast, a 3-marker panel of plasma proteins (APOD, PSMA7 and HPT) predicted endometrial cancer with an AUC of 0.87 (0.81-0.93), sensitivity of 75% (64%-86%), and specificity of 84% (75%-93%). The parsimonious model AUC values for detection of stage I endometrial cancer in cervico-vaginal fluid and blood plasma were 0.92 (0.87-0.97) and 0.88 (0.82-0.95) respectively. INTERPRETATION: Here, we leveraged the natural shed of endometrial tumours to potentially develop an innovative approach to endometrial cancer detection. We show proof of principle that endometrial cancers secrete unique protein signatures that can enable cancer detection via cervico-vaginal fluid assays. Confirmation in a larger independent cohort is warranted. FUNDING: Cancer Research UK, Blood Cancer UK, National Institute for Health Research.

The ATR inhibitor ceralasertib potentiates cancer checkpoint immunotherapy by regulating the tumor microenvironment.

The Ataxia telangiectasia and Rad3-related (ATR) inhibitor ceralasertib in combination with the PD-L1 antibody durvalumab demonstrated encouraging clinical benefit in melanoma and lung cancer patients who progressed on immunotherapy. Here we show that modelling of intermittent ceralasertib treatment in mouse tumor models reveals CD8+ T-cell dependent antitumor activity, which is separate from the effects on tumor cells. Ceralasertib suppresses proliferating CD8+ T-cells on treatment which is rapidly reversed off-treatment. Ceralasertib causes up-regulation of type I interferon (IFNI) pathway in cancer patients and in tumor-bearing mice. IFNI is experimentally found to be a major mediator of antitumor activity of ceralasertib in combination with PD-L1 antibody. Improvement of T-cell function after ceralasertib treatment is linked to changes in myeloid cells in the tumor microenvironment. IFNI also promotes anti-proliferative effects of ceralasertib on tumor cells. Here, we report that broad immunomodulatory changes following intermittent ATR inhibition underpins the clinical therapeutic benefit and indicates its wider impact on antitumor immunity.

A genomic region associated with iteroparous spawning phenology is linked with age-at-maturity in female steelhead trout.

Age-at-maturity and iteroparity are two life history variations of steelhead trout (Oncorhynchus mykiss) that are believed to increase population resilience and stability. While repeat-spawning individuals are thought to have historically made up a substantial portion of the reproductive population in the Columbia River and the majority of females still attempt outmigration as kelts, return rates of repeat-spawner are low throughout the basin and below 1% for the furthest migrating stocks. Notably, outmigrating adults exhibit variation in rematuration phenology, displaying either "consecutive" (reproduce immediately the following season) or "skip" (delay spawning for future seasons) spawning patterns. Here, we use low coverage whole genome sequencing of consecutive versus skip spawning female Columbia River steelhead from two populations to test for genomic differences between these two iteroparous phenotypes. We identified genomic regions on several chromosomes which were associated with the phenology of iteroparity, including a region on chromosome 25 containing two genes, estradiol receptor beta (ERß) and glycoprotein hormone beta-5 (GPHB5), which, in mammals, are estrogen-sensitive and expressed in reproductive tissues. Allele frequencies in this ERß/GPHB5 region differed among female steelhead of different age at maturity, but not males. These genes also shared an island of linkage disequilibrium with the SIX6 gene, 600Kbp away on the same chromosome, a region of known association with age-at-maturity. These observations contribute to growing evidence that age-at-maturity and the phenology of iteroparity are determined by overlapping physiological processes and genetic pathways.

Role of Topical Tranexamic Acid on Blood Loss and Transfusion Requirements in Spinal Fusion for Neuromuscular and Syndromic Scoliosis.

STUDY DESIGN: Retrospective case control study. OBJECTIVES: To determine the role of TXA when used as topical soaked sponges (tTXA) on peri-operative blood loss and changes in hemoglobin following posterior spinal fusion (PSF) for neuromuscular and syndromic scoliosis (NMS). METHODS: A single center review of NMS patients who underwent PSF was conducted. The initial set of patients where no tTXA (control) was used were compared to consecutive NMS patients in whom tTXA was used. In the tTXA group, sponges soaked in 1g TXA in 500 mL normal saline were packed in the wound instead of dry sponges. Estimated blood loss (EBL) was calculated intraoperatively using a standard way. Pre-operative, intra-operative and immediate post-operative variables were collected and compared between the 2 groups. RESULTS: 33 patients were included (mean age- 13.5 yrs., BMI- 21, 17 patients in tTXA and 16 patients in control group). Pre-op demographic and radiographic variables were similar between the 2 groups. EBL, EBL per level, EBVL, operative time and number of levels fused were similar in both groups. tTXA group received less intra-operative pRBC transfusion as compared to the control group (150 ± 214 vs 363 ± 186 cc, P = .004). No difference was noted in post-op blood transfusion and drain output for 3 days in both the groups. tTXA group had lesser hospital (5.1 vs 8.9 days) and ICU length of stay (2 vs 4.2 days) and fewer immediate post-operative complications (23.5 vs 52.9%) compared to the control group but not statistically significant (P > .05). CONCLUSION: Administration of tTXA-soaked sponges is an effective and safe method to reduce intraoperative blood transfusion requirements in the correction of spinal deformity in patients with NMS.

Patient-selection algorithm for outpatient shoulder arthroplasty in ambulatory surgery center: a retrospective update.

BACKGROUND: Outpatient total shoulder arthroplasty (TSA) presents a safe alternative to inpatient arthroplasty, while helping meet the rapidly rising volume of shoulder arthroplasty needs and minimizing health care costs. Identifying the correct patient for outpatient surgery is critical to maintaining the safety standards with TSA. This study sought to update an ambulatory surgery center (ASC) TSA patient-selection algorithm previously published by our institution. METHODS: A retrospective chart review of TSAs was performed in an ASC at a single institution to collect patient demographics, perioperative risk factors, and postoperative outcomes with regard to reoperations, hospital admissions, and complications. The existing ASC algorithm for outpatient TSA was altered based on collected perioperative information, review of pertinent literature, and anesthesiology recommendations. RESULTS: A total of 319 TSAs were performed in an ASC in 298 patients over 7 years. Medically related complications occurred in 3 patients (0.9%) within 90 days of surgery, 2 of whom required hospital admission (0.6%) for acute kidney injury and pulmonary embolus. There were no instances of major cardiac events. Orthopedic-related complications occurred in 11 patients (3.4%), with hematoma development requiring evacuation and instability requiring revision being the most common causes. CONCLUSIONS: There was a low rate of perioperative complications and hospital admissions, confirming the safety of TSAs in an ASC setting. Based on prior literature and the population included, a pre-existing patient-selection algorithm was updated to better reflect increased comfort, knowledge, and data regarding safe patient selection for TSA in an ASC.

Cortiva vs AlloDerm in Prepectoral and Partial Submuscular Implant-Based Breast Reconstruction: A Randomized Clinical Trial.

BACKGROUND: Several acellular dermal matrices (ADMs) are utilized for soft tissue support in prosthetic breast reconstruction. Little high-level evidence supports the use of one ADM over another. Therefore, we sought to compare Cortiva 1mm Allograft Dermis to AlloDerm RTU, the most studied ADM in the literature. METHODS: A single-blinded randomized controlled trial comparing Cortiva to AlloDerm in prepectoral and subpectoral immediate prosthetic breast reconstruction was performed at two academic hospitals from March 2017 to December 2021. Reconstructions were direct-to-implant (DTI) or tissue expander (TE). Primary outcome was reconstructive failure, defined as TE explantation prior to planned further reconstruction, or explantation of DTI reconstructions before 3 months postoperatively. Secondary outcomes were additional complications, patient-reported outcomes (PROs), and cost. RESULTS: There were 302 patients included - 151 AlloDerm (280 breasts), 151 Cortiva (277 breasts). Reconstructions in both cohorts were majority TE (62% vs 38% DTI), smooth device (68% vs 32% textured), and prepectoral (80% vs 20% subpectoral). Reconstructive failure was no different between ADMs (AlloDerm 9.3% vs Cortiva 8.3%, p=0.68). There were no additional differences in any complications or PROs between ADMs. Seromas occurred in 7.6% of Cortiva but 12 % of AlloDerm cases, whose odds of seroma formation were two-fold (OR 1.93, 95% CI 1.01-3.67, p=0.047) higher. AlloDerm variable cost was 10-15% more than Cortiva, and there were no additional cost differences. CONCLUSION: When assessing safety, clinical performance, PROs, and cost, Cortiva is non-inferior to AlloDerm in immediate prosthetic breast reconstruction and may be cheaper with lower risk of seroma formation.

Identification of curaxin as a potential new therapeutic for JAK2 V617F mutant patients.

Myelofibrosis is a myeloproliferative neoplasm (MPN) which typically results in reduced length and quality of life due to systemic symptoms and blood count changes arising from fibrotic changes in the bone marrow. While the JAK2 inhibitor ruxolitinib provides some clinical benefit, there remains a substantial unmet need for novel targeted therapies to better modify the disease process or eradicate the cells at the heart of myelofibrosis pathology. Repurposing drugs bypasses many of the hurdles present in drug development, such as toxicity and pharmacodynamic profiling. To this end we undertook a re-analysis of our pre-existing proteomic data sets to identify perturbed biochemical pathways and their associated drugs/inhibitors to potentially target the cells driving myelofibrosis. This approach identified CBL0137 as a candidate for targeting Jak2 mutation-driven malignancies. CBL0137 is a drug derived from curaxin targeting the Facilitates Chromatin Transcription (FACT) complex. It is reported to trap the FACT complex on chromatin thereby activating p53 and inhibiting NF-kB activity. We therefore assessed the activity of CBL0137 in primary patient samples and murine models of Jak2-mutated MPN and found it preferentially targets CD34+ stem and progenitor cells from myelofibrosis patients by comparison with healthy control cells. Further we investigate its mechanism of action in primary haemopoietic progenitor cells and demonstrate its ability to reduce splenomegaly and reticulocyte number in a transgenic murine model of myeloproliferative neoplasms.

Quantitative SWATH-based proteomic profiling of urine for the identification of endometrial cancer biomarkers in symptomatic women.

BACKGROUND: A non-invasive endometrial cancer detection tool that can accurately triage symptomatic women for definitive testing would improve patient care. Urine is an attractive biofluid for cancer detection due to its simplicity and ease of collection. The aim of this study was to identify urine-based proteomic signatures that can discriminate endometrial cancer patients from symptomatic controls. METHODS: This was a prospective case-control study of symptomatic post-menopausal women (50 cancers, 54 controls). Voided self-collected urine samples were processed for mass spectrometry and run using sequential window acquisition of all theoretical mass spectra (SWATH-MS). Machine learning techniques were used to identify important discriminatory proteins, which were subsequently combined in multi-marker panels using logistic regression. RESULTS: The top discriminatory proteins individually showed moderate accuracy (AUC > 0.70) for endometrial cancer detection. However, algorithms combining the most discriminatory proteins performed well with AUCs > 0.90. The best performing diagnostic model was a 10-marker panel combining SPRR1B, CRNN, CALML3, TXN, FABP5, C1RL, MMP9, ECM1, S100A7 and CFI and predicted endometrial cancer with an AUC of 0.92 (0.96-0.97). Urine-based protein signatures showed good accuracy for the detection of early-stage cancers (AUC 0.92 (0.86-0.9)). CONCLUSION: A patient-friendly, urine-based test could offer a non-invasive endometrial cancer detection tool in symptomatic women. Validation in a larger independent cohort is warranted.

HMG20B stabilizes association of LSD1 with GFI1 on chromatin to confer transcription repression and leukemia cell differentiation block.

Pharmacologic inhibition of LSD1 induces molecular and morphologic differentiation of blast cells in acute myeloid leukemia (AML) patients harboring MLL gene translocations. In addition to its demethylase activity, LSD1 has a critical scaffolding function at genomic sites occupied by the SNAG domain transcription repressor GFI1. Importantly, inhibitors block both enzymatic and scaffolding activities, in the latter case by disrupting the protein:protein interaction of GFI1 with LSD1. To explore the wider consequences of LSD1 inhibition on the LSD1 protein complex we applied mass spectrometry technologies. We discovered that the interaction of the HMG-box protein HMG20B with LSD1 was also disrupted by LSD1 inhibition. Downstream investigations revealed that HMG20B is co-located on chromatin with GFI1 and LSD1 genome-wide; the strongest HMG20B binding co-locates with the strongest GFI1 and LSD1 binding. Functional assays demonstrated that HMG20B depletion induces leukemia cell differentiation and further revealed that HMG20B is required for the transcription repressor activity of GFI1 through stabilizing LSD1 on chromatin at GFI1 binding sites. Interaction of HMG20B with LSD1 is through its coiled-coil domain. Thus, HMG20B is a critical component of the GFI1:LSD1 transcription repressor complex which contributes to leukemia cell differentiation block.

Improvement in Serum Vitamin D Following Dental Rehabilitation to Treat Severe Early Childhood Caries.

Purpose: The purpose of this study was to investigate changes in 25-hydroxyvitamin D (25(OH)D) levels in children with severe early childhood caries (S-ECC) following rehabilitative surgery using general anesthesia (GA). Methods: Children with S-ECC were recruited on the day of surgery for a prospective study investigating changes in nutritional status and well-being before and after surgery. Venipunctures for 25(OH)D were performed while children were in the operating room, and parents completed a questionnaire regarding nutritional intake, oral health, quality of life, and family demographics. Participants returned at a minimum of three months for a follow-up venipuncture, questionnaire, and dental examination. Analyses included descriptive, bivariate, and multivariable regression analyses. A P-value of ≤ 0.05 was significant. Results: Overall, 150 children participated, with a mean age of 47.7±14.1 months. The mean baseline 25(OH)D concentration was 49.8±16.9 nmol/L, with 17 percent having deficient levels. Overall, 106 returned for follow-up. Paired t-tests revealed significant improvements in the mean 25(OH)D levels following rehabilitation (50.1±17.1 nmol/L versus 61.2±18.7, P<0.001). The proportion with optimal and adequate 25(OH)D levels increased from 9.2 percent to 24.1 percent and from 48.3 percent to 67.8 percent, respectively, while those classified as deficient decreased from 17.2 percent to 8.1 percent from baseline to follow-up. Conclusions: Significant improvements in vitamin D concentrations were observed following dental rehabilitation. This provides additional evidence of the association between oral health and nutritional status.

Capturing and Improving Case Charge Accuracy in Robotic Surgery Programs.

SUMMARY: The robotic platform offers many benefits to patients and surgeons; however, incorporating this new surgical tool has also introduced challenges in intraoperative documentation accuracy. In 2019, we began to investigate our institution's robotic intraoperative supply documentation accuracy. We identified a 60% case error rate between the robotic items logged by the operating room staff in the electronic medical record and the true robotic items used for a case as logged on the Intuitive platform. This can be a widespread and unrecognized problem for other organizations as well. We then addressed this problem through patient safety and quality improvement-based interventions including error notification to operating room personnel, a barcode scanning system, peer-to-peer education, improving robotic item descriptions, and procedure receipt messaging. These interventions helped us decrease our institution's case error rate from 60% to 16.9% during the past 2 years, which generated a cumulative 2.1% net increase in our billed robotic items, through the addition and/or subtraction of robotic items from each case. Through our multiple interventions, we have created a robust, flexible, and efficient item-capturing system for robotic surgery cases.

Combination of curaxin and tyrosine kinase inhibitors display enhanced killing of primitive Chronic Myeloid Leukaemia cells.

Despite the big increase in precision medicine targeted therapies developing curative treatments for many cancers is still a major challenge due mainly to the development of drug resistance in cancer stem cells. The cancer stem cells are constantly evolving to survive and targeted drug treatment often increases the selective pressure on these cells from which the disease develops. Chronic myeloid leukaemia is a paradigm of cancer stem cell research. Targeted therapies to the causative oncogene, BCR/ABL, have been developed but drug resistance remains a problem. The introduction of tyrosine kinase inhibitors targeting BCR/ABL were transformative in the management of CML. However, patients are rarely cured as the tyrosine kinase inhibitors fail to eradicate the leukaemic stem cell which often leads to loss of response to therapy as drug resistance develops and progression to more fatal forms of acute leukaemia occurs. New treatment strategies targeting other entities within the leukemic stem cell either alone or in combination with tyrosine kinase are therefore required. Drawing on our previous published work on the development of potential novel targets in CML and other myeloproliferative diseases along with analysis of the facilitates chromatin transcription (FACT) complex in CML we hypothesised that curaxin, a drug that targets the FACT complex and is in clinical trial for the treatment of other cancers, could be of use in the treatment of CML. We therefore assessed the curaxin CBL0137 as a new agent to extinguish CML primitive cells and show its ability to preferentially target CML cells compared to healthy control cells, especially in combination with clinically relevant tyrosine kinase inhibitors.

Improvement in Iron and Iron-Related Nutritional Status Following Pediatric Dental Surgery To Treat Severe Early Childhood Caries.

Purpose: To investigate improvement in iron and iron-related nutritional status of children with severe-early childhood caries (S-ECC) following dental rehabilitation under general anesthesia (GA). Methods: Children with S-ECC were recruited into a prospective study investigating changes in nutritional status before and after surgery. Parents completed a questionnaire, as their child had a venipuncture while under GA. Children returned for follow-up at a minimum of three months postsurgery, and parents completed a follow-up questionnaire and their child had an additional venipuncture and dental examination. Statistical analyses included descriptive, bivariate, and multivariable regression analyses. Results: A total of 150 children participated (mean age 47.7±14.1 months). The mean baseline ferritin concentration was 27.9±19.1 µg/L, while mean iron and hemoglobin levels were 12.3±4.3 µmol/L and 107.5±9.2 g/L, respectively. Overall, 53 percent were anemic, 30 percent had iron deficiency (ID), and 20 percent had iron deficiency anemia (IDA) at baseline. In total, 106 participants returned for follow-up. Paired t-tests revealed significant improvements in ferritin (27.0±18.4 µg/L versus 34.3±18.2 µg/L, P<0.001) and hemoglobin (108.2±8.3 g/L versus 123.7±9.4 g/L, P<0.001) levels. There was a 16 percent reduction in children with ID (P<0.001) and a 20 percent reduction in children experiencing IDA (P=0.011) from baseline to follow-up. Multivariable regression revealed that follow-up ferritin levels were associated with baseline ferritin concentrations, red meat intake, and difficulty purchasing food because of cost. Conclusions: Improvements in iron and iron-related nutritional status were observed post GA. Dental surgery for S-ECC may contribute to improved children's eating practices and resolve oral inflammation, thus leading to better nutritional status.

The multi-specific VH-based Humabody CB213 co-targets PD1 and LAG3 on T cells to promote anti-tumour activity.

BACKGROUND: Improving cancer immunotherapy long-term clinical benefit is a major priority. It has become apparent that multiple axes of immune suppression restrain the capacity of T cells to provide anti-tumour activity including signalling through PD1/PD-L1 and LAG3/MHC-II. METHODS: CB213 has been developed as a fully human PD1/LAG3 co-targeting multi-specific Humabody composed of linked VH domains that avidly bind and block PD1 and LAG3 on dual-positive T cells. We present the preclinical primary pharmacology of CB213: biochemistry, cell-based function vs. immune-suppressive targets, induction of T cell proliferation ex vivo using blood obtained from NSCLC patients, and syngeneic mouse model anti-tumour activity. CB213 pharmacokinetics was assessed in cynomolgus macaques. RESULTS: CB213 shows picomolar avidity when simultaneously engaging PD1 and LAG3. Assessing LAG3/MHC-II or PD1/PD-L1 suppression individually, CB213 preferentially counters the LAG3 axis. CB213 showed superior activity vs. αPD1 antibody to induce ex vivo NSCLC patient T cell proliferation and to suppress tumour growth in a syngeneic mouse tumour model, for which both experimental systems possess PD1 and LAG3 suppressive components. Non-human primate PK of CB213 suggests weekly clinical administration. CONCLUSIONS: CB213 is poised to enter clinical development and, through intercepting both PD1 and LAG3 resistance mechanisms, may benefit patients with tumours escaping front-line immunological control.

The neutrophil protein CD177 is a novel PDPN receptor that regulates human cancer-associated fibroblast physiology.

The cancer-associated fibroblast (CAF) marker podoplanin (PDPN) is generally correlated with poor clinical outcomes in cancer patients and thus represents a promising therapeutic target. Despite its biomedical relevance, basic aspects of PDPN biology such as its cellular functions and cell surface ligands remain poorly uncharacterized, thus challenging drug development. Here, we utilize a high throughput platform to elucidate the PDPN cell surface interactome, and uncover the neutrophil protein CD177 as a new binding partner. Quantitative proteomics analysis of the CAF phosphoproteome reveals a role for PDPN in cell signaling, growth and actomyosin contractility, among other processes. Moreover, cellular assays demonstrate that CD177 is a functional antagonist, recapitulating the phenotype observed in PDPN-deficient CAFs. In sum, starting from the unbiased elucidation of the PDPN co-receptome, our work provides insights into PDPN functions and reveals the PDPN/CD177 axis as a possible modulator of fibroblast physiology in the tumor microenvironment.

Retrospective analysis of Schlafen11 (SLFN11) to predict the outcomes to therapies affecting the DNA damage response.

BACKGROUND: The absence of the putative DNA/RNA helicase Schlafen11 (SLFN11) is thought to cause resistance to DNA-damaging agents (DDAs) and PARP inhibitors. METHODS: We developed and validated a clinically applicable SLFN11 immunohistochemistry assay and retrospectively correlated SLFN11 tumour levels to patient outcome to the standard of care therapies and olaparib maintenance. RESULTS: High SLFN11 associated with improved prognosis to the first-line treatment with DDAs platinum-plus-etoposide in SCLC patients, but was not strongly linked to paclitaxel-platinum response in ovarian cancer patients. Multivariate analysis of patients with relapsed platinum-sensitive ovarian cancer from the randomised, placebo-controlled Phase II olaparib maintenance Study19 showed SLFN11 tumour levels associated with sensitivity to olaparib. Study19 patients with high SLFN11 had a lower progression-free survival (PFS) hazard ratio compared to patients with low SLFN11, although both groups had the benefit of olaparib over placebo. Whilst caveated by small sample size, this trend was maintained for PFS, but not overall survival, when adjusting for BRCA status across the olaparib and placebo treatment groups, a key driver of PARP inhibitor sensitivity. CONCLUSION: We provide clinical evidence supporting the role of SLFN11 as a DDA therapy selection biomarker in SCLC and highlight the need for further clinical investigation into SLFN11 as a PARP inhibitor predictive biomarker.

Comprehensive Library Generation for Identification and Quantification of Endometrial Cancer Protein Biomarkers in Cervico-Vaginal Fluid.

Endometrial cancer is the most common gynaecological malignancy in high-income countries and its incidence is rising. Early detection, aided by highly sensitive and specific biomarkers, has the potential to improve outcomes as treatment can be provided when it is most likely to effect a cure. Sequential window acquisition of all theoretical mass spectra (SWATH-MS), an accurate and reproducible platform for analysing biological samples, offers a technological advance for biomarker discovery due to its reproducibility, sensitivity and potential for data re-interrogation. SWATH-MS requires a spectral library in order to identify and quantify peptides from multiplexed mass spectrometry data. Here we present a bespoke spectral library of 154,206 transitions identifying 19,394 peptides and 2425 proteins in the cervico-vaginal fluid of postmenopausal women with, or at risk of, endometrial cancer. We have combined these data with a library of over 6000 proteins generated based on mass spectrometric analysis of two endometrial cancer cell lines. This unique resource enables the study of protein biomarkers for endometrial cancer detection in cervico-vaginal fluid. Data are available via ProteomeXchange with unique identifier PXD025925.