Effective Clinical Response Research Articles

The psychodynamics of self-harm

SUMMARY This article examines the complex phenomenon of self-harm, exploring its motivations, theoretical underpinnings and the intricate transference and countertransference reactions that arise in clinical settings. It aims to integrate psychiatric understanding with contemporary theories of the impact of trauma on both the body and the mind, to deepen the knowledge of self-harm and increase the effectiveness of treatment approaches. The article argues for a nuanced view of self-harm and emphasises the need for compassionate, well-informed care. By addressing the psychodynamics of self-harm, the article seeks to improve therapeutic outcomes and foster an empathetic and effective clinical response. Fictitious case studies are used to illustrate these concepts, demonstrating the critical role of early attachment experiences and the challenges faced by healthcare providers in management.

Serum HSP70 and VEGF levels are effective predictive factors of chemoradiosensitivity and prognosis of pancreatic cancer patients.

To evaluate the value of serum HSP70 and VEGF levels for predicting the chemoradiosensitivity of the pancreatic cancer patients. A total of 255 patients with pancreatic cancer and 60 healthy subjects were enrolled in this study. Serum levels of HSP70 and VEGF were measured using enzyme-linked immunosorbent assay (ELISA) for the pre-treatment, during-treatment and post- chemoradiotherapy time-points. The results were analyzed to evaluate the potential of serum HSP70 and VEGF levels for predicting the chemoradiosensitivity of pancreatic cancer patients. The serum levels of both HSP70 and VEGF were found to be elevated in pancreatic cancer patients as compared to healthy subjects. After chemoradiotherapy treatment, 179 patients showed effective clinical response [complete response (CR) + partial response (PR)] while 76 patients showed ineffective clinical response [stable disease (SD) + progressive disease (PD)]. Compared with the pre-treatment levels, serum levels of HSP70 and VEGF were higher during chemoradiotherapy, and lower post-treatment in the effective group. However, serum levels of HSP70 and VEGF were higher during and after treatment in the ineffective group. At any given timepoint, serum levels of HSP70 and VEGF were higher in the ineffective group as compared to those of the effective group. The overall survival (OS) and progression free survival (PFS) trends were: HSP70 High/VEGFHigh < HSP70High/VEGFLow or HSP70Low/VEGFHigh < HSP70Low/VEGFLow. Serum levels of HSP70 and VEGF were individually effective, and their combination was even more effective in predicting the chemoradiosensitivity of pancreatic cancer patients. HSP70 and VEGF expression were independent risk factors for OS and PFS of pancreatic cancer patients. Higher levels of serum HSP70 and VEGF were associated with lower radiosensitivity and worse prognosis, while lower levels of serum HSP70 and VEGF were associated with improved radiosensitivity and better prognosis of pancreatic cancer patients.

Abstract 5342: Evaluation of autologous and allogeneic T cell-based therapies in ex-vivo and in-vivo xenograft tumor models

Abstract The field of adoptive T cell-based immunotherapy, including tumor-infiltrating lymphocytes (TILs), T cell receptor (TCR) &amp; Chimeric antigen receptor (CAR) - T cells, has undergone unprecedented growth, specifically later in delivering effective and durable clinical response. Notable success with CAR-T cells is limited to hematological malignancies while clinical gains with solid tumors is still a challenge. Solid tumors’ heterogenous target expression and loss, T cell status and metabolic fitness, T cell trafficking into the tumor, and the hostile immunosuppressive tumor microenvironment (TME) have hampered T cell efficacy in the patients. There is a lack of clinically relevant solid tumor models for the translation of T cell-based therapies into the clinic. We report the development of translational ex-vivo and in-vivo platforms for evaluating cell line-derived and patient-derived xenografts (CDX and PDX) models (BarneyOI™️ model), validated with hCD3 T-cells, autologous TILs and/or allogeneic 3rd generation CAR-T cells (scFv(HER2)-CD28-4-1BB-CD3zeta CAR-T). Anti-hPDL1 but not anti-hPD1 significantly enhanced hCD3 T-cell and autologous TIL-mediated killing of tumor cells in an ex-vivo co-culture assay using Incucyte-based live cell imaging. Also, a dose-dependent killing of HER-2 expressing CDX (A549 &amp; Colo205) and PDX was observed with HER-2 targeting CAR-T cells in an ex-vivo co-culture assay. This was in concordance with the activation, effector function, and differentiation status of the CAR-T cells, immune phenotype by Cytek aurora spectral flow cytometry. Further, to imitate the patient population and the effect of solid TME, HER-2 targeting CAR-T cells were assessed for their in-vivo efficacy and immune response differences in the subcutaneous and orthotopically implanted HER-2 expressing PDX in immunodeficient NOG mice. Our findings highlight the importance of testing T cell-based immune therapies in the appropriate translational tumor models with better certainty of clinical outcome. Citation Format: Sherry Liu, Jasmine Borroel, Carmen Sunico, Emily Eastwood, Bridget Corcoran, Bianca Carapia, Jantzen Sperry, Jonathan Nakashima, Rajeev Shrimali. Evaluation of autologous and allogeneic T cell-based therapies in ex-vivo and in-vivo xenograft tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5342.

Efficacy and Safety of Isoprenaline during Unstable Third-Degree Atrioventricular Block.

Unstable and symptomatic complete atrioventricular block represents a potentially fatal condition that requires prompt therapy while waiting for definitive pacemaker implantation. Although transcutaneous pacing is included in acute management, it could be a difficult approach due to its painfulness and the occasional failure of mechanical capture. Drug therapy is a feasible choice, and current guidelines encompass the use of atropine, dopamine, or epinephrine. Isoprenaline has never been investigated in this setting, and no specific indication of its use has been provided despite its potentially more favorable pharmacological profile. The study population included a consecutive series of patients who presented to the emergency department because of unstable third-degree atrioventricular block and were treated with either isoprenaline or dopamine infusion while waiting for definitive pacemaker implantation. Asymptomatic patients or those with reversible causes of complete atrioventricular block were excluded. The clinical response to the drug was deemed poor if, despite achieving a full drug dose, patients remained symptomatic and/or with hemodynamic instability, ventricular rate and rhythm did not improve or worsened, including if ventricular arrhythmias or asystolic pauses and/or irrepressible nausea/vomiting occurred. Isoprenaline infusion has proved to be safe and tolerated with no arrhythmia induction or hypotensive issues. Isoprenaline has also proven to be more satisfactory in achieving an effective clinical response in 84% of patients rather than dopamine (31%, p < 0.001), reducing the need for temporary artificial pacing. Our data point out the efficacy and safety of isoprenaline infusion and its greater tolerability over dopamine in the acute management of unstable third-degree AV block while waiting for definitive pacemaker implantation.

Patient-Reported Outcome Measures for Patients With CKD: The Case for Patient-Reported Outcomes Measurement Information System (PROMIS) Tools

Chronic kidney disease (CKD), kidney failure, and kidney replacement therapies are associated with high symptom burden and impaired health-related quality of life (HRQOL). Symptoms change with disease progression or transition between treatment modalities and frequently go unreported and unmanaged. Tools that reliably monitor symptoms may improve the management of patients with CKD. Patient-reported outcome measures (PROMs) assess symptom severity; physical, psychological, social, and cognitive functioning; treatment-related side effects; and HRQOL. Systematic use of PROMs can improve patient-provider communication, patient satisfaction, clinical outcomes, and HRQOL. Potential barriers to their use include a lack of engagement, response burden, and limited guidance about PROM collection, score interpretation, and workflow integration. Well-defined, acceptable, and effective clinical response pathways are essential for implementing PROMs. PROMs developed by the Patient-Reported Outcomes Measurement Information System (PROMIS) address some challenges and may be suitable for clinical use among patients with CKD. PROMIS tools assess multiple patient-valued, clinically actionable symptoms and functions. They can be administered as fixed-length, customized short forms or computer adaptive tests, offering precise measurement across a range of symptom severities or function levels, tailored questions to individuals, and reduced question burden. Here we provide an overview of the potential use of PROMs in CKD care, with a focus on PROMIS.

Clinical Efficacy and Safety Evaluation of Ceftazidime-Avibactam in the Treatment of Klebsiella pneumoniae Infection: A Retrospective Analysis from a Hospital in China.

Ceftazidime-avibactam (CAZ-AVI) is a new cephalosporin/β-lactamase inhibitor combination that received clinical approval in China in 2019. This study aims to investigate the efficacy and safety of CAZ-AVI in the treatment of Klebsiella pneumoniae (KP) infection in a hospital, and differences in efficacy among various infection sites and between monotherapy and combination therapy, providing valuable insights for its further application. Patients who used CAZ-AVI between January 2019 and April 2023 were identified through the hospital information system. Demographic information, details of the infection site, KP strain's drug sensitivity report, treatment duration, combination therapies, adverse drug reactions (ADR), and 28-day survival were recorded. Clinical and microbiological efficacies were analyzed using SPSS 23.0 software to compare different infection sites and combination therapies. The overall effective clinical response (CR) rate of CAZ-AVI against KP infection was 62.13%, with a favorable microbial response (MR) rate was 65.68% and a 28-day survival rate was 63.91%. No significant difference occurred in effective CR and 28-day survival rate among different infection sites (P = 0.709 and 0.862, respectively). The favorable MR rate for abdominal infections was slightly lower than that for other sites of infection (P = 0.021). No significant differences in effective CR, favorable MR, and 28-day survival between monotherapy and combination therapy were present (P values were 0.649, 0.123, and 0.280, respectively). The incidence of ADR was 1.78%, including increased creatinine, elevated transaminase, hematuria, and thrombocytopenia. CAZ-AVI demonstrates good clinical efficacy and safety in the treatment of KP infections. The clinical efficacy of CAZ-AVI was similar across different infection sites, and combination therapy did not show an advantage over monotherapy. Further studies are warranted. It should be noted that CAZ-AVI may induce thrombocytopenia and hematuria.

Effective clinical response of lung adenocarcinoma harboring EGFR 19Del/T790M/in cis-C797S osimertinib to osimertinib and gefitinib combination therapy.

Effective clinical response of lung adenocarcinoma harboring EGFR 19Del/T790M/in cis-C797S osimertinib to osimertinib and gefitinib combination therapy.

Targeting crosstalk of STAT3 between tumor-associated M2 macrophages and Tregs in colorectal cancer

ABSTRACT A comprehensive analysis of the molecular mechanism underlying colorectal tumor evaluated the development of colorectal cancer (CRC) and proposed targeting small molecular inhibitors. Nonetheless, the adoptive resistance of these therapies remains a challenge with respect to achieving an effective clinical response. Thus, identifying the molecular mechanisms guiding CRC growth is essential. The results of The Cancer Genome Atlas (TCGA) dataset analysis demonstrated a critical role of signal transducer and activator of transcription 3 (STAT3) pathway in tumor immune suppression via modulation of the recruitment of Treg cells and M2 type tumor-associated macrophages. The in vivo experiments elucidate that targeting STAT3 pathways markedly reduce the proportions of TAMs and Tregs by inhibiting tumor progression. These findings revealed crosstalk between Treg cells and M2 macrophages, proving a potential therapeutic strategy for CRC therapy. Combinatorial treatment with STAT3 inhibitor and programmed death 1 (PD-1) antibody therapy effectively prevents CRC tumor growth in a mouse model with high anti-tumor immunity. In summary, targeting STAT3 disrupts the interaction between Treg cells and M2 macrophages and improves the anti-tumor response in CRC, thereby offering a promising strategy to treat patients with CRC.

Efficacy and safety of anlotinib hydrochloride combined with nivolumab in the treatment of advanced upper gastrointestinal tumor as second-line or later-line therapy: The results of gastric cancer cohort.

e16015 Background: The upper gastrointestinal tumors, such as gastric adenocarcinoma (GAC) and esophageal squamous cell carcinoma (ESCC), have high rates of incidence and poor prognosis in our country, lacking of efficient therapy after failure of first-line regimen. Despite available treatment, there are still huge unmet medical needs of second-line or later-line therapy for patients with GAC or ESCC. Therefore, we will investigate the efficacy and safety of Anlotinib Hydrochloride (a multi-target tyrosine kinase inhibitor) combined with Nivolumab (PD-1 antibody) in GAC and ESCC. Methods: Patients with unresectable or metastatic GAC or ESCC who have failed standard therapy were treated by Anlotinib Hydrochloride 12mg/day orally for two weeks and Nivolumab 360mg every 3 week until the disease progression or intolerable adverse effects occurring. The study protocol was registered on ClinicalTrial.gov (NCT04503967,07/08/2020). The primary endpoint of this study was ORR (Objective Response Rate). The secondary endpoints were PFS (Progression-Free Survival), OS (Overall Survival), DCR (Disease Control Rate), and safety. Results: Gastric adenocarcinoma cohort would be reported only. From December 2020 to September 2022, 45 patients were enrolled in gastric adenocarcinoma cohort. There were 34 male patients and 11 female patients. The median age was 59 years. The percentage of gastric cancer patients with second-line and later-line treatment were 62.2% and 37.8%, respectively. 2 patients (4.4%) achieved complete remission (CR), 11 patients (24.4%) got partial remission (PR), and 15 patients (33.3%) got stable disease (SD). The ORR (CR+PR) was 28.9%, and DCR (CR+PR+SD) was 62.2%. Among 28 patients (62.2%) treated as second-line therapy, ORR was 32.1%, and DCR was 57.0%. As for later-line therapy of 17 patients, ORR and DCR were 23.5% and 70.6%, respectively. The median follow-up duration was 15.0 months (95% CI 8.17~21.83), then median PFS was 3.80±0.94 months, and median OS was 11.10±3.04 months. When the patients were treated as second-line therapy, median PFS was 3.0±0.97 months, and median OS was 14.50±3.89 months. Median PFS and OS in later-line patients of gastric adenocarcinoma were 3.80±1.30 months and 8.0±0.68 months, respectively. 36 patients (80%) had treatment-related adverse events (TRAEs). More than 10% of incidence rate included hypothyroidism (n=8), liver dysfunction (n=6), and rash (n=6). G3-4 of TRAEs were hypothyroidism (n=1), liver dysfunction (n=1), palmar-plantar erythrodysesthesia (n=1), rash (n=1), and hypophysitis (n=1). Conclusions: Anlotinib hydrochloride combined with Nivolumab showed effective clinical response and tolerable safety in second-line or later-line treatment of advanced gastric adenocarcinoma. Clinical trial information: NCT04503967 .

Comparison of CAR-T cell-mediated cytotoxicity assays with suspension tumor cells using high-throughput plate-based image cytometry method

Abstract In the recent decade, chimeric antigen receptor (CAR)-T cell therapy has revolutionized strategies for cancer treatments due to its highly effective clinical efficacy and response for B cell malignancies. Currently, there are six CAR-T cell products available in the market including Kymriah, Yescarta, Tecartus, Breyanzi, Abecma, and Carvykt. The success of CAR-T cell therapy has stimulated the increase in the research and development of various CAR constructs to target different tumor types. Therefore, a robust and efficient in vitro potency assay is needed to quickly identify potential CAR gene design from a library of construct candidates. Traditionally, in vitro CAR-T cell-mediated cytotoxicity is assessed using release assays such as 51Cr (radioactivity), calcein (fluorescence), and LDH (enzymatic). Image cytometry methodologies have been utilized for various CAR-T cell-mediated cytotoxicity assay using different fluorescent labeling methods, mainly due to their ease-of-use, ability to capture cell images for verification, and higher throughput performance. In this work, we employed the Celigo high-throughput plate-based Image Cytometer to evaluate and compare two CAR-T cell-mediated cytotoxicity assays using GFP-expressing or fluorescent dye-labeled myeloma and plasmacytoma cells. Performing time- and E:T ratio-dependent CAR-T cell-mediated cytotoxicity assays, the GFP-based method demonstrated higher sensitivity in detecting the level of cytotoxicity when compared to the CMFDA/DAPI viability method. We have established the criteria and considerations for the selection of cytotoxicity assays that are fit-for-purpose to ensure the results produced are meaningful for the specific testing conditions. None

Abstract 5326: Comparison of CAR-T cell-mediated cytotoxicity assays with suspension tumor cells using high-throughput plate-based image cytometry method

Abstract In the recent decade, chimeric antigen receptor (CAR)-T cell therapy has revolutionized strategies for cancer treatments due to its highly effective clinical efficacy and response for B cell malignancies. Currently, there are six CAR-T cell products available in the market including Kymriah, Yescarta, Tecartus, Breyanzi, Abecma, and Carvykt. The success of CAR-T cell therapy has stimulated the increase in the research and development of various CAR constructs to target different tumor types. Therefore, a robust and efficient in vitro potency assay is needed to quickly identify potential CAR gene design from a library of construct candidates. Traditionally, in vitro CAR-T cell-mediated cytotoxicity is assessed using release assays such as 51Cr (radioactivity), calcein (fluorescence), and LDH (enzymatic). However, release assays indirectly measure cell death via molecules released in supernatant and typically limited to only endpoint assays. In addition, handling and disposing of 51Cr hazardous materials is less preferred. Luciferase reporter assay, although highly sensitive, has similar drawbacks as the release assays. Finally, flow cytometry method can directly measure cell death and viability, but can be time-consuming and requires a large number of CAR-T cells when the effector-to-target (E:T) ratio is high. Furthermore, additional steps are required for adherent cells that require trypsinization. Image cytometry methodologies have been utilized for various CAR-T cell-mediated cytotoxicity assay using different fluorescent labeling methods, mainly due to their ease-of-use, ability to capture cell images for verification, and higher throughput performance. In this work, we employed the Celigo high-throughput plate-based Image Cytometer to evaluate and compare two CAR-T cell-mediated cytotoxicity assays using GFP-expressing or fluorescent dye-labeled myeloma and plasmacytoma cells. Performing time- and E:T ratio-dependent CAR-T cell-mediated cytotoxicity assays, the GFP-based method demonstrated higher sensitivity in detecting the level of cytotoxicity when compared to the CMFDA/DAPI viability method. We have established the criteria and considerations for the selection of cytotoxicity assays that are fit-for-purpose to ensure the results produced are meaningful for the specific testing conditions. Citation Format: Leo Li-Ying Chan, Yu-Jun Sun, Yi-Chun Chen, Wei-Kai Hua, Sariena Chiung-Yuan Wu. Comparison of CAR-T cell-mediated cytotoxicity assays with suspension tumor cells using high-throughput plate-based image cytometry method. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5326.

INTERACTION OF ANTIMICROBIAL SUBSTANCES IN ESCHERICHIA COLI

The effectiveness of the combined antimicrobial drug primarily depends on the interaction of its active substances in the target species of microorganisms, which can be manifested in synergism, antagonism or indifference (additive effect). The guarantee of an effective clinical response of an animal suffering from a bacterial infection to the use of a combined drug is the synergism of its active pharmaceutical ingredients (API) with respect to a microorganism sensitive to their action, the causative agent of the disease.&#x0D; The article presents the results of the study of the interaction of various antimicrobial substances, which are the active substances of combined chemotherapeutic drugs present on the veterinary market of Ukraine, in Escherichia coli. The indications for the use of these drugs include the treatment of colibacteriosis, one of the most common bacterial zoonotic diseases in young farm animals.&#x0D; The study of the interaction of antimicrobial substances was carried out by the checkerboard method, based on the minimum inhibitory concentrations (MIC) of each API of the combination for Escherichia coli. The reference test microorganism Escherichia coli ATCC 11105 was used for the study.&#x0D; The interaction of oxytetracycline and neomycin caused an additive effect in Escherichia coli, when the result of the action of both substances is equal to the sum of the effects caused by each of the substances separately.&#x0D; The interaction of enrofloxacin and trimethoprim, enrofloxacin and gentamicin, enrofloxacin and colistin, doxycycline and colistin, and sulfadiazine and trimethoprim was manifested in synergism against Escherichia coli. In each case, the synergistic effect depends on various factors: the mechanisms of action of antimicrobial substances in combination directed at different target sites in the bacterial cell; the nature of their effect on the bacterium (act bactericidal or bacteriostatic); action in the same direction, as in the case of sulfadiazine and trimethoprim, when they compete for inhibition of different enzymatic stages of folate metabolism.

Evaluation of Efficacy and Safety of Topical Nanoliposomal Amphotericin B 0.4% Gel as a Potential Treatment for Onychomycosis: An Interventional Pilot Clinical Study

Onychomycosis is a frequent fungal nail disease that is hard to treat and, in most cases, needs long‐term therapy with oral agents. Traditionally, oral agents are favored over topical agents, but it should not be overlooked that they come with broad adverse effects and concomitant drug interactions, which can be unsuitable for many individuals. Therefore, alternative approaches need to be addressed by the medical team for numerous cases. On the other hand, local administration of antimicrobials can come as advantageous because of having a more selective site of activity, avoiding off‐target systemic adverse effects, and rapid administration at the site of infection. In this study, we are evaluating a new topical delivery method of amphotericin B. To investigate the efficacy and safety of topical nanoliposomal amphotericin B 0.4% as a possible therapeutic option, this pilot, single‐group, before‐after clinical study was conducted on 15 onychomycosis patients. The evaluation was processed during 36 weeks of follow‐up and on three endpoints of week 12, week 24, and week 36, for both clinical and mycological responses. Three patients were excluded; of the remaining 12, 50% showed a complete cure, 16.66% had an effective clinical response, 16.66% had a partial clinical response, and 16.66% showed no response at week 12. Mycological cure was calculated as 50% at week 12. At week 24, our measurements were calculated as 91.66% for complete cure, 8.33% for no response, and 91.66% for mycological cure. One patient reported nail plate detachment at week 2 but continued the topical application; follow‐up between weeks 2 and 24 showed a complete cure and regrowth of healthy nails. No other adverse effects were detected. Overall, our study suggests that topical nanoliposomal amphotericin B 0.4% is an effective treatment, which is accessible, affordable, and user‐friendly, has minimum adverse effects, and could be regarded as an alternative treatment for those ineligible for systemic therapy. This trial is registered with IRCT20150101020514N18.

An 8-month-old boy with infantile nephrotic syndrome caused by semaphorin 3B-associated membranous nephropathy.

We present a case of nephrotic syndrome caused by semaphorin 3B-associated membranous nephropathy. The patient was an 8-month-old male infant who presented with severe proteinuria and hypertension. He was treated with prednisolone (PSL) for nephrotic syndrome; however, remission was not achieved within 4weeks. He was diagnosed with steroid-resistant nephrotic syndrome and underwent kidney biopsy. Pathological examination revealed membranous nephropathy with IgG deposits on both the glomerular basement membrane (GBM) and the tubular basement membrane (TBM). He was treated with cyclosporine (CsA) in addition to PSL and achieved complete remission. However, frequent relapses occurred after the discontinuation or tapering of immunosuppressants. Two years after treatment initiation, a second biopsy was performed and showed worsening of the disease, which required treatment with several immunosuppressants to achieve complete remission. After that, we performed additional immunostaining for semaphorin 3B, which confirmed the diagnosis of semaphorin 3B-associated membranous nephropathy. Although extremely rare in infantile cases, semaphorin 3B-associated membranous nephropathy should be considered in the differential diagnosis, as strong treatment with immunosuppressants might be needed. In addition, mycophenolate mofetil showed an effective clinical response in this case, indicating that it can be considered for future treatment strategies.

Osilodrostat in Cushing’s disease: the management of its efficacy and the pitfalls of post-surgical results

Osilodrostat is a novel, orally administered cortisol synthesis inhibitor, approved in 2020 by the European Medicines Agency (EMA) for the treatment of Cushing's syndrome in adults. A significant amount of the studies currently available in the literature focus on treatment in patients with Cushing's disease. However, data collected from patients treated with osilodrostat in real-life settings still represents a small entity. For this reason, in this article, we will discuss two real-life cases of patients with Cushing's disease treated with this drug. The first report is about a 35-year-old woman with an adrenocorticotrophic hormone (ACTH)-secreting adenoma. After non-curative trans-nasal-sphenoidal (TNS) surgery, due to a small remnant of the adenoma, medical therapy with osilodrostat achieved fast and effective biochemical and clinical response. During treatment, progressive increase of ACTH levels and an enlargement of the pituitary remnant were documented, with planned radiosurgical treatment. The second case reports a 32-year-old man diagnosed with Cushing's disease in 2020, who, after surgery refusal, started osilodrostat at progressively up-titrated doses, according to 24 h urinary free cortisol levels, up to 5 mg twice a day. With osilodrostat, the patient reached biochemical and clinical control of disease until TNS surgery in October 2021, with complete remission. The first post-surgical biochemical assessment was equivocal in spite of a transient clinical hypoadrenalism, reverted after 2 months with the restoration of physiological hypothalamic-pituitary-adrenal axis (HPA) function. Osilodrostat is a potent oral drug viable for Cushing's disease as medical therapy when surgery is not feasible or remission cannot be reached. Osilodrostat proves to be a safe drug and its main adverse effect is hypoadrenalism, due to the adrenolytic action of the compound. Osilodrostat needs a very tailored approach in its clinical use because there is no correlation between the level of hypercortisolism pre-treatment and the dose required to reach disease control.

Dual B-cell targeting therapy ameliorates autoimmune cholangitis

ObjectiveThe ability to regulate B cell development has long been recognized to have therapeutic potential in a variety of autoimmune diseases. However, despite the presence of a classic autoantibody in primary biliary cholangitis (PBC), B cell depleting therapy and indeed therapy with other biologic agents has been disappointing. Unsuccessful treatment using Rituximab is associated with elevation of B-cell activating factor (BAFF) level. Indeed, therapies for PBC remain directed at modulating bile salt biology, rather than targeting effector pathways. With these data in mind, we proposed that targeting two major stages of B cell development, namely long-lived memory B cells and short-lived peripheral autoreactive plasma cells would have therapeutic potential. MethodsTo address this thesis, we administrated anti-BAFF and anti-CD20 monoclonal antibody to ARE-Del mice, a well-characterized murine model of human PBC. We evaluated and compared the therapeutic efficacy of the two agents individually and the combination of anti-BAFF and anti-CD20 in female mice with well-established disease. ResultsOur data demonstrate that there was an increased level of B cell depletion that resulted in a significantly more effective clinical and serologic response using the combination of agents as compared with the use of the individual agents. The combination of anti-BAFF and anti-CD20 treatment was more effective in reducing serum levels of antimitochondrial antibody (AMA), total IgM and IgG compared to mice treated with the 2 individual agents. Combination treatment efficiently depleted B cells in the peripheral blood, peritoneal cavity and spleen. Importantly, we identified a unique IgM+ FCRL5+ B cell subset which was sensitive to dual B-cell targeting therapy and depletion of this unique population was associated with reduced portal infiltration and bile duct damage. Taken together, our data indicate that dual B cell targeting therapy with anti-BAFF and anti-CD20 not only led to the efficient depletion of B cells both in the peripheral blood and tissues, but also led to significant clinical improvement. These findings highlight the potential application of combination of anti-BAFF and anti-CD20 in treating patients with PBC. However, additional studies in other animal models of PBC should be undertaken before considering human trials in those PBC patients who have incomplete responses to conventional therapy.

Long-term remission under Disitamab Vedotin (RC48) in HR-positive/HER2-positive metastatic breast cancer with brain meningeal, and bone marrow involvement: A case report.

Breast cancer (BC) with overexpression of human epidermal growth factor receptor 2 (HER2) is closely associated with an elevated risk of multiple distant metastases and unfavorable prognosis. Disitamab Vedotin (RC48) is a newly developed antibody-drug conjugate targeting HER2, which is comprised of hertuzumab coupled to monomethyl auristatin E via a cleavable linker. Pre-clinical studies indicated its strong anti-tumor activity in HER2-positive and low HER2 expression models of BC. The present study reported on the case of a 60-year-old postmenopausal female who suffered from fatigue and was diagnosed with a right-sided BC tumor. The diagnosis was stage IV (cT4N3M1) hormone receptor (HR)-positive and HER2-positive invasive ductal carcinoma with systemic metastases (brain included). The patient initially responded well to 26 cycles of the first-line anti-HER2 targeted therapy plus chemotherapy (trastuzumab+pertuzumab+nab-paclitaxel) combined with whole-brain radiotherapy. However, both extracranial and intracranial lesions achieved progressive disease (PD), which eventually occurred during 5 sequential cycles of maintenance therapy. Subsequently, 4 cycles of second-line treatment (trastuzumab + pyrotinib + capecitabin) were continued until the levels of blood tumor markers CEA, CA15-3 and CA125 were elevated, and systemic PD was able to be attained (the brain metastases were rated as stable disease). Finally, the patient received RC48 as the third-line therapy and achieved a durable and effective clinical response. To date, the patient has benefited from 12 cycles of RC48 without any severe adverse effects. The overall survival was >3 years. The present study showcased that RC48 was effective and tolerable for a patient with HR- and HER2-positive BMBC.

Comparison of chimeric antigen receptor-T cell-mediated cytotoxicity assays with suspension tumor cells using plate-based image cytometry method.

In the recent decade, chimeric antigen receptor (CAR)-T cell therapy has revolutionized strategies for cancer treatments due to its highly effective clinical efficacy and response for B cell malignancies. The success of CAR-T cell therapy has stimulated the increase in the research and development of various CAR constructs to target different tumor types. Therefore, a robust and efficient in vitro potency assay is needed to quickly identify potential CAR gene design from a library of construct candidates. Image cytometry methodologies have been utilized for various CAR-T cell-mediated cytotoxicity assay using different fluorescent labeling methods, mainly due to their ease-of-use, ability to capture cell images for verification, and higher throughput performance. In this work, we employed the Celigo Image Cytometer to evaluate and compare two CAR-T cell-mediated cytotoxicity assays using GFP-expressing or fluorescent dye-labeled myeloma and plasmacytoma cells. The GFP-based method demonstrated higher sensitivity in detecting CAR-T cell-mediated cytotoxicity when compared to the CMFDA/DAPI viability method. We have established the criteria and considerations for the selection of cytotoxicity assays that are fit-for-purpose to ensure the results produced are meaningful for the specific testing conditions.

Rationale and Clinical Use of Bronchodilators in Adults with Bronchiectasis.

Currently, there is much controversy surrounding the therapeutic approach to pulmonary function abnormalities in patients with bronchiectasis and, consequently, whether and when to use bronchodilators in these patients. National and international guidelines on the treatment of bronchiectasis in adults do not recommend the routine use of bronchodilators because there is no evidence that a significant response to a bronchodilator or the presence or hyperresponsiveness of the airway are good predictors of future effective clinical response. However, some guidelines recommend them in the presence of airway obstruction and/or special conditions, which vary according to the guideline in question, although there are no recommendations on optimal dosing and bronchodilator treatment combined with or without inhaled corticosteroids. Nonetheless, in contrast with guideline recommendations, bronchodilators are overused in real-world patients with bronchiectasis even in the absence of airway obstruction, as demonstrated by analysis of national and international registries. This overuse can be explained by the awareness of the existence of a solid pharmacological rationale that supports the use of bronchodilators in the presence of chronic airway obstruction independent of its aetiology. We performed a systematic review of the literature and were able to verify that there are no randomised controlled trials (apart from a small study with methodological limitations and a very recent trial involving a not-very-large number of patients), or any long-term observational studies on the short- or long-term effect of bronchodilators in patients with bronchiectasis. Therefore, we believe that it is essential and even urgent to evaluate the effects of bronchodilators in these patients with appropriately designed studies.

Serum Concentrations of Antigen-Specific IgG4 in Patients with Japanese Cedar Pollinosis

Purpose: To elucidate the usefulness of Japanese cedar pollen (JCP)-specific antigen-specific immunoglobulin (IgG) 4 as a biomarker for predicting the efficacy of sublingual immunotherapy for cedar pollen-induced allergic rhinitis. Methods: We divided a total of 105 cases with Japanese cedar pollinosis into three groups: “SLIT Successful,” SLIT Unsatisfactory,” and “SCIT” groups. The SLIT group patients were treated with JCP Droplet (Torii Pharmaceutical Co. Ltd., Tokyo, Japan) for one year from 2015 and were divided into two groups, the SLIT Successful group or the SLIT Unsatisfactory group. The SLIT Successful group (n = 16) were subjects treated by SLIT only, who were able to experience control of their naso-ocular symptoms without the need for antiallergic rescue agents during the peak season of atmospheric pollen. The SLIT Unsatisfactory group (n = 76) comprised subjects treated with SLIT only, who did not respond successfully, and were administered with rescue agents to control their naso-ocular symptoms. The SCIT group had been treated with standardized JCP extract (Torii Pharmaceutical Co., Ltd., Tokyo, Japan) for three years from 2012, and were also able to experience control of their symptoms during the peak pollen season without the need for antiallergic rescue agents. We determined the serum level of JCP-specific immunoglobulin E (IgE), IgG, and IgG4 used in the 3gAllergy-specific IgE assay (3gAllergy). The serum levels of periostin and SCCA2 were measured using established ELISA procedures (clones SS18A and SS17B; Shino-Test, Japan) following the manufacturer’s instructions. We then made ROC curves for each group and assessed which index was best able to predict the efficacy of sublingual immunotherapy. Results: Serum JCP-specific IgE was significantly lower in the SCIT group than in the SLIT Successful group and the SLIT Unsatisfactory group (p &lt; 0.05). Serum JCP-specific IgG was significantly higher in the SCIT group and the SLIT Successful group than in the SLIT Unsatisfactory group (p &lt; 0.05). Serum JCP-specific IgG4 was also significantly higher in the SCIT group and the SLIT Successful group than in the SLIT Unsatisfactory group (p &lt; 0.05). There was no significant difference among serum levels of periostin in the SCIT group, the SLIT Successful group, or the SLIT Unsatisfactory group. There was also no significant difference in SCCA2 among the three groups. In terms of ROC curves, a serum JCP-specific IgG4 value greater than 989.5 UA/mL showed the best sensitivity (93.3%) and specificity (94.7%) (p &lt; 0.05) among other parameters. Conclusions: The serum JCP-specific IgG4 level is significantly correlated with the clinical efficacy of SLIT. Serum JCP-specific IgG4 cutoff levels greater than 989.5 UA/mL were correlated with an effective clinical response to SLIT, with a sensitivity of 93.3% and a specificity of 94.7%.