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.

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.

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.

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.

[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.

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 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.

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.

Analysis of raw hams using SELDI-TOF-MS to predict the final quality of dry-cured hams.

The relationship between protein profiles of Gluteus medius (GM) muscles of raw hams obtained from 4 pure breed pigs (Duroc, Large White, Landrace, and Piétrain) with the final quality of the Semimembranosus and Biceps femoris muscles of dry-cured hams was investigated. As expected, Duroc hams showed higher levels of marbling and intramuscular fat content than the other breeds. Piétrain hams were the leanest and most conformed, and presented the lowest salt content in dry-cured hams. Even if differences in the quality traits (colour, water activity, texture, composition, intramuscular fat, and marbling) of dry-cured hams were observed among the studied breeds, only small differences in the sensory attributes were detected. Surface-enhanced laser desorption/ionisation time-of-flight mass spectrometry (SELDI-TOF-MS) was used to obtain the soluble protein profiles of GM muscles. Some associations between protein peaks obtained with SELDI-TOF-MS and quality traits, mainly colour (b*) and texture (F(0), Y(2), Y(90)) were observed. Candidate protein markers for the quality of processed dry-cured hams were identified.

Surface-enhanced laser desorption/ionisation time-of-flight mass spectrometry: a tool to predict pork quality.

Expression of water soluble proteins of fresh pork Longissimus thoracis from 4 pure breed pigs (Duroc, Large White, Landrace, and Piétrain) was studied to identify candidate protein markers for meat quality. Surface-enhanced laser desorption/ionisation time-of-flight mass spectrometry (SELDI-TOF-MS) was used to obtain the soluble protein profiles of Longissimus thoracis muscles. The pure breeds showed differences among the studied meat quality traits (pHu, drip loss, androstenone, marbling, intramuscular fat, texture, and moisture), but no significant differences were detected in sensory analysis. Associations between protein peaks obtained with SELDI-TOF-MS and meat quality traits, mainly water holding capacity, texture and skatole were observed. Of these peaks, a total of 10 peaks from CM10 array and 6 peaks from Q10 array were candidate soluble protein markers for pork loin quality. The developed models explained a limited proportion of the variability, however they point out interesting relationships between protein expression and meat quality.

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.

Cell encapsulation technology as a novel strategy for human anti-tumor immunotherapy.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) as an adjuvant in autologous cell-based anti-tumor immunotherapy has recently been approved for clinical application. To avoid the need for individualized processing of autologous cells, we developed a novel strategy based on the encapsulation of GM-CSF-secreting human allogeneic cells. GM-CSF-producing K562 cells showed high, stable and reproducible cytokine secretion when enclosed into macrocapsules. For clinical development, the cryopreservation of these devices is critical. Thawing of capsules frozen at different time points displayed differences in GM-CSF release shortly after thawing. However, similar secretion values to those of non-frozen control capsules were obtained 8 days after thawing at a rate of >1000 ng GM-CSF per capsule every 24 h. For future human application, longer and reinforced capsules were designed. After irradiation and cryopreservation, these capsules produced >300 ng GM-CSF per capsule every 24 h 1 week after thawing. The in vivo implantation of encapsulated K562 cells was evaluated in mice and showed preserved cell survival. Finally, as a proof of principle of biological activity, capsules containing B16-GM-CSF allogeneic cells implanted in mice induced a prompt inflammatory reaction. The ability to reliably achieve high adjuvant release using a standardized procedure may lead to a new clinical application of GM-CSF in cell-based cancer immunization.

Alteration of gene expression in mammary gland tissue of dairy cows in response to dietary unsaturated fatty acids.

The aim of this study was to determine the effects of supplementing unprotected dietary unsaturated fatty acids (UFAs) from different plant oils on gene expression in the mammary gland of grazing dairy cows. A total of 28 Holstein-Friesian dairy cows in mid-lactation were blocked according to parity, days in milk, milk yield and fat percentage. The cows were then randomly assigned to four UFA sources based on rapeseed, soybean, linseed or a mixture of the three oils for 23 days, after which, all 28 cows were switched to a control diet for an additional 28 days. On the last day of both periods, mammary gland biopsies were taken to study genome-wide differences in gene expression on Affymetrix GeneChip® Bovine Genome Arrays (no. 900493) by ServiceXS (Leiden, The Netherlands). Supplementation with UFAs resulted in increased milk yield but decreased milk fat and protein percentages. Furthermore, the proportion of de novo fatty acids (FAs) in the milk was reduced, whereas that of long-chain FAs increased. Applying a statistical cut-off of false discovery rate of q-values <0.05 together with an absolute fold change of 1.3, a total of 972 genes were found to be significantly affected through UFA supplementation, indicating that large transcriptional adaptations occurred in the mammary gland when grazing dairy cows were supplemented with unprotected dietary UFA. Gene sets related to cell development and remodeling, apoptosis, nutrient metabolic process, as well as immune system response were predominantly downregulated during UFA supplementation. Such molecular knowledge on the physiology of the mammary gland might provide the basis for further functional research on dairy cows.

Comparative proteomic profiling of 2 muscles from 5 different pure pig breeds using surface-enhanced laser desorption/ionization time-of-flight proteomics technology.

The objectives of this study were to evaluate the influence of different pure pig breeds and muscle types on the expression of muscle proteins, as well as their interactions, and second, to find biomarkers for breed and muscle types. A total of 126 male pigs, including 43 Landrace, 21 Duroc, 43 Large White, 13 Pietrain, and 6 Belgian Landrace, were slaughtered at the age of 174 +/- 6 d. Samples from the semimembranosus muscle (SM) and LM were collected 24 h postmortem. Proteomic spectra were generated on an anion exchanger (Q10), a cation exchanger (CM10), and on immobilized metal affinity capture (IMAC30) ProteinChip arrays and analyzed using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry ProteinChip techniques. Breed and muscle type did not affect the number of peaks per spectrum but, interestingly, affected the average intensity of the peaks. Of these peaks, a total of 4 proved to be potential protein biomarkers to differentiate LM or SM muscles, and 2 to classify specific breed types. Additionally, several peaks influenced by the interaction between muscle and breed types could correctly classify pig muscles according to their breed. Further studies need to be carried out to validate and identify these potential protein biomarkers for breed and muscle types in finishing pigs.

Effects of crude glycerin supplementation on performance and meat quality of Holstein bulls fed high-concentrate diets.

Forty-eight bulls (335 +/- 8.6 kg of initial BW) were randomly assigned to 4 glycerin levels (0, 4, 8, and 12% of concentrate DM) with the objective of evaluating the effects of glycerin supplementation on performance, ruminal fermentation, metabolism, and carcass and meat quality in Holstein bulls fed high-concentrate diets. Concentrates were formulated to be isonitrogenous and isocaloric (assuming a glycerin ME content of 3.47 Mcal/kg of DM). Concentrate and straw were fed for ad libitum intake. Bull BW and feed consumption were recorded monthly. Additionally, rumen and blood samples were collected every month. Bulls were slaughtered after 91 d of study (460 +/- 11 kg of final BW). Hot carcass weight, carcass backfat, and conformation were recorded. The area, Warner-Bratzler shear force, and intramuscular fat content of LM were determined. Glycerin level did not affect daily concentrate intake (6.89 +/- 0.34 kg/d of DM), straw intake (1.38 +/- 0.069 kg/d of DM), total DMI (8.27 +/- 0.32 kg/d of DM), ADG (1.36 +/- 0.087 kg/d), or G:F (0.17 +/- 0.009). Similarly, rumen molar proportions of propionic, acetic, and butyric acids, and rumen liquid osmolality were unaffected by treatment. However, a decreased rumen pH (P < 0.05), and greater rumen total VFA concentration (P = 0.09), serum insulin concentration (P < 0.05), and insulin to glucose ratio (P < 0.05) were observed in bulls fed 8% glycerin in concentrate compared with those receiving 0, 4, or 12%. No changes were observed in carcass and meat quality. The ME content of glycerin (86% glycerol) can be assumed to be 3.47 Mcal/kg of DM in Holstein bulls fed high-concentrate diets. In addition, feeding concentrate containing up to 12.1% of glycerin does not lead to detrimental effects on performance, ruminal fermentation, metabolism, and carcass and meat quality variables.

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.