Pharmacokinetic Consideration of Venetoclax in Acute Myeloid Leukemia Patients: A Potential Candidate for TDM? A Short Communication.

BACKGROUND: Venetoclax (VNX)-based regimens have demonstrated significantly favorable outcomes in patients with acute myeloid leukemia (AML) and are now becoming the standard treatment. Tyrosine kinase inhibitors are administered at a fixed dose, irrespective of body surface area or weight. For such orally targeted therapies, real-world data have highlighted a larger pharmacokinetic (PK) interindividual variability (IIV) than expected. Even if VNX PKs have been well characterized and described in the literature, only 1 clinical trial-based PK study has been conducted in patients with AML. This study aimed to evaluate the PK of VNX in AML patients. MATERIAL AND METHODS: We retrospectively analyzed all patients treated with a combination of VNX-azacitidine between January and July 2022 at our center, using at least 1 available VNX blood sample. Based on a previously published population PK model, individual PK parameters were estimated to evaluate the exposure and IIV. RESULTS: and Discussion. Twenty patients received VNX in combination with azacitidine, according to the PK data. A total of 93 plasma concentrations were collected. The dose of VNX was 400 mg, except in 7 patients who received concomitant posaconazole (VNX 70 mg). The patients' weight ranged from 49 kg to 108 kg (mean = 78 kg). Mean individual clearance was 13.5 ± 9.4 L/h with mean individual daily area under the concentration-time curves of 35.8 mg.h/L with significant IIV (coefficient of variation = 41.1%). Ten patients were still alive (8 in complete response), but all experienced at least 1 hematological toxicity of grade ≥ 3. CONCLUSIONS: Based on the observed large PK variability in the data from our real-world AML patients, the risk of drug interactions and the recommended fixed-dosage regimen of VNX therapeutic drug monitoring may be useful.

Dual role of histone variant H3.3B in spermatogenesis: positive regulation of piRNA transcription and implication in X-chromosome inactivation.

The histone variant H3.3 is encoded by two distinct genes, H3f3a and H3f3b, exhibiting identical amino-acid sequence. H3.3 is required for spermatogenesis, but the molecular mechanism of its spermatogenic function remains obscure. Here, we have studied the role of each one of H3.3A and H3.3B proteins in spermatogenesis. We have generated transgenic conditional knock-out/knock-in (cKO/KI) epitope-tagged FLAG-FLAG-HA-H3.3B (H3.3BHA) and FLAG-FLAG-HA-H3.3A (H3.3AHA) mouse lines. We show that H3.3B, but not H3.3A, is required for spermatogenesis and male fertility. Analysis of the molecular mechanism unveils that the absence of H3.3B led to alterations in the meiotic/post-meiotic transition. Genome-wide RNA-seq reveals that the depletion of H3.3B in meiotic cells is associated with increased expression of the whole sex X and Y chromosomes as well as of both RLTR10B and RLTR10B2 retrotransposons. In contrast, the absence of H3.3B resulted in down-regulation of the expression of piRNA clusters. ChIP-seq experiments uncover that RLTR10B and RLTR10B2 retrotransposons, the whole sex chromosomes and the piRNA clusters are markedly enriched of H3.3. Taken together, our data dissect the molecular mechanism of H3.3B functions during spermatogenesis and demonstrate that H3.3B, depending on its chromatin localization, is involved in either up-regulation or down-regulation of expression of defined large chromatin regions.

Permeation measurement of 27 chemotherapy drugs after simulated dynamic testing on 15 surgical and examination gloves: A knowledge update.

PURPOSE: Exposure to anticancer drugs is one of the known risks for people working in specialist oncology units. Wearing gloves is a vital form of personal protection. The aim of this study was to assess, in close to real use dynamic conditions, the permeability of 15 surgical and examination gloves made from different materials when exposed to 27 anticancer drugs included in the list from international Guides and Recommendations. METHODS: Gloves were tested by using controlled dynamic conditions replicating flexion and extension movements that mimic typical clinical applications. Tests were performed at 37°C or at 43°C for 30 min and anticancer drugs were tested at the highest concentration used in clinical practice. To determine the permeation rate, the quantification of anticancer drugs was performed with selective and sensitive analytical methods such as inductively coupled plasma-mass spectroscopy and liquid chromatography-mass spectrometry. RESULTS: All the gloves met the EN 16523-1 European standard (1000 ng/(min.cm2)). The penetration rate of busulfan, carmustine and thiotepa exceeded the ASTM D-6978-05 American standard (10 ng/(min.cm2)) with several surgical and/or examination gloves. This standard was met in all of cases when double gloving was used. Breakage of several nitrile gloves was observed in relation with the excipient used by drugs suppliers. CONCLUSIONS: Permeation is a complex multifactorial phenomenon. However, we have suggested that the thickness of the glove and three physicochemical parameters (molecular weight, topological polar surface area and hydrogen bond donor) of the drug were the main parameters affecting permeation.

[Reducing the exposure of patients and healthcare teams to cytotoxins]. / Réduire l'exposition des patients et des équipes soignantes aux cytotoxiques.

In order to prevent human and environmental risks related to the handling of cytotoxins and cytostatics, health care institutions are implementing precautionary measures. Information and training actions for health professionals, nurses, orderlies and pharmacy assistants are also part of the system. Example with a team in Lyon.

Histone H3.3 regulates mitotic progression in mouse embryonic fibroblasts.

H3.3 is a histone variant that marks transcription start sites as well as telomeres and heterochromatic sites on the genome. The presence of H3.3 is thought to positively correlate with the transcriptional status of its target genes. Using a conditional genetic strategy against H3.3B, combined with short hairpin RNAs against H3.3A, we essentially depleted all H3.3 gene expression in mouse embryonic fibroblasts. Following nearly complete loss of H3.3 in the cells, our transcriptomic analyses show very little impact on global gene expression or on the localization of histone variant H2A.Z. Instead, fibroblasts displayed slower cell growth and an increase in cell death, coincident with large-scale chromosome misalignment in mitosis and large polylobed or micronuclei in interphase cells. Thus, we conclude that H3.3 may have an important under-explored additional role in chromosome segregation, nuclear structure, and the maintenance of genome integrity.

Transferability of health cost evaluation across locations in oncology: cluster and principal component analysis as an explorative tool.

BACKGROUND: The transferability of economic evaluation in health care is of increasing interest in today's globalized environment. Here, we propose a methodology for assessing the variability of data elements in cost evaluations in oncology. This method was tested in the context of the European Network of Excellence "Connective Tissues Cancers Network". METHODS: Using a database that was previously aimed at exploring sarcoma management practices in Rhône-Alpes (France) and Veneto (Italy), we developed a model to assess the transferability of health cost evaluation across different locations. A nested data structure with 60 final factors of variability (e.g., unit cost of chest radiograph) within 16 variability areas (e.g., unit cost of imaging) within 12 objects (e.g., diagnoses) was produced in Italy and France, separately. Distances between objects were measured by Euclidean distance, Mahalanobis distance, and city-block metric. A hierarchical structure using cluster analysis (CA) was constructed. The objects were also represented by their projections and area of variability through correlation studies using principal component analysis (PCA). Finally, a hierarchical clustering based on principal components was performed. RESULTS: CA suggested four clusters of objects: chemotherapy in France; follow-up with relapse in Italy; diagnosis, surgery, radiotherapy, chemotherapy, and follow-up without relapse in Italy; and diagnosis, surgery, and follow-up with or without relapse in France. The variability between clusters was high, suggesting a lower transferability of results. Also, PCA showed a high variability (i.e. lower transferability) for diagnosis between both countries with regard to the quantities and unit costs of biopsies. CONCLUSION: CA and PCA were found to be useful for assessing the variability of cost evaluations across countries. In future studies, regression methods could be applied after these methods to elucidate the determinants of the differences found in these analyses.

Impact of Early Access Reform on Oncology Innovation in France: Approvals, Patients, and Costs.

BACKGROUND: An ambitious reform of the early access (EA) process was set up in July 2021 in France, aiming to simplify procedures and accelerate access to innovative drugs. OBJECTIVE: This study analyzes the characteristics of oncology drug approvals through the EA process and its impact on real-life data for oncology patients. METHODS: The number and characteristics of EA demands concerning oncology drugs submitted to the National Health Authority (HAS, Haute Autorité de Santé) were reviewed until 31 December 2022. A longitudinal retrospective study on patients treated with an EA oncology drug between 1 January 2019 and 31 December 2022 was also performed using the French nationwide claims database (Systeme National des Données de Santé [SNDS]) to assess the impact of the reform on the number of indications and patients, and the costs. RESULTS: Among 110 published decisions, the HAS granted 88 (80%) EA indications within 70 days of assessment on average, including 46 (52%) in oncology (67% in solid tumors and 33% in hematological malignancies). Approved indications were mostly supported by randomized phase III trials (67%), whereas refused EA relied more on non-randomized (57%) trials. Overall survival was the primary endpoint of 28% of EA approvals versus none of denied EAs. In the SNDS data, the annual number of patients with cancer treated with an EA drug increased from 3137 patients in 2019 to 18,341 in 2022 (+ 484%), whereas the number of indications rose from 12 to 62, mainly in oncohematology (n = 17), lung (n = 12), digestive (n = 9) and breast cancer (n = 9). Reimbursement costs for EA treatments surged from €42 to €526 million (+ 1159%). CONCLUSION: The French EA reform contributed to enabling rapid access to innovations in a wide range of indications for oncology patients. However, the findings highlight ongoing challenges in financial sustainability, warranting continued evaluation and adjustments.

Can Digital Health Improve Therapeutic Compliance in Oncology?

PURPOSE: Therapeutic compliance, or adherence, is critical in oncology because of the complexity and duration of cancer treatment regimens. Nonadherence can lead to suboptimal therapeutic outcomes, increased disease progression, higher mortality rates, and elevated health care costs. Traditional methods to enhance compliance, such as patient education and regular follow-ups, have shown limited success. MATERIALS AND METHODS: This review examines the potential of digital health technologies to improve adherence in oncology. Various studies and trials are analyzed to assess the effectiveness of these technologies in supporting patients with cancer. RESULTS: mHealth applications have been shown to improve medication adherence through features like medication reminders and symptom tracking. Telemedicine facilitates continuous care and reduces the need for travel, significantly improving adherence and patient satisfaction. Patient-reported outcome measures enhance clinical decision making and personalized treatment plans by incorporating patient feedback. Electronic medical records and patient portals improve compliance by providing easy access to medical information and fostering better patient-provider communication. Connected pillboxes aid in consistent medication intake and reduce dispensing errors. CONCLUSION: Digital health technologies offer significant benefits in oncology by enhancing patient engagement, improving adherence to treatment protocols, and enabling comprehensive cancer care management. However, challenges such as the digital divide, data privacy concerns, and the need for tailored interventions must be addressed. Future research should focus on evaluating the effectiveness of digital interventions and developing personalized digital health tools to maximize therapeutic compliance.

Early morning immune checkpoint blockade and overall survival of patients with metastatic cancer: An In-depth chronotherapeutic study.

INTRODUCTION: Recent retrospective studies suggest potential large patient's benefit through proper timing of immune checkpoint blockers (ICB). The association between ICB treatment timing and patient survival, neoplastic response and toxicities was investigated, together with interactions with performance status (PS) and sex. METHODS: A cohort of patients with metastatic or locally advanced solid tumors, who received pembrolizumab, nivolumab, atezolizumab, durvalumab, or avelumab, alone or with concomitant chemotherapy, between November 2015 and March 2021, at the Centre Leon Bérard (France), was retrospectively studied. RESULTS: 361 patients were investigated (80% non-small cell lung cancer patients, mean [SD] age: 63 [11] years, 39% of women, 83% PS0-1 at first infusion, 19% received concomitant chemotherapy). ICB were administered from 07:25 to 17:21 and optimal morning/afternoon cut-off was 11:37. Morning infusions were associated with increased OS as compared to afternoon (median 30.3 vs 15.9 months, p = 0.0024; HR 1.56 [1.17-2.1], p = 0.003). A strong PS-timing interaction was found (PS0-1 patients, HR=1.53 [1.10-2.12], p = 0.011; PS2-3 patients, HR=0.50 [0.25-0.97], p = 0.042). Morning PS0-1 patients displayed increased OS (median 36.7 vs 21.3 months, p = 0.023), partial/complete response rate (58% vs 41%, p = 0.027), and grade1-3 toxicities (49% vs 34%, p = 0.028). Mortality risk ratio between infusions at worst time-of-day, estimated at 13:36 [12:48-14:23], and in early morning was equal to 4.8 ([2.3-10.1], p = 0.008). Timing differences in toxicities resulted significant only in female patients (women vs men: p < 0.001 vs 0.4). CONCLUSIONS: Early morning ICB infusion was associated with increased OS, response, and toxicities in patients with PS0-1 as compared to later infusions within the day. Prospective randomized trials are needed to confirm this retrospective study.

A novel injectable radiopaque hydrogel with potent properties for multicolor CT imaging in the context of brain and cartilage regenerative therapy.

Cell therapy is promising to treat many conditions, including neurological and osteoarticular diseases. Encapsulation of cells within hydrogels facilitates cell delivery and can improve therapeutic effects. However, much work remains to be done to align treatment strategies with specific diseases. The development of imaging tools that enable monitoring cells and hydrogel independently is key to achieving this goal. Our objective herein is to longitudinally study an iodine-labeled hydrogel, incorporating gold-labeled stem cells, by bicolor CT imaging after in vivo injection in rodent brains or knees. To this aim, an injectable self-healing hyaluronic acid (HA) hydrogel with long-persistent radiopacity was formed by the covalent grafting of a clinical contrast agent on HA. The labeling conditions were tuned to achieve sufficient X-ray signal and to maintain the mechanical and self-healing properties as well as injectability of the original HA scaffold. The efficient delivery of both cells and hydrogel at the targeted sites was demonstrated by synchrotron K-edge subtraction-CT. The iodine labeling enabled to monitor the hydrogel biodistribution in vivo up to 3 days post-administration, which represents a technological first in the field of molecular CT imaging agents. This tool may foster the translation of combined cell-hydrogel therapies into the clinics.

Paclitaxel and cetuximab combination efficiency after the failure of a platinum-based chemotherapy in recurrent/metastatic head and neck squamous cell carcinoma.

The addition of cetuximab (CTX) to the combination of cisplatin and 5-fluorouracil increases the overall survival (OS) in recurrent/metastatic head and neck squamous cell carcinoma. Only a few patients are eligible for this treatment because of its toxicity. The combination of CTX and paclitaxel (TXL) could be included in sequential treatment strategies. Patients were treated with CTX (400/250 mg/m) and TXL (60-80 mg/m) weekly until disease progression or unacceptable toxicity. Efficacy and safety outcomes were determined retrospectively. A total of 42 patients were included in this analysis. The overall response rate was 38% [95% confidence interval (CI); 23-53%]. The disease control rate with TXL and CTX combination was 74%. Seven (17%) patients progressed before the first evaluation. The median progression-free survival was 3.9 months [95% CI; 3.1-4.7 months] and the median OS was 7.6 months [95% CI; 5.3-9.9 months]. Neurotoxicity and skin rash were the most frequent grade≥2 toxicities, reported in 17 and 12% of patients, respectively. Previous chemotherapy seems to be associated with a lower response rate and progression-free survival but not with the OS. The combination of CTX and TXL was an active and well-tolerated treatment in this series of patients with a poor prognosis and who were mostly symptomatic.

Mouse Models of Osteoarthritis: A Summary of Models and Outcomes Assessment.

Osteoarthritis (OA) is a multidimensional health problem and a common chronic disease. It has a substantial impact on patient quality of life and is a common cause of pain and mobility issues in older adults. The functional limitations, lack of curative treatments, and cost to society all demonstrate the need for translational and clinical research. The use of OA models in mice is important for achieving a better understanding of the disease. Models with clinical relevance are needed to achieve 2 main goals: to assess the impact of the OA disease (pain and function) and to study the efficacy of potential treatments. However, few OA models include practical strategies for functional assessment of the mice. OA signs in mice incorporate complex interrelations between pain and dysfunction. The current review provides a comprehensive compilation of mouse models of OA and animal evaluations that include static and dynamic clinical assessment of the mice, merging evaluation of pain and function by using automatic and noninvasive techniques. These new techniques allow simultaneous recording of spontaneous activity from thousands of home cages and also monitor environment conditions. Technologies such as videography and computational approaches can also be used to improve pain assessment in rodents but these new tools must first be validated experimentally. An example of a new tool is the digital ventilated cage, which is an automated home-cage monitor that records spontaneous activity in the cages.

In vitro reconstitution of kallikrein-kinin system and progress curve analysis.

Human kallikrein-kinin system (KKS) is a proteolytic cascade with two serine-protease zymogen couples (Factor XII and prekallikrein (PK) and their activated forms, FXIIa, PKa, respectively), releasing bradykinin by cleavage of native high-molecular-weight kininogen (nHK) into cleaved HK. For KKS investigation in human plasma, this cascade is usually triggered on ice eventually by mixing with purified proteins. It has been established that purified FXIIa, PK, and nHK required a fixed order and timing for mixing protein on ice to ensure reproducibility of testing, we investigated the activation kinetics of both enzymes. The activation process of this in vitro minimal reconstitution of KKS was studied by progress curve analysis, in condition of high enzyme/substrate ratio and by using on natural rather than peptide substrates. FXIIa and PKa were found five-times less active on ice than at 37°C: kcat = 0.133 ± 0.034 and 0.0119 ± 0.0027 s-1, KM = 672 ± 150 and 115 ± 24 nM, respectively. The progress curve analysis of our in vitro KKS reconstitutions differed from a Michaelis-Menten mathematical simulation by a faster initial rate and a slower late rate. These two features were also observed ex vivo by using dextran sulfate-activated plasma and could reinforce the hypothesis of a maximal local effect (bradykinin release) and a minimal systemic consequence (PK preservation) in KKS activation process. Analyzing the complete curve of cold KKS activation would provide valuable information for ex vivo investigation of KKS in samples from patients presenting with hereditary angioedema and other inflammatory conditions.

Identification of human gene research articles with wrongly identified nucleotide sequences.

Nucleotide sequence reagents underpin molecular techniques that have been applied across hundreds of thousands of publications. We have previously reported wrongly identified nucleotide sequence reagents in human research publications and described a semi-automated screening tool Seek & Blastn to fact-check their claimed status. We applied Seek & Blastn to screen >11,700 publications across five literature corpora, including all original publications in Gene from 2007 to 2018 and all original open-access publications in Oncology Reports from 2014 to 2018. After manually checking Seek & Blastn outputs for >3,400 human research articles, we identified 712 articles across 78 journals that described at least one wrongly identified nucleotide sequence. Verifying the claimed identities of >13,700 sequences highlighted 1,535 wrongly identified sequences, most of which were claimed targeting reagents for the analysis of 365 human protein-coding genes and 120 non-coding RNAs. The 712 problematic articles have received >17,000 citations, including citations by human clinical trials. Given our estimate that approximately one-quarter of problematic articles may misinform the future development of human therapies, urgent measures are required to address unreliable gene research articles.

Rituximab in combination with adapted-dose of ifosfamide and etoposide as salvage treatment in elderly refractory/relapsed diffuse large B-cell lymphoma patients non-candidate for high dose therapy: a retrospective study.

We retrospectively reviewed for 72 relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) patients ineligible for autologous stem-cell transplantation (ASCT) treated between 2004 and 2017, efficacy and safety profile of rituximab (375 mg/m2) in combination with etoposide (300 mg/m2) and ifosfamide (1500 mg/m2) at 2, 3, or 4-week intervals. Median age was 79 years (range, 64-92). The median number of previous line was 1 (range 1-8). Patients received a median of six cycles (1-12). Fourteen patients (19%) presented partial and 14 complete responses (19%). Among the 369 cycles, nine patients developed febrile neutropenia (13%), 14 a grade 3-4 neutropenia (19%), 7 a grade 3-4 thrombocytopenia (10%) without grade 3-4 non-hematological toxicity. With a median follow up of 7.8 months, the median progression-free survival, overall survival, and duration of response were 4.4 months, 9.4 months, and 12 months, respectively. This regimen represents a therapeutic option in R/R DLBCL patients ineligible to ASCT.

Survival and risk of COVID-19 after SARS-COV-2 vaccination in a series of 2391 cancer patients.

BACKGROUND: Patients with cancer are at high risk of severe or lethal COVID-19. The impact of SARS-COV-2 vaccination on the risk of developing COVID-19 was investigated in an exhaustive series of patients from a comprehensive cancer center. METHODS: This is a study of the exhaustive population of 2391 cancer patients who were prescribed SARS-COV-2 vaccination until 09/21. Patient characteristics, documented SARS-COV-2 infection with RT-PCR, and survival were collected. The primary endpoint was the rate of COVID-19 after vaccination. Secondary endpoints included risk factors to develop COVID-19 after vaccination, with a comparison with the cohort of vaccinated health care workers (HCW), and risk factors for death. RESULTS: From January to September 2021, among 2391 patients with cancer under active treatment in whom a SARS-COV-2 vaccine was prescribed, 659 (28%), 1498 (63%) and 139 (6%) received 1, 2, and 3 doses, respectively. Ninety five patients received a single dose of vaccine after a previous COVID-19. Two thousand two hundred eighty five health care workers (HCW) received one (N = 17, 0.7%), 2-3 (N = 2026, 88.7%) vaccine doses and one dose after COVID-19 (N = 242, 10.6%). With a median follow-up of 142 and 199 days for patients and HCW, respectively. Thirty nine (1.6%) patients and 35 (1.5%) HCW developed COVID-19 after vaccination. Six of 39 cancer patients and no HCW died because ofCOVID-19 within 50 days after diagnosis. Independent risk factors for COVID-19 in vaccinated patients were age, single dose of vaccine without previous COVID-19 and anti-CD20 treatment in the last three months. Independent risk factors for death included metastatic disease, gender, cancer type, but also documented COVID-19 before vaccination. CONCLUSIONS: Patients receiving two or more doses of COVID-19 vaccine have reduced risk of COVID-19. The risk of death of vaccinated cancer patients presenting COVID-19 remains high. COVID-19 before vaccination is associated with an increased overall risk of death.

Chemotherapy for metastatic breast cancer. Comparison of clinical practice and cost of drugs in two cohorts of patients: 1994-1998 and 2003-2006.

Although new chemotherapeutic drugs for metastatic breast cancer (MBC) have been approved over the past decade, it is unclear whether this has changed the overall outcome of patients. This study assessed the clinical and economic impacts of these drugs. We retrospectively studied MBC patients receiving chemotherapy in our institution over two time periods, 1994-1998 and 2003-2006. Patient characteristics and outcomes, and treatment characteristics and costs (€, 2008) were compared. Three hundred and one patients were identified, 149 patients in the first cohort and 152 in second one. The median number of lines of chemotherapy was similar in the two cohorts (three lines). The median costs of chemotherapy per patient nearly doubled over time, from 6,272 € in the 1994-1998 cohort to 13,035 € in the 2003-2006 cohort (P < 0.001). No survival difference was observed between the two groups, with a 3-year survival rate estimated to 41% in the 1994-1998 cohort and 44% in the 2003-2006 cohort (P = 0.52). In multivariate analysis, prognostic factors associated with longer overall survival were single metastatic site (HR 0.48; P < 10⁻³), bone metastases (HR = 0.67; P = 0.007) and positive hormone receptors (HR 0.56; P = 0.0002). New chemotherapeutic agents induced a significant cost increase over time. The limited size and heterogeneity of our cohort do not allow any conclusion concerning their impact on survival.

Calcified cartilage revealed in whole joint by X-ray phase contrast imaging.

Objective: X-ray Phase Contrast Imaging (PCI) is an emerging modality that will be in the next few years available in a wider range of preclinical set-ups. In this study, we compare this imaging technique with conventional preclinical modalities in an osteoarthritis mouse model. Method: Phase contrast technique was performed on 6 post-mortem, monoiodoacetate-induced osteoarthritis knees and 6 control knees. The mice knees were then imaged using magnetic resonance imaging and conventional micro computed tomography. Examples of imaging surrogate markers are reported: local distances within the articular space, cartilage surface roughness, calcified cartilage thickness, number, volume and locations of osteophytes. Results: Thanks to PCI, we can show in 3D calcified cartilage without contrast agent by a non-invasive technique. The phase contrast images reveal more details than conventional imaging techniques, especially at smaller scales, with for instance a higher number of micro-calcifications detected (57, 314 and 329 for MRI, conventional micro-CT and phase contrast imaging respectively). Calcified cartilage thickness was measured with a significant difference (p â€‹< â€‹0.01) between the control (23.4 â€‹± â€‹17.2 â€‹µm) and the osteoarthritis induced animal (46.9 â€‹± â€‹19.0 â€‹µm). Conclusions: X-ray phase contrast imaging outperforms the conventional imaging modalities for assessing the different tissue types (soft and hard). This new imaging modality seems to bring new relevant surrogate markers for following-up small animal models even for low-grade osteoarthritis.

Mediation of Interleukin-23 and Tumor Necrosis Factor-Driven Reactive Arthritis by Chlamydia-Infected Macrophages in SKG Mice.

OBJECTIVE: ZAP-70W163C BALB/c (SKG) mice develop reactive arthritis (ReA) following infection with Chlamydia muridarum. Since intracellular pathogens enhance their replicative fitness in stressed host cells, we examined how myeloid cells infected with C muridarum drive arthritis. METHODS: SKG, Il17a-deficient SKG, and BALB/c female mice were infected with C muridarum or C muridarum luciferase in the genitals. C muridarum dissemination was assessed by in vivo imaging or genomic DNA amplification. Macrophages were depleted using clodronate liposomes. Anti-tumor necrosis factor (anti-TNF) and anti-interleukin-23p19 (anti-IL-23p19) were administered after infection or arthritis onset. Gene expression of Hspa5, Tgtp1, Il23a, Il17a, Il12b, and Tnf was compared in SKG mice and BALB/c mice. RESULTS: One week following infection with C muridarum, macrophages and neutrophils were observed to have infiltrated the uteri of mice and were also shown to have carried C muridarum DNA to the spleen. C muridarum load was higher in SKG mice than in BALB/c mice. Macrophage depletion was shown to reduce C muridarum load and prevent development of arthritis. Compared with BALB/c mice, expression of Il23a and Il17a was increased in the uterine and splenic neutrophils of SKG mice. The presence of anti-IL-23p19 during infection or Il17a deficiency suppressed arthritis. Tnf was overexpressed in the joints of SKG mice within 1 week postinfection, and persisted beyond the first week. TNF inhibition during infection or at arthritis onset suppressed the development of arthritis. Levels of endoplasmic reticulum stress were constitutively increased in the joints of SKG mice but were induced, in conjunction with immunity-related GTPase, by C muridarum infection in the uterus. CONCLUSION: C muridarum load is higher in SKG mice than in BALB/c mice. Whereas proinflammatory IL-23 produced by neutrophils contributes to the initiation of C muridarum-mediated ReA, macrophage depletion reduces C muridarum dissemination to other tissues, tissue burden, and the development of arthritis. TNF inhibition was also shown to suppress arthritis development. Our data suggest that enhanced bacterial dissemination in macrophages of SKG mice drives the TNF production needed for persistent arthritis.

Paclitaxel is effective in relapsed head and neck squamous cell carcinoma: a retrospective study of 66 patients at a single institution.

The standard first-line treatment of recurrent/metastatic head and neck squamous cell carcinoma is cisplatin-based chemotherapy, but taxanes can also be beneficial after progression or in patients not eligible for cisplatin. The objective of this retrospective study was to evaluate paclitaxel in this population. We reviewed 66 patients who were treated with paclitaxel at a single institution (Lyon, France) between January 2003 and November 2008. Paclitaxel was administered as first, second or more line of treatment; alone or in combination with carboplatin or cetuximab; every 3 weeks (175 mg/m(2)) or weekly (80 mg/m(2)). Forty-six (70%) patients received paclitaxel as first-line therapy after relapse and 26 (39%) patients as monotherapy. The objective response rate was 30% [95% confidence interval (CI): 20-43%]; 37% (95% CI: 23-52%) in the first line after relapse, and 20% (95% CI: 4-48%) in the second line. Rates were 19% (95% CI: 7-39%) after monotherapy and 36% (95% CI: 20-55%) after combination with carboplatin. Two of the six patients receiving cetuximab had a partial response. The overall survival of all patients was 7.2 months (95% CI: 5.2-8.8). Paclitaxel can be used in symptomatic patients. Although no improvement of overall survival can be expected, paclitaxel treatment is safe and achieves interesting response rates.