Initial Therapeutic Success Research Articles

Indications and Outcomes of Emergency Keratoplasty in a Major New Zealand Eye Tertiary Referral Center, 2000 to 2021.

To report the indications and outcomes of emergency keratoplasty over a 21-year period in Greenlane Clinical Centre, the major tertiary eye referral center in Auckland, New Zealand (Aotearoa). A retrospective review of medical records of all emergency keratoplasties performed in Greenlane Clinical Centre from January 2000 to September 2021 was conducted. Demographic, preoperative, intraoperative, and 1-year postoperative data were collected. Emergency keratoplasty was performed in 102 eyes of 97 patients (54 men), comprising 5.6% of transplants performed (N = 1830) in this period. The mean age was 53 years (range = 4-95 years, SD = 20). Patients of Māori ethnicity were overrepresented (31%). Corneal perforation was present in 90% of eyes, and microbial keratitis was the most common indication. Bacteria were the most commonly isolated organisms (38%). The mean preoperative and 12-month postoperative best potential corrected distance visual acuity was 1.6 and 1.2 (logMAR), respectively. All cases of therapeutic keratoplasty achieved initial therapeutic success, with no eyes lost or requiring repeat emergency keratoplasty. Complications included nonhealing epithelial defects (19%), cataract (19%), glaucoma (15%), allograft rejection (13%), and corneal melting (5%). Fifteen cases (15%) had documented graft failure at 12 months. Multivariate analysis revealed that younger age was the only statistically significant factor associated with failure at 12 months. Emergency keratoplasty was the indication for 5.6% of keratoplasties performed. Our results compare favorably with those in the literature, possibly because of early intervention and lower incidence of fungal keratitis. The reported overrepresentation of Māori has important implications for health access and delivery in New Zealand.

Generation and Characterization of Trastuzumab/Pertuzumab-Resistant HER2-Positive Breast Cancer Cell Lines.

The combination of trastuzumab and pertuzumab as first-line therapy in patients with HER2-positive breast cancer has shown significant clinical benefits compared to trastuzumab alone. However, despite initial therapeutic success, most patients eventually progress, and tumors develop acquired resistance and invariably relapse. Therefore, there is an urgent need to improve our understanding of the mechanisms governing resistance in order to develop targeted therapeutic strategies with improved efficacy. We generated four novel HER2-positive cell lines via prolonged exposure to trastuzumab and pertuzumab and determined their resistance rates. Long-term resistance was confirmed by a significant increase in the colony-forming capacity of the derived cells. We authenticated the molecular identity of the new lines via both immunohistochemistry for the clinical phenotype and molecular profiling of point mutations. HER2 overexpression was confirmed in all resistant cell lines, and acquisition of resistance to trastuzumab and pertuzumab did not translate into differences in ER, PR, and HER2 receptor expression. In contrast, changes in the expression and activity of other HER family members, particularly HER4, were observed. In the same vein, analyses of the receptor and effector kinase status of different cellular pathways revealed that the MAPK pathway may be involved in the acquisition of resistance to trastuzumab and pertuzumab. Finally, proteomic analysis confirmed a significant change in the abundance patterns of more than 600 proteins with implications in key biological processes, such as ribosome formation, mitochondrial activity, and metabolism, which could be relevant mechanisms in the generation of resistance in HER2-positive breast cancer. We concluded that these resistant BCCLs may be a valuable tool to better understand the mechanisms of acquisition of resistance to trastuzumab and pertuzumab-based anti-HER2 therapy.

Folliculotropic Mycosis Fungoides: Current Guidance and Experience from Clinical Practice

IntroductionFolliculotropic mycosis fungoides (FMF) is the most frequent variant of mycosis fungoides (MF), with clinical features which differ from the classic form. As for therapeutic options, the latest guidelines on MF agree on a stage-driven strategy, in consideration of clinical presentation, symptom burden and patient’s comorbidities.Materials and MethodsA search on MEDLINE, PubMed, Scopus and Cochrane Library was conducted to gather the latest evidence on FMF clinical management. Manuscripts published in the last five years (January 2017–April 2022) were included. Our single-center experience was also described.ResultsA total of 15 articles were analyzed, with a total of 432 patients (disease stage from IA to IVA2). The most widely-used treatment was psoralen ultra-violet A (PUVA) in monotherapy or in association with other drugs. Oral retinoid-based therapy was also described as a therapeutic option alone or in combination. Other therapy reported were based on Brentuximab Vedotin, Mogamulizumab, Carmustine, topical steroids, tazarotene and excimer laser, interferon, nitrogen mustard, imiquimod, systemic chemotherapy, extracorporeal photopheresis and stem cell transplantation.DiscussionFMF is characterized by specific clinical-pathologic features. Advanced forms assume characteristics more similar to classic MF (infiltrated plaques and nodules), whilst early stages can present in a wide range of clinical forms (acneiform lesions, follicular-like keratoses, erythematous patches). As for therapeutic options, in absence of specific guidelines, a high number of treatments are described in clinical practice, with variable results. Phototherapy in all its forms, especially as PUVA, appears to have the greatest initial therapeutic success. Retinoids, although widely used, appear to be poorly effective in monotherapy, particularly acitretin. Combination treatment with phototherapy seems to be advisable. Ionizing treatments, such as radiotherapy and TSEBT, appear effective, at least in the short term. Overall, an integrated approach is mandatory for the inconstant course of the disease and its multidisciplinary nature.

The Role of TCF7L2 in Type 2 Diabetes.

TCF7L2 is the most potent locus for type 2 diabetes (T2D) risk and the first locus to have been robustly reported by genomic linkage studies. TCF7L2 is a transcription factor that forms a basic part of the Wnt signaling pathway. This gene has highly conserved sequence regions that correspond to functional domains. The association of TCF7L2 with T2D is one of the most powerful genetically discovered in studies of complex diseases, as it has been consistently replicated in multiple populations with diverse genetic origins. The mechanisms over which TCF7L2 exerts its effect on T2D are still not well understood. In this article, we describe the main molecular mechanisms of how TCF7L2 is related to T2D. TCF7L2 variants associated with T2D risk exert an influence on the initial therapeutic success of the hypoglycemic oral agent sulfonylurea. Thus, it is important to know whether there are other TCF7L2 variants associated with T2D that can influence treatment with oral hypoglycemic agents. Resequencing of the TCF7L2 gene in diverse ethnic groups is required to reveal common and rare variations and their role in different pathologies and in adverse reactions to drugs. Identification of TCF7L2-susceptibility disease variants will permit, at a given moment, offering of therapies to patients according to their genotype.

Abstract 4026: Mechanism of cisplatin resistance and enhanced cell migration in cervical cancer cells expressing PIK3CA-E545K mutation

Abstract Platinum-based drugs, in particular cisplatin, are among the most widely used chemotherapeutic agents, used in the treatment of a wide array of solid malignancies. Despite initial therapeutic success, cisplatin treatment often results in the development of resistance, which can lead to therapeutic failure. Despite significant advances in understanding mechanisms of cisplatin resistance in other tumor sites, there are substantial gaps in our molecular knowledge of resistance in cervical cancer. Our group has examined the role of the PI3K/AKT/mTOR pathway in cervical cancer patients treated with cisplatin and radiation therapy. The PI3K/AKT/mTOR pathway is a promising therapeutic target because it is activated in several human cancers, which is frequently mediated by “hotspot” mutations including E542K, E545K and H1047R in the PIK3CA gene. Moreover, multiple PI3K/AKT/mTOR pathway inhibitors have been developed and are currently being evaluated in clinical trials. We previously reported that PIK3CA mutation in patients with early stage (IB/II) cervical cancer was associated with poor survival after treatment with radiation and cisplatin (McIntyre et al. Gynecol Oncol. 2013, PMID: 23266353), and that PIK3CA-E545K mutation renders cervical cancer cells more resistant to cisplatin or cisplatin plus radiation and results in a more migratory phenotype than cell lines with wild type-PIK3CA. Moreover, these phenotypes were reversed by the PI3K inhibitor GDC-0941 (Wani et al. Oncotarget. 2016, PMID: 27489350). The aim of the present study is to explore the mechanism of cisplatin resistance and enhanced migration in cervical cancer cells engineered to express PIK3CA-E545K mutation. Gene expression analysis identified 161 genes that were up regulated and 189 that were down regulated in cervical cancer cells stably expressing PIK3CA-E545K, some of which are involved in pathways relevant to cisplatin resistance. On further validation, we found that Fibronectin1 (FN1) was upregulated at both the mRNA and protein level in cervical cancer cells expressing PIK3CA-E545K. FN1 is a glycoprotein that is widely expressed in multiple cell types and is involved in cellular adhesion and migration. Recent studies have reported that FN1 might have a role in regulating chemoresistance in tumors. However, the effect of FN1 on cisplatin resistance in cervical cancer cells expressing E545K mutation has not been investigated. The present study aims to determine the effect of FN1 expression on cisplatin resistance in cervical cancer cells expressing the PIK3CA-E545K mutation and to explore potential mechanisms of cisplatin resistance and enhanced cell migration in cervical cancer cells. Citation Format: Arjumand Wani, Shiekh Tanveer Ahmad, Nicholas Jette, Siddhartha Goutam, Corinne M. Doll, Susan P. Miller. Mechanism of cisplatin resistance and enhanced cell migration in cervical cancer cells expressing PIK3CA-E545K mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4026.

A Strategy to Delay the Development of Cisplatin Resistance by Maintaining a Certain Amount of Cisplatin-Sensitive Cells

Cisplatin (ddp), which is commonly employed in the treatment of many advanced cancers, often results in initial therapeutic success; however, rapid progression of ddp-resistant cells remains the main reason for treatment failure. Facd with such a problem, we investigated the fitness differences between ddp-sensitive and ddp-resistant cell lines. We found that the growth of ddp-resistant cells was significantly slower than that of sensitive cells due to elevated ROS levels, which suggested that the ddp resistance mechanisms may have negative impacts on the growth of resistant cells. Furthermore, we observed that, when mixed with ddp-sensitive cells, ddp-resistant cells failed to compete, and the growth of ddp-resistant cells could therefore be suppressed by treatment in vivo. We propose a mathematical model parameterized based on in vivo experiments to describe the allometric growth of tumors consisting of two competing subclones. According to our model, a quantitative strategy with a variant drug-dosing interval is proposed to control tumor growth. Taking advantage of intratumoral competition, our strategy with appropriate dosing intervals could remarkably delay the development of ddp resistance and prolong overall survival. Maintaining a certain number of ddp-sensitive cells rather than eradicating the tumor with continuous treatment is feasible for future tumor treatment.

Synergistic interaction of β-galactosyl-pyrrolidinyl diazeniumdiolate with cisplatin against three tumor cells

Cisplatin is a platinum-based compound that is largely employed as an effective antitumor drug against a wide spectrum of solid neoplasms for many years. Despite of its initial therapeutic success, cisplatin often results in high incidence of chemoresistance and high-dose cytotoxicity. Consequently, considerable efforts in hopes of reducing the dose-dependent side effects of cisplatin while retaining, or even enhancing, its antitumor properties have been undertaken throughout the past three decades. Nitric oxide (NO) is a small lipophilic free radical gas possessing versatile biological functions, including antitumor activities. However, NO, of itself, is difficult to be used, because of its extreme instability and short half-life. Previously, we have reported a stable NO donor, β-galactosyl-pyrrolidinyl diazeniumdiolate (β-Gal-NONOate), which exerts tumor killing effects through site-specific intracellular release of exogenous NO. In this study, we further investigated the combined inhibitory effect of β-Gal-NONOate and cisplatin against C6/LacZ, 9L/LacZ, and HeLa/LacZ tumor cells. It was shown that, in combination with β-Gal-NONOate, the antitumor effects of cisplatin against these common tumor cell lines were increased in a dose-dependent manner. Furthermore, the combination of these chemicals resulted in a synergistic suppression on tumor growth, which was achieved under a much lower cisplatin dosage. Collectively, our findings indicate that β-Gal-NONOate can synergistically improve the antitumor effect of cisplatin, and may therefore reduce its side effects caused by high dose cisplatin monochemotherapies. Accordingly, β-Gal-NONOate is an important therapeutic assistant reagent with great potential of clinical applicability, and thus worth of continuous research in the coming future.

Targeted agents for the treatment of metastatic melanoma.

In the last year, the armamentarium of melanoma therapeutics has radically changed. Recent discoveries in melanoma biology and immunology have led to novel therapeutics targeting known oncogenes and immunotherapeutic antibodies. Phase III clinical trials of these agents have reported measurable and meaningful benefits to patients with metastatic disease. In this article, we review recent findings and discuss their significance in melanoma therapy. As our understanding of melanoma biology grows, this initial therapeutic success may be enhanced through the use of molecular markers to select patients, and new targeted immunotherapies in sequential or combination drug regimens.

Methotrexate in ulcerative colitis: A Spanish multicentric study on clinical use and efficacy

BackgroundFew data are available on the efficacy of methotrexate (MTX) in ulcerative colitis (UC). AimTo evaluate the efficacy and safety of MTX in UC patients. Patients and methodsUC patients who had been treated with MTX were identified from the databases of 8 Spanish IBD referral hospitals. Patients were included in the study if they received MTX for steroid dependency or steroid refractoriness. Therapeutic success was defined as the absence of UC-related symptoms, complete steroid withdrawal and no requirement of rescue therapies within the first 6months after starting MTX. ResultsForty patients were included, 70% treated for steroid dependency and 27% for steroid refractoriness. Thiopurines had been previously attempted in 87.5% of patients. The median dose of MTX used for induction was 25mg (IIQ 17.5–25) weekly given parenterally in 82.5% of cases. Eighty-five percent of patients were on steroids when MTX was started. Forty-five percent of patients met criteria for therapeutic success. Initial treatment failures were mainly due to inefficacy (50%) or intolerance (36%). After a median follow-up of 28months (IQR 22–47), 38% of patients with initial therapeutic success required new steroid courses, 22% started biological therapy, and only 1 patient required colectomy. The cumulative probability of maintaining steroid-free clinical remission was 60%, 48%, and 35% at 6, 12, and 24months after starting MTX, respectively. Eleven patients (27.5%) experienced adverse events, leading to MTX discontinuation in only 8 of them. ConclusionsMTX appears to be effective to maintain clinical remission in UC, at least in the short-term, with an acceptable safety profile.

Clinical use of E. coli Nissle 1917 in inflammatory bowel disease

The probiotic Escherichia coli strain Nissle 1917 is in addition to some Lactobacilli sp. one of the best-studied probiotic strains. This particular E. coli strain was isolated in 1917 based on its potential to protect from presumably infectious gastroenteritis. Initial therapeutic success was noted in the management of gastrointestinal infectious disorders and infections affecting the urinary tract; the focus shifted later to chronic inflammatory conditions. The unique combination of fitness and survival factors to support intestinal survival, the lack of virulence, and obvious probiotic properties make this microorganism a safe and effective candidate in the treatment of chronic inflammatory bowel diseases. Three large clinical trials have assessed the potential in the maintenance of remission of ulcerative colitis and equivalence to standard 5-ASA medication was documented. This review aims to discuss important mechanisms of E. coli Nissle 1917 and will review the available literature regarding treatment of inflammatory bowel diseases.

Ablación de taquicardia ventricular mediante radiofrecuencia en pacientes con cardiopatía isquémica

We analyze the efficacy of radiofrequency catheter ablation and the clinical significance of inducible ventricular tachycardia that had never been documented before (non clinical ventricular tachycardia) in patients with ventricular tachycardia and coronary artery disease. Thirty-four patients (30 men, aged 61 +/- 10 years, left ventricular ejection fraction 31 +/- 10%) with coronary artery disease and documented clinical ventricular tachycardia underwent radiofrequency ablation. Thirty-four clinical ventricular tachycardia and 11 non clinical ventricular tachycardia were treated with radiofrequency. Initial therapeutic success was considered when none of the ventricular tachycardia treated with radiofrequency could no longer be induced at the last stimulation protocol before discharge. Clinical ventricular tachycardia was successfully ablated in 23 patients (68%). Initial therapeutic success was obtained in 21 patients (62%). In 6 of them, 7 non clinical ventricular tachycardia poor tolerated were also induced. During a mean follow-up of 26 +/- 15 months ventricular tachycardia recurred in 6 patients (29%). Five of the 6 patients who recurred were discharged with no inducible non clinical ventricular tachycardia. Three patients died during the follow-up. Two of them from heart failure (one with previous recurrence) and the other suddenly with documented asystole after loss of consciousness without previous recurrence. In our series of patients with ventricular tachycardia and coronary artery disease selected for radiofrequency ablation, acute success was obtained in 62%. After a mean follow-up of 2 years, 44% of all the patients were free from ventricular tachycardia. Although the possibility of ventricular tachycardia recurrence is high (29%), the recurrence rate is not increased by the inducibility of non clinical ventricular tachycardia.

The etiology and treatment of infective prostatitis

Prostatitis is a common disorder which remains poorly understood. The causes of nonbacterial prostatitis and prostadynia are unclear, but new molecular methods show promise in uncovering some infectious agents. Bacterial prostatitis constitutes 5 to 10% of the total cases of prostatitis, but causative organisms are well-delineated. Unfortunately the high initial therapeutic success rates using antibiotics directed against these susceptible organisms are too often associated with high relapse rates. Quinolones, such as ciprofloxacin, ofloxacin, and trovafloxain, are the agents of choice for antibacterial therapy of prostatitis. More information is needed concerning the antibiotic levels and activity in infected prostatic tissue and secretions, optimum duration of therapy, and benefit of long-term suppressive therapy.