Treatment Approaches Research Articles

Updates in the management of hypertension

Hypertension is the leading cause of cardiovascular diseases and nephropathies. Its treatment and management require long-term follow-up which can be facilitated by the emergence of device-based therapies. Novel recommendations have been well described in the latest ESH guidelines as well as new risk factors have been identified. The authors summarized the published evidence on hypertension management. The authors also cited in this review novel treatment approaches in different settings and the intervention of medication adherence in treatment success. Such non-communicable disease requires long-term follow-up and monitoring, which is quite facilitated in the era of digitalization by cuff-less devices based on prediction tools.

Evaluating the efficacy of neoadjuvant endocrine therapy in HER2 low vs. HER2 negative breast cancer: An NCBD analysis.

599 Background: Neoadjuvant endocrine therapy (NET) is an important treatment option for hormone receptor (HR)-positive breast cancer (BC). Innovative ADCs targeting HER2 low tumors has sparked debate regarding the distinct nature of HER2 low tumors and whether it merits a unique treatment approach. With favorable outcomes in metastatic disease, there is interest in adopting similar strategies for early-stage treatment approaches. Methods: We examined the National Cancer Database for stage I-III ER-positive BC in women who underwent neoadjuvant endocrine therapy (NET) from 2010 to 2017, for at least 90 days to a maximum of 270 days. Patients with prior neoadjuvant chemotherapy, other malignancies, HER2-positive disease by either IHC or FISH, metastatic disease, or unknown stage were excluded. HER2 status was grouped as negative or low per 2023 ASCO-CAP guidelines. Patients’ response to therapy included pathologic complete response (CR), partial pathologic response (PR), stable pathologic response, or progression in primary tumor at time of resection. We employed multivariable binomial logistic regression to examine how clinicopathologic factors influence the probability of any response (combining CR and PR) to neoadjuvant hormonal therapy. Results: 3,808 patients met the inclusion criteria. 1,055 (27.8%) patients had HER2 negative disease, and 2,753 (72.2%) patients were HER2-low. 48 (1.2%) patients had primary tumor CR, and 1,484 (39%) had PR. Among HER2-low patients, 37 (1.3%) had pathologic CR, and 1,134 (41.1%) had PR. Among HER2-negative patients, 11 (1.0%) had pathologic CR, and 350 (33.1%) had PR. Multivariable logistic models revealed that age, duration of NET, and HER2 status were significant predictors of any response to NET. HER2-low tumors were more likely to have any response compared to HER2-negative (aOR=1.16, 95% CI 1.01 - 1.34, p=0.04). Patients who received >150 days of hormonal therapy were more likely to respond (aOR=1.33, 95% CI 1.16 - 1.52, p=<0.001); patients >50 years old were more likely to have any response (aOR=1.41, 95% CI 1.07 - 1.90, p=0.02). Clinical node positivity and tumor grade did not have significant effect on response to NET at time of resection. Conclusions: Our study offers a real-world estimate of outcomes associated with NET in localized BC. HER2 low tumors had greater significant clinical responses to NET when compared to HER2 negative, suggesting that HER2 low tumors may benefit from tailored treatment in the neoadjuvant setting. [Table: see text]

Effectiveness of giving dragon fruit and ambon banana to increase hemoglobin levels in anemic adolescent girls

Background: Anaemia is a common health problem among adolescent girls, especially in areas with limited access to nutritious food. One of the efforts to overcome anaemia is to increase the consumption of iron-rich fruits, such as dragon fruit and ambon banana. Objective: to evaluate the effectiveness of dragon fruit and ambon banana administration in increasing haemoglobin levels in anaemic adolescent girls Method: Qualitative research combines observational and interventional approaches. The research sample amounted to 2 adolescent female respondents. Instrument of treatment activities using a checklist sheet on elevated haemoglobin levels. Results: An increase in haemoglobin levels was obtained in adolescents given dragon fruit juice, where the first week was 10.1 g / dl, the second week was 11.2 g / dl, and the fourth week was 12.3 g / dl. There was a slightly slower increase in haemoglobin levels in adolescents who were given Ambonese bananas in the first week of 10.2 g / dl, the second week of 10.8 g / dl, and the fourth week of 11.3 g / dl. Conclusion: Respondents who consume dragon fruit increase haemoglobin levels faster than bananas. It is expected to be used as an alternative midwifery care for the midwife profession by giving dragon fruit juice to increase haemoglobin levels. Teenagers are advised to maintain a balanced diet by consuming fruits rich in iron and nutrients, such as dragon fruit, ambon, bananas, and other essential nutrients. By maintaining a balanced diet and increasing the consumption of iron-rich fruits, adolescents can improve their haemoglobin levels and maintain overall body health.

Collaboration matters: A randomized controlled trial of patient-clinician collaboration in suicide risk assessment and intervention

BackgroundClinician collaboration can help high-risk individuals to manage their suicidal crises. However, limited research has directly examined how higher patient-clinician collaboration during assessment and intervention can effectively reduce suicidal ideation. This novel randomized clinical trial compared a high vs. low level of patient-clinician collaboration by pairing commonly used assessment (Structured Interview vs. Narrative Assessment) and intervention approaches (Safety Planning Intervention vs. Crisis Response Planning). We hypothesized that the interventions involving higher (than lower) patient-clinician collaboration during assessment (Narrative Assessment) or intervention (Crisis Response Planning) would lead to larger reductions in suicidal ideation. MethodsEighty-two participants with a history of suicide ideation and/or attempts were randomly assigned to one of the four interventions varying in patient-clinician collaboration. After attrition, sixty-six participants completed the study. Suicidal ideation via ecological momentary assessment was measured 14 days before and 14 days after treatment. ResultsAlthough the severity of suicidal ideation decreased in all groups, the two groups that included highly collaborative assessment had larger pre-post reductions in suicidal ideation (Narrative Assessment+Safety Plan; dwithin = 0.26, and Narrative Assessment+Crisis Response Plan; dwithin = 0.19) than the groups that included a checklist-based assessment (Structured Interview). LimitationsLonger follow-up periods with a larger sample would have provided an understanding of the durability of intervention effects. ConclusionResults suggest that the inclusion of higher patient-clinician collaboration techniques during suicide risk assessment can effectively reduce suicidal thoughts. Thus, clinician-led collaborative risk assessment approaches can enhance the effects of safety planning-type interventions among patients with elevated risk for suicide versus checklist-based assessment approaches.

Reactive oxygen species produced by photodynamic therapy enhance docosahexaenoic acid lipid peroxidation and induce the death of breast cancer cells

Breast cancer remains a serious threat to women's physical and emotional health. The combination therapies can overcome the deficiency of single therapy, enhance the therapeutic effects and reduce the side effects at the same time. In this study, we synthesize a novel nanomedicine that enhanced the therapeutic effects of breast cancer treatment by combining photodynamic therapy and chemotherapy. The doxorubicin (DOX) and photosensitizer methyl pyropheophorbide-a (MPPa) are loaded into the nano-drug delivery system as DPSPFA/MPPa/DOX. In response to near-infrared (NIR) laser, the drugs were quickly released to the cancer cells. The MPPa produces reactive oxygen species (ROS) under the action of photodynamics. Unsaturated fatty acids with ROS promotes lipid peroxidation and the combination of chemotherapy and photodynamic therapy. The data shows that the DPSPFA/MPPa/DOX has a spherical shape, good dispersibility and stability, and the particle size is roughly 200 nm. The drug loading capability of DOX is about 13 %. Both of MCF7 cell model in vitro and breast cancer model in vivo, DPSPFA/MPPa/DOX showed an excellent anti-tumor effect of 86.9 % and without any obvious side effects. These findings might offer potential for a new approach for breast cancer treatment.

Characterization of novel compounds that directly bind to and inactivate the HPV E6 protein for treatment of HPV-associated cervical and oropharyngeal cancers.

e15122 Background: The human papillomavirus (HPV) E6 protein is necessary for viral genome replication and is always expressed in HPV-induced malignancies. We performed in silico screening of chemical libraries for molecules that bind to a pocket on the cancer associated HPV-16 E6 protein. We focused on the protein-protein interaction of E6 with one of its cellular binding partners, the ubiquitin ligase E6AP. In a trimolecular complex with E6, E6AP ubiquitinates p53, leading to its destruction by the proteasome. We designed, synthesized, and characterized >300 compounds that 1) bind to the E6AP interaction surface of the HPV-16 E6 protein; 2) are armed with a ‘warhead’ to make an irreversible bond with a specific cysteine in this HPV-16 E6 binding pocket; 3) and restore levels of p53 and selectively decrease viability of HPV-16 expressing tumor derived cells. Methods: E6 inhibitor optimization was guided by in silico docking strategies, co-crystallization, and medicinal chemistry, followed by biochemical and cellular assays to iteratively design and synthesize molecules with increased E6 inhibitory activities. Results: We used whole protein mass spectrometry to interrogate covalent bonding to E6, showing irreversible binding to the cysteine in the targeted E6 binding pocket without the other 13 cysteines in E6, with Ki in the range of seconds. Biolayer interferometry and fluorescence polarimetry measured blockade of E6 with E6AP, with IC50 in the range of 400-600 nM. To establish in cell inactivation of E6, human cervical cancer derived SiHa cells that express HPV-16 E6 were incubated with compounds, showing dose dependent increase of p53 levels up to 8-fold after 24 hrs, an effect that was not observed in the HPV-16- cell line RPE-1 expressing wild-type p53. Viability of two cervical (SiHa, CaSki) and two oropharyngeal HPV-16+ cancer cell lines (UM-SC-47, UM-SCC-104) was reduced with an IC50 of ~2-3 µM, with an IC50>30µM in RPE-1 cells and telomerase immortalized human keratinocytes. These in vitro and cell-based experiments revealed dependence on the cysteine residue in the E6AP binding pocket of E6. For in vivo proof-of-concept studies, we developed mouse xenograft models, performed by engrafting SiHa, UM-SC-47 and UM-SCC-104 cancer derived cells subcutaneously into the flank of immunodeficient mice. Lead compounds were administered by intraperitoneal injection and demonstrated nearly complete inhibition (> 70% tumor reduction) in HPV-16 tumor growth compared to vehicle. Anti-tumor activity was not observed with the HPV-negative tumor cell line C33A. Conclusions: HPV-16 is identified in about 50% of all cervical cancers and the majority of head and neck malignancies. Inactivation of the HPV E6 protein represents the opportunity for a novel molecular targeted approach for medical treatment of HPV-16 expressing cancers of the cervix and oropharynx.

Microfluidic formulation of diazoxide-loaded solid lipid nanoparticles as a Novel approach for Friedreich's ataxia treatment

Friedreich ataxia (FRDA) is a hereditary autosomal recessive disorder characterized by frataxin deficiency, impacting mitochondrial function and causing oxidative damage. Diazoxide (DZX), a vasodilating drug used in the management of systemic hypertension, has shown promise in preclinical models but faces challenges in crossing the blood-brain barrier and potential toxicity at higher doses. This study aimed to create solid lipid nanoparticles (SLNs) loaded with DZX by microfluidic technique to improve blood-brain barrier (BBB) penetration and reduce side effects. Employing an in vitro BBB model, SLN-DZX demonstrated enhanced permeability compared to plain DZX. Cell viability assays carried out on FRDA fibroblast cells indicated enhanced viability with 1 μM SLN-DZX. Cellular uptake studies confirmed SLN internalization in FRDA fibroblasts, and subsequent treatment with SLN-DZX significantly reduced both total and mitochondrial ROS levels compared to control and empty SLN-treated cells. These findings suggest SLN-DZX as a potential therapeutic approach for FRDA, mitigating oxidative stress with improved BBB penetration and reduced toxicity.

Performance of the silica adsorbent from snake fruit peel for removing heavy metals of Ag, Cu, Mn, and Cr in SCW

Silver crafts wastewater (SCW) typically contains environmentally harmful heavy metals, including Ag, Cu, Mn, and Cr, necessitating treatment before disposal. This study explores a promising solution using silica (SiO2) adsorbents derived from snake fruit peel through acidic activation with HCl concentrations of 2, 4, and 6 M. Qualitative analysis of the adsorbent involved Fourier-transform infrared spectrometer (FTIR) and x-ray fluorescence (XRF) techniques. XRF analysis revealed major compositions of Si (26%) and Cl (71.46%), with minor elements such as Ca (0.91%), P (0.42%), K (0.37%), Fe (0.12%), and others. FTIR analysis indicated the presence of siloxane (Si-O-Si) and silanol (Si-OH) on the adsorbent. The SiO2 adsorbent demonstrated effectiveness in removing heavy metals (Ag, Cu, Mn, and Cr) from SCW, achieving removal percentages of approximately 16.96%, 24.38%, 19.34%, and 9.82%, respectively. This research contributes to the development of an environmentally friendly approach for SCW treatment using silica adsorbents derived from agricultural waste.

Establishment of a Mouse Model of Mycoplasma pneumoniae-Induced Plastic Bronchitis.

Plastic bronchitis (PB) constitutes a life-threatening pulmonary disorder, predominantly attributed to Mycoplasma pneumoniae (MP) infection. The pathogenic mechanisms involved remain largely unexplored, leading to the absence of reliable approaches for early diagnosis and clear treatment. Thus, the present investigation aimed to develop an MP-induced mouse model of PB, thereby enhancing our understanding of this complex condition. In the first stage, healthy BALB/c mice were utilized to investigate the optimal methods for establishing PB. This involved the application of nebulization (15-20 min) and intratracheal administration (6-50 μL) with 2-chloroethyl ethyl sulfide (CEES) concentrations ranging from 4.5% to 7.5%. Subsequently, the MP model was induced by administering an MP solution (2 mL/kg/day, 108 CFU/50 μL) via the intranasal route for a duration of five consecutive days. Ultimately, suitable techniques were employed to induce plastic bronchitis in the MP model. Pathological changes in lung tissue were analyzed, and immunohistochemistry was employed to ascertain the expression levels of vascular endothelial growth factor receptor 3 (VEGFR-3) and the PI3K/AKT/mTOR signaling pathway. The administration of 4.5% CEES via a 6 µL trachea was the optimal approach to establishing a PB model. This method primarily induced neutrophilic inflammation and fibrinous exudate. The MP-infected group manifested symptoms indicative of respiratory infection, including erect hair, oral and nasal secretions, and a decrease in body weight. Furthermore, the pathological score of the MP+CEES group surpassed that of the groups treated with MP or CEES independently. Notably, the MP+CEES group demonstrated significant activation of the VEGFR-3 and PI3K/AKT/mTOR signaling pathways, implying a substantial involvement of lymphatic vessel impairment in this pathology. This study successfully established a mouse model of PB induced by MP using a two-step method. Lymphatic vessel impairment is a pivotal element in the pathogenetic mechanisms underlying this disease entity. This accomplishment will aid in further research into treatment methods for patients with PB caused by MP.

FKBP10-inhibited β-catenin ubiquitination in the malignant transformation of breast epithelial cells.

e12580 Background: Current model of breast cancer (BCa) progression suggests a linear and three-stage process from normal epithelial tissue to ductal carcinoma in situ (DCIS), and then invasive ductal carcinoma (IDC). Since the detailed mechanisms for BCa oncogenesis remain largely unclear and there is still a lack of root-cause level interventions, exploring the underlying molecular alterations during three-stage process of BCa carcinogenesis is urgently needed. Methods: Three-stage specimens from the very same patients were collected. High-throughput sequencing was applied to obtain the differentially expressed genes among normal, DCIS, and IDC samples. Expression level and prognostic value of the selected gene were evaluated by PCR, western blot, tissue chip, and bioinformatics analysis. MCF10DCIS and MCF10Ca cell lines were respectively used to establish DCIS and IDC tumor models in breast epithelial cell-specific gene knockout mice. Patient-matched DCIS and IDC organoids were also constructed. Signaling pathways associated with malignant transformation of breast epithelial cells were detected by using high-throughput sequencing in mouse models and organoids. Protein binding was evaluated by protein mass spectrometry and co-immunoprecipitation. Results: By using high-throughput sequencing, we found that FKBP10 levels were gradually increased in three-stage specimens from the very same patients and were associated with poor prognosis. By establishing DCIS and IDC models in FKBP10flox/floxCre+/- and FKBP10flox/floxCre-/- control mice, we confirmed that FKBP10 deficiency could suppress BCa formation. Besides, FKBP10 knockdown could reduce oncogenic potentials in patient-matched DCIS and IDC organoids. Wnt/β-catenin signaling pathway was related to malignant transformation of breast epithelial cells, when MCF10DCIS+FKBP10flox/floxCre+/- model, MCF10Ca+FKBP10flox/floxCre+/- model, FKBP10-knockdown DCIS and IDC organoids, and their corresponding controls were comprehensively compared. Moreover, FKBP10 was found to inhibit β-catenin ubiquitination with the help of deubiquitinase Trim13, thus activating Wnt/β-catenin signaling pathway and accelerating malignant transformation of breast epithelial cells. Increased level of β-catenin was able to promote FKBP10 expression in a feedback loop. We also confirmed that exosome-loaded FKBP10-targeting peptide could suppress tumor growth both in vitro and in vivo. Conclusions: FKBP10-inhibited β-catenin ubiquitination was responsible in the malignant transformation from normal tissue to DCIS, and then IDC. Our study would uncover novel regulatory mechanisms of FKBP10 in three-stage process of BCa carcinogenesis and provide a new therapeutic approach for clinical treatment.

Burst sine wave electroporation (B-SWE) for expansive blood-brain barrier disruption and controlled non-thermal tissue ablation for neurological disease.

The blood-brain barrier (BBB) limits the efficacy of treatments for malignant brain tumors, necessitating innovative approaches to breach the barrier. This study introduces burst sine wave electroporation (B-SWE) as a strategic modality for controlled BBB disruption without extensive tissue ablation and compares it against conventional pulsed square wave electroporation-based technologies such as high-frequency irreversible electroporation (H-FIRE). Using an in vivo rodent model, B-SWE and H-FIRE effects on BBB disruption, tissue ablation, and neuromuscular contractions are compared. Equivalent waveforms were designed for direct comparison between the two pulsing schemes, revealing that B-SWE induces larger BBB disruption volumes while minimizing tissue ablation. While B-SWE exhibited heightened neuromuscular contractions when compared to equivalent H-FIRE waveforms, an additional low-dose B-SWE group demonstrated that a reduced potential can achieve similar levels of BBB disruption while minimizing neuromuscular contractions. Repair kinetics indicated faster closure post B-SWE-induced BBB disruption when compared to equivalent H-FIRE protocols, emphasizing B-SWE's transient and controllable nature. Additionally, finite element modeling illustrated the potential for extensive BBB disruption while reducing ablation using B-SWE. B-SWE presents a promising avenue for tailored BBB disruption with minimal tissue ablation, offering a nuanced approach for glioblastoma treatment and beyond.

Invasive Aquatic Plants as Potential Sustainable Feedstocks for Biochar Production and as an Innovative Approach for Wastewater Treatment

Biochar (BC) is a well-established physical treatment method. The high-cost BC limits their use as adsorbents in wastewater. Thus, deriving BC from cheap and locally available waste materials is needed to develop a feasible waste removal technology. Nowadays, BC technology makes it possible to envision a new strategy to manage invasive plants by converting them into value-added products like BC. Hence, the present study was designed to evaluate the potential utilization of BC as an efficient filter medium made by invasive aquatic plants, Salvinia spp., and Eichhornia spp. A mass of 50 g of prepared activated and nonactivated BC was incorporated in a sand and gravel filter to treat rubber-manufactured wastewater. Wastewater was passed through the filter, and both raw and treated water samples were analyzed for pH, Total Suspended Solids (TSS), Biological Oxygen Demand (BOD5), Chemical Oxygen Demand (COD), Total Kjeldahl Nitrogen (TKN), Ammoniacal-Nitrogen (NH3-N), Electrical Conductivity (EC), Total Dissolved Solids (TDS), Total Phosphates (TP), Nitrate (NO3-N), turbidity and heavy metals (Zinc, Chromium). The control filter was developed only with sand and gravel, excluding BC. Fourier Transform-Infrared Spectroscopy (FT-IR) and Scanning electron microscopy (SEM) were used to analyze BC’s chemical and physical characteristics. A brine shrimp lethality assay was carried out for toxicological evaluation. OH stretching (3,550-3,200 cm−1), C=C aromatic stretching (1400-1660 cm−1), and Phenol-O-H bending (1,300-1,400 cm−1) were recorded in all BC samples that involved the adsorption mechanism. Observed images indicated differences in surface morphology of both activated and nonactivated BC were observed under SEM observation. The study concludes that the filter unit incorporated with activated Eichhornia spp. Gave the best treatment efficiency when compared to filter units incorporated with other activated and nonactivated BC. The toxicity assay revealed 100% mortality in the control setup and raw wastewater but only 60–70% in the nonactivated BC integrated filters. Activated BC-incorporated filters showed no mortalities. Hence, the study’s outcomes suggest a green approach using invasive aquatic plants for sustainable wastewater treatment.

Contact electro catalysis driven degradation of malachite green dye by RGO/ZnO nanohybrid

This work demonstrates the potential of reduced graphene/zinc oxide (RGO/ZnO) nanohybrid for the degradation of malachite green dye (MG) via involving the mechanochemistry contact electro catalysis (CEC) approach through electronic transfer. Dielectric and piezoelectric RGO/ZnO nanohybrid in contact with aqueous medium offers electron transfer via direct catalytic reaction at solid-liquid interface which promotes CEC process than that of conventional photocatalysis. RGO/ZnO nanohybrid is prepared via ultrafast microwave irradiation method in 60 s using Mangifera indica leaves extract as a green reducing agent. The prepared RGO/ZnO nanohybrid is characterized by X-ray diffraction (XRD), Raman spectroscopy, Fourier-transform infrared spectroscopy (FTIR) and UV–Visible (UV–Vis) spectroscopy. XRD analysis reveals the formation of pure ZnO with wurtzite hexagonal phase and signature reflection of the RGO. Raman, FTIR and UV–Vis spectroscopy results confirm the presence of bands corresponding to ZnO and RGO and hence the formation of RGO/ZnO nanohybrid without any impurity phase. Field emission-scanning electron microscopy (FE-SEM) reveals the growth of spherical shaped ZnO nanoparticles over the RGO matrix. The average particle size of ZnO nanoparticles is ⁓ 9.2 nm. Catalytic properties of RGO/ZnO nanohybrid is investigated by using 10 mg and 20 mg dosage in aqueous solution of MG. About 85.72 % degradation efficiency for MG in 60 min is achieved by using 20 mg RGO/ZnO nanohybrid via sonication through CEC process. Probably, contact electrolysis at ZnO-water interface induces electronic exchange and generation of free radicals to degrade the dye molecules. Reaction kinetics analysis reveals the suitability of the pseudo first-order kinetics for dye degradation and reusability of RGO/ZnO nanohybrid confirms its excellent stability up to three cycles with 60 % degradation ability. This research establishes RGO/ZnO nanohybrid as highly promising catalytic agents for wastewater treatment and hazard free CEC approach.

Effect of blocking CD96 on CD8+ T cell–mediated elimination of tumor dormancy.

e14679 Background: Dormant tumor cells, characterized by quiescent state, exhibit superior tumorigenic capacity, chemotherapy resistance, and expression of stemness genes, along with reduced immune infiltration. Tumor recurrence frequently emerges from persistent dormant tumor cells, posing a formidable challenge for targeted intervention. Methods: In this study, we established a reporter gene system to isolate dormant tumor cells from implanted tumors and reimplanted them into C57BL/6 mice. The effectiveness of the anti-CD96 antibody against dormant tumor cells was assessed by measuring tumor volumes and survival. Subsequently, anti-EpCAM CAR-T cells with CD96 knockout were administered to NSG mice with established dormant tumor cells to evaluate their efficacy and toxicity in vivo. Results: In this study, we identify a novel therapeutic target for dormant tumor cells. Administering anti-CD96 antibodies, rather than anti-PD-1 antibodies, in a systemic treatment of mice effectively eradicates dormant tumor cell-mediated recurrence in a CD96 T cell-dependent manner. Notably, dormant tumor cells exhibit resistance to adoptive cell transfer therapy. Consequently, the blockade of CD96 in anti-EpCAM CAR-T cells, either through antibody treatment or knock-out approaches, holds promise for eliminating dormant tumor cells in colorectal cancer (CRC). Furthermore, knockout CD96 in CAR-T cells enhances CAR-T cell memory formation via regulating mitochondria function but also inhibits T cell exhaustion. Conclusions: In summary, targeting CD96 serves as a valuable checkpoint against dormant tumor cells, presenting a therapeutically actionable strategy for preventing disease relapse.

Predicting CDK4/6 inhibitors outcomes in pts with HR+/HER2- metastatic breast cancer: A machine learning approach.

1074 Background: CDK4/6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) are the current standard of care for pts with newly diagnosed HR+/HER2- metastatic breast cancer (MBC). Although multiple pivotal trials showed a robust benefit of CDK4/6i over ET alone in all the subgroups, there is a subset of pts with a suboptimal response that is difficult to characterize. To predict the benefit on first line CDK4/6i in pts with HR+/HER2- MBC, we created a machine-learning (ML) model based on clinico-pathological features (CPFs) at baseline. Methods: We identified 854 consecutive pts with HR+/HER2- MBC receiving CDK4/6i as 1st line therapy between 12/2013 and 10/2023 from our MSK translational database. OncoCast-MPM ML framework was used to stratify pts based on progression-free survival (PFS) on 1st line CDK4/6i. CPFs of interest were selected as input for the models. Pts with missing data in any of the key inputs were excluded and used as hold out set. We tested 4 algorithms (GBM, ENET, LASSO and SVM), and selected the only model that returned predictions when tested on the hold out dataset containing missing data. The Kaplan-Meier estimator and the log-rank test were used to assess differences in PFS, and Cox regression was used to measure hazard ratios (HR) between groups. Results: Overall, 651 out of 854 pts and 15 CPFs were used in models' creation. The median PFS of the cohort was 15.95 months (95%CI: 14.04-17.95). Of the 4 tested architectures, GBM was the selected architecture based on its ability to be tested on the holdout cohort containing missing data. GBM identified 3 risk groups: good-response risk group (N=279), with a median PFS of 23.8 months (95%CI: 19.6-29.9), intermediate-response risk group (N=231), with a median PFS of 14.7 (I95%CI: 12.2-16.9), and poor-response risk group (N=141), with a median PFS 7.4 (95%CI: 5.3,9.1). The HR between good-response and poor-response RGs was 2.55 (95%CI: 2.0,3.2) with a of p = 2.54e-14. The first 5 CPFs by importance, sorted by Garson algorithm score are: disease-free interval, liver involvement, age at metastatic disease, adjuvant treatment-free interval, and progesterone receptor status. No statistically significant differences were observed between the 3 risk groups identified in the train-validation and tested in the holdout cohort, in terms of median, 1yr, 3yr survival times, as well as in HR. Conclusions: ML-based models have the potential to identify subsets of pts likely to poorly respond to first line CDK4/6i leveraging clinico-pathological features. Risk stratification can help clinicians to select pts who may benefit from short-term interval imaging and potential cfDNA monitoring, as well as to identify the right population to design clinical trials with escalating treatment approaches.

The gut microbiota patterns of patients with COVID-19: protocol for a case-control study

BackgroundSARS-CoV-2 caused an outbreak in late December 2019. It has been suggested that gut microbiota dysbiosis influences the severity, mortality, and quality of life of patients with COVID-19. So, identifying the gut microbiota pattern could be helpful to determine the prognosis of the disease, and maybe determine some potential treatment approaches. Our aim will be to compare gut microbiota patterns between patients with severe or non-severe COVID-19, and healthy controls.MethodsWe will include 183 samples: 122 samples from COVID-19 patients, including 61 severe patients and 61 non-severe patients, and 61 samples from healthy controls. Total bacterial DNA will be extracted from samples and 16 S rRNA gene will be amplified through two polymerase chain reaction (PCR) stages. Fecal samples will be analyzed using a targeted metabolomics technique. The differences in each RNA or DNA expression between patients with severe COVID-19, patients with non-severe COVID-19, and controls will be compared. Also, we will assess the relationships between each DNA or RNA and the risk of COVID-19 severity, sort of clinical manifestations, and comorbidities. Concurrent medication data will be collected and patients will also be grouped based on their drug history.ResultsWe hypothesize that the gut microbiota composition will be affected by the COVID-19 severity and there might be differences in terms of sex and age.ConclusionsThe results of our study could be the backbone for further trials which might lead to the development of prognostic factors and treatment options. Further studies can also consider the limitations of the study like potential confounders and selection and recall biases.

Neglected Developmental Hip Dysplasia Treated With External Iliofemoral Distraction, Open Reduction, and Pelvic Osteotomy: Eleven-Year Follow-Up.

Neglected untreated developmental hip dysplasia can result in severe deformities and functional disabilities. This report describes the treatment and 11-year follow-up of a patient who underwent the procedure in two stages. At the time of treatment, the patient was 7 years of age and was diagnosed with acetabular dysplasia and neglected right hip dysplasia. A stepwise treatment approach, including gradual distraction of the iliofemoral joint, open reduction, and pelvic osteotomy, was performed. Subsequent postoperative rehabilitation and regular follow-up assessments were performed over 11 years. The long-term results indicated notable improvements in hip joint congruency, functional range of motion, and overall quality of life. Early diagnosis and appropriate intervention are crucial for patients with developmental hip dysplasia, and the treatment methods described here are effective.

Impact of pathogenic germline variants in HRR genes on gastroesophageal cancer in a large real-world Chinese population: A comprehensive study.

10588 Background: Genetic testing in gastroesophageal cancer has been limited to those with hereditary cancer syndromes, restricting understanding of the impact of germline variants in sporadic cancers. Our study expands this by exploring germline and somatic characteristics in a broad Chinese cohort, enhancing risk assessment and guiding treatment strategies in a wider population. Methods: From October 2017 to April 2023, we retrospectively analyzed 2596 Chinese gastroesophageal cancer (GEC) patients, including 2003 with gastric cancer (GC), 196 with gastroesophageal junction cancer (GEJC), and 397 with esophageal cancer (EC). A 520-gene panel including 62 genes associated with cancer predisposition, was employed for genomic profiling of paired tumor and white blood cell samples. The pathogenicity of germline variants was determined according to ACMG guidelines. Results: In this retrospective cohort, the proportion of patients carrying pathogenic/likely pathogenic (P/LP) germline variants was 5.3% in GC, 5.6% in GEJC, and 5.0% in EC, respectively. Notably, genes associated with HRR exhibited the highest rates of P/LP germline mutations in GEC (94, 3.7%), with the majority occurring in non-BRCA HRR genes (77, 3.0%). The top five genes with the highest mutation rates were ATM, PALB2, FANCA, CHEK2, and RAD54L. Compared to the East Asian population without cancer in the genomAD database, a higher proportion of P/LP germline mutations were found in the CDH1(Inf [6.46-Inf], p < 0.001), PALB2 (5.60 [1.61-13.09], p = 0.002), SDHA (8.99 [1.29-99.42], p = 0.012), ATM (2.15 [1.08-4.09], p = 0.02), and CHEK2 (3.83 [1.06-13.32], p = 0.02) genes in GC. Similarly, significant increases in PALB2 (10.36 [2.32-37.28], p = 0.002) and ATM (4.42 [0.86-14.33], p = 0.036) were also observed in EC and GEJC. The HRR P/LP variant group exhibited a higher incidence of biallelic inactivation (loss of wildtype allele) compared to the B/LB variant group (24.7% vs 6.6%, p<0.001). Moreover, the similar trend was observed for the moderately/uncertainly penetrant gene ATM and FANCA (38.5% vs 0.6%, p < 0.001; 42.9% vs 9.8%, p = 0.025), which suggests that ATM and FANCA may be associated with a high risk. The HRR genes ATM(56 vs 61, p = 0.052), CDH1(33 vs 61, p = 0.003), and FANCI(48 vs 61, p = 0.041) with P/LP variants were associated with a younger age of onset. Carriers of HRR P/LP variants had less prevalent somatic TP53 variants in GC and GEC and higher HRD score compared to non-carriers (p=0.005). Conclusions: Our research delineates the germline P/LP variant landscape in Chinese GEC, revealing the significant role of HRR P/LP variants. The presence of P/LP variants in HRR genes in GEC is linked to distinct disease characteristics and progression, underscoring their importance in guiding personalized treatment approaches and risk evaluation.

The safety and efficacy of immune checkpoint inhibitor in combination with FOLFOX as neoadjuvant/adjuvant therapy in patients with locally advanced colon cancer.

e15621 Background: The recurrence rate of locally advanced colon cancer (T3-4 or N+, M0) after surgery is significantly high. Emerging data indicate that the combination of immunotherapy and chemotherapy demonstrates synergistic effects in other solid tumors. Consequently, a combination of immunotherapy and chemotherapy holds the potential to benefit patients with MSS and pMMR colon cancer. We have designed a prospective trial to investigate whether the immune checkpoint inhibitor (ICI) in combination with chemotherapy represents a safe and beneficial treatment approach for locally advanced colon cancer. Methods: Inclusive Criteria: Patients with locally advanced colon cancer (T3-4 or N+, M0) confirmed through pathological biopsy, with confirmed indications for neoadjuvant/adjuvant chemotherapy by the multidisciplinary team. Patients must be eligible for surgery, and a measurable mass must be identified according to RECIST version 1.1. All individuals aged over 18 years, with an estimated life expectancy of over one year and an ECOG score within 0-1, are eligible. The neoadjuvant chemoimmunotherapy group (NACI) includes mFOLFOX 6 (Q2W) and the anti-PD-1 monoclonal antibody (Toripalimab) (3mg/kg, Q2W), while the neoadjuvant chemotherapy group (NAC) receives only mFOLFOX 6 for neoadjuvant/adjuvant therapy (a total of 12 cycles, 6 cycles pre-surgery and 6 cycles post-surgery). The primary endpoint is the pathological complete response (pCR) rate. Results: From 2019 to 2022, a total of 22 patients were enrolled in the study, with 13 in the NACI group and 9 in the NAC group. The research findings indicate that in the NACI group, over 30% (4/13) of patients achieved a pathological complete response (pCR), whereas none of the patients in the NAC group reached pCR (0/9). Among the pCR patients, one was identified as MSI-H/dMMR, two as MSS/pMMR, and one had an unknown status. Tumor regression grade (TRG) levels also revealed that all patients in the NACI group were below grade 2, significantly outperforming the NAC group (P < 0.05), with statistically significant differences. However, no significant differences were observed between the NAC and NACI groups in terms of CT regression percentage, R0 resection, vascular cancer emboli, and the level of neural invasion. Adverse reactions did not show significant differences between the two groups. Conclusions: The combination of immunotherapy and chemotherapy exhibits a synergistic effect in treating locally advanced colorectal cancer. Tolerable adverse reactions suggest that neoadjuvant chemoimmunotherapy could potentially serve as a novel therapeutic option. Clinical trial information: NCT03985891 .

Advancements in Urothelial Cancer Care: Optimizing Treatment for Your Patient.

The standard treatment paradigm for muscle invasive bladder cancer has been neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy. However, efforts are ongoing to personalize treatment by incorporating biomarkers to better guide treatment selection. In addition, bladder preservation strategies are aimed at avoiding cystectomy in well-selected patients. Similarly, in the metastatic urothelial cancer space, the standard frontline treatment option of platinum-based chemotherapy has changed with the availability of data from EV-302 trial, making the combination of enfortumab vedotin (EV) and pembrolizumab the preferred first-line treatment option. Here, we examine the optimization of treatment intensity and sequencing, focusing on the challenges and opportunities associated with EV/pembrolizumab therapy, including managing toxicities and exploring alternative dosing approaches. Together, these articles provide a comprehensive overview of contemporary strategies in bladder cancer management, highlighting the importance of individualized treatment approaches, ongoing research, and multidisciplinary collaboration to improve patient outcomes in this complex disease landscape.