Greenslopes Private Hospital

The poor response to current systemic treatments in liver cancer has been associated with the activation of cancer-associated fibroblasts (CAFs). Herein, we aimed to investigate the effects of chemotherapy on hepatic stellate cells (HSCs), the main origin of CAFs in liver cancer, and regulate HSC activation to improve treatment efficacy. CAF subpopulations and alpha-smooth muscle actin expression were analyzed using a single-cell RNA sequencing dataset and immunohistochemical staining in patients. Alpha-smooth muscle actin expression was significantly increased as the proportion of CAFs enriched by COL1A1+ and ACTA2+ subpopulations in patients after transarterial chemoembolisation. In vitro experiments demonstrated that cisplatin activated HSCs through a paracrine effect of excessive reactive oxygen species (ROS) generated from tumor cells of hepatocellular carcinoma (HCC) and biliary tract cancer origin. RNA sequencing revealed that the PI3K signaling pathway underlined the activation of HSCs in response to excessive ROS. This was further analyzed in HCC mouse models on nonfibrotic and fibrotic livers. A 12-parameter flow cytometry panel validated a significant increase in activated CAF subsets in tumors following cisplatin treatment. Alpelisib, an α-specific PI3K inhibitor, selectively targeted PI3K p110α and completely inhibited HSC activation induced by cisplatin. A marked decrease in fibrosis areas was achieved along with a significant reduction of tumor burden in murine HCC models. This study demonstrates the role of platinum-based chemotherapy in HSC activation in liver cancer. Selective targeting of PI3K p110α may provide a novel strategy to inhibit chemotherapy-induced HSC activation and improve treatment response.

The multidisciplinary healthcare model is integral for minimizing postoperative pain following shoulder surgery. Accordingly, the Australian and New Zealand College of Anasthetists stipulates that all health professionals involved in postoperative care require an adequate level of understanding in postoperative pain management. However, no known peer-reviewed study investigates healthcare professionals' opinions regarding pain following shoulder surgery. This study aimed to assess the perception of patient postoperative pain and subsequent opioid use across medical practitioners, physiotherapists and nurses. To address this aim, a 20-part questionnaire was developed to quantify the opinions of healthcare professionals regarding several shoulder surgery outcomes. The questionnaire utilized visual analog scales to allow participants to quantify their subjective assessments of postoperative outcomes across 5 common types of shoulder procedures. Participants were recruited between 1 January 2021 and 31 December 2021 through contact with representatives from their affiliated organizations. Answers to pain-related questions were subsequently analyzed. The questionnaire netted 200 responses, of which 132 were complete, and 68 were partial completions. Responses from nursing (35%), allied health (40%), and medical (23%) were included for analysis. Nursing participants assigned higher immediate postoperative pain scores and longer opioid usage following all 5 types of shoulder surgery, when compared to the values assigned by either physiotherapists or doctors (P < .05). There is no statistically significant difference in immediate postoperative pain scores, or duration of opioid use assigned between doctors and physiotherapists (P > .05 for all 5 types of shoulder procedures). When examined in the context of current peer-reviewed guidelines, the results of this study showed that all 3 study cohorts overestimated the duration of opioid requirement for all 5 types of shoulder surgeries assessed in this study - albeit to different degrees. These findings suggest the need for uniform education for doctors, nurses and physiotherapists regarding pain assessment and management immediately following shoulder surgery. While Australian guidelines are readily available online, the awareness of their existence may not be uniformed across all 3 professions - thus potentially accounting for the differences observed in this study.

Despite treatment advances, most patients with metastatic hormone-sensitive prostate cancer (mHSPC) experience disease progression to castration-resistant disease within 5 years. The placebo-controlled, double-blind, phase III KEYNOTE-991 study evaluated the efficacy and safety of adding pembrolizumab to enzalutamide and androgen deprivation therapy (ADT) in participants with mHSPC. Eligible participants were aged ≥18 years with next-generation hormonal agent-naive mHSPC. Participants were randomly assigned (1 : 1) to receive intravenous pembrolizumab 200 mg or placebo every 3 weeks for ≤35 cycles, with oral enzalutamide 160 mg and continuous ADT. Primary endpoints were radiographic progression-free survival (rPFS) and overall survival (OS). Safety was a secondary endpoint. Between 2 March 2020 and 9 August 2021, 626 participants were randomly assigned to receive pembrolizumab plus enzalutamide and ADT and 625 participants to receive placebo plus enzalutamide and ADT. At the first interim analysis, the median follow-up was 21.1 months (range 14.8-32.0 months). rPFS was not superior with pembrolizumab versus placebo [median not reached in both arms; hazard ratio (HR) 1.20, 95% confidence interval (CI) 0.96-1.49, P = 0.9467]. Median OS was not reached in either arm (HR 1.16, 95% CI 0.88-1.53; not formally statistically tested as per the multiplicity strategy). Grade ≥3 adverse events (AEs) and serious AEs (SAEs) were reported in 61.9% versus 38.1% and 40.3% versus 23.2% of participants in the pembrolizumab versus the placebo arm, respectively. Any-grade rash occurred at a higher frequency with pembrolizumab (25.1%) versus placebo (9.3%). KEYNOTE-991 did not meet its primary endpoint and was stopped for futility. The addition of pembrolizumab to enzalutamide and ADT was associated with higher frequencies of grade ≥3 AEs and SAEs than with placebo. Rash was identified as an additional safety signal with pembrolizumab plus enzalutamide and ADT.

BackgroundMalalignment of the humeral and glenoid components in total shoulder arthroplasty is associated with complications such as instability, implant loosening, and restricted motion. While the accuracy of patient-specific instrumentation (PSI) for glenoid component orientation is well documented, the precision of PSI for humeral osteotomy has not yet been published for a noncadaveric environment. This study aims to calculate the deviation between the planned and achieved orientations of humeral and glenoid components using PSI in a clinical, in vivo setting.MethodsForty-six patients were enrolled. One patient was excluded due to an intraoperative change to humeral component selection. The gender, etiology for arthroplasty (osteoarthritis or cuff tear arthropathy), severity of glenoid wear based on the Walch classification, and procedure (anatomic or reverse) were recorded. Computed tomography (CT) scans were obtained preoperatively for 3-dimensional reconstruction, from which the target humeral and glenoid component orientations for each patient were selected by the surgeon in the ASTRA surgical planning platform (Enovis, Austin, TX, USA). Humeral and glenoid PSIs were designed and 3-dimensionally printed to execute the planned alignments. A postoperative CT scan was acquired and used to calculate the deviation between the planned and achieved humeral version, humeral neck-shaft angle, humeral osteotomy height, glenoid version, and glenoid inclination. Humeral version was able to be calculated for 22 patients (48.9%) with a CT scan which extended distally beyond the humeral epicondyles.ResultsA total of 8 outliers (17.8%) were identified across all orientation parameters: 5 outliers (11.1%) for humeral orientation and 3 (6.7%) for glenoid orientation. The average deviation was 2.9°, 2.2°, 1.3 mm, 1.7° and 1.4° for humeral version, humeral neck-shaft angle, humeral osteotomy height, glenoid version, and glenoid inclination, respectively. The mean deviation in glenoid version was greater in males than females (P = .007). However, no other statistically significant difference was found between the mean or variance in deviation when comparing cohorts stratified by etiology of arthroplasty, severity of glenoid wear, or surgical procedure.ConclusionPSI generated from CT-based planning can achieve precise execution of preoperative plans in 89% of humeral and 93% of glenoid components in both anatomic and reverse procedures across a variety of patient morphologies. The humeral guide, when used in a more challenging in vivo environment, demonstrates accuracy comparable to those observed in existing ex vivo studies.

Abstract Background: MDNA11 is an engineered IL-2 agonist fused with human albumin that preferentially stimulates CD8+ T and NK cells with minimal effect on immune-suppressive Tregs. The ABILITY-1 (A Beta-only IL-2 ImmunoTherapY) study evaluates the safety, pharmacokinetics (PK), pharmacodynamics, and preliminary clinical activity of MDNA11, both as single agent and in combination with pembrolizumab, in heavily pre-treated patients with advanced solid tumors. We present updated interim safety, PK, PD and efficacy data from the monotherapy portion of the ABILITY-1 study. Method: The monotherapy dose escalation/evaluation portion of the ABILITY-1 study (NCT05086692) uses a modified 3+3 design. Schedule 1 (IV Q2W) at 3, 10, 30, 60, 90 and 120 μg/kg is complete; enrollment to schedule 2 (IV Q3W) is ongoing at the 120 μg/kg dose level. Step-up dosing (SUD) was implemented at doses ≥60 μg/kg across both schedules. Monotherapy dose expansion with IV Q2W at 90 μg/kg (OBD) is currently enrolling selected tumor indications. Primary endpoints were to evaluate safety and tolerability including dose-limiting toxicity (DLT), with secondary endpoint of anti-tumor activity assessed by RECIST 1.1 and iRECIST. Results: As of November 18, 2024, 30 patients have enrolled in monotherapy dose-escalation/evaluation on schedule 1: 16 melanoma, 3 NSCLC, 3 PDAC, 2 RCC, 2 sarcoma, 2 ovarian cancer, 1 tonsillar squamous cell carcinoma and 1 gastro-esophageal adenocarcinoma. No protocol-defined DLTs were observed. The majority of treatment-related adverse events were grade 1-2 and transient, resolving within 72 hours. PK analysis showed dose-dependent increase in exposure. Robust and durable lymphocyte expansion without eosinophilia (associated with vascular leak syndrome) was observed following each dose administration. At data cut off, 12 patients have been enrolled in monotherapy dose expansion, including melanoma (n=4), non-melanoma skin cancer (n=4) and MSI-H/dMMR tumors (n=3). Objective response was achieved in 5 of 20 monotherapy efficacy-evaluable patients treated with MDNA11 ≥60 μg/kg in the phase 2 eligible population who had progressed on immune checkpoint inhibitors (ICI) [ORR of 25%; 95% CI (6-44)], with 1 confirmed complete response (CR: melanoma, continuing on study) and 4 partial responses (PR: 2 MSI-H PDAC and 2 melanoma). Six patients had best response of stable disease, including 3 with duration &amp;gt;6 months (clinical benefit rate of 40%). Analysis of specific immune effector cells is ongoing to further understand mechanism and correlate with response. Conclusions: MDNA11 shows a favorable tolerability profile with no DLTs observed up to 120 μg/kg Q2W. Robust evidence of single agent clinical activity include 1 confirmed CR and 4 PR in patients who had progressed on ICI. Monotherapy dose expansion and combination dose escalation with pembrolizumab continue to enrol. Citation Format: Victoria G. Atkinson, Warren Brenner, Jacqueline T. Brown, Luis Cabezón-Gutiérrez, Pablo Gajate, Seung T. Kim, Jenny Lee, Charlotte Lemech, Kim A. Margolin, Irene Moreno, Victor Moreno, Do-Youn Oh, Isabella Glitza Oliva, John J. Park, Hong Shue, Przemyslaw Twardowski, Ira Winer, Michael J. Chisamore, Amy Prawira, Fahar Merchant, Melissa Coello, Minh D. To, Rosemina Merchant, Arash Yavari, Paolo A. Ascierto. Interim results from the phase 1/2 ABILITY-1 study of a long-acting ‘beta-enhanced not-alpha’ IL-2 superkine in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT047.

A case series of five women with genital tract fistula formation as a complication of vaginal pessary use for pelvic organ prolapse is presented, along with treatment provided and patient outcomes. Review on this topic reveals specific pessary types more commonly associated with severe complications. Recommendations to reduce such complications include careful patient selection, regular follow-up with physical examination, vigilance to enable early recognition of such complications and offering alternative treatment options. Surgical repair of genital tract fistula with concurrent prolapse surgery is feasible and effective.

Nivolumab (NIVO) + ipilimumab (IPI) combination and NIVO monotherapy have demonstrated durable clinical benefit in patients with unresectable/metastatic melanoma. This analysis describes long-term overall survival (OS) with the combination or monotherapy pooled across all major company-sponsored trials, as well as clinical factors associated with survival, in patients with immune checkpoint inhibitor (ICI) treatment-naïve unresectable/metastatic melanoma. Data were pooled from six CheckMate studies in ICI treatment-naïve patients receiving NIVO + IPI (NIVO 1 mg/kg + IPI 3 mg/kg or NIVO 3 mg/kg + IPI 1 mg/kg) or NIVO monotherapy (3 mg/kg). OS was assessed for each treatment, as well as in select subgroups. Cox proportional multivariate analysis (MVA) and classification and regression tree (CART) analyses were performed within treatment arms. Median follow-up for OS was 45.0 months for patients treated with NIVO + IPI (n = 839) and 35.8 months for patients treated with NIVO (n = 536). OS was longer with NIVO + IPI versus NIVO monotherapy (hazard ratio, 0.78 [95% CI, 0.67 to 0.91]), with 6-year OS rates of 52% versus 41%, respectively. Consistent benefit was observed in BRAF-mutant and BRAF-wild-type patients and those with normal and elevated lactate dehydrogenase (LDH). Numerical difference in OS was also observed across PD-L1 expression levels, although more pronounced with no/low PD-L1 expression. Clinical factors associated with decreased survival in both the MVA and CART analyses were LDH > upper limit of normal with either treatment, age ≥65 years with NIVO + IPI, and the presence of liver metastases with NIVO monotherapy. In this large, pooled nonrandomized retrospective analysis, we observed that NIVO + IPI provides longer OS than NIVO in patients with ICI treatment-naïve advanced melanoma and identifies clinical factors that appear to be associated with survival for each treatment, which may assist with treatment decision making.