Phase I study of sorafenib combined with radiation therapy and temozolomide as first-line treatment of high-grade glioma.

This corrects the article DOI: 10.1038/bjc.2014.209.

[Head and neck cancer treatment in the elderly]. / Traitement des carcinomes épidermoïdes ORL chez la personne âgée.

We compared the treatment modalities as well as the oncologic outcome between young elderly (65-79 years old), elderly (>80 years old) and the reference population (<65 years old.) We reviewed 1047 patients treated between 2002 and 2012. Tumor sites, TNM stages, type of treatment, and the oncologic results are compared with survival statistics. The elderly group was associated with an increase in palliative treatment, more women and advanced T stages. For the 947 patients treated with curative intent, 5 year recurrence free survival was comparable. The overall-survival decreases with the age because of intercurrent deaths. Nevertheless, the treatment efficacy is similar. In conclusion, an advanced age is associated with worse survival, without a decrease in loco-regional control. The chronological age should not be used as a predictive factor for treatment response.

Phase I study of sorafenib combined with radiation therapy and temozolomide as first-line treatment of high-grade glioma.

BACKGROUND: Sorafenib (Sb) is a multiple kinase inhibitor targeting both tumour cell proliferation and angiogenesis that may further act as a potent radiosensitizer by arresting cells in the most radiosensitive cell cycle phase. This phase I open-label, noncontrolled dose escalation study was performed to determine the safety and maximum tolerated dose (MTD) of Sb in combination with radiation therapy (RT) and temozolomide (TMZ) in 17 patients with newly diagnosed high-grade glioma. METHODS: Patients were treated with RT (60 Gy in 2 Gy fractions) combined with TMZ 75 mg m(-2) daily, and Sb administered at three dose levels (200 mg daily, 200 mg BID, and 400 mg BID) starting on day 8 of RT. Thirty days after the end of RT, patients received monthly TMZ (150-200 mg m(-2) D1-5/28) and Sb (400 mg BID). Pharmacokinetic (PK) analyses were performed on day 8 (TMZ) and on day 21 (TMZ&Sb) (Clinicaltrials ID: NCT00884416). RESULTS: The MTD of Sb was established at 200 mg BID. Dose-limiting toxicities included thrombocytopenia (two patients), diarrhoea (one patient) and hypercholesterolaemia (one patient). Sb administration did not affect the mean area under the curve(0-24) and mean Cmax of TMZ and its metabolite 5-amino-imidazole-4-carboxamide (AIC). Tmax of both TMZ and AIC was delayed from 0.75 (TMZ alone) to 1.5 h (combined TMZ/Sb). The median progression-free survival was 7.9 months (95% confidence interval (CI): 5.4-14.55), and the median overall survival was 17.8 months (95% CI: 14.7-25.6). CONCLUSIONS: Although Sb can be combined with RT and TMZ, significant side effects and moderate outcome results do not support further clinical development in malignant gliomas. The robust PK data of the TMZ/Sb combination could be useful in other cancer settings.

[The Onco-hematology clinical research unit at the Geneva University Hospital: example of a fruitful public-private partners]. / L'Unité de recherche clinique en onco-hématologie aux HUG: un exemple réussi de partenariat public-privé.

A better understanding of the molecular deregulation leading to carcinogenesis allows the development of numerous novel targeted therapeutic candidates. Clinical research in oncology is a critical step to evaluate in a thorough manner the safety and efficacy of these innovative compounds. During the last four years the fruitful partnership between the Geneva University Hospitals and the Dr. Henri Dubois-Ferriere Dinu Lipatti Foundation lead to a dedicated clinical research unit for cancer patients with a staff of ten people. Since 2010, more than 300 patients were enrolled in more than 70 distinct clinical trials evaluating novel therapies for both solid tumors and hematologic malignancies. Interestingly, classical cytostatic drugs now represent only a small fraction of the new anti-cancer therapies in the pipeline.

Patient-centric comparative analysis of experiences in open upright and conventional closed MRI scanners.

INTRODUCTION: MRI often induces anxiety, leading to incomplete scans and claustrophobia-related distress. Open MRI systems aim to enhance patient comfort. This study examines how prior MRI experiences impact subsequent encounters in an open upright MRI scanner. METHODS: In this cross-sectional study, 118 adult patients completed a self-administered questionnaire from August 2022 to October 2023. It covered previous MRI experiences, including questions about claustrophobia, premature scan terminations, sedative medication usage, general MRI experiences, and interactions with radiology technologists. RESULTS: Patients in open upright MRI reported less claustrophobia compared to closed MRI systems (18.4% vs. 58.3%), fewer premature scan terminations (5.3% vs. 31.0%), and less sedative use (5.3% vs. 46.9%). Moderate positive correlations were found between past and current claustrophobic events and premature scan terminations. Effective communication with radiology technologists was essential for patient comfort and reduced claustrophobia. Scan duration and noise triggered discomfort in 26.1% and 21.6% of study participants respectively. Persons without prior MRI experience were more satisfied with the examination and expressed no clear preference for future MRI settings, contrasting those with previous exposure favoring the open MRI setup. CONCLUSION: The study emphasizes the benefits of open upright MRI for high-risk claustrophobic patients. It identifies the lasting impact of negative MRI experience on future examinations and highlights the crucial role of radiology technologists. IMPLICATIONS FOR PRACTICE: Integrating open MRI scanners in medical facilities and prioritizing effective communication with radiology technologists enhances patient comfort. Positive experiences with open MRI may improve patient compliance and offer greater flexibility for future examinations.

Dietary effects of linseed on fatty acid composition of milk and on liver, adipose and mammary gland metabolism of periparturient dairy cows.

During the transition period in dairy cows, drastic adaptations within and between key tissues and cell types occur in a coordinated manner to support late gestation, the synthesis of large quantities of milk and metabolic homoeostasis. The start of lactation coincides with an increase of triacylglycerols in the liver, which has been associated with several economically important diseases in dairy cows (i.e. hepatic lipidiosis, mastitis). The polyunsaturated fatty acids have been used to improve liver metabolism and immune function in the mammary gland. Therefore, the effects of dietary linseed supplementation on milk quality and liver, adipose and mammary gland metabolism of periparturient dairy cows were studied in 14 cows that were randomly assigned to control or linseed supplementation. Animals were treated from 3 weeks antepartum until 6 weeks post-partum. Linseed did not modify dry matter intake, but increased milk yield and lactose yield, and decreased milk fat concentration, which coincided with lower proportion of C16 and higher proportions of stearic acid, conjugated linoleic acid and α-linolenic acid in milk fat. Linseed supplementation did not significantly change the expression of key lipid metabolism genes in liver and adipose tissues, except of glucose transporter 2 (GLUT2) in liver, which was increased in cows supplemented with linseed, suggesting that more glucose was secreted and probably available for lactose synthesis compared with cows fed control diet. Large adaptations of transcription occurred in the mammary gland when dairy cows were supplemented with linseed. The main affected functional modules were related to energy metabolism, cell proliferation and remodelling, as well as the immune system response.

[The role of surgery in early stage small cell lung cancer: should it be re-evaluated?]. / Chirurgie du cancer pulmonaire à petites cellules de stade précoce: doit-on réévaluer son rôle?

Two historical randomized controlled trials have demonstrated that chemo-radiotherapy offers the best survival advantage over surgery in small cell lung carcinoma (SCLC) and led to abandon surgery for the treatment of SCLC. Yet, widespread use of CT scanning increases the detection of early and very early stage SCLC. Therefore, the traditional 2 stages classification scheme--namely limited and extensive stage disease--is no longer sufficient for such early stage disease and must be completed by the TNM classification. Although randomized controlled trials are lacking, retrospective case series and large population databases suggest a beneficial role of surgery for the earliest SCLC stages. It is thus currently recommended to consider surgery in the multimodal treatment of stage I SCLC.

Transcriptomic signature related to poor welfare of sport horses.

The improvement of horse welfare through housing conditions has become a real issue in recent years and have highlighted the detrimental effect of individual housing of horses on their health and behaviour. In this new study, we analysed the blood transcriptome of 45 sport horses housed individually that were previously examined for their behaviour and gut microbiota. We performed differential and regression analyses of gene expression, followed by downstream bioinformatic analyses, to unveil the molecular pathways related to the behavioural changes associated with welfare impairment in these sport horses. We found that aggressiveness towards humans was the behavioural indicator the most correlated to blood gene expression and that the pathways involved belonged mainly to systemic inflammation. In contrast, the correlations between genes, alert postures and unresponsiveness towards the environment were weak. When blood gene expression profiling was combined with faecal microbiota of a sub-population of horses, stereotypies came out as the most correlated to blood gene expression. This study shows that aggressiveness towards humans and stereotypies are behavioural indicators that covary with physiological alterations. Further studies are needed regarding the biological correlates of unresponsiveness to the environment and alert postures.

Pembrolizumab versus methotrexate, docetaxel, or cetuximab in recurrent or metastatic head and neck squamous cell carcinoma (KEYNOTE-040): Subgroup analysis by pattern of disease recurrence.

BACKGROUND: In the phase 3 KEYNOTE-040 study, pembrolizumab prolonged OS versus chemotherapy in previously treated recurrent or metastatic (R/M) HNSCC. We present a post hoc subgroup analysis by disease recurrence pattern: recurrent-only, recurrent and metastatic (recurrent-metastatic), and metastatic-only HNSCC. MATERIALS AND METHODS: Patients had HNSCC that progressed during or after platinum-containing treatment for R/M disease or had recurrence or progression within 3-6 months of previous platinum-containing definitive therapy for locally advanced disease. Patients were randomly assigned (1:1) to pembrolizumab 200 mg Q3W or investigator's choice of standards of care (SOC): methotrexate, docetaxel, or cetuximab. Outcomes included OS, PFS, ORR, and DOR. The data cutoff was May 15, 2017. RESULTS: There were 125 patients (pembrolizumab, 53; SOC, 72) in the recurrent-only subgroup, 204 in the recurrent-metastatic subgroup (pembrolizumab, 108; SOC, 96), and 166 in the metastatic-only subgroup (pembrolizumab, 86; SOC, 80). The hazard ratio (95% CI) for death for pembrolizumab versus SOC was 0.83 (0.55-1.25) in the recurrent-only, 0.78 (0.58-1.06) in the recurrent-metastatic, and 0.74 (0.52-1.05) in the metastatic-only subgroups. PFS was similar between treatment arms in all subgroups. ORR was 22.6% for pembrolizumab versus 16.7% for SOC in the recurrent-only, 10.2% versus 6.3% in the recurrent-metastatic, and 15.1% versus 8.8% in the metastatic-only subgroups. DOR was numerically longer with pembrolizumab in all subgroups. CONCLUSION: Pembrolizumab provided numerically longer OS and durable responses in all subgroups compared with SOC, suggesting that patients with previously treated R/M HNSCC benefit from pembrolizumab regardless of recurrence pattern.

Pleiotropic effects of polymorphism of the gene diacylglycerol-O-transferase 1 (DGAT1) in the mammary gland tissue of dairy cows.

Microarray analysis was used to identify genes whose expression in the mammary gland of Holstein-Friesian dairy cows was affected by the nonconservative Ala to Lys amino acid substitution at position 232 in exon VIII of the diacylglycerol-O-transferase 1 (DGAT1) gene. Mammary gland biopsies of 9 homozygous Ala cows, 13 heterozygous cows (Ala/Lys), and 4 homozygous Lys cows in midlactation were taken. Microarray ANOVA and factor analysis for multiple testing methods were used as statistical methods to associate the expression level of the genes present on Affymetrix bovine genome arrays (Affymetrix Inc., Santa Clara, CA) with the DGAT1 gene polymorphism. The data was also analyzed at the level of functional modules by gene set enrichment analysis. In this small-scale experimental setting, DGAT1 gene polymorphism did not modify milk yield and composition significantly, although expected changes occurred in the yields of C14:0, cis-9 C16:1, and long-chain fatty acids. Diacylglycerol-O-transferase 1 gene polymorphism affected the expression of 30 annotated genes related to cell growth, proliferation, and development, remodeling of the tissue, cell signaling and immune system response. Furthermore, the main affected functional modules were related to energy metabolism (lipid biosynthesis, oxidative phosphorylation, electron transport chain, citrate cycle, and propanoate metabolism), protein degradation (proteosome-ubiquitin pathways), and the immune system. We hypothesize that the observed differences in transcriptional activity reflect counter mechanisms of mammary gland tissue to respond to changes in milk fatty acid concentration or composition, or both.

[Targeted therapy in lung cancer: molecular testing using cytological specimens]. / Thérapies ciblées du cancer pulmonaire: tests moléculaires à partir d'échantillons cytologiques.

Important advances in lung cancer treatment have been made over the last decade. Several drugs designed to target molecular pathways involved in cancer-cell growth and survival have been shown to be effective in a selected fraction (<20%) of non-small cell lung cancer patients. Somatic mutations in several genes (i.e.: EGFR and KRAS) can predict patient's response to targeted therapies. Those mutations are commonly detected on histopathological samples (core-needle biopsy/ surgical resection). However, when tissue biopsies are not available, molecular testing has to be performed on cytological specimens. Issues raised by molecular testing on cytological specimen are discussed in this article.

[Anticancer drugs under pressure]. / Anticancéreux sous haute tension.

Angiogenesis inhibitor drugs, targeting VEGF (vascular endothelial growth factor) are used increasingly in oncology for a wide range of advanced cancers (colorectal cancer, lung cancer, renal cell cancer,...). Generally, they are well tolerated but cardiovascular and renal side effects may appear. The most frequent complications are hypertension and proteinuria which, very often, remain asymptomatic. Therefore, they have to be searched for systematically before and during the treatment. Sometimes, anti-hypertensive medication is needed. We are just beginning to understand the pathophysiological mechanisms of antiangiogenic therapies. Only a multidisciplinary approach will improve our knowledge of those target agents and allow a better management of the cancer patient.

Serum acylcarnitine profile in endurance horses with and without metabolic dysfunction.

Mitochondrial ß-oxidation is essential in fat metabolism and can be monitored with blood acylcarnitine profiling, as partly degraded fatty acids accumulate as their carnitine esters. To guarantee continuous energy supply during long-distance exercise, endurance horses oxidise considerable amounts of fat in the mitochondrion. In endurance races over 80 km, glycogen depletion is evident in equine slow-twitch high oxidative muscle fibres and as a consequence, horses participating in endurance races over 80 km rely almost entirely on ß-oxidation of fatty acids. This study investigated mitochondrial fatty acid ß-oxidation in endurance horses exposed to long-distance exercise. Electrospray tandem mass spectrometry analysis of serum acylcarnitine profiles from 10 Arab horses was performed before and after a 160 km endurance race. Results were analysed statistically using ANOVA. Mean speed over the entire race in finishing horses was 16.7 ± 1.2 km/h. Endurance exercise increased mitochondrial ß-oxidation approximately eight-fold (pre-race, 5648.62 ± 1508.52 nmol/L; post-race, 44,243.17 ± 11,504.45 nmol/L; P = 0.001). In these horses, there was an approximately 17-fold increased lipolysis, as demonstrated by elevated serum concentrations of non-esterified fatty acids (NEFA; pre-race, 0.08 ± 0.08 mmol/L; post-race, 1.32 ± 0.36 mmol/L; P < 0.001). In comparison, four Arab horses with poor performance showed an approximately five-fold increase in mitochondrial ß-oxidation (pre-race, 5286.17 ± 3355.16 nmol/L; post-race, 26,660.57 ± 10,064.27 nmol/L; P = 0.009); there was a 29-fold increase in NEFA (pre-race, 0.02 ± 0.01 mmol/L; post-race, 0.58 ± 0.07 mmol/L; P = 0.006) in these horses. Similar post-exercise free carnitine:acetylcarnitine ratios in both groups suggest that the availability of carnitine in long-distance endurance horses might limit performance.

Burdizzo pre-pubertal castration effects on performance, behaviour, carcass characteristics, and meat quality of Holstein bulls fed high-concentrate diets.

The effects of Burdizzo pre-pubertal castration on performance, behaviour, carcass, and meat quality of Holstein bulls fed high-concentrate diets were evaluated. Two hundred bulls (8.0±0.42 months old) were randomly assigned to control (CTR) or Burdizzo castration (BURD). After 121d, ADG, BW, and HCW were greater in CTR animals than in BURD animals, as well as, the agonistic and sexual behaviour. However, carcass fatness and intramuscular LT (longissimus thoracis) fat percentage were greater in BURD animals than in CTR animals. Additionally, CTR animals showed lower L(∗), a(∗), and b(∗) than BURD. The WBSF was smaller (P<0.01) in BURD than in CTR bulls at all ageing days, and in both treatments decreased (P<0.01) from 0 to 7d of ageing. Additionally, at day 0 of ageing, meat from BURD animals showed similar WBSF to meat from CTR bulls after 7d of ageing. However, 23% of BURD animals did not have a complete testicular atrophy, suggesting that the method of castration was not completely effective.

Multicenter phase II trial of gefitinib first-line therapy followed by chemotherapy in advanced non-small-cell lung cancer (NSCLC): SAKK protocol 19/03.

BACKGROUND: Gefitinib is active in patients with pretreated non-small-cell lung cancer (NSCLC). We evaluated the activity and toxicity of gefitinib first-line treatment in advanced NSCLC followed by chemotherapy at disease progression. PATIENTS AND METHODS: In all, 63 patients with chemotherapy-naive stage IIIB/IV NSCLC received gefitinib 250 mg/day. At disease progression, gefitinib was replaced by cisplatin 80 mg/m(2) on day 1 and gemcitabine 1250 mg/m(2) on days 1, 8 for up to six 3-week cycles. Primary end point was the disease stabilization rate (DSR) after 12 weeks of gefitinib. RESULTS: After 12 weeks of gefitinib, the DSR was 24% and the response rate (RR) was 8%. Median time to progression (TtP) was 2.5 months and median overall survival (OS) 11.5 months. Never smokers (n = 9) had a DSR of 56% and a median OS of 20.2 months; patients with epidermal growth factor receptor (EGFR) mutation (n = 4) had a DSR of 75% and the median OS was not reached after the follow-up of 21.6 months. In all, 41 patients received chemotherapy with an overall RR of 34%, DSR of 71% and median TtP of 6.7 months. CONCLUSIONS: First-line gefitinib monotherapy led to a DSR of 24% at 12 weeks in an unselected patients population. Never smokers and patients with EGFR mutations tend to have a better outcome; hence, further trials in selected patients are warranted.

Association between animal, transportation, slaughterhouse practices, and meat pH in beef.

The objective of this study was to evaluate the influence of factors related to animal, farm, transportation, and animal handling at the slaughterhouse, as well as their interactions, on pH of beef meat. A total of 5494 cattle (343±45d of age) from 181 different Spanish farms were surveyed during three seasons (spring, summer, and winter) and a total of 25 pre-slaughter variables were recorded. Meat pH was measured at the Longissimus dorsi 24h post-mortem (pH(24)). After a variable selection procedure, a mixed-effects logistic regression model was conducted with 5 variables (1 random and 4 fixed) to identify the main factors, and their interactions, affecting meat pH(24). Average incidences of meat pH(24) greater than 5.8 and 6.0 were 13.89% and 4.02%, respectively. The variability of meat pH(24) explained with studied factors and their interactions was only 4.9%, a value too low to allow making technical decisions to improve meat pH(24) in the Spanish market considering the variables studied.

Cytokine-secreting tumor cell vaccines.

Modification of the tumor microenvironment with gene transfer techniques stimulates two immune mechanisms that effectuate tumor destruction. One involves improved tumor-antigen presentation for the development of specific cellular and humoral immunity. The second involves compromise of the tumor vasculature by soluble factors and leukocytes.

Guarantying the quality of chemotherapy: from the order to the administration.

Ensuring the quality and security when prescribing drugs like chemotherapies is a complex task if one wants to cover the whole chain from the prescribing physician to the administrant nurse. At the University hospitals of Geneva, new applications covering the whole chain from the prescription up to and including the fabrication of the products have been developed in three phases and are being used in a production stage. In order to cover the "last yard" at the bed level, a fourth phase has been started with a pilot study based on labels containing RFID chips for preparations and for patients. The last phase will make use of all traceability data acquired from the prescription to the preparation to validate that the right product is administered to the right patient, and to record who is administrating it.

Differences in dendritic cells stimulated in vivo by tumors engineered to secrete granulocyte-macrophage colony-stimulating factor or Flt3-ligand.

Both granulocyte-macrophage colony-stimulating factor (GM-CSF) and flt3-ligand (FL) induce the development of dendritic cells (DCs). To compare the functional properties of DCs stimulated by these cytokines in vivo, we used retroviral-mediated gene transfer to generate murine tumor cells secreting high levels of each molecule. Injection of tumor cells expressing either GM-CSF or FL resulted in the dramatic increase of CD11c+ cells in the spleen and tumor infiltrate. However, vaccination with irradiated, GM-CSF-secreting tumor cells stimulated more potent antitumor immunity than vaccination with irradiated, FL-secreting tumor cells. The superior antitumor immunity elicited by GM-CSF involved a broad T cell cytokine response, in contrast to the limited Thl response elicited by FL. DCs generated by GM-CSF were CD8alpha- and expressed higher levels of B7-1 and CD1d than DCs cells generated by FL. Injection sites of metastatic melanoma patients vaccinated with irradiated, autologous tumor cells engineered to secrete GM-CSF demonstrated similar, dense infiltrates of DCs expressing high levels of B7-1. These findings reveal critical differences in the abilities of GM-CSF and FL to enhance the function of DCs in vivo and have important implications for the crafting of tumor vaccines.

Tumor cell vaccine elicits potent antitumor immunity after allogeneic T-cell-depleted bone marrow transplantation.

Allogeneic bone marrow transplantation (BMT) is currently restricted to hematological malignancies because of a lack of antitumor activity against solid cancers. We have tested a novel treatment strategy to stimulate specific antitumor activity against a solid tumor after BMT by vaccination with irradiated tumor cells engineered to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF). Using the B16 melanoma model, we found that vaccination elicited potent antitumor activity in recipients of syngeneic BMT in a time-dependent fashion, and that immune reconstitution was critical for the development of antitumor activity. Vaccination did not stimulate antitumor immunity after allogeneic BMT because of the post-BMT immunodeficiency associated with graft-versus-host disease (GVHD). Remarkably, vaccination was effective in stimulating potent and long-lasting antitumor activity in recipients of T-cell-depleted (TCD) allogeneic bone marrow. Recipients of TCD bone marrow who showed significant immune reconstitution by 6 weeks after BMT developed B16-specific T-cell-cytotoxic, proliferative, and cytokine responses as a function of vaccination. T cells derived from donor stem cells were, therefore, able to recognize tumor antigens, although they remained tolerant to host histocompatibility antigens. These results demonstrate that GM-CSF-based tumor cell vaccines after allogeneic TCD BMT can stimulate potent antitumor effects without the induction of GVHD, and this strategy has important implications for the treatment of patients with solid malignancies.