Treatment Options Research Articles

Research progress on the mechanism of exercise against depression

The substantial global health burden of depression encourages the development of innovative and broadly effective interventions. This paper aimed to examine recent advancements by which exercise works as an antidepressant and recommends optimal types and quantity of exercise as supplemental therapies in treating depression. Sedentary behavior and low physical activity significantly influence the onset of depression. Being an effective treatment option, exercise can significantly reduce depression risk. Exercise exerts antidepressant effects as it modulates neurotransmitters, neuroplasticity, the immune system, and hormone levels. Effective exercise forms include yoga, strength training, and walking/jogging. Tailored exercise regimens that consider individual preferences and tolerability can improve outcomes. Regular exercise enhances general well-being and reduces depressive symptoms. Additional research is needed to understand the complex basis of exercise's effects on depression. Exercise is a cost-effective and accessible intervention for depression management that needs additional exploration. Thus, customized exercise programs, as per each patient’s needs, are essential for their successful implementation clinically.

Real-world safety of spesolimab in generalized pustular psoriasis: Evidence from an expanded access program in Argentina

Introduction: Generalized pustular psoriasis (GPP) is a heterogeneous, systemic, neutrophilic, inflammatory disease associated with chronic symptoms and periods of flaring. Spesolimab is an anti-interleukin-36 receptor monoclonal antibody approved for the treatment of flares in adult patients with GPP in Argentina (17 Aug 2023).1 Here, we present safety data from a real-world expanded access program (EAP: 22 Feb 2023–10 Jan 2024) in Argentina which provided early access to spesolimab intravenous (IV) for GPP patients presenting with a flare with no other treatment options. Methods: Patients (18–75 years old) diagnosed with GPP received a 900mg dose of spesolimab IV for flare treatment, with an optional second dose after 1 week for persistent flare symptoms. Adverse events (AEs), serious AEs (SAEs), and AEs of special interest (AESIs) were recorded for up to 16 weeks after the last spesolimab infusion.Results: Six female patients were treated with spesolimab IV (1 dose, n=2; 2 doses, n=4).Mean (standard deviation [SD]) age: 49.3 (11.5) years (range: 30–60 years), mean (SD) body mass index: 28.1 (5.8) kg/m2, and mean (SD) follow-up: 3.85 (0.11) months. At baseline, GPP had been diagnosed within ≤1 year (n=2), >1–≤5 years (n=1), and >10 years (n=3). Reported flare triggers were stress (n=2), treatment withdrawal (n=1), heat (n=1), lack of current treatment efficacy (n=1), and unknown (n=1). At baseline, 4 patients had ≥1 comorbidity, including hypertension (n=2), tachycardia, hypothyroidism, chronic gastritis, arthritis, and epilepsy (each n=1). Five patients reported use of ≥1 concomitant medication (including immunosuppressants and corticosteroids) during the EAP; 1 patient had discontinued ustekinumab (biologic). Three patients had signs of plaque psoriasis within the past year and had received treatment for plaque psoriasis; 1 patient had ongoing plaque psoriasis. In total, 4 patients had any AEs (all 4 patients had mild AEs [influenza, catarrh, pruritis, rash, pain] and 1 of these patients also had a moderate AE [headache]). Two drug-related AEs (pruritus and rash) were reported in 1 patient. The hypersensitivity event (rash) was non-serious. There were no reports of SAEs, AESIs, or AEs that led to discontinuation/death. Conclusion: Spesolimab showed a favorable safety profile in patients with GPP, including patients with comorbidities and those taking concomitant medication. Findings were comparable with a Phase 2a randomized controlled trial in patients with GPP flares (EFFISAYIL 1).

The Initial Exploration of Polidocanol Sclerotherapy for the Treatment of Axillary Osmidrosis: A Retrospective Study

BACKGROUND Axillary osmidrosis (AO) is a strong, unpleasant odor that originates from the apocrine axillary glands. Treatments of AO include surgical treatment and nonsurgical treatment. The surgical procedure yields effective results with a low recurrence rate but requires a longer recovery time and has more postoperative complications. Nonsurgical treatments are minimally invasive and safe, but short-term recurrence may occur in some cases. OBJECTIVE Polidocanol sclerotherapy was first described for management of AO. This retrospective study explored the clinical efficacy in relieving symptom of AO assessed by AO severity using the axillary osmidrosis grading system and safety of polidocanol sclerotherapy in treating AO. PATIENTS AND METHODS This retrospective study included 25 patients with AO single-site study, with 12 patients receiving polidocanol (1%) sclerotherapy (the polidocanol group) and 13 receiving botulinum toxin A (BTX-A) injection (the BTX-A group). The short-term efficacy (7 days after injection), the long-term efficacy (6 months after injection), the recurrence rate, and complications were compared between the 2 groups. A p-value of <0.05 was considered statistically significant. RESULTS The short-term efficacies of polidocanol sclerotherapy and BTX-A injection were 100% and 69.2%, which was not clinically significant (p > .05), whereas their long-term efficacies were 100% and 46.2%, respectively (p < .05). The recurrence rates in the polidocanol and BTX-A groups were 25.0% and 84.6%, respectively (p < .05). The complications did not differ significantly between the 2 groups (p > .05). Although the short-term efficacy and complications were comparable between the 2 groups, the long-term efficacy of polidocanol sclerotherapy was superior to BTX-A injection. The polidocanol group has a lower recurrence rate than the BTX-A group. CONCLUSION Polidocanol sclerotherapy may provide an effective and safe treatment with longer efficacy compared to toxin, which is an effective and safe option for AO treatment.

High level non-carbapenemase carbapenem resistance by overlaying mutations of mexR , oprD, and ftsI in Pseudomonas aeruginosa

ABSTRACT Carbapenem-resistant Pseudomonas aeruginosa (CRPA) is a global threat, but the mechanism of non-carbapenemase carbapenem resistance is still unclear. In the current study, we investigated the contributions of point mutations in mexR , oprD , and ftsI to carbapenem resistance in P. aeruginosa during in vivo evolution studies with consecutive clinical isolates. Real-time qPCR and Electrophoretic Mobility Shift Assay demonstrated that MexR (Gln55Pro) mutation increased MexAB efflux pump genes expression by altering MexR’s binding capacity, leading to a four- to eight-fold increase in meropenem MIC in the Pae d1 Green ∆ mexR and PAO1∆ mexR mutants. The OprD (Trp415*) truncation affected porin structure, and the constructed mutant Pae d1 Green oprD Trp415* increased meropenem MIC by 16-fold (from 0.25 to 4 µg/mL). The contribution of ftsI mutation to meropenem resistance was confirmed by clinical linkage analysis and was estimated to cause a two-fold increase in meropenem MIC by comparing the resistant clinical isolate with the Pae d1 Green oprD Trp415*∆ mexR double mutant. The study found that the oprD Trp415* allele alone accounts for the imipenem MIC in clinical isolates, while the ∆ mexR and ftsI Arg504Cys alleles do not contribute to imipenem resistance. In conclusion, we identified and explored the contributions of mexR , oprD, and ftsI mutations to high level non-carbapenemase carbapenem resistance in P. aeruginosa . These findings highlight the interplay of different mutations in causing non-carbapenemase carbapenem-resistance in P. aeruginosa . IMPORTANCE The emergence of carbapenem-resistant Pseudomonas aeruginosa (CRPA) poses a significant global health threat, complicating treatment options for infections caused by this pathogen. Understanding the mechanisms behind non-carbapenemase carbapenem resistance is critical for developing effective therapeutic strategies. This study provides crucial insights into how specific point mutations in key genes- mexR , oprD , and ftsI -contribute to carbapenem resistance, particularly the MexR (Gln55Pro) mutation’s effect on efflux pump expression and the OprD (Trp415*) truncation’s impact on porin structure. The findings elucidate the complex interplay of these mutations, highlighting their roles in conferring high-level resistance, and underscore the imperative for continued research to inform therapeutic strategies against CRPA infections.

Targeted 308-nm Excimer Laser A Safe and Effective Solution for Inflammatory Skin Disorders

Background: The 308-nanometer excimer laser is a targeted ultraviolet B (UVB) light therapy that delivers high-intensity UVB rays directly to affected skin. It has shown considerable efficacy in managing various inflammatory skin conditions, including Psoriasis, Vitiligo, Atopic dermatitis (Eczema), Leukoderma, Alopecia Areata, Chronic recalcitrant dermatitis, Lichen planus, Cutaneous T-cell Lymphoma (e.g. Mycosis fungoides/ Sezary Syndrome), Parapsoriasis, Pityriasis lichenoides chronica, Pruritus, Urticaria pigmentosa, Superficial mycoses (e.g., dermatophytosis [ringworm]. The patient demographic of some of these conditions (e.g. Vitiligo) tends to skew towards patients with darker skin tones. Results: The excimer laser is particularly effective for treating resistant areas, such as the scalp, palmoplantar psoriasis, and hand and foot dermatitis, which often do not respond well to conventional therapies. It has also demonstrated notable success in promoting repigmentation in facial vitiligo, especially in patients with Fitzpatrick skin types IV–VI. Treatment results are typically observed quickly after 5-10 sessions, with sustained improvement and psoriasis clearance evident even at 1-year follow-up. Over the years, access to the Excimer laser procedures has expanded with the availability of these procedures in many private clinics as well as academic facilities. That has increased the availability of the treatment modality and patient choice of therapy. Conclusions: The excimer laser provides a safe, non-invasive treatment option with a strong record of efficacy for multiple inflammatory skin conditions. It is a viable alternative to systemic therapies and can be used either alone or in conjunction with other treatments for optimal patient outcomes.

Evaluating the safety and efficacy of aminolevulinic acid 20% topical solution activated by blue light in the treatment of facial cutaneous squamous cell carcinoma in situ

Background: Cutaneous squamous cell carcinoma in situ (isSCC) is a common skin cancer occurring from sun exposure and often appears on the face. Treatment is primarily surgical but less invasive treatments are desirable. Currently, aminolevulinic acid for photodynamic therapy (ALA-PDT) is approved in the US and Canada for the treatment of single and multiple non-hyperkeratotic actinic keratoses of the face and scalp. This study evaluated the safety, tolerability, and efficacy of ALA-PDT for treatment of facial isSCC.Methods: Thirty-two patients with biopsy-confirmed isSCC on the face were recruited. Lesions 0.4–1.3 cm in diameter were included. Per the actinic keratosis treatment protocol, the lesion was debrided with a 4 x 4 gauze and ALA 20% topical solution was applied to the lesion and adjacent skin and incubated for 18–24 hours, followed by blue light therapy 16 minutes 40 seconds at 10 J/cm2. Patients underwent two treatments with ALA-PDT spaced 28 +/- 3 days apart. The area of the original lesion was excised eight weeks following the second treatment for histopathological assessment. The primary efficacy endpoint was the complete absence histologically of the isSCC at end of treatment. The secondary efficacy endpoint was the achievement of clinical clearance of the skin lesion. Safety assessment was done through adverse events and local skin reactions (LSRs; erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation, and erosion/ulceration) and site pain within 15 minutes of each treatment session.Results: Of the 32 patients enrolled, two did not complete the study. No residual SCCis was detected in 30/30 (100%) patients. Clinical clearance was achieved in 30/30 (100%) of the patients by the end of treatment. None of the patients experienced related adverse events and only 2/30 (5%) experienced an AE of hypertension and was considered to be unrelated. The most common LSRs were erythema and scaling and were primarily mild, seen to occur immediately after both treatments and diminished over time. The average median ± SD immediate post-treatment pain score was 2.56 ± 2.15 on the VAS scale.Conclusion: The ALA-PDT protocol outlined in this study appears to be a very effective, safe and well-tolerated treatment option for isSCC on the face.

Treatments Used Among Patients with Psoriasis: A First Look at a New Patient-Centered Psoriasis Registry

Introduction: Psoriasis management in the US has changed substantially, with increasing treatment options including new topical, oral, and biologic medications. The objective of this study was to examine the demographics, disease characteristics, and treatment usage in the first patients enrolled in the new patient-centered psoriasis registry, the FORWARD Psoriasis Registry. Methods: Adult patients with psoriasis were recruited from dermatology offices as part of a national practice group, through a patient support program for deucravacitinib, and online from the FORWARD registry website between August and December 2023. Patients were not required to be on therapy for psoriasis. We descriptively report demographics, disease characteristics, and current treatments at enrollment. Results: A total of 702 patients met inclusion criteria and completed the full enrollment questionnaire. Mean age was 53 years and 66% were female; mean BMI was 30 (SD 7); 88% self-reported as White and 6% as Hispanic. A diagnosis of psoriatic arthritis was reported by 28%. Most (75%) had private insurance. Median psoriasis duration was 10 (IQR 3–23) years. 85% had plaque psoriasis, 19% guttate, 14% inverse, 6% generalized pustular, and 3% erythrodermic. Body surface area as assessed by the PREPI questionnaire was minimal (<1% BSA) in 21%, mild (1%–2%) in 39%, moderate (3%–10%) in 34%, and severe (>10%) in 6%. The most commonly used therapies included IL-23 inhibitors (11%), IL-17 inhibitors (8%), apremilast (7%), and TNF inhibitors (5%). Additionally, 14% of the cohort were using deucravacitinib; 62% reported using topicals, and 48% reported use of any systemic agent.Conclusion: The FORWARD psoriasis registry represents a new patient-centered approach and proof of concept for studies seeking to understand the natural history of the disease, treatment outcomes, and treatment needs relevant for individuals with psoriasis, and long-term outcomes related to comorbidities.

Location of Vascular Structures at Risk in Relation to Sacroiliac Joint Fusion

Study Design: Retrospective Cohort Objective: This study seeks to establish the normal distribution of the vasculature surrounding the SI joint while also demonstrating associations between distribution and laterality, sex, and ethnicity. Summary of Background Data: Sacroiliac (SI) joint fusion surgery has emerged as a viable treatment option for patients suffering from low back pain due to chronic SI joint dysfunction. Due to potential complications from iatrogenic injury to vasculature, it becomes critical to understand normal anatomy and locations with a high vasculature concentration surrounding the SI joint. Methods: The authors retrieved medical and radiographic records of patients who underwent computed tomography angiography (CTA) of the pelvis. Anterior and posterior compartments of the SI joint were established on the transverse view by creating an even coronal division of the SI joint. The superior, middle, and inferior compartments were established on the coronal view as three equal transverse compartments. The compartments in which vasculature was visualized were recorded. Results: Distribution of vasculature around the right and left hemipelvis concentrated in the inferior compartments and decreased in concentration while moving superiorly. Anterior compartments contain a higher vascularity than posterior compartments. Vasculature was present in less than 3% of the posterior middle, and posterior superior compartments while present in more than 83% of the inferior compartments. There were no significant differences with respect to vascular distribution when comparing the laterality of the right versus left hemipelvis. There were statistically significant relationships between vascular distribution and sex (P<0.05), as well as across self-reported ethnicity (P<0.05). Conclusion: SI screw placement in the posterior superior has the lowest risk of iatrogenic vascular injury. Careful consideration should be taken during SI joint fusion surgery in the inferior compartments due to its high vasculature density.

Alternative lengthening of telomere-based immortalization renders H3G34R -mutant diffuse hemispheric glioma hypersensitive to PARP inhibitor combination regimens

Abstract Background Diffuse hemispheric glioma, H3G34R/V-mutant (DHG-H3G34) is characterized by poor prognosis and lack of effective treatment options. DHG-H3G34R further harbor deactivation of Alpha-Thalassemia/Mental Retardation Syndrome X-linked protein (ATRX; DHG-H3G34R_ATRX) suggesting a unique interaction of these two oncogenic alterations. In this study, we dissect their cell biological interplay, investigate the impact on telomere stabilization and, consequently, validate a targeted therapy approach. Methods We characterized patient-derived primary pediatric high-grade glioma (pHGG) models for telomere-maintenance mechanisms, DNA damage stress (including protein expression, pH2AX/Rad51 foci, cell-cycle arrest) and their sensitivity towards poly-ADP polymerase inhibitor (PARPi) combinations. Human induced pluripotent stem cells (iPSCs) were used for modelling the disease. The anticancer activity of PARPi combinations in vivo was studied in Chorioallantoic Membrane (CAM) and orthotopic in vivo experiments. Finally, we treated a DHG-H3G34R_ATRX patient with a PARPi combination therapy. Results We elaborate that alternative lengthening of telomeres (ALT) is a key characteristic of DHG-H3G34R_ATRX. A dominant cooperative effect between H3G34R and ATRX loss in ALT activation also became apparent in iPSCs, which endogenously exert telomerase activity. In both, patient-derived DHG-H3G34R_ATRX models and H3G34R+/ATRX- iPSCs, the ALT phenotype was associated with increased basal DNA damage stress, mediating synergistic susceptibility towards PARPi (talazoparib, niraparib) combinations with topoisomerase-I inhibitors (topotecan, irinotecan). In a first-of-its-kind case, treatment of a DHG-H3G34R_ATRX patient with the brain-penetrant PARP inhibitor niraparib and topotecan resulted in a significant tumor reduction. Conclusion Our preclinical and clinical data strongly support the further development of PARPis together with DNA damage stress-inducing treatment regimens for DHG-H3G34R_ATRX.

NICE proposes adding cytisine as treatment option for smoking cessation

NICE proposes adding cytisine as treatment option for smoking cessation

A Comprehensive Review of Advanced Treatment Technologies for the Enhanced Reuse of Produced Water

Produced water (PW) is considered to be the largest source of industrial wastewater associated with oil and gas extraction operations for industrial production. It is a mixture of organic and inorganic compounds that has high complexity in terms of various characteristics. Globally, the volume of PW is increasing along with the expansion of gas and oil fields, leading to major impacts on the environment. Existing treatment technologies involve partially treating the PW through removing the suspended solids, heavy metals, without removing organic components and re-injecting the water underground using water disposal injection wells. The treatment process consists of a primary treatment unit to remove the particles, followed a secondary biological or chemical processing treatment, while the final treatment stage involves the use of a tertiary treatment unit to improve the water quality and remove the remainder of the undesired components. Moreover, while PW is considered one of the available options to be utilized as a water source, no alternate advanced treatment options on a commercial scale are available at present due to the limitations of existing PW treatment technologies, associated with their maintainability, sustainability, cost, and level of quality improvement. As such, research focused on finding an optimal treatment approach to improve the overall process continues to be conducted, with the aim of reusing the water instead of injecting it underground. This literature review discusses the latest advanced technologies for PW treatment aimed at reusing the full stream capacity of PW and eliminating the need for wastewater disposal via injection. It is concluded that researchers should focus on hybrid treatment technologies in order to remove the pollutants from PW, effectively allowing for its reuse.

Efficacy and safety of fezolinetant for moderate-severe vasomotor symptoms associated with menopause in individuals unsuitable for hormone therapy: phase 3b randomised controlled trial

Abstract Objectives To assess the efficacy and safety of the non-hormonal, neurokinin 3 receptor antagonist, fezolinetant, to treat moderate-severe vasomotor symptoms associated with menopause in individuals unsuitable for hormone therapy. Design Phase 3b randomised controlled trial. Setting 16 countries. Participants 453 individuals aged 40-65 years with moderate-severe vasomotor symptoms associated with menopause who were considered unsuitable candidates for hormone therapy (contraindicated, caution (based on medical history), stoppers (previous discontinuation of hormone therapy), or averse (informed choice not to use hormone therapy)) were randomised to receive fezolinetant (n=227) or placebo (n=226). Intervention Fezolinetant 45 mg or placebo once daily for 24 weeks. Main outcome measures The primary endpoint was mean change in daily frequency of moderate-severe vasomotor symptoms from baseline to week 24. Secondary endpoints were mean change in symptom severity, sleep disturbance using the Patient-Reported Outcome Measurement Information System Sleep Disturbance Short Form (PROMIS SD-SF) 8b total score, and safety. Results 370 (81.7%) participants completed the study (fezolinetant=195, placebo group=175). The safety and full analysis sets comprised 452 participants who received at least one dose of study drug. Mean age was 54.5 (standard deviation 4.7) years and most of the participants (435 (96.7%) were white and categorised as either hormone therapy averse (168 (37.2%)) or caution (165 (36.5%)). At week 24, fezolinetant significantly reduced the frequency (least squares mean difference –1.93, 95% confidence interval (CI) –2.64 to –1.22; P<0.001) and severity of vasomotor symptoms (–0.39, –0.57 to –0.21; P<0.001). At week 24, the fezolinetant group had a greater reduction in sleep disturbance (PROMIS SD-SF 8b total score) compared with placebo (–2.5, –3.9 to –1.1; P<0.001). Improvements over placebo were observed as early as week 1. Both groups showed similar incidences of treatment emergent adverse events (TEAEs, 147 (65.0%) in the fezolinetant group, 138 (61.1%) in the placebo group) and serious TEAEs (10 (4.4%) and 8 (3.5%), respectively). The most common TEAEs in the fezolinetant group were covid-19 (30 (13.3%)), headache (20 (8.8%)), and fatigue (13 (5.8%)). Conclusions Fezolinetant was efficacious and well tolerated over a six month period for treating moderate-severe vasomotor symptoms in individuals considered unsuitable for hormone therapy. These results highlight the utility of fezolinetant as an effective treatment option for those who have contraindications to or choose not to use hormone therapy. Trial registration ClinicalTrials.gov NCT05033886 ; EudraCT 2021-001685-38.

Endoscopic ultrasound‐guided gallbladder drainage for acute cholecystitis

With technological advances in endoscopic ultrasonography, endoscopic ultrasound‐guided gallbladder drainage (EUS‐GBD) was introduced as a treatment option for acute cholecystitis. Recently, new studies have emerged, suggesting that EUS‐GBD has a lower adverse event rate and reintervention rate, when compared to percutaneous drainage and endoscopic transpapillary gallbladder drainage. There is growing interest in the different technical aspects of EUS‐GBD, such as the puncture approach, choice of stents, and long‐term management. There are also cohorts on performing EUS‐GBD in potential surgical candidates. This review article gathers the latest evidence on EUS‐GBD, including its indications, procedural techniques, choice of equipment, outcomes, postprocedural care, and the controversial extended indications.

Abstract C043: Alprazolam abrogates the secretion of proinflammatory cytokines in PDAC CAFs

Abstract The present study sets out to determine how commonly prescribed triazolobenzodiazepines (triazoloBZDs) modulate the tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC), and how this can be leveraged therapeutically to improve patient outcomes. PDAC is one of the most lethal cancer subtypes with a 5-year survival rate of ∼13%. The poor prognosis of this disease is, in part, attributable to the dense, fibrotic tumor microenvironment (TME), and lack of durable responses to standard-of-care treatment options. A recent study from our lab reported that over 40% of PDAC patients at Roswell Park are prescribed benzodiazepines (BZDs) to manage anxiety, nausea, and other disease-related side effects. Importantly, survival outcomes in these patients varied in a compound-specific manner, as the usage of the n-unsubstituted BZD lorazepam was associated with poorer outcomes, while usage of the n-substituted triazoloBZD alprazolam was associated with improved progression-free survival. In vitro and in vivo data from the aforementioned study suggested that these findings may be a result of BZD-specific regulation of interleukin-6 (IL6), a proinflammatory cytokine with a known role in PDAC pathogenesis. More specifically, alprazolam-treated cancer-associated fibroblasts (CAFs) exhibited a potent reduction in IL6 transcription and secretion, while lorazepam treatment increased IL6 production. Based on these data, we hypothesized that triazoloBZDs may uniquely reduce intratumoral inflammation to alleviate immunosuppression in PDAC. We now find that triazoloBZDs such as alprazolam suppress the secretion of several proinflammatory cytokines (IL6, CCL2, CXCL12, IL8) by CAFs, the stromal components of the PDAC TME responsible for fibrosis and exclusion of immune infiltrates. Furthermore, we have observed that this phenotype is likely a result of triazoloBZD-mediated inhibition of the platelet- activating factor (PTAFR) signaling cascade. Investigations are currently underway to determine the impact of triazoloBZDs on regulating the immune landscape of the PDAC TME in vivo. Altogether, these findings provide a basis to inform clinical selection of BZDs for symptom management and present a novel therapeutic opportunity to repurpose FDA-approved compounds for treatment of PDAC. Citation Format: Hunter D. Reavis, Arwen A. Tisdale, Kathryn E. Maraszek, Michael E. Feigin. Alprazolam abrogates the secretion of proinflammatory cytokines in PDAC CAFs [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C043.

Abstract A006: Investigating the effects of fibroblasts derived from the primary versus the metastatic organ on 3D biomimetic models of pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the 3rd leading cause of cancer death in the United States with a 5-year survival rate of only 13%. Early diagnosis is very difficult and thus 53% of patients are diagnosed after metastasis has already occurred, with the liver being the most frequently affected site. Both primary tumors and metastases have dense desmoplastic stroma due to a high percentage of fibroblasts within the tumor microenvironment (TME). Previously, we developed a tunable 3D biomimetic model of the liver metastatic niche (LMN) to investigate how local fibroblasts affect tumor growth and chemoresistance in PDAC liver metastasis. This study aims to investigate the contributions of fibroblasts at the primary versus metastatic sites. We used matched primary PDAC and liver metastatic (LM) organoids derived from the Kras+/LSL-G12D; Trp53+/LSL-R172H; Pdx1-Cre (“KPC”) genetically engineered mouse model. This allows us to compare the effects of primary PDAC cancer associated fibroblasts (CAFs) and liver metastasis associated fibroblasts (MAFs) on tumor cell growth and chemoresistance. Rheometry analyses were conducted to study the impact of local fibroblasts on the extracellular matrix (ECM) stiffness. Our results showed that both storage and loss moduli were enhanced only when PDAC CAFs were present in the co-cultured gels compared to gels with MAFs. Additionally, the 3D biomimetic model showed fibroblasts increased tumor growth and chemoresistance to gemcitabine, only when they were derived from the same site as the tumor cells. This highlighted the importance of studying the organ-specific microenvironment to develop better treatment options for patients with metastatic PDAC. To delve deeper into the molecular basis of these observations, we conducted RNA-sequencing to identify and compare the gene expression profiles in primary and metastatic tumor organoids exposed to conditioned media from CAFs and MAFs using a transwell membrane co-culture model. Our results showed significant differences in gene expression based on the type of fibroblasts co-cultured with the organoids. Moreover, we investigated the role of MAF-derived exosomes on LM growth and chemoresistance using exosome depletion and direct exosome addition to LM organoids. Lastly, we performed exosomes size and distribution characterizations using dynamic light scattering (DLS) analysis. Taken together, these findings highlight the critical role of the organ-specific microenvironment in tumor progression and the necessity of targeted therapies to improve patient outcomes in metastatic PDAC. Our results underscore the importance of developing a tunable 3D biomimetic model of the LMN, as it enables the testing of novel therapeutic strategies designed to disrupt interactions between MAFs and tumor cells, and potentially advancing treatments for metastatic PDAC. Citation Format: Mahsa Pahlavanneshan, Weikun Xiao, Eileen Fung, Vaidhyanathan Mahaganapathy, Chae Young Eun, Chang-Il Hwang, Shannon Mumenthaler, Reginald Hill. Investigating the effects of fibroblasts derived from the primary versus the metastatic organ on 3D biomimetic models of pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr A006.

Metabolic and bariatric surgery for adolescents with severe obesity: Benefits, risks, and specific considerations

International and national guidelines recommend metabolic and bariatric surgery (MBS) as a treatment option for adolescents with severe obesity, but few countries offer MBS to adolescents in routine clinical care. This narrative review summarizes existing adolescent MBS guidelines and the available underpinning evidence. Two randomized trials and additional prospective studies have demonstrated efficacy and safety in adolescent MBS, and the health benefits appear to be similar or superior to outcomes in adults. However, there are specific challenges regarding the intervention during adolescence related to decision-making capacity and a peak in risk-taking behavior. Adolescents with severe obesity have—as a group—a mental health vulnerability, and specific nutritional concerns need to be addressed in relation to MBS. This review also describes how study findings can be translated into clinical care. We use Sweden as an example, where the National Board of Health and Welfare recommends MBS for selected adolescents with severe obesity aged 15 years or older. We present practical advice for implementing and integrating MBS in adolescents in the framework of multidisciplinary pediatric and adolescent care for obesity.

Abstract C020: Discovery & characterization of small molecules to enhance Natural Killer cell cytotoxicity against solid tumors

Abstract While adoptive cellular therapies (ACT) such as CAR-T and NK therapy have shown clinical efficacy against hematologic malignancies, their use against solid tumors (such as ovarian or pancreatic cancer) has had limited success to date. In particular, CAR-T therapy for solid cancers has led to severe toxicities, including on-target, off-tumor killing of healthy cells and graft vs. host disease (GVHD) with allogeneic transplant. NK cell therapies, in contrast, have fewer associated toxicities due to specific and innate recognition/killing of cancer cells. This greater safety profile makes NK therapies an attractive treatment option for solid cancers. NK therapies are currently limited by insufficient in vivo tumor clearance, caused largely by their lower cytotoxicity and in vivo expansion compared to CAR-T cells. To address this, we have screened 300,000 small molecule compounds for their ability to enhance NK cytotoxicity against ovarian cancer (OVCAR) cells. Our primary screen identified 11 lead compounds which increase NK killing activity against OVCAR cells >= 10% over baseline (vehicle-treated control). Secondary in vitro assays have confirmed that at least 3 out of 11 lead compounds enhance NK cytotoxicity by at least 10% over baseline. As such, we hypothesize that our lead compounds will increase in vivo NK cytotoxicity and tumor clearance, through mechanisms which might include I) upregulation of NK activating receptors, II) downregulation of NK inhibitory receptors, and/or III) modulation of NK metabolism in the immunosuppressive tumor microenvironment. Immediate future studies include in vivo testing of our lead compounds’ ability to enhance NK cytotoxicity, using immunodeficient mouse models of subcutaneous OVCAR tumors. Moreover, we will utilize 2D and 3D in vitro culture techniques alongside flow cytometry and RNA sequencing to identify how lead compounds impact markers of NK activation and metabolism. This will include expression of activating/inhibitory receptors, exhaustion markers, and key metabolic factors. Finally, we will assess the effect of lead compounds on NK function within an immunosuppressive tumor environment. Our findings will contribute to effective future NK cell therapies for solid tumors. Citation Format: Indrani Das, Olubukola Abiona, Riufu Liu, Grace K. Lee, David N. Wald. Discovery & characterization of small molecules to enhance Natural Killer cell cytotoxicity against solid tumors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C020.

Abstract B012: Understanding the role of VISTA in regulating T cell function and the therapeutic potential of blocking VISTA in triple negative breast cancer

Abstract Triple-negative breast cancer (TNBC) is the most aggressive and highly metastatic breast cancer subtype with limited effective treatment options. Immunotherapy with immune checkpoint inhibitors (ICIs) targeting checkpoint molecules have been widely used and have shown therapeutic efficacy in treating multiple malignancies in the last decade. In TNBC, ICI targeting PD-1, alone or in combination with chemotherapy has been approved for the treatment of patients with both early and advanced stage of the disease. Although, there has been significant clinical benefit achieved from anti-PD-1 and chemotherapy, treatment efficacy is often limited to a subgroup of patients. The limited response to ICIs has been attributed to the increased infiltration of immunosuppressive cells (including MDSCs, neutrophils and tumor-associated macrophages), more importantly, the upregulation of alternative immune checkpoint receptors/ligands that may further suppress cytotoxic T cells (CD8+ T cells) in the tumor microenvironment (TME). Therefore, it has been suggested that targeting other immune checkpoint molecules may be more effective in bolstering anti-tumor immune response. V- domain Ig suppressor of T-cell activation (VISTA) is one of the immune checkpoint molecules attracting increasing attention in the context of anti-tumor immunity due to its broad expression across various cancer types and increased expression upon development of immune checkpoint resistance. However, the role of VISTA in regulating the anti-tumor immune response and its therapeutic potential in TNBC remains unclear. In our study, we observed that VISTA is expressed in TNBC patients, predominantly in neutrophils and macrophages. In the Py230 murine breast cancer model, VISTA expression increased upon paclitaxel (PTX), anti-PD-L1 and paclitaxel combined with anti-PD-L1 treatment compared to the control group, suggesting its potential role as a resistance mechanism in sustaining or further inhibiting T cells. In the Py230 model, VISTA blockade increased the infiltration and activation of CD8+ T cells, as evidenced by the higher number of CD8+ T cells, increased CD69+CD8+ T cells, and Granzyme B production, indicating that VISTA blockade improved CD8+ T cells mediated anti-tumor immunity. To functionally test the role of VISTA, we stimulated CD8+ T cells and co-cultured them with naïve macrophages or tumor educated macrophages in the presence or absence of VISTA blocking antibody. Tumor educated macrophages showed increased immunosuppressive activity which was abrogated with VISTA blockade. Moreover, we found that the immunosuppressive effect of macrophages on T cell activation needs direct cell-cell interaction between VISTA on macrophages and T cells. In conclusion, this study shows the mechanism of action of VISTA in the regulation of T cells mediated anti-tumor immune response and provides the rationale for targeting VISTA in TNBC. Citation Format: Maidinaimu Abudula, Yuliana Astuti, Meirion Raymant Raymant, Vijay Sharma, Michael Schmid, Ainhoa Mielgo. Understanding the role of VISTA in regulating T cell function and the therapeutic potential of blocking VISTA in triple negative breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr B012.

MPOX (Monkeypox): Current Epidemiology, Clinical Manifestations, and Advances in Treatment and Prevention Strategies

MPOX (formerly known as monkeypox) has emerged as a significant public health concern in recent years, necessitating a comprehensive understanding of its epidemiology, clinical manifestations, treatment options, prevention strategies, and global health impact. This literature review synthesizes the latest data on the spread and incidence of MPOX, with a focus on geographic distribution, affected populations, and emerging trends in transmission. The clinical presentation of MPOX, including symptoms, disease progression, and complications, is explored, with particular attention to variations across different demographics. Recent advances in the treatment of MPOX are analyzed, covering current antiviral therapies, the role of supportive care, and the potential of new treatments under investigation. Prevention strategies are also examined, highlighting the effectiveness of vaccination efforts, public health measures, and containment and control strategies. The review further considers the broader impact of MPOX on global health, discussing its implications for public health policy and pandemic preparedness. Through this comprehensive analysis, the review aims to provide a robust foundation for understanding MPOX and inform future research, clinical practice, and public health initiatives.

Case report: VEXAS syndrome with excellent response to treatment with azacitidine.

Vacuoles, E1 enzyme, X-linked, auto inflammatory, somatic (VEXAS) syndrome is an inflammatory disorder caused by somatic UBA1 variants and is characterized by late-onset systemic autoimmune inflammation and blood abnormalities. Glucocorticoids ameliorate symptoms effectively. However, other treatment options have limited efficacy and a transient effect. Herein, we describe a case of a 69-year-old male patient with VEXAS syndrome with skin, lung and hematologic involvement. He was treated with glucocorticoids and after the failure with anti IL-1 he began treatment with azacitidine with excellent hematological and clinical response. Azacitidine may be a suitable option for treating VEXAS syndrome, especially due to the relationship between inflammatory symptoms and response to azacitidine.