Influence of serum inflammatory cytokines on cytochrome P450 drug metabolising activity during breast cancer chemotherapy: a patient feasibility study

AbstractIndividual response to chemotherapy in patients with breast cancer is variable. Obesity and exercise are associated with better and worse outcomes, respectively, and it is known that both impact the systemic cytokine milieu. Cytochrome P450 (CYP) enzymes are responsible for the metabolism of many chemotherapy agents, and CYP enzyme activity has been shown to be modified by inflammatory cytokines in vitro and in vivo. Cytokine-associated changes in CYP metabolism may alter chemotherapy exposure, potentially affecting treatment response and patient survival. Therefore, better understanding of these biological relationships is required. This exploratory single arm open label trial investigated changes in in vivo CYP activity in twelve women treated for stage II or III breast cancer, and demonstrated for the first time the feasibility and safety of utilising the Inje phenotyping cocktail to measure CYP activity in cancer patients receiving chemotherapy. Relative CYP activity varied between participants, particularly for CYP2C9 and CYP2D6, and changes in serum concentrations of the inflammatory cytokine monocyte chemoattractant protein 1 inversely correlated to CYP3A4 activity during chemotherapy. Future use of phenotyping cocktails in a clinical oncology setting may help guide drug dosing and improve chemotherapy outcomes.Clinical Trial Registration: Trial was retrospectively registered to the Australia New Zealand Clinical Trial Registry (ANZCTR). ACTRN12620000832976, 21 Aug 2020, https://www.anzctr.org.au/ACTRN12620000832976.aspx.

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Clinical and immunological benefits of convalescent plasma therapy in severe COVID-19: insights from a single center open label randomised control trial

10.1101/2020.11.25.20237883 ◽

2020 ◽

Cited By ~ 1

Author(s):

Yogiraj Ray ◽

Shekhar Ranjan Paul ◽

Purbita Bandopadhyay ◽

Ranit D’Rozario ◽

Jafar Sarif ◽

...

Keyword(s):

Clinical Trial ◽

Passive Immunization ◽

Neutralizing Antibody ◽

Randomised Control Trial ◽

Single Center ◽

Clinical Trial Registry ◽

Open Label ◽

Plasma Therapy ◽

Clinical Trial Registration ◽

Clinical Benefits

AbstractIntroductionA single center open label phase II randomised control trial was done to assess the pathogen and host-intrinsic factors influencing clinical and immunological benefits of passive immunization using convalescent plasma therapy (CPT), in addition to standard of care (SOC) therapy in severe COVID-19 patients, as compared to patients only on SOC therapy.MethodsConvalescent plasma was collected from patients recovered from COVID-19 following a screening protocol which also included measuring plasma anti SARS-CoV2 spike IgG content. Retrospectively, neutralizing antibody content was measured and proteome was characterized by LC-MS/MS for all convalescent plasma units that were transfused to patients. Severe COVID-19 patients with evidence for acute respiratory distress syndrome (ARDS) with PaO2/FiO2 ratio 100-300 (moderate ARDS) were recruited and randomised into two parallel arms of SOC and CPT, N=40 in each arm. Peripheral blood samples were collected on the day of enrolment (T1) followed by day3/4 (T2) and day 7 (T3). RT-PCR and sequencing was done for SARS-CoV2 RNA isolated from nasopharyngeal swabs collected at T1. A panel of cytokines and neutralizing antibody content were measured in plasma at all three timepoints. Patients were followed up for 30 days post-admission to assess the primary outcomes of all cause mortality and immunological correlates for clinical benefits.ResultsWhile across all age-groups no statistically significant clinical benefit was registered for patients in the CPT arm, significant immediate mitigation of hypoxia, reduction in hospital stay as well as survival benefit was recorded in severe COVID-19 patients with ARDS aged less than 67 years receiving convalescent plasma therapy. In addition to its neutralizing antibody content a prominent effect of convalescent plasma on attenuation of systemic cytokine levels possibly contributed to its benefits.ConclusionPrecise targeting of severe COVID-19 patients is necessary for reaping the clinical benefits of convalescent plasma therapy.Clinical trial registrationClinical Trial Registry of India No. CTRI/2020/05/025209

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PREDIX II HER2: Improving pre-operative systemic therapy for human epidermal growth factor receptor 2 (HER2) amplified breast cancer (BC).

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.tps605 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. TPS605-TPS605

Author(s):

Renske Kornalijnslijper-Altena ◽

Anne Andersson ◽

Yvonne Brandberg ◽

Luisa Edman Kessler ◽

Ellinor Elinder ◽

...

Keyword(s):

Breast Cancer ◽

Clinical Trial ◽

Systemic Therapy ◽

Checkpoint Inhibitors ◽

Growth Factor Receptor ◽

Tumor Infiltrating Lymphocytes ◽

Predictive Marker ◽

Complete Response ◽

Clinical Trial Registry ◽

Open Label

TPS605 Background: Neo-adjuvant systemic therapy (NAT) is the standard of care for most patients with early HER2-amplified and triple negative breast cancer (BC). Increasing the rate of pathological complete response (pCR) is highly meaningful for those patients, as pCR is strongly predictive for improved long-term disease-related outcomes. Clinical and preclinical evidence support the hypothesis that pCR-rates may be augmented by the addition of checkpoint inhibitors, such as monoclonal antibodies targeting the Programmed Death Ligand receptor 1 (PD-L1), to standard systemic NAT. Studies in different BC patient cohorts (e.g., IMPassion130, PANACEA, KATE2) have indicated that PD-L1 protein expression on tumor-infiltrating lymphocytes (TIL’s) is a predictive marker for checkpoint inhibitor efficacy. Methods: We have initiated a phase II open-label, 2:1 randomized clinical trial where women with early HER2-amplified, PD-L1+ BC (cT2-3 and/or cN+) are treated with standard NAT (composed of anti-HER2 antibodies with a chemotherapy backbone of sequentially taxanes + carboplatin and epirubicin + cyclophosphamide [EC]) +/- atezolizumab during EC. N = 190 patients will be accrued in nine centers in Sweden to be able to demonstrate a 20% increase in pCR-rate, with a power of 80% and a two-sided alpha of 10%. Firstly, a prescreening is performed to select patients with a PD-L1 expression of > 1% on TIL’s. Important exclusion criteria are significant organ dysfunction and (with some exceptions) active auto-immune diseases. Extensive translational side-studies are performed to explore predictive markers for treatment efficacy, including clinicopathologic studies, molecular imaging and microbiome analyses, as well as monitoring of acute and chronic treatment-related toxicity, objective cognitive function and quality of life. As of February 11th, 4 patients have been prescreened and 1 enrolled in the trial. The clinical trial registry number is NCT03894007. Clinical trial information: NCT03894007 .

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Expression of inflammatory mediators in biofilm samples and clinical association in inflammatory bowel disease patients—a preliminary study

Clinical Oral Investigations ◽

10.1007/s00784-021-04093-2 ◽

2021 ◽

Author(s):

Mayte Buchbender ◽

Jakob Fehlhofer ◽

Peter Proff ◽

Tobias Möst ◽

Jutta Ries ◽

...

Keyword(s):

Clinical Trial ◽

Inflammatory Bowel Disease ◽

Oral Cavity ◽

Bowel Disease ◽

Trial Registry ◽

Clinical Trial Registry ◽

Clinical Trial Registration ◽

Expression Levels ◽

Inflammatory Bowel ◽

Group 2

Abstract Objectives Inflammatory bowel disease (IBD) has multiple impacts on soft and hard tissues in the oral cavity. The aim of this study was to analyze the expression of cytokines in biofilm samples from patients suffering from IBD and compare them to healthy patients. It was hypothesized that different cytokine expression levels and clinical associations might be drawn. Material and methods A total of 56 biofilm samples from three different patient cohorts (group 0 = healthy, HC n = 30; group 1 = Crohn’s disease, CD, n = 19; group 2 = ulcerative colitis, UC, n = 7) were examined for the expression levels of the cytokine interleukins IL-2, -6, and -10; matrix metalloproteinases 7 and 9; and surface antigens CD90/CD11a by quantitative real-time PCR and according to clinical parameters (plaque index, BOP, PD, DMFT, CAL). Relative gene expression was determined using the ∆∆CT method. Results The mean BOP values (p = 0.001) and PD (p = 0.000) were significantly higher in the CD group compared to controls. Expression of IL-10 was significantly higher in the CD (p = 0.004) and UC groups (p = 0.022). Expression of MMP-7 was significantly higher in the CD group (p = 0.032). IBD patients treated with TNF inhibitors (p = 0.007) or other immunosuppressants (p = 0.014) showed significant overexpression of IL-10 compared to controls. Conclusion Different expression levels of IL-10 and MMP-7 were detected in plaque samples from IBD patients. As only BOP was significantly increased, we conclude that no clinical impairment of periodontal tissue occurred in IBD patients. Clinical relevance With the worldwide increasing incidence of IBD, it is important to obtain insights into the effects of the disease on the oral cavity. The study was registered (01.09.2020) at the German clinical trial registry (DRKS00022956). Clinical trial registration The study is registered at the German clinical trial registry (DRKS00022956).

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Creation of a primary breast cancer culture repository from patients with a BMI >30 kg/m2: A Mexican endeavor.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e12574 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e12574-e12574

Author(s):

Daniela Shveid Gerson ◽

Alejandro Zentella - Dehesa ◽

Raquel Gerson Cwilich ◽

Benigno Rodriguez ◽

Omar Serrano Villamayor ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Primary Breast Cancer ◽

Medical Center ◽

Primary Cultures ◽

Obese Women ◽

Cellular Analysis ◽

Response To Chemotherapy

e12574 Background: Currently there are no primary cultures or cell lines derived from patients with breast cancer and obesity. It has been postulated that breast cancer in obese women behaves differently as it does in non-obese women, as is composed of distinct biological features, as was generated in a different metabolic environment, as well as pertains to a different prognosis and different response to chemotherapy, lower rates of overall survival and a greater probability of recurrence. By creating a primary breast cancer culture bank of breast cancer tumors from women with obesity (BMI > 30kg/m2), we will establish a cell line exclusive to obese women in Mexico, where targeted therapy may be tested and treatment may be individualized depending on the characteristics of the patient. Methods: This study recruited 32 women with breast cancer and a BMI > 30 kg/m2, matched by 6 controls with are non-obese women with breast cancer. Elegibility criteria was determined by women with breast cancer confirmed by pathology, who had not been subjected to prior treatment regarding the neoplasm. The breast cancer removing surgeries and the patients were selected from the ABC Medical Center in Mexico City and all procedures were approved by the research and ethics committee of the hospital in question. Results: Through extensive communication a cooperative protocol was established between the departments of surgery, oncology, pathology and nursing to coordinate efforts and be able to take a 2 – 5 mm sample of the breast tumor removed from the patient. To be able to distinguish cancer cells from non-cancer cells (epithelial cells, fibroblasts, adipocytes) the Hayflick limit was be utilized. Once a primary breast cancer culture was established, 12 million cells will be injected into the subscapular area of athymic, nu-nu mice to be able to monitor tumoral growth in vivo and conduct a subsequent cellular analysis, determining it still pertains to the same characteristics of the tumor from which it was obtained. Conclusions: A primary breast cancer culture repository from patients with a BMI > 30 kg/m2 was established. This is the first primary breast cancer culture for both Mexican and obese women with breast cancer, the first in vitro method of analysis of specific characteristics typical of the Mexican population. Translational research may now be conducted on these new tumoral cultures to create individualized therapy for women with the distinct, aforementioned characteristics.

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Practical and conceptual issues of clinical trial registration for Brazilian researchers

Sao Paulo Medical Journal ◽

10.1590/1516-3180.2014.00441803 ◽

2015 ◽

Vol 134 (1) ◽

pp. 28-33 ◽

Cited By ~ 3

Author(s):

Carolina Gomes Freitas ◽

Thomas Fernando Coelho Pesavento ◽

Maurício Reis Pedrosa ◽

Rachel Riera ◽

Maria Regina Torloni

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

International Committee ◽

New Drugs ◽

Trial Registration ◽

Clinical Trial Registry ◽

Clinical Trial Registration ◽

Registration Process ◽

Trial History ◽

Definition Of

CONTEXT AND OBJECTIVE: Clinical trial registration is a prerequisite for publication in respected scientific journals. Recent Brazilian regulations also require registration of some clinical trials in the Brazilian Clinical Trials Registry (ReBEC) but there is little information available about practical issues involved in the registration process. This article discusses the importance of clinical trial registration and the practical issues involved in this process. DESIGN AND SETTING: Descriptive study conducted by researchers within a postgraduate program at a public university in São Paulo, Brazil. METHODS: Information was obtained from clinical trial registry platforms, article reference lists and websites (last search: September 2014) on the following topics: definition of a clinical trial, history, purpose and importance of registry platforms, the information that should be registered and the registration process. RESULTS: Clinical trial registration aims to avoid publication bias and is required by Brazilian journals indexed in LILACS and SciELO and by journals affiliated to the International Committee of Medical Journal Editors (ICMJE). Recent Brazilian regulations require that all clinical trials (phases I to IV) involving new drugs to be marketed in this country must be registered in ReBEC. The pros and cons of using different clinical trial registration platforms are discussed. CONCLUSIONS: Clinical trial registration is important and various mechanisms to enforce its implementation now exist. Researchers should take into account national regulations and publication requirements when choosing the platform on which they will register their trial.

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Enhanced Anticancer Activity of Nanoformulation of Dasatinib against Triple-Negative Breast Cancer by Reduced Metabolic Degradation

10.20944/preprints202104.0724.v1 ◽

2021 ◽

Author(s):

Fatemah Bahman ◽

Valeria Pittalà ◽

Mohamed Haider ◽

Khaled Greish

Keyword(s):

Breast Cancer ◽

Anticancer Activity ◽

Triple Negative Breast Cancer ◽

Tyrosine Kinases ◽

Triple Negative ◽

Growth Factor Receptor ◽

Initial Response ◽

Response To Chemotherapy

Triple negative breast cancer (TNBC) is the most aggressive breast cancer accounting for around 15% of identified breast cancer cases. TNBC, by lacking estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), is unresponsive to current targeted therapies. Existing treatment relies on chemotherapeutic treatment but, despite an initial response to chemotherapy, the inception of resistance and relapse is unfortunately common. Dasatinib is an approved second-generation inhibitor of multiple tyrosine kinases and literature data strongly support its use in the management of TNBC. However, dasatinib binds to plasma proteins and undergoes extensive metabolism through oxidation and conjugation. To protect dasatinib from fast pharmacokinetic degradation and to prolong its activity, it was encapsulated on poly(styrene-co-maleic acid) (SMA) micelles. The obtained SMA-dasatinib nanoparticles (NPs) were evaluated for their physicochemical properties, in vitro antiproliferative activity in different TNBC cell lines, and in vivo anticancer activity in a syngeneic model of breast cancer. Obtained results showed that SMA-dasatinib is more potent against 4T1 TNBC tumor growth in vivo compared to free drug. This enhanced effect was ascribed to the encapsulation of the drug protecting it from a rapid metabolism. Our finding highlights the often-overlooked value of nanoformulations in protecting its cargo from degradation. Overall, results may provide an alternative therapeutic strategy for TNBC management.

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Hibiscus sabdariffa tea affects diet-induced thermogenesis and subjective satiety responses in healthy men, but not in women: a randomized crossover trial

Applied Physiology Nutrition and Metabolism ◽

10.1139/apnm-2021-0051 ◽

2021 ◽

Author(s):

Natália Cristina de Faria ◽

Ana Paula da Costa Soares ◽

Guilherme Fonseca Graciano ◽

Maria Isabel Toulson Davisson Correia ◽

Magda Carvalho Pires ◽

...

Keyword(s):

Clinical Trial ◽

Food Intake ◽

Energy Expenditure ◽

Resting Energy Expenditure ◽

Hibiscus Sabdariffa ◽

Clinical Trial Registry ◽

Open Label ◽

Satiety Response ◽

Diet Induced Thermogenesis ◽

Desire To Eat

The aim of this study was to investigate the effect of Hibiscus sabdariffa tea on energy expenditure, satiety response and food intake. This is an open-label, crossover, randomized clinical trial (RBR-5HZ86T), including 21 subjects (11 women, 10 men). The individuals were evaluated at acute moments (fasting and after eating standardized breakfast accompanied by water or Hibiscus sabdariffa tea). Resting energy expenditure was measured by indirect calorimetry, subjective satiety responses were evaluated with a visual analogue scale and food intake was assessed by using food records. The volunteers who drank the Hibiscus sabdariffa tea had lower perception of hunger (p=0.002) and greater feeling of satiety (p=0.010) and fullness (p=0.009) compared to control. Men who ingested the Hibiscus sabdariffa tea had an increase in nitrogen energy expenditure (water: 1501±290.7kcal, Hibiscus sabdariffa tea: 1619±288.9kcal; p=0.029). In comparison to control, men presented less perception of hunger (p=0.003) and desire to eat (p=0.016), increased satiety (p=0.021) and fullness (p=0.010), and women oxidized more fat (p=0.034) when they drank Hibiscus sabdariffa tea. There was no difference between treatments regarding the energy and macronutrient intake from the first meal and throughout the day (p>0.050) for all participants. The Hibiscus sabdariffa tea only affected energy expenditure and satiety responses in men. Clinical trial registry: ReBEC Platform of the Brazilian Clinical Trials Registry - RBR-5HZ86T Novelty bullets • Hibiscus sabdariffa tea promoted an increase in energy expenditure and caused less perception of hunger/desire to eat in men. • Hibiscus sabdariffa tea intake increased postprandial fat oxidation in women.

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A randomized, open-label, phase 3 study of low-dose selinexor and lenalidomide (Len) versus len maintenance post autologous stem cell transplant (ASCT) for newly diagnosed multiple myeloma (NDMM): ALLG MM23, Sealand.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.tps8055 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. TPS8055-TPS8055

Author(s):

Hang Quach ◽

Masa Lasica ◽

David Routledge ◽

Anna Kalff ◽

Andrew Lim ◽

...

Keyword(s):

Clinical Trial ◽

Nuclear Export ◽

Low Dose ◽

Performance Status ◽

Cell Transplant ◽

Weekly Schedule ◽

Open Label ◽

Phase 3 ◽

Clinical Trial Registration ◽

National Cooperative

TPS8055 Background: Len maintenance post ASCT is standard of care for patients (pts) with NDMM. Deep responses (CR or better) post ASCT correlates with better progression free survival (PFS). In a meta-analysis of len maintenance post ASCT (McCarthy PL et al. J Clin Oncol. 2017), only 10.7% of pts achieve CR post ASCT, and 72% of pts who discontinued len maintenance did so because of progressive disease (PD). Selinexor is a selective inhibitor of nuclear export that blocks exportin 1, thus retaining tumour suppressor proteins within the nucleus while blocking proto-oncoprotein translation. It is approved in combination with bortezomib and dexamethasone (dex) for pts with MM who have had at least 1 prior line of treatment, or with dex for pts with penta-refractory MM by the FDA. The oral bioavailability and weekly schedule of selinexor makes it suitable in combination with len for maintenance therapy. Given the encouraging activity (ORR 92%) and tolerability of selinexor, len and dex from the phase 1b/2 STOMP study, we hypothesise that combination low-dose selinexor and len (XR) will be well tolerated and effective, increasing CR and MRD negativity rate post ASCT, thus prolonging PFS compared to len. Methods: ALLG MM23 SeaLAND, is an ongoing randomised, multi-centre, phase 3 trial. Eligible pts ( > 17 years of age) have measurable disease, have undergone 3-6 cycles (C) of induction containing a proteasome inhibitor (PI) and/or immunomodulatory drug and recovered post melphalan-conditioned ASCT with adequate haematopoiesis, renal and liver function, and with ECOG performance status. Registration occurs prior to ASCT with screening between 75 to 115 days post ASCT. The study includes a lead-in safety phase of 20 patients with XR: Len 10mg daily days 1 to 21 and Selinexor 40mg weekly in a 28-day cycle. If well tolerated, Selinexor escalates to 60mg po weekly from C2 and Len to 15mg po daily from C4. Two safety reviews will occur after the 10th and 20th patients completes C2, respectively. Upon meeting safety criteria, a sample size of 290 pts will be randomised 1:1 to XR or lenalidomide (R). Therapy will continue until PD. The primary endpoint is PFS at 3 years post randomisation. Secondary endpoints include ORR and MRD-negativity rate (International Myeloma Working Group Response Criteria), PFS on next treatment line (PFS2), OS, safety and tolerability, quality of life, and cost effectiveness. Main analysis occurs after 232 patients complete 3-years of follow-up. Exploratory objective is to correlate immunological and molecular profiles to treatment response and resistance. ALLG MM23 SeaLAND is a multisite bi-national investigator-initiated trial lead by Australia and New Zealand’s national cooperative group, the Australasian Leukaemia & Lymphoma Group. Clinical trial registration: ACTRN12620000291987p. Clinical trial information: 12620000291987.

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Relationship between corneal stiffness parameters and lamina cribrosa curvature in normal tension glaucoma

European Journal of Ophthalmology ◽

10.1177/1120672120982521 ◽

2020 ◽

pp. 112067212098252

Author(s):

Yunxiao Sun ◽

Yiqin Guo ◽

Kai Cao ◽

Yue Zhang ◽

Yuan Xie ◽

...

Keyword(s):

Clinical Trial ◽

Amplitude Ratio ◽

Statistical Significance ◽

Normal Tension Glaucoma ◽

Lamina Cribrosa ◽

Clinical Trial Registry ◽

Clinical Trial Registration ◽

Curvature Index ◽

Biomechanical Parameters ◽

The Relationship

Purpose: To evaluate the relationship between corneal biomechanical parameters and lamina cribrosa (LC) curvature in normal tension glaucoma (NTG). Methods: 95 eyes of 56 NTG patients were enrolled in this prospective, observational study. Corneal biomechanical parameters, including stiffness parameters at applanation 1 (SP-A1), deformation amplitude ratio (DA ratio), inverse concave radius and biomechanically corrected intraocular pressure estimate (bIOP), were captured using the Corneal Visualization Scheimpflug Technology instrument (Corvis-ST). LC curvature was evaluated by mean adjusted LC curvature index (maLCCI) averaged by the measurements on 12 radial B-scan images obtained using swept-source optical coherence tomography (SS-OCT). Linear mixed models were constructed to assess the relationship between corneal biomechanical parameters and LC curvature. Results: The mean age of participants was 51.04 ± 13.74 years (range, 24–82 years). The SP-A1 and maLCCI were 93.50 ± 13.82 mm Hg/mm and 7.57 ± 1.58, respectively. In univariate and multivariate analysis, SP-A1 ( p < 0.001 and p = 0.001) and age ( p = 0.010 and p = 0.024) were both significantly associated with maLCCI. The LC curvature increased with softer cornea demonstrated by lower SP-A1 and younger eyes. There was no statistical significance interaction between SP-A1 and age ( p = 0.194). Conclusions: The greater posterior LC curvature was associated with lower corneal stiffness parameters and younger eyes in NTG patients. Clinical Trial Registration: Chinese Clinical Trial Registry, ChiCTR1900021465.

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