HER2-overexpressing metastatic breast cancers are challenging practice in oncology when they become resistant to anti-HER2 therapies such as trastuzumab. In these clinical situations, ...HER2-overexpression persists in metastatic localizations, and can thus be used for active targeting using innovative therapeutic approaches. Functionalized gold nanoparticles with anti-HER2 antibody can be stimulated by near-infrared light to induce hyperthermia.
Here, hybrid anti-HER2 gold nanoshells were engineered for photothermal therapy to overcome trastuzumab resistance in HER2-overexpressing breast cancer xenografts.
When gold nanoshells were administered in HER2-tumor xenografts, no toxicity was observed. A detailed pharmacokinetic study showed a time-dependent accumulation of gold nanoshells within the tumors, significantly greater with functionalized gold nanoshells at 72 h. This enabled us to optimize the treatment protocol and irradiate the mice when the anti-HER2 gold nanoshells had accumulated most in the tumors. After weekly injections of anti-HER2 gold nanoshells, and repeated irradiations with a femtosecond-pulsed laser over four weeks, tumor growth was significantly inhibited. Detailed tissue microscopic analyses showed that the tumor growth inhibition was due to an anti-angiogenic effect, coherent with a preferential distribution of the nanoshells in tumor microvessels. We also showed a direct tumor cell effect with apoptosis and inhibition of proliferation, coherent with an immune-mediated targeting of tumor cells by anti-HER2 nanoshells.
This preclinical study thus supports the use of anti-HER2 gold nanoshells and photothermal therapy to overcome trastuzumab resistance in HER2-overexpressing breast cancer.
Despite major therapeutic advances for two decades, including the most recently approved anti-HER2 drugs, brain metastatic localizations remain the major cause of death for women with metastatic HER2 ...breast cancer. The main reason is the limited drug passage of the blood-brain barrier after intravenous injection and the significant efflux of drugs, including monoclocal antibodies, after administration into the cerebrospinal fluid. We hypothesized that this efflux was linked to the presence of a FcRn receptor in the blood-brain barrier. To overcome this efflux, we engineered two Fab fragments of trastuzumab, an anti-HER2 monoclonal antibody, and did a thorough preclinical development for therapeutic translational purpose. We demonstrated the safety and equal efficacy of the Fabs with trastuzumab in vitro, and in vivo using a patient-derived xenograft model of HER2 overexpressing breast cancer. For the pharmacokinetic studies of intra-cerebrospinal fluid administration, we implemented original rat models with catheter implanted into the cisterna magna. After intraventricular administration in rats, we demonstrated that the brain-to-blood efflux of Fab was up to 10 times lower than for trastuzumab, associated with a two-fold higher brain penetration compared to trastuzumab. This Fab, capable of significantly reducing brain-to-blood efflux and enhancing brain penetration after intra-cerebrospinal fluid injection, could thus be a new and original effective drug in the treatment of HER2 breast cancer brain metastases, which will be demonstrated by a phase I clinical trial dedicated to women in resort situations.
In 2018, dosing regimens of the two most prescribed immune check point inhibitors (ICI), nivolumab (Opdivo
) and pembrolizumab (Keytruda
), in the treatment of lung cancer were changed from ...weight-based dosing to fixed dosing. The aim of this study was to compare the economic impact of this change in our university hospital group and then across Ile-de-France, the most inhabited French region. A budget impact analysis (BIA) has been performed on the French public health insurance data. The duration of treatment and the weight of the patients were calculated using data from the patients treated at our health facility and from clinical studies. The cost of treatment was calculated at the local level of our health facility and then for Ile-de-France. Our model demonstrates an additional cost of €550,115 in our hospital and €9,704,778 in Ile-de-France for a fixed dose prescription in 2018. In 2019, the BIA concluded an additional cost, according to the respective low and high assumptions, of €556,969 and €756,544 locally and € 10,201,027 to €14,486,141 for Ile-de-France for an equivalent efficacy between the two different drug dosing regimens of nivolumab and pembrolizumab. The adoption of the fixed dose regimen would lead, according to the least expensive hypothesis, to an additional cost of 26% for the ICI. These results encourage reflection on the strict adoption of this dosage modification. The option of maintaining the free choice between a prescription adapted to weight or in a fixed dose seems a relevant option and should be considered.
Background
Our hospital organization raised the possibilities of outsourcing their sterile pediatric chemotherapy preparations to another hospital conditional on analyzing the potential hazardous ...events that need to be anticipated.
Methods
The study was conducted by a multidisciplinary working group from September 2015 to January 2016 with the support of a risk manager. A list of hazardous situations that could occur during outsourcing process was assessed. First, a map of hazardous situations was developed by crossing outsourcing processes divided into phases classified as critical or not. Second, a map of risk was established by crossing potential consequences of these hazardous situations and elaborating corrective actions to reduce the initial risks.
Results
The map of hazardous situations identified 183 relevant hazardous situations, 78 of which were considered high priority and 154 scenarios were developed. Slightly more than half of these hazardous situations concerned information system (30%), human resources (14%), and management (11%). The generic hazards of information system and human generated 37 (24%) and 41 (27%) scenarios, respectively. To reduce critical risks, 33 corrective actions were proposed. Working time required was estimated at 35 days. The subcontractor personnel for this new organization included an estimated extra time of 0.7-pharmacist working day and 1.4-pharmacy dispenser working day.
Conclusions
The preliminary hazard analysis method appeared to apply to our system of outsourcing sterile cytotoxic preparations in another hospital. Regardless, this analysis is complex and requires time and expertise.
Abstract Outcome of patients with high risk MDS and CMML who failed treatment with azacitidine remains poor with a median survival of 6 months, without established therapy available except allogeneic ...hematopoietic stem cell transplantation. The objective of our study was to evaluate efficacy of decitabine after azacitidine failure in a relatively large patient cohort based on conflicting results with 0–28% response rates (RR) in this setting in small patient series. Thirty-six consecutive high risk MDS and CMML patients who received decitabine after azacitidine failure were retrospectively reviewed. Response was based on IWG 2006 criteria for MDS and CMML with WBC <13 G/l and also included for proliferative CMML the evolution of WBC, splenomegaly (SMG) and extramedullary disease (EMD). Patients received a median number of 3 (range 1–27) cycles of decitabine and 12 patients received at least 6 cycles. Seven (19.4%) patients were responders including 3 marrow CR (mCR), 2 stable disease (SD) with HI-E, 1 SD with HI-N and HI-P and 1 SD with HI-N. In a CMML patient with SD, specific skin lesions resolved with decitabine. Responses were generally short lived (2–5 months) except 1 responder currently ongoing with +11 months follow up. Two non-responders had prolonged SD (without HI) of 21 and 27 months duration respectively. Median OS from onset of decitabine was 7.3 months, without significant difference between responders and non-responders. Treatment with decitabine after azacitidine failure yielded modest ORR (19.4%) with short response duration and poor OS. Thus, use of decitabine in such patients who failed or progressed after azacitidine cannot be recommended, underscoring the need for novel strategies in this setting.
Background
Brain metastases are challenging daily practice in oncology and remain a compartmental problem since most anti-cancer drugs do not cross the blood–brain barrier at relevant pharmacological ...concentrations.
Methods
In a young woman with HER2-overexpressing breast cancer resistant to standard treatments, at the time of brain metastases progression, a ventricular reservoir was implanted for intrathecal drug injections and detailed pharmacokinetic studies.
Results
A first association of intrathecal trastuzumab with intravenous cisplatin was offered to the patient. For trastuzumab, the mean cerebrospinal fluid trough concentration of 53.4 mg/L reached relevant levels, enabling the stabilization of the metastases. Adding intravenous cisplatin was not beneficial, since the cerebrospinal fluid exposure was almost undetectable under 0.08 mg/L. We then offered the patient an intrathecal combination of trastuzumab and methotrexate, because of their in vitro synergic cytotoxicity. The cerebrospinal fluid peak of methotrexate was 1037 µmol/L at 2 h, and the concentrations remained above the theoretical therapeutic concentration. After 2 months of this drug combination, we obtained an excellent response on the brain metastases.
Conclusion
Our preliminary study supports the interest of a compartmental approach through a direct administration of drugs into the cerebrospinal fluid for the treatment of breast cancer brain metastases.
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Outcome of patients with high risk MDS and CMML who failed treatment with AZA remains poor with a median survival of 5-6 months (Prebet; JCO 2011 29:3322). No established therapy is available for ...the majority of those patients at this stage except allogeneic bone marrow transplantation in a few eligible patients. The rationale for DAC treatment after AZA failure is based on somewhat different pharmacological properties between those 2 hypomethylating agents (HMAs) (Hollenbach; Plos One 2010 5:e9001). Conflicting results for DAC salvage after AZA failure have been reported with 0-28% response rates (RR) in small patient series, and an overall survival up to 11 months (Borthakur; Leuk Lymphoma 2008 49:690; Prebet; JCO 2011 29:3322; Bhatnagar, ASH 2012 Abstr #3858). We retrospectively reviewed a larger cohort of 36 patients in this setting.
Characteristics, overall response rate (ORR) and outcome were studied in high risk MDS and CMML patients who received DAC after AZA failure from June 2007 to April 2013 in three French hematology departments. Response criteria were based on IWG 2006 for MDS and CMML with WBC <13G/L and also included for CMML with WBC >13 G/L evolution of WBC, splenomegaly (SMG) and extramedullary disease (EMD) (based on Wattel; Blood 1996 88:2480).
Median age of the 36 patients was 70.5 years (range 53-84), and M/F: 21/15. Median time from diagnosis to AZA onset was 5.7 months and all patients at AZA onset had IPSS ≥ int-2 MDS/CMML or CMML-2 (EU label for AZA). Median number of cycles of AZA received was 8 (3-41) and 8 patients had received less than 6 cycles (2-5) including 1 who received HSCT, 1 with progressive disease (PD) and 6 in whom AZA was considered ineffective after less than 6 cycles. Overall, 20 patients had primary AZA failure, 1 PD and 15 had relapsed after achieving CR (n=9), PR (n=1), mCR (n=1), mCR+HI (n=2) or SD+HI (n=2), 3 of whom had been allografted. Apart from the 3 last patients, responders were still receiving AZA when relapse occurred. Median number of treatments received after AZA and before DAC was 0 (range 0-3), including low dose cytarabine (n=5), intensive chemotherapy (n=5), clofarabine (n=5) and rigosertib (n=3). Twenty patients received DAC immediately after AZA failure and median time from AZA to DAC treatment for all patients was 3.6 months. At onset of DAC, 22 patients had AML post MDS (including 11 RAEB-t), 8 had RAEB-2, 1 RAEB-1, 1 CMML-2 and 4 CMML-1.Median marrow blast count was 23% (range 7-82). Karyotype was normal in 15 (41.7%) patients, 9 (25%) patients had unfavorable cytogenetics including 7 complex karyotypes and 2 monosomy 7, five (13.9%) patients had +8, three (8.3%) del 20q, 3 (8.3%) other anomalies and 1 (2.8%) cytogenetic failure. IPSS-R was intermediate for 3, high for 11 and very high for 6 patients and could not be evaluated for 16 patients, mainly those with overt AML. 2 CMML patients had SMG and 1 skin involvement. Median number of DAC cycles administered was 3 (1-27) with 12 patients receiving at least 6 cycles. Seven patients (19.4%) were responders to DAC according to IWG 2006 criteria including 3 marrow CR, 2 stable disease (SD)+HI-E, 1 SD+HI-P and 1 SD+HI-N. In a CMML patient with SD, specific skin lesions resolved upon treatment with DAC and a patient with marrow CR underwent HSCT. Median OS from onset of DAC was 7.3 months without significant difference between responders and non-responders. Responses were short lived (2.5-6 months) with 2 responders currently ongoing with short follow up (2.5+ and 3+ months respectively) and 2 non-responders had prolonged SD (without HI) of 21 and 27 months duration respectively. Of note, 6 of the responses were seen in patients who did not receive DAC immediately after AZA.
Treatment of DAC after AZA failure yielded modest ORR (19.4%) and no CR was achieved in this patient cohort. Responses were generally short lived but 2 patients had prolonged stable disease for 21 and 27 cycles respectively. OS remained poor. Those results do not support absence of cross resistance between AZA and DAC, at least in most higher risk MDS.
No relevant conflicts of interest to declare.
Colicins are divided into two groups according to the proteins required for their import into sensitive bacteria. The Tol and TonB pathways are involved in import of group A and group B colicins ...respectively. Because previous analyses have shown that colicin El and colicin A (two group A colicins) interact in vitro with the C-terminal domain of TolA (TolAlll) while colicin B (group B colicin)does not, attention was focused on these interactions with purified proteins.TolA has been described as a three-domain protein with an N-terminal inner-membrane anchor and a long periplasmic region formed by two domains(TolAII and TolAlll). TolAIII, TolAll and TolAII-Ill soluble domains with an N-terminal hexa-histidine extension were purified. The interactions of colicins with the purified TolA domains were analysed by overlay Western blotting,which indicated that both N-terminal domains of colicins A and E l interacted with TolAIII, while a gel shift procedure detected no interaction with colicin El.The binding kinetic values of the N-terminal domains of colicins A and E l to TolAlll were estimated by surface plasmon resonance and were shown to be similar.
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