Additional Options Research Articles

Mindfulness-based cognitive therapy v. treatment as usual in people with bipolar disorder: A multicentre, randomised controlled trial

AbstractBackgroundMindfulness-based cognitive therapy (MBCT) seems a promising intervention for bipolar disorder (BD), but there is a lack of randomised controlled trials (RCT) investigating this. The purpose of this multicentre, evaluator blinded RCT was to investigate the added value of MBCT to treatment as usual (TAU) in BD up to 15 months follow-up (NCT03507647).MethodsA total of 144 participants with BD type I and II were randomised to MBCT + TAU (n = 72) and TAU (n = 72). Primary outcome was current depressive symptoms. Secondary outcomes were current (hypo)manic and anxiety symptoms, recurrence rates, rumination, dampening of positive affect, functional impairment, mindfulness skills, self-compassion, and positive mental health. Potential moderators of treatment outcome were examined.ResultsMBCT + TAU was not more efficacious than TAU in reducing current depressive symptoms at post-treatment (95% CI [−7.0 to 1.8], p = 0.303, d = 0.24) or follow-up (95% CI [−2.2 to 6.3], p = 0.037, d = 0.13). At post-treatment, MBCT + TAU was more effective than TAU in improving mindfulness skills. At follow-up, TAU was more effective than MBCT + TAU in reducing trait anxiety and improving mindfulness skills and positive mental health. Exploratory analysis revealed that participants with higher depressive symptoms and functional impairment at baseline benefitted more from MBCT + TAU than TAU.ConclusionsIn these participants with highly recurrent BD, MBCT may be a treatment option in addition to TAU for those who suffer from moderate to severe levels of depression and functional impairment.Trial registrationClinicalTrials.gov, NCT03507647. Registered the 25 April 2018, https://www.clinicaltrials.gov/ct2/show/NCT01126827.

A Relational Agent Intervention for Adolescents Seeking Mental Health Treatment: Protocol for a Randomized Controlled Trial.

Unmet pediatric mental health (MH) needs are growing as rates of pediatric depression and anxiety dramatically increase. Access to care is limited by multiple factors, including a shortage of clinicians trained in developmentally specific, evidence-based services. Novel approaches to MH care delivery, including technology-leveraged and readily accessible options, need to be evaluated in service of expanding evidence-based services to youths and their families. Preliminary evidence supports the use of Woebot, a relational agent that digitally delivers guided cognitive behavioral therapy (CBT) through a mobile app, for adults with MH concerns. However, no studies have evaluated the feasibility and acceptability of such app-delivered relational agents specifically for adolescents with depression and/or anxiety within an outpatient MH clinic, nor compared them to other MH support services. This paper describes the protocol for a randomized controlled trial evaluating the feasibility and acceptability of an investigational device, Woebot for Adolescents (W-GenZD), within an outpatient MH clinic for youths presenting with depression and/or anxiety. The study's secondary aim will compare the clinical outcomes of self-reported depressive symptoms with W-GenZD and a telehealth-delivered CBT-based skills group (CBT-group). Tertiary aims will evaluate additional clinical outcomes and therapeutic alliance between adolescents in W-GenZD and the CBT-group. Participants include youths aged 13-17 years with depression and/or anxiety seeking care from an outpatient MH clinic at a children's hospital. Eligible youths will have no recent safety concerns or complex comorbid clinical diagnoses; have no concurrent individual therapy; and, if on medications, are on stable doses, based on clinical screening and as well as study-specific criteria. Recruitment began in May 2022. As of December 8, 2022, we have randomized 133 participants. Establishing the feasibility and acceptability of W-GenZD within an outpatient MH clinical setting will add to the field's current understanding of the utility and implementation considerations of this MH care service modality. The study will also evaluate the noninferiority of W-GenZD against the CBT-group. Findings may also have implications for patients, families, and providers looking for additional MH support options for adolescents seeking help for their depression and/or anxiety. Such options expand the menu of supports for youths with lower-intensity needs as well as possibly reduce waitlists and optimize clinician deployment toward more severe cases. ClinicalTrials.gov NCT05372913; https://clinicaltrials.gov/ct2/show/NCT05372913. DERR1-10.2196/44940.

A six-month prospective, randomised, double-blinded, placebo-controlled, crossover, dietary trial design to investigate the potential of psychobiotics on seizure semiology and comorbidities in canine epilepsy: study protocol

BackgroundEpilepsy is the most common chronic neurological disease in dogs. More than two-thirds of these patients suffer from associated behavioural comorbidities. The latter could have their origin in partially overlapping pathomechanisms, with the intestinal microbiome as a potential key link between them. The current arsenal of drugs for epilepsy management remains limited. Most canine patients continue to have seizures despite treatment and the occurrence of comorbidities is not sufficiently addressed, limiting quality of life of affected dogs and owners. Therefore, novel additional epilepsy management options are urgently needed. The microbiome-gut-brain axis may serve as a new target for the development of innovative multimodal therapeutic approaches to overcome current shortcomings in epilepsy management.MethodsA six-month prospective, randomised, double-blinded, placebo-controlled, crossover, dietary trial was designed to investigate the potential of the psychobiotic Bifidobacterium longum on behavioural comorbidities in canine epilepsy. Seizure semiology will be evaluated as a secondary outcome measure. Thirty-four privately owned dogs are planned to be included in the ongoing study meeting the following inclusion criteria: Dogs displaying increased anxiety/fear behaviour since the start of the idiopathic epilepsy. Tier II confidence level of the International Veterinary Epilepsy Task Force for the diagnosis of idiopathic epilepsy, with a maximum seizure interval of 3 month and a minimum of three generalised seizures within that period and chronically treated with at least one antiseizure drug without improvement in seizure frequency Each dog will receive the allocated supplement (probiotic vs. placebo) alongside its normal diet for a 3-month period. After a three-week wash out period, the second phase starts by administering the respective other supplement for another 3 months.DiscussionThe current study considers modern high-quality standards for epilepsy medication trials. Common biasing effects should be limited to a possible minimum (regression-to-the mean effect, placebo effect, observer effect), ensuring a high validity and accuracy of the acquired results, thus enabling a representative nature of the efficacy of Bifidobacterium longum as add-on supplement for dogs suffering from epilepsy and its comorbidities. This publication should provide a description of the study procedure and data acquisition methods, including prognosed statistical analysis.

Prediction of violence: Part contagious disease, part unpredictable individual: Is a public health assessment approach an additional option and at what cost?

On a population level, violence shares many similarities with communicable disease states and other public health issues. Therefore, there has been a push to apply public health interventions to the problem of societal violence and for some to even identify violence as the product of a disease state (e.g., changed brain). This conceptualization could lead to the development of new risk violence assessment tools and approaches predicated more on the public health model rather than existing instruments that have often been based on inpatient mental health populations or incarcerated populations. In this article, we will discuss aspects of legal obligation for risk violence "prediction/stratification", the application of the public health communicable disease model to violence, as well as identify why it may not always translate to the individual with whom a clinician or forensic mental health evaluator interacts.

Renal tamponade in a patient with hydronephrosis-related Page kidney.

A 48-year-old woman presented with hyperreninemic hypertension and renal dysfunction and was diagnosed with hydronephrosis-related Page kidney. The pathophysiology was "renal tamponade", in which the kidney was compressed by the renal pelvis and Gerota's fascia, resulting in intrarenal microvascular ischemia. Ureteral stent placement promptly improved the hyperreninemic hypertension and renal dysfunction, and additional perirenal fluid drainage gradually improved these conditions. These observations indicated the following three points. First, renal compression-induced renin-angiotensin-aldosterone system upregulation plays an important role in the pathogenesis of Page kidney. Second, physicians should consider perirenal fluid drainage as a therapeutic option in addition to ureteral stenting in patients with hydronephrosis-related Page kidney. Third, bilateral perirenal subcapsular hematomas in this case could be caused by hydronephrosis. Hydronephrosis-induced intrarenal pressure elevation possibly caused chronic perirenal subcapsular hemorrhage at the vulnerable sites of the renal cortex and peeling of the renal capsule from the cortex, resulting in the bilateral massive subcapsular hematomas and Page kidney.

Abstract OT2-10-01: A phase 2, randomized study of magrolimab combination therapy in adult patients with unresectable locally advanced or metastatic triple-negative breast cancer

Abstract Background: Improving outcomes for patients (pts) with triple-negative breast cancer (TNBC) remains a high unmet need. Immune checkpoint inhibitors (ICIs) + chemotherapy (chemo) and single-agent sacituzumab govitecan, a trophoblast cell-surface antigen 2–targeted antibody-drug conjugate coupled to SN38 via a proprietary, hydrolysable linker, are approved in newly diagnosed pts with programmed death-ligand 1 (PD-L1)–positive tumors and pts who received ≥2 prior systemic therapies (≥1 for metastatic disease), respectively. However, additional options are urgently needed, particularly for pts with tumors that do not express PD-L1 and for those with progression on chemo ± ICI. Magrolimab is an antibody blocking CD47, a “don’t eat me” signal overexpressed on cancer cells, including TNBC, inducing tumor phagocytosis by macrophages. Magrolimab has shown preclinical activity and promising clinical efficacy in hematologic and solid tumors. Chemo agents, including taxanes, can enhance prophagocytic signals on tumor cells, leading to the potential for synergistic antitumor activity with magrolimab. This study is evaluating the safety/tolerability and efficacy of magrolimab in combination with nab-paclitaxel/paclitaxel or with sacituzumab govitecan in unresectable locally advanced/metastatic TNBC. Trial Design: This open-label, 2-cohort (C) study consists of safety run-in and phase (ph)2 portions evaluating nab-paclitaxel/paclitaxel (choice) + magrolimab (safety run-in) or ± magrolimab (ph2, randomized 1:1) in pts with untreated, advanced/metastatic TNBC ineligible for ICI (C1) and magrolimab + sacituzumab govitecan (safety run-in and ph2) in pts with advanced TNBC who received 1 prior systemic treatment in the metastatic setting (C2). Stratification factors for C1 are neoadjuvant and/or adjuvant taxane therapy, liver metastases, and nab-paclitaxel vs paclitaxel. In both cohorts, magrolimab will be administered intravenously (IV) in de-escalating doses to establish the recommended ph2 dose (RP2D). Nab-paclitaxel/paclitaxel and sacituzumab govitecan will be administered IV per standard of care. Eligibility Criteria: Eligible pts are ≥18 y with PD-L1–negative, untreated, unresectable locally advanced/metastatic TNBC (C1) or unresectable locally advanced/metastatic TNBC who received 1 prior line of therapy in the advanced setting, including a taxane and an ICI if PD-L1 positive (C2), with measurable disease per RECIST v1.1. Exclusion criteria include active central nervous system disease, red blood cell transfusion dependence, or prior treatment with CD47/signal regulatory protein α–targeting agents for both cohorts. Additional exclusions are disease progression within 6 months of (neo)adjuvant therapy or rapid visceral progression and/or symptomatic disease, for which single-agent chemo would not be appropriate (C1); chronic inflammatory bowel disease and a history of bowel obstruction or gastrointestinal perforation within 6 months of enrollment, prior treatment with topoisomerase I inhibitors or antibody-drug conjugates containing a topoisomerase inhibitor, and receipt of high-dose systemic corticosteroids within 2 weeks of cycle 1 day 1 (C2). Specific Aims: The primary objectives are safety/tolerability and magrolimab RP2D (safety run-in) and efficacy (ph2: C1, progression-free survival [PFS]; C2, objective response rate [ORR]; both by investigator). Secondary objectives include ORR, PFS, and duration of response by investigator and independent central review, overall survival, and magrolimab concentration vs time and antidrug antibodies. Present and Target Accrual: The study is enrolling in the US, Australia, and Hong Kong. Target accrual is 144 pts. Contact Information: ClinicalTrials.gov: NCT04958785. Citation Format: Natalie Rainey, Rohit Joshi, Joanne Win Yang Chiu, Ann Chen, Hao Wang, Jared Odegard, Michael Howland, Sylvia Adams. A phase 2, randomized study of magrolimab combination therapy in adult patients with unresectable locally advanced or metastatic triple-negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-10-01.

Abstract P6-09-01: Treatment goals and quality of life (QOL) in a survey of patients with ER+/HER2- metastatic breast cancer (mBC)

Abstract Introduction: In patients (pts) with ER+/HER2- mBC, insights into the foremost concerns regarding their mBC treatment goals and QOL are often assumed by providers but are vastly understudied. The objectives of this survey were to better comprehend treatment goals and QOL concerns in pts with ER+/HER2- mBC. Methods: The 42-question, online EQUALS (ESR1 QUAlity of Life Survey) survey was sent to US subjects in June 2022 from 1) the Cure Media Group (n=6,625) by email, 2) private Facebook groups of pts with mBC and 3) members of a BC clinic. Subjects were eligible if they had ER+/HER2- mBC. A $10 gift card was obtained at survey completion. Survey answers were summarized descriptively. Results: 213 pts completed the survey. Respondents had a mean age of 57 y (range, 31–83 y), and were mostly white (91%), living in an urban/suburban setting (75%), with a higher education degree (71%) and household income ≥$75k (53%). Mean year of mBC diagnosis was 2018 (range, 1995–2022). Most common first-line mBC treatments were aromatase inhibitor (AI) + CDK4/6 inhibitor (CDK4/6i; 44%), AI alone (18%), or fulvestrant + CDK4/6i (16%);54% had received chemotherapy in the metastatic setting. Pts most frequently received information about new mBC treatments from other people living with mBC (42%), followed by physicians (34%), social media (31%), or medical journals/conferences (28%). Two-thirds of pts (64%) reported good/very good QOL, with 12% reporting poor/very poor QOL. Common side effects mostly/moderately impacting QOL were: fatigue (74%), joint pain (64%), vaginal atrophy/dryness (56%), and vasomotor symptoms (47%). Most (84%) were comfortable/very comfortable discussing side effects with their medical team (MT). Worry about disease progression occurred often: everyday (38%), a few times a week (21%) or month (18%), or only before scans (15%). Upon progression, pts worried more about efficacy of new treatment (76%) and having additional options (70%) than they did about side effects (33%). Pts’ current treatment goals were: control cancer growth/spread (93%), prolong life (82%), maintain QOL (81%), tolerate side effects (61%), and relieve suffering/pain (57%); similar to their goals at diagnosis. Almost two-thirds of MTs addressed these goals at the beginning of treatment (63%) and continued annually (60%). Most pts (70%) were very concerned that their mBC diagnosis impacted their family although 81% felt supported at home. Since diagnosis, major/moderate life impacts were: side effects (82%), mental health/stress (78%), QOL (71%), inability to engage in activities (62%), and finances (61%). Most pts (64%) thought their mBC or treatment impacted their intimate/sexual relationship negatively and half (50%) worried about sexual intimacy. Only 44% of pts were comfortable discussing intimacy/sexual side effects with their MT. More pts were comfortable/very comfortable discussing sexual side effects with their MT if their oncologists were female (64%) vs male (51%), BC (73%) vs general (45%), or academic (70%) vs community hospital (52%) or office-based practice (49%). Most (92%) were concerned that their treatments may have a negative impact on their bones. Conclusion: In this survey of pts with ER+/HER2- mBC, >70% received information about new mBC treatments from other pts or social media vs physicians. Pts’ primary concerns were disease control and treatment options, although treatment side effects had the most impact on QOL. Mental health/stress, intimacy and relationships, and bone health were also impacted. Respondents to online surveys in mBC may portray non-representative populations lacking diversity and attempts to diversify future research are much needed, and further efforts are ongoing to address this knowledge gap. Citation Format: Sarah L. Sammons, Jane Meisel, Kelly Shanahan, Timothy Pluard, Monica Kozlowski, Dominic Carroll, Elizabeth Attias. Treatment goals and quality of life (QOL) in a survey of patients with ER+/HER2- metastatic breast cancer (mBC) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-09-01.

Report of consensus panel 2 from the 11th international workshop on Waldenström's macroglobulinemia on the management of relapsed or refractory WM patients

The consensus panel 2 (CP2) of the 11th International Workshop on Waldenström's macroglobulinemia (IWWM-11) has reviewed and incorporated current data to update the recommendations for treatment approaches in patients with relapsed or refractory WM (RRWM). The key recommendations from IWWM-11 CP2 include: (1) Chemoimmunotherapy (CIT) and/or a covalent Bruton tyrosine kinase (cBTKi) strategies are important options; their use should reflect the prior upfront strategy and are subject to their availability. (2) In selecting treatment, biological age, co-morbidities and fitness are important; nature of relapse, disease phenotype and WM-related complications, patient preferences and hematopoietic reserve are also critical factors while the composition of the BM disease and mutational status (MYD88, CXCR4, TP53) should also be noted. (3) The trigger for initiating treatment in RRWM should utilize knowledge of patients’ prior disease characteristics to avoid unnecessary delays. (4) Risk factors for cBTKi related toxicities (cardiovascular dysfunction, bleeding risk and concurrent medication) should be addressed when choosing cBTKi. Mutational status (MYD88, CXCR4) may influence the cBTKi efficacy, and the role of TP53 disruptions requires further study) in the event of cBTKi failure dose intensity could be up titrated subject to toxicities. Options after BTKi failure include CIT with a non-cross-reactive regimen to one previously used CIT, addition of anti-CD20 antibody to BTKi, switching to a newer cBTKi or non-covalent BTKi, proteasome inhibitors, BCL-2 inhibitors, and new anti-CD20 combinations are additional options. Clinical trial participation should be encouraged for all patients with RRWM.

The availability of gonadotropin therapy from FDA-approved pharmacies for men with hypogonadism and infertility.

Recent changes to the Biologics Price Competition and Innovation Act of 2009 have created barriers to accessing therapy for men utilizing gonadotropins for hypogonadism and infertility. In this study we sought to investigate ways to decrease disparities in the treatment of male hypogonadism by increasing access to gonadotropin therapy by identifying 503b outsourcing pharmacies which currently provide gonadotropin therapy. A review of 503b compounding pharmacies was performed using the online published registry available from the US Food and Drug Administration (FDA). Each pharmacy was contacted regarding their ability to provide gonadotropin therapy. Pharmacies were also queried regarding the impact of FDA-related legal changes and cost considerations. The study outcomes were the number and location of FDA-approved 503b compounding pharmacies supplying human chorionic gonadotrophin (hCG) and/or follicle-stimulating hormone (FSH) for the treatment of male hypogonadism and infertility. The 81 503b-compounding pharmacies approved by the FDA to produce hCG and FSH therapy were identified using the FDA registry. Seventy-five of the 81 pharmacies responded to the survey (response rate92.6%). Of the contacted pharmacies, 5 provided hCG (6.67%). Of the pharmacies offering compounded hCG, 4 offered FSH. No additional pharmacies offered compounded FSH. Eight pharmacies had previously provided hCG and FSH. Six of the 8 pharmacies that stopped making hCG and FSH cited the 2020 FDA mandate as the reason for halting compounding services. Of the 75 pharmacies that responded, only 1 pharmacy provided the cost for FSH ($287 per 100-IU vial), and 3 pharmacies provided the cost for hCG ($50-$83 per 10 000-IU vial). There are few FDA-approved outsourcing pharmacies currently providing male gonadotropin therapy, and increasing awareness of these pharmacies may decrease barriers to care for patients with male hypogonadism and infertility. The strengths of this article are the clinical utility of the data presented, as this article may serve as a tool for clinicians to increase patient access to therapy. All FDA-approved 503b outsourcing pharmacies were contacted, and 92.6% participated in this project. Limitations of this article were the following: no non-FDA-approved compounding pharmacies such as 503a pharmacies were contacted, participant-reported outcomes were utilized, and only 3 contacted outsourcing pharmacies provided a cost for FSH or hCG, allowing for an unknown degree of cost variability between outsourcing pharmacies. There currently exists limited access to FDA-approved compounded gonadotropin therapies for hypogonadism and male infertility, and these results demonstrate the barriers to hCG and FSH access and the need for additional treatment options for this vulnerable patient population.

Percutaneous ablation of low-risk papillary thyroid cancer.

Minimalistic management options such as active surveillance and thyroid lobectomy are increasingly being accepted as reasonable management options for properly selected patients with low-risk papillary thyroid cancer. Leveraging technologies developed for the treatment of benign thyroid nodules, ultrasound-guided percutaneous thermal ablation is now being evaluated as a potential additional minimalistic management option for small, intrathyroidal, low-risk papillary thyroid cancer. Published retrospective data on more than 5000 low-risk papillary thyroid cancer patients treated with thermal ablation indicate that with appropriate training and proper patient selection, these technologies can be safely and effectively applied to papillary microcarcinomas. When compared to immediate surgery, thermal ablation appears to have lower complication rates with similar short-term rates of recurrence. Proper patient selection is facilitated by the use of a clinical framework which integrates imaging characteristics, patient characteristics, and medical team characteristics to classify a patient as ideal, appropriate, or inappropriate for minimalistic management options (active surveillance, thyroid lobectomy, or thermal ablation). While retrospective in nature and lacking randomized prospective clinical trial data, currently available data do support the proposition that thermal ablation technologies reliably destroy papillary thyroid microcarcinoma lesions and are associated with clinically acceptable oncologic outcomes when done by experienced teams in properly selected patients.

Preventing progression in IgA nephropathy: a managed care focus on emerging therapies.

Immunoglobulin A nephropathy (IgAN) is an autoimmune disease that is the most common cause of glomerulonephritis. In IgAN, the glomeruli are impaired by deposits of IgA-complexes in the kidney, which leads to the progression of chronic kidney disease, often resulting in end-stage renal disease requiring dialysis or kidney transplantation. This progression is associated with impaired health-related quality of life and a significant economic burden. Better overall patient outcomes have been seen in patients who are diagnosed and receive treatment earlier in the disease process. Supportive therapy is the mainstay of treatment, but there have also been recent advances with targeted therapies that may provide additional therapeutic options to meet treatment goals. Managed care professionals are well positioned to design clinical programs and pathways to promote earlier diagnosis, better efficacy and safety monitoring, and timely access to targeted therapies to slow progression, reduce kidney damage, and delay or prevent end-stage renal disease.

Abstract P3-11-06: Chromatin landscape analysis based on ATAC-seq and RNA- seq reveals that GRHL2 is a novel key transcription factor for endocrine therapy resistance

Abstract Current data using gene expression and DNA modification profiles yield limited information for evaluating the potential resistance to therapies. Recent studies show that the chromatin landscape is dynamic and defines cell identity and disease status. Thus, changes in open chromatin sites could provide important information on disease progression and identify potential therapeutic targets. The majority of breast cancers express estrogen receptor (ER) and initially respond to endocrine therapies blocking ER activity. However, endocrine therapy resistance (ETR) occurs de novo or follows an initial response. Recent studies have identified new drivers of ETR, such as mTOR and CDK4/6. Therapy with these inhibitors in combination with endocrine therapy have improved patient survival, but the molecular mechanism of ETR is not fully understood and additional therapeutic options for ETR are needed. To investigate the molecular mechanisms of ETR, we established in vitro Long-Term Estrogen Deprivation (LTED) model using multiple human ER-positive breast cancer cell lines. These cells showed differential time-dependent patterns of ESR1 expression upon LTED with ESR1 upregulation in some cell lines and downregulation in others. LTEDs with ESR1 upregulation were sensitive to fulvestrant, while the others were resistant. We analyzed time-course of chromatin landscape transitions during acquisition of ETR in ESR1 up- and downregulated LTEDs cells by Assay for Transposase Accessible Chromatin (ATAC-seq) combined with RNA-seq. Because transcription factors play a primary key role in gene expression and in cell-fate changes including response to therapies, we performed bioinformatic analysis to uncover differential open chromatin sites, select enhancer signatures and identify digital footprints of transcription factors. Unlike ChIP-seq, which identifies binding sites for a known transcription factor, ATAC-seq permits analysis of all sites potentially accessible to the transcriptional machinery and predict occupancy by ~700 different transcription factors at once. With these algorithms, we found that Grainyhead-like 2 (GRHL2) is associated with development of both ESR1 overexpressed and downregulated types of LTEDs. Furthermore, RNA-seq analysis showed that GRHL2 target genes are upregulated in LTEDs. Furthermore, in the METABRIC database, high GRHL2 expression is significantly associated with poor outcome in ER+ breast cancer patients treated with endocrine therapy. Taken together, these data suggest that GRHL2 may be a novel important transcription factor in endocrine therapy resistant breast cancer regardless of fulvestrant sensitivity. Our studies provide evidence that chromatin landscape analysis, coupled with the transcription factor network algorithm, is capable of identifying novel biomarkers or therapeutic targets, This approach will expand the range of translational research as it is applicable to many cancers and diseases. Citation Format: Saori Fujiwara, Songjoon Baek, Kaustubh Wagh, Diana Stavreva, Lyuba Varticovski, Gordon Hager. Chromatin landscape analysis based on ATAC-seq and RNA- seq reveals that GRHL2 is a novel key transcription factor for endocrine therapy resistance [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-11-06.

CU06-1004 alleviates vascular hyperpermeability in a murine model of hereditary angioedema by protecting the endothelium.

Over-release of the vasoactive peptide bradykinin (BK) due to mutation in the SERPING1 gene is the leading cause of hereditary angioedema (HAE). BK directly activates endothelial cells and increases vascular permeability by disrupting the endothelial barrier, leading to angioedema affecting face, lips, extremities, gastrointestinal tract, and larynx. Although various pharmacological treatment options for HAE became available during the last decade, they are presently limited and pose a major economic burden on patients. To identify additional therapeutic options for HAE, we evaluated the effect of CU06-1004, an endothelial dysfunction blocker, on BK-induced vascular hyperpermeability and the HAE murine model. To investigate the effect of CU06-1004 on BK-induced vascular hyperpermeability in vivo, we pre-administrated WT mice with the drug and then induced vascular leakage through intravenous injection of BK and observed vascular alternation. Then, SERPING1 deficient mice were used for a HAE murine model. For an in vitro model, the HUVEC monolayer was pre-treated with CU06-1004 and then stimulated with BK. Bradykinin disrupted the endothelial barrier and formed interendothelial cell gaps, leading to hyperpermeability in vivo and in vitro. However, CU06-1004 treatment protected the endothelial barrier by suppressing Src and myosin light chain activation via BK and alleviated hyperpermeability. Our study shows that CU06-1004 oral administration significantly reduced vascular hyperpermeability in the HAE murine model by protecting the endothelial barrier function against BK stimulation. Therefore, protecting endothelium against BK with CU06-1004 could serve as a potential prophylactic/therapeutic approach for HAE patients.

Abstract PD18-09: ACE-Breast-03: Efficacy and safety of ARX788 in patients with HER2+ metastatic breast cancer previously treated with T-DM1

Abstract Background: Amplification of the human epidermal growth factor receptor 2 (HER2) gene with consequent HER2 protein overexpression occurs in approximately 20% of breast cancers (BC) and is a major driver of tumor development and progression. The HER2-targeted ADC trastuzumab emtansine (T-DM1) has been approved for the treatment of HER2-positive metastatic BC (mBC) after prior trastuzumab and taxane therapy. However, disease progression occurs in all patients requiring additional therapeutic options. The use of second-generation anti-HER2 ADCs using alternative molecules is being investigated to overcome drug resistance. ARX788 is a next-generation ADC using a technology platform whereby a HER2-specific monoclonal antibody is conjugated with Amberstatin269, a potent cytotoxic tubulin inhibitor. Site-specificity, high homogeneity, and stable covalent conjugation of ARX788 lead to its slow release and prolongation of the peak serum pAF-AS269 concentration, which may contribute to the lower systemic toxicity and increased targeted delivery of payload to tumor cells at a lower effective dose compared to other HER2 ADCs. Here, early evidence of activity of ARX788 in patients previously treated with T-DM1 is shown. Methods: ACE-Breast-03 (NCT04829604) is an ongoing global, phase 2, single-arm study evaluating ARX788 in patients with HER2+ mBC whose disease has progressed following T-DM1, T-DXd, and/or tucatinib-containing regimens. The ARX788 is administered with an initial dose of 1.5 mg/kg Q4W and subsequent doses of 1.3 mg/kg Q4W. Eligibility criteria included central laboratory confirmed HER2+ mBC per ASCO/CAP guidelines, measurable disease, and adequate organ function. Stable treated brain metastases are allowed. Patients with interstitial lung disease (ILD) or pneumonitis in prior 12 months; active ocular infections or any chronic corneal disorder; are excluded. The primary endpoint is overall response rate (ORR). Results: At the data cutoff of 11-Jul-2022, 7 patients were enrolled in ACE-Breast-03 (v1.0) who previously experienced disease progression on T-DM1 and had response-evaluable disease. Pts had a median age of 59 years and had received a median of 5 lines of prior anti-HER2 cancer therapy (range: 2-8). None of the pts in this subset had received T-DXd or tucatinib. 5 pts were previously treated with HER2-targeted TKIs (neratinib and lapatinib), as well as an investigational HER2 ADC and responded to ARX788 (3 PR; 2 SD). Two patients had hormone receptor (HR)-positive disease and 5 had HR-negative mBC. Treatment with ARX788 remains ongoing with the median time of ARX788 therapy of 4.5 months. The confirmed ORR was 57.1% (4/7 pts) and an unconfirmed ORR of 71.4% (5/7 pts) as one pt experienced an unconfirmed response with PR after 2 cycles. The disease control rate (DCR) was 100% (7/7 pts). No drug-related grade ≥3 AEs were reported; 57.1% (4/7 pts) reported ocular AEs including grade 1 events in 3 pts (i.e., dry eye, blurred vision) and a grade 2 event in one pt (lagophthalmos). No pneumonitis or ILD was observed. ARX788 was well-tolerated, and AEs were manageable. Conclusion: In this small cohort of patients previously treated with T-DM1, ARX788 had a manageable AE profile and demonstrated promising clinical activity (confirmed ORR 57%; DCR 100%). Figure 1: ACE-Breast-03 Spider Plot for patients with mBC who were previously treated with T-DM1 Figure 1: ACE-Breast-03 Spider Plot for patients with mBC who were previously treated with T-DM1 ARX788 demonstrated promising clinical activity in patients previously treated with T-DM1. Citation Format: Sara Hurvitz, Kevin Kalinsky, Vinod Ganju, Kashif Ali, Laila Agrawal, William Gradishar, George Sledge, Anu Thummala, Arlene Chan, Sophia Frentzas, Joo Hyuk Sohn, Kyong-Hwa Park, Keon Uk Park, Catherine Shannon, Joshua Drago, Sara Tolaney, Hope Rugo, Michael F. Press, Alex Alika, Dong Xu, Janice Lu, Debu Tripathy. ACE-Breast-03: Efficacy and safety of ARX788 in patients with HER2+ metastatic breast cancer previously treated with T-DM1 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD18-09.

First-in-Human µCAB™ Coronary Revascularization Surgery.

Less invasive coronary artery bypass grafting surgery is underused despite more than 25 years of interest from surgeons and growing patient demands for less pain and rapid full recovery. New approaches may offer surgeons additional options to provide enhanced clinical results through reliable subxiphoid bilateral internal thoracic artery harvesting and the creation of durable anastomoses through very small thoracotomy incisions. This first-in-human case report describes 2 patients who received surgical coronary revascularization using the µCAB™ technology and techniques. The encouraging early results indicate that the µCAB™ approach may offer a new ergonomic, affordable method for coronary revascularization with less surgical trauma.

Response to Commentary "Are Parenchyma-Sparing Resections Really Appropriate for Small (

Response to Commentary "Are Parenchyma-Sparing Resections Really Appropriate for Small (<3 cm) Non-Functional Pancreatic Neuroendocrine Tumors?"

Precision Oncology in Pancreatic Cancer: Experiences and Challenges of the CCCMunichLMU Molecular Tumor Board.

In pancreatic cancer, systemic treatment options in addition to chemotherapy remain scarce, and so far only a small proportion of patients benefit from targeted therapies. The patients with pancreatic cancer discussed in the CCCMunichLMU Molecular Tumor Board were reviewed to gain a better real-world understanding of the challenges and chances of precision oncology in this hard-to-treat cancer. Patients with pancreatic cancer who received comprehensive genomic profiling and were discussed in the interdisciplinary Molecular Tumor Board between May 2017 and July 2022 were included. These patients' medical charts, comprehensive genomic profiling results, and Molecular Tumor Board recommendations were analyzed in this retrospective cohort study. Molecular profiles of 165 patients with pancreatic cancer were discussed in the Molecular Tumor Board. In the 149 cases where comprehensive genomic profiling was successful, KRAS mutations were detected in 87.9%, TP53 in 53.0%, and CDKN2A in 14.1%. 33.3% of KRAS wild-type patients harbored targetable mutations, while these were only found in 19.1% of patients with the KRAS mutation; however, this difference was not statistically significant. 63.8% of patients with successful testing received a targeted treatment recommendation by the Molecular Tumor Board; however, only 3.2% of these were put into practice. Compared to a historic cohort of patients with pancreatic cancer with synchronous metastatic disease diagnosed between 2010 and 2017, the patients from the pancreatic cancer cohort with synchronous metastatic disease had a longer survival. This single-center experience emphasizes the challenges of targeted treatment in pancreatic cancer. Very few patients ultimately received the recommended therapies, highlighting the need for more and better targeted treatment options in pancreatic cancer, early comprehensive genomic profiling to allow sufficient time to put Molecular Tumor Board recommendations into practice, and close cooperation with clinical trial units to give patients access to otherwise not available targeted treatments.

Rate-distortion optimized quantization for geometry-based point cloud compression

Limited by the network bandwidth, three-dimensional (3D) point cloud needs to be efficiently compressed before transmission. As one of the three attribute coding methods adopted in the geometry-based point cloud compression (G-PCC) standard developed by MPEG, predicting transform (PT) has received increasing attention. To further improve the coding efficiency of PT, we propose a rate-distortion optimized quantization (RDOQ) in which an additional option for quantization results is added by setting the quantized residuals to zero forcedly. Rate-distortion optimization is then used to determine whether the final quantized residual should be zero or nonzero. Experimental results show that average BD rates of −0.5 % , −3.0 % , and −3.0 % can be achieved for Luma, Chroma Cb, and Chroma Cr components, respectively, with negligible increment of time complexity.

Ретроспективна оцінка дефіциту доступної кістки у пацієнтів в Україні за даними застосування дентальних імплантатів різних розмірів

The purpose of the study was to determine a number of clinical cases of dental implantation with insuficient height of the alveolar ridge based on data of consumption of the dental implants of various designs in dental healthcare institutions during 10 years. Materials and methods. The research was performed on the provided information on the sales of dental implants produced by the DENTIUM corporation, “SuperLine” and “SuperLine NEW” (Korea) from the official supplier in Ukraine (“Stamil” group of companies) for the period 2013–2022. Results and discussion. Quality and sufficient volume of bone tissue around the dental implant is an important condition to achieve an optimal level of osseointegration. In cases of a shortage of available bone an additional option in the choice of treatment tactics is the installation of short dental implants. Compared with dental implants of standard and extended length the short implants showed a higher frequency of rejection and early disintegration. The length of the dental implant body is a critical factor in the long-term successful functioning of implants which is ambiguously evaluated and described in the professional literature. The analysis in the subgroups of the use of short implants showed that in the vast majority of cases, dental implants with a length of 8.00 mm were used – in the volume of ten-year implementation, their specific weight was 24.92%. Accordingly, it can be assumed that the volume of application of such structures is identical to the specific gravity of cases of minimal deficit in the height of the bone tissue of the alveolar crest of the jaws – 2.00 mm. The use of descriptive statistics methods made it possible to calculate the average percentage of such clinical cases – 23.92 ± 5.71 mm (M=25.37 mm). In calculations per decade the specific weight of cases of the alveolar ridge height deficiency of the jaws (lack of available bone tissue) was 30.03%. The average value was 28.80 ± 6.74% (M=30.95%), the minimum – 19.11% and the maximum – 38.08%. There were only 1.42% cases of “compensation” of the short implant length by increasing its diameter (upto 6.00 and 7.00 mm) in the overall structure of the performed operations. The usage of average annual number of short dental implants of increased diameter (from 6.00 mm) was 0.67 ± 0.28% (M=0.56%). The analysis of dynamics of the usage of short dental implants (7.00 mm and 8.00 mm) over ten years period revealed unevenness. For implants with a length of 8.00 mm frequency varied between 15.00–30.00%. The usage of shorter structures (length 7.00 mm) did not have such critical changes – minor deviations near 5.00%. Conclusion. The obtained results allowed to determine indirectly the prevalence of the alveolar ridge height deficiency in patients of “implantation cohort” in Ukraine during the last 10 years

Progestin intrauterine devices versus copper intrauterine devices for emergency contraception.

The copper intrauterine device (Cu-IUD) is a highly effective method of contraception that can also be used for emergency contraception (EC). It is the most effective form of EC, and is more effective than other existing oral regimens also used for EC. The Cu-IUD provides the unique benefit of providing ongoing contraception after it is inserted for EC; however, uptake of this intervention has been limited. Progestin IUDs are a popular method of long-acting, reversible contraception. If these devices were also found to be effective for EC, they would provide a critical additional option for women. These IUDs could not only provide EC and ongoing contraception, but additional non-contraceptive benefits, including a reduction in menstrual bleeding, cancer prevention, and pain management. To examine the safety and effectiveness of progestin-containing IUDs for emergency contraception, compared with copper-containing IUDs, or compared with dedicated oral hormonal methods. We considered all randomized controlled trials and non-randomized studies of interventions that compared outcomes for individuals seeking a levonorgestrel IUD (LNG-IUD) for EC to a Cu-IUD or dedicated oral EC method. We considered full-text studies, conference abstracts, and unpublished data. We considered studies irrespective of their publication status and language of publication. We included studies comparing progestin IUDs with copper-containing IUDs, or oral EC methods for emergency contraception. We systematically searched nine medical databases, two trials registries, and one gray literature site. We downloaded all titles and abstracts retrieved by electronic searching to a reference management database, and removed duplicates. Three review authors independently screened titles, abstracts, and full-text reports to determine studies eligible for inclusion. We followed standard Cochrane methodology to assess risk of bias, and analyze and interpret the data. We used GRADE methodology to assess the certainty of the evidence. We included only one relevant study (711 women); a randomized, controlled, non-inferiority trial comparing LNG-IUDs to Cu-IUDs for EC, with a one-month follow-up. With one study, the evidence was very uncertain for the difference in pregnancy rates, failed insertion rates, expulsion rates, removal rates and the difference in the acceptability of the IUDs. There was also uncertain evidence suggesting the Cu-IUD may slightly increase rates of cramping and the LNG-IUD may slightly increase bleeding and spotting days. AUTHORS' CONCLUSIONS: This review is limited in its ability to provide definitive evidence regarding the LNG-IUD's equivalence, superiority, or inferiority to the Cu-IUD for EC. Only one study was identified in the review, which had possible risks of bias related to randomization and rare outcomes. Additional studies are needed to provide definitive evidence related to the effectiveness of the LNG-IUD for EC.