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(1) Background: recent evidence suggests that long low-dose capecitabine regimens have a synergistic effect with endocrine therapy as aromatase inhibitors (AIs), and might increase overall survival for hormone-receptor-positive, HER2-negative, metastatic breast cancer compared to both treatments. We performed a retrospective study to confirm the efficacy and expand the safety data for capecitabine plus AI (a combination henceforth named XELIA) for this indication. (2) We conducted a single-center retrospective cohort study of 163 hormone receptor-positive metastatic breast cancer patients who received either the XELIA regimen, capecitabine, or an aromatase inhibitor (AI) as single agents in first-line treatment. The primary endpoint was progression-free survival, and the secondary endpoints were overall survival, best objective response, and toxicity incidence. (3) Results: the median progression-free survival for patients receiving XELIA, AI, and capecitabine was 29.37 months (20.91 to 37.84; 95% CI), 20.04 months (7.29 to 32.80; 95% CI) and 10.48 (8.69 to 12.28; 95% CI), respectively. The overall response rate was higher in the XELIA group (29.5%) than in the AI (14.3%) and capecitabine (9.1%) groups. However, the differences in overall survival were not statistically significant. Apart from hand–foot syndrome, there were no statistically significant differences in adverse events between the groups. (4) Conclusions: this retrospective study suggests that progression-free survival and overall response rates improved with the XELIA regimen compared to use of aromatase inhibitors and capecitabine alone. Combined use demonstrated an adequate safety profile and might represent an advantageous treatment in places where CDK 4/6 is not available. Larger studies and randomized clinical trials are required to confirm the effects shown in our study.

Background The cryopreservation of filarial nematodes has been studied for nearly 70 years. Largely, these studies examined the effectiveness of cryopreservation methods by using the post-thaw survival of microfilariae (mf) and the development to third-stage larvae (L3s) following inoculation into a competent insect vector. Only one study reported complete reestablishment of a filarial nematode (Brugia malayi) life-cycle in a competent vertebrate host from cryopreserved stock. Expanding on this previous research, a cryopreservation method was developed to cryopreserve the mf of the dog heartworm, Dirofilaria immitis. Methods A combination of cryoprotectants, dimethyl sulfoxide (DMSO) and polyvinyl pyrolidone (PVP) at 6% and 4 mM, respectively, provided acceptable post-thaw survival of mf that developed into L3s in Aedes aegypti. L3s developed from cryopreserved and freshly collected mf in mosquitoes were inoculated into ferrets and dogs and were assessed after a sufficient duration post-inoculation for development into adult heartworms. Results Fewer adult heartworms derived from cryopreserved stocks of mf were recovered from ferrets compared to adult heartworms derived from freshly collected mf, and the former were smaller by weight and length. The onset of patency (circulating mf) occurred at similar post-inoculation time points and at similar mf densities in dogs infected with L3s sourced from cryopreserved stocks or freshly collected mf. Adults derived from cryopreserved mf have survived and produced viable mf for more than 3 years in dogs. Approximately 60% of inoculated L3s were recovered as adults from dogs at 2 and 3.5 years post-inoculation. Conclusions The results from these direct comparisons demonstrate that cryopreserved mf can develop into L3s in vector mosquitoes and that these L3s are infective to both dogs and ferrets, where they undergo normal development into adult worms. These worms are able to mate and produce viable mf and complete the heartworm lifecycle in dog. Graphical Abstract

Smoking is the main cause of lung cancer. It plays a role in the etiology, and depending on the intensity and duration, it also has an influence on histology, stage and therapeutic outcome. Therefore, it is never too late to stop smoking. Tobacco smoke is so toxic, that there is no safe smoking modality. Filters, light cigarettes, pipes, water pipes, etc. are prohibitively harmful. In addition, the electronic nicotine delivery systems, besides promoting addiction, cause acute respiratory and cardiovas¬cular effects. In addition, even though long-term consequences are yet to be known, cell proliferation and tumor progression have been identified. Tobacco control efforts should look at all these new products as its main threat.

Additional file 1.

Over the last decade, the isoxazoline motif has become the intense focus of crop protection and animal health companies in their search for novel pesticides and ectoparasiticides. Herein we report the discovery of sarolaner, a proprietary, optimized-for-animal health use isoxazoline, for once-a-month oral treatment of flea and tick infestation on dogs.

La detección temprana de cáncer pulmonar (CP) en población de alto riesgo tiene el potencial de diagnosticar la enfermedad en estadios tempranos y facilitar el tratamiento oportuno con el fin de disminuir la tasa de mortalidad. En México, como en otros países en vías de desarrollo, además del tabaquismo, la exposición al humo de leña se posiciona como uno de los principales factores de riesgo para desarrollar CP, lo cual no se ha considerado en estudios de tamizaje previamente publicados. Distintas interrogantes surgen en relación con quiénes son las personas que presentan un alto riesgo de desarrollar CP en América Latina, cuál es el costo-beneficio de poner en marcha un programa de detección oportuna de CP en México y cuáles son los obstáculos que los países de la región enfrentan para su implementación.Lung cancer screening has the potential to be diagnosed at an early stage which increases the possibility of curative treatment in order to decrease the mortality rate. In Mexico, as in other developing nations, along with wood smoke exposure is one of the main risk factors for developing lung cancer, not considered in previously published screening trials. Different questions arise concerning the population at higher risk to develop lung cancer in Latin America, the cost-benefit of implementing a lung cancer screening program and the obstacles facing developing countries when implementing a detection program. To knowledge, there are no lung cancer screening trials in Mexico.

Smoking is the main cause of lung cancer. It plays a role in the etiology, and depending on the intensity and duration, it also has an influence on histology, stage and therapeutic outcome. Therefore, it is never too late to stop smoking. Tobacco smoke is so toxic, that there is no safe smoking modality. Filters, light cigarettes, pipes, water pipes, etc. are prohibitively harmful. In addition, the electronic nicotine delivery systems, besides promoting addiction, cause acute respiratory and cardiovascular effects. In addition, even though long-term consequences are yet to be known, cell proliferation and tumor progression have been identified. Tobacco control efforts should look at all these new products as its main threat.El tabaquismo es la principal causa de cáncer de pulmón. Participa en la etiología y, dependiendo de la intensidad y duración, influye en el tipo histológico, el estadio de la enfermedad y el efecto del tratamiento, por lo que nunca es tarde para dejar de fumar. La toxicidad del humo del tabaco es tan alta que no existe ninguna modalidad segura de tabaquismo. Los filtros, las diferentes variedades de cigarros light, los puros, pipas de agua, etc. son prohibitivamente dañinas. Inclusive los diferentes dispositivos electrónicos para la administración de nicotina, además de promocionar la adicción, tienen efectos respiratorios y cardiovasculares a corto plazo y, aunque aún es pronto para conocer sus consecuencias a largo plazo, se han identificado efectos en la proliferación celular y progresión tumoral. Por lo anterior, las campañas para el control del tabaquismo deben considerar estos productos como su principal amenaza.

La detección temprana de cáncer pulmonar (CP) en población de alto riesgo tiene el potencial de diagnosticar la enfermedad en estadios tempranos y facilitar el tratamiento oportuno con el fin de disminuir la tasa de mortalidad. En México, como en otros países en vías de desarrollo, además del tabaquismo, la exposición al humo de leña se posiciona como uno de los principales factores de riesgo para desarrollar CP, lo cual no se ha considerado en estudios de tamizaje previamente publicados. Distintas interrogantes surgen en relación con quiénes son las personas que presentan un alto riesgo de desarrollar CP en América Latina, cuál es el costo-beneficio de poner en marcha un programa de detección oportuna de CP en México y cuáles son los obstáculos que los países de la región enfrentan para su implementación.

El tabaquismo es la principal causa de cáncer de pulmón. Parti­cipa en la etiología y, dependiendo de la intensidad y duración, influye en el tipo histológico, el estadio de la enfermedad y el efecto del tratamiento, por lo que nunca es tarde para dejar de fumar. La toxicidad del humo del tabaco es tan alta que no existe ninguna modalidad segura de tabaquismo. Los filtros, las diferentes variedades de cigarros light, los puros, pipas de agua, etc. son prohibitivamente dañinas. Inclusive los diferentes dispositivos electrónicos para la administración de nicotina, además de promocionar la adicción, tienen efectos respiratorios y cardiovasculares a corto plazo y, aunque aún es pronto para conocer sus consecuencias a largo plazo, se han identificado efectos en la proliferación celular y progre­sión tumoral. Por lo anterior, las campañas para el control del tabaquismo deben considerar estos productos como la principal amenaza para el control del tabaquismo.

Ganciclovir has shown in vitro anti-human herpesvirus-8 activity, Kaposi sarcoma agent. We analyzed all Kaposi sarcoma patients from 1985 to 1996 pre-HAART era and identified Kaposi sarcoma/AIDS patients who achieved complete remission prior to HAART use.We saw 155 Kaposi sarcoma patients up to 1996, 150 with enough information, only 12 received ganciclovir, eight of them for ≥ 21 days; four died within 16 weeks of ganciclovir administration. We identified four male patients with extensive Kaposi sarcoma with complete remission achieved after ganciclovir for CMV end-organ disease. Complete remission was achieved (9, 5, 10 and 5 months) after ganciclovir, which persisted even after antiretroviral therapy failure. All received two nucleosides and indinavir was later added with irregular compliance. The CD4 counts when ganciclovir was started: 11 (4%), 60 (5%), 127 (14%), and 38 (3%) and when they achieved complete remission: 37 (4%), 109 (9%), 313 (13%) and 136 (9%), respectively. Two patients died with no Kaposi sarcoma relapse three years later, with wasting syndrome and other pulmonary-embolism seven years later. One was lost to follow-up in complete remission in the year 2000, the other was alive in 2014 with 27% 820 CD4 cells/ml. The use of ganciclovir was statistically significantly associated with Kaposi sarcoma remission p = 0.001.Ganciclovir use was associated to complete remission of Kaposi sarcoma in the pre-HAART era.

SUMMARYThe cat flea, Ctenocephalides felis, is a major pest species on companion animals thus of significant importance to the animal health industry. The aim of this study was to develop sampling and storage protocols and identify stable reference genes for gene expression studies to fully utilize the growing body of molecular knowledge of C. felis. RNA integrity was assessed in adult and larvae samples, which were either pierced or not pierced and stored in RNAlater at ambient temperature. RNA quality was maintained best in pierced samples, with negligible degradation evident after 10 days. RNA quality from non-pierced samples was poor within 3 days. Ten candidate reference genes were evaluated for their stability across four group comparisons (developmental stages, genders, feeding statuses and insecticide-treatment statuses). Glyceraldehyde 3 phosphate dehydrogenase (GAPDH), 60S ribosomal protein L19 (RPL19) and elongation factor-1α (Ef) were ranked highly in all stability comparisons, thus are recommended as reference genes under similar conditions. Employing just two of these three stable reference genes was sufficient for accurate normalization. Our results make a significant contribution to the future of gene expression studies in C. felis, describing validated sample preparation procedures and reference genes for use in this common pest.

The novel isoxazoline ectoparasiticide, sarolaner, was identified during a lead optimization program for an orally-active compound with efficacy against fleas and ticks on dogs. The aim of the discovery program was to identify a novel isoxazoline specifically for use in companion animals, beginning with de novo synthesis in the Zoetis research laboratories. The sarolaner molecule has unique structural features important for its potency and pharmacokinetic (PK) properties, including spiroazetidine and sulfone moieties. The flea and tick activity resides in the chirally pure S-enantiomer, which was purified to alleviate potential off-target effects from the inactive enantiomer. The mechanism of action was established in electrophysiology assays using CHO-K1 cell lines stably expressing cat flea ( Ctenocephalides felis ) RDL (resistance-to-dieldrin) genes for assessment of GABA-gated chloride channel (GABACls) pharmacology. As expected, sarolaner inhibited GABA-elicited currents at both susceptible (CfRDL-A285) and resistant (CfRDL-S285) flea GABACls with similar potency. Initial whole organism screening was conducted in vitro using a blood feeding assay against C. felis. Compounds which demonstrated robust activity in the flea feed assay were subsequently tested in an in vitro ingestion assay against the soft tick, Ornithodoros turicata . Efficacious compounds which were confirmed safe in rodents at doses up to 30 mg/kg were progressed to safety, PK and efficacy studies in dogs. In vitro sarolaner demonstrated an LC 80 of 0.3 μg/mL against C. felis and an LC 100 of 0.003 μg/mL against O. turicata . In a head-to-head comparative in vitro assay with both afoxolaner and fluralaner, sarolaner demonstrated superior flea and tick potency. In exploratory safety studies in dogs, sarolaner demonstrated safety in dogs ≥ 8 weeks of age upon repeated monthly dosing at up to 20 mg/kg. Sarolaner was rapidly and well absorbed following oral dosing. Time to maximum plasma concentration occurred within the first day post-dose. Bioavailability for sarolaner was calculated at >85% and the compound was highly protein bound (>99.9%). The half-life for sarolaner was calculated at 11–12 days. Sarolaner plasma concentrations indicated dose proportionality over the range 1.25–5 mg/kg, and these same doses provided robust efficacy (> 99%) for ≥35 days against both fleas ( C. felis ) and multiple species of ticks ( Rhipicephalus sanguineus , Ixodes ricinus and Dermacentor reticulatus ) after oral administration to dogs. As a result of these exploratory investigations, sarolaner was progressed for development as an oral monthly dose for treatment and control of fleas and ticks on dogs.

This article presents an analysis of national data from the Advanced Technological Education (ATE) program regarding articulation agreements for the transfer of 2-year technical degrees to baccalaureate degrees. Quantitative and qualitative data are illustrated to help explain the extent to which ATE projects improve access to universities for technical students

The German Cartilage Registry (KnorpelRegister DGOU) has been introduced in October 2013 and aims on the evaluation of patients who underwent cartilage repair for symptomatic cartilage defects. It represents a nation-wide cohort study which has been introduced by the working group "Tissue Regeneration" of the Germany Society of Orthopaedic Surgery and Traumatology and is technically based upon a web-based remote data entry (RDE) system. The present article describes first experiences with the registry including patient and treatment characteristics. Between October 2013 and April 2014, a total of 230 patients who had undergone surgical cartilage repair for symptomatic full-thickness cartilage defects of the knee has been included in the German Cartilage Registry from 23 cartilage repair centres. Mean age was 37.11 years (SD 13.61) and mean defect size was 3.68 cm(2) (SD 0.23). Since the introduction of the KnorpelRegister DGOU the total number of registered patients has increased steadily up to the most recent figure of 72 patients within one month. Patients were treated mainly according to the recommended therapies. The highest percentage in therapy is represented by the bone marrow stimulation techniques (55.02 %) as well as by the autologous chondrocyte transplantation (34.92 %). Unlike the patient collective in the majority of prospective randomised controlled trials, the patient population within the registry shows a high proportion of patients with accompanying pathologies, with an age of more than 50 years at the time of treatment and with unfavourably assessed accompanying pathologies such as an affection of the opposite cartilage surface or a previously resected meniscus. In summary, the technical platform and forms of documentation of the KnorpelRegister DGOU have proved to be very promising within the first six months. Unlike data from other clinical trials, the previous analysis of the patients' data and therapies reflects successfully the actual medical care situation of patients with cartilage defects of the knee joint. This analysis also provides new information on subgroups of patients that have not yet been recorded in the scientific literature. This will be part of the first analysis of clinical treatment data. An expansion of the KnorpelRegister DGOU to patients with cartilage defects of the ankle and hip joints is already decided upon and initialised.

Haematobia irritans (horn fly) infestation in cattle is responsible for over a billion dollars a year in global economic loss due to decreased milk production and lower feed conversion. There is significant need for new insecticidal agents since current treatments such as organophosphates and pyrethroids suffer from field resistance. Isoxazoline oxime ethers represent a new class of γ-aminobutyric acid (GABA) receptor channel blockers which show good activity (LD(90) = 1.0 μg/mL) against horn flies in an in vitro feed assay and have demonstrated efficacy (>90% reduction at 1.0mg/kg) as a topical treatment in a field study.

Background Oral etoposide administration is a suitable alternative to the intravenous route; therefore, commercial capsules have been developed. Before these capsules were available in Mexico, we studied drug bioavailability after oral administration of the intravenous etoposide solution (IVES). Methods Eight adult cancer patients received a 50-mg oral etoposide dose as IVES and blood samples were collected over a period of 24 h. Plasma etoposide concentration was determined by high-performance liquid chromatography, plasma concentration against time curves were constructed, and bioavailability parameters were calculated. Results Oral IVES yielded an adequate bioavailability profile because C max was 2.38 ± 0.30 μg/mL, AUC was 12.87 ± 2.02 μg/mL and half-life was 6.72 ± 0.97 h. Conclusions Considering that the pharmacokinetic aim is to maintain plasma concentrations between 0.5 and 1.0 μg/mL for several hours while avoiding high concentrations, i.e., of 10 μg/mL or higher, oral administration of 50-mg etoposide as IVES appears to be a suitable dosing option. In addition, oral IVES is considerably less expensive than intravenous administration in terms of both drug presentation and administration.

Autologous chondrocyte transplantation/implantation (ACT/ACI) is an established and recognised procedure for the treatment of localised full-thickness cartilage defects of the knee. The present review of the working group "Clinical Tissue Regeneration" of the German Society of Orthopaedics and Traumatology (DGOU) describes the biology and function of healthy articular cartilage, the present state of knowledge concerning potential consequences of primary cartilage lesions and the suitable indication for ACI. Based on current evidence, an indication for ACI is given for symptomatic cartilage defects starting from defect sizes of more than 3-4 cm2; in the case of young and active sports patients at 2.5 cm2. Advanced degenerative joint disease is the single most important contraindication. The review gives a concise overview on important scientific background, the results of clinical studies and discusses advantages and disadvantages of ACI.

The aim of the study was to evaluate the therapeutic benefit of CaReS®, a type I collagen hydrogel-based autologous chondrocyte implantation technique, for the treatment of osteochondral defects of the knee (Outerbridge grades III and IV) within a prospective multicenter study.A total of 116 patients in 9 clinical centers were treated with CaReS between 2003 and 2008. The Cartilage Injury Evaluation Package 2000 of the International Cartilage Repair Society (ICRS) was employed for data acquisition and included the subjective International Knee Documentation Committee score (IKDC score), the pain level (visual analog scale, VAS), the physical and mental SF-36 score, the overall treatment satisfaction and the functional IKDC status of the indexed knee. Follow-up evaluation was performed 3, 6 and 12 months after surgery and annually thereafter.The mean defect size treated was 5.4 ± 2.7 cm(2) with 30% of the cartilage defects being ≤4 cm(2) and 70% ≥4 cm(2). The mean follow-up period was 30.2 ± 17.4 months (minimum 12 months and maximum 60 months). The mean IKDC score significantly improved from 42.4 ± 13.8 preoperatively to 70.5 ± 18.7 (p 0.01) in the mean follow-up period. Global pain level significantly decreased (p 0.001) from 6.7 ± 2.2 preoperatively to 3.2 ± 3.1 at the latest follow-up. Both the physical and mental components of the SF-36 score significantly increased. At the latest follow-up 80% of the patients rated the overall treatment satisfaction as either good or very good. The functional IKDC knee status clearly improved from preoperative to the latest follow-up when 23.4% of the patients reported having no restriction of knee function (I), 56.3% had mild restriction (II), 17,2% had moderate restriction (III) and 3.1% revealed severe restriction (IV).The CaReS technique is a clinically effective and safe method for the reconstruction of isolated osteochondral defects of the knee joint and reveals promising clinical outcome up to 5 years after surgery. A longer follow-up period and larger patient cohorts are needed to evaluate the sustainability of CaReS treatment.

KHEYLRF-NH2 (AF2) is a FMRFamide-related peptide (FaRP) present in parasitic and free-living nematodes. At concentrations as low as 10 pM, AF2 induces a biphasic tension response, consisting of a transient relaxation followed by profound excitation, in neuromuscular strips prepared from Ascaris suum. In the present study, the effects of AF2 on cyclic adenosine monophosphate (cAMP), cyclic guanosine monophosphate (cGMP) and inositol-1,4,5-triphosphate (IP3) levels were measured following muscle tension recordings from 2 cm neuromuscular strips prepared from adult A. suum. AF2 induced a concentration- and time-dependent increase in cAMP, beginning at 1 nM; cAMP levels increased by 84-fold following 1 h exposure to 1 μM AF2. cGMP and IP3 levels were unaffected by AF2 at concentrations ≤1 μM. AF2-induced stimulation of cAMP was unaffected by removal of the dorsal or ventral nerve cord, even though this form of denervation abolished the excitatory phase of the tension response. The effects of 0.1 and 1 μM AF2 on cAMP were also unaffected by 10 μM SDPNFLRF-NH2 (PF1, an inhibitory FaRP) and 10 μM PF1022A (an inhibitory cyclodepsipeptide), even though each of these peptides abolished the excitatory phase of the tension response induced by AF2. Within an alanine-scan series of AF2 analogues, only KH A YLRF-NH 2 stimulated cAMP production with equipotency to AF2; the effects of this peptide on muscle tension also mimicked AF2. Another excitatory FaRP present in nematodes, KNEFIRF-NH2 (AF1), also stimulated cAMP production, but was 100-fold less potent than AF2. The stimulatory effects of AF1 on tension and cAMP levels were blocked by an alanine-substituted analogue of this peptide (Ala6-AF1, KNEFI A F-NH 2 ), while the stimulatory effects of AF2 on tension and cAMP were not affected by this analogue. AF2 and AF1 increase A. suum somatic muscle cAMP by targeting different receptors. Increases in cAMP stimulated by AF2 can be decoupled from the excitatory response caused by this peptide, and it is not possible to establish a causal linkage between the contractile response elicited by this peptide and its effects on cAMP accumulation.

Oxindole alkaloids in the paraherquamide/marcfortine family exhibit broad-spectrum anthelmintic activity that includes drug-resistant strains of nematodes. Paraherquamide (PHQ), 2-deoxoparaherquamide (2DPHQ), and close structural analogs of these compounds rapidly induce flaccid paralysis in parasitic nematodes in vitro, without affecting adenosine triphosphate (ATP) levels. The mechanism of action of this anthelmintic class was investigated using muscle tension and microelectrode recording techniques in isolated body wall segments of Ascaris suum. None of the compounds altered A. suum muscle tension or membrane potential. However, PHQ blocked (when applied before) or reversed (when applied after) depolarizing contractions induced by acetylcholine (ACh) and the nicotinic agonists levamisole and morantel. These effects were mimicked by the nicotinic ganglionic blocker mecamylamine, suggesting that the anthelmintic activity of PHQ and marcfortines is due to blockade of cholinergic neuromuscular transmission. The effects of these compounds were also examined on subtypes of human nicotinic ACh receptors expressed in mammalian cells with a Ca2+ flux assay. 2DPHQ blocked nicotinic stimulation of cells expressing alpha3 ganglionic (IC50 approximately 9 microm) and muscle-type (IC50 approximately 3 microm) nicotinic cholinergic receptors, but was inactive at 100 microm vs. the alpha7 CNS subtype. PHQ anthelmintics are nicotinic cholinergic antagonists in both nematodes and mammals, and this mechanism appears to underlie both their efficacy and toxicity.

Three distinct chemical classes for the control of gastrointestinal nematodes are available: benzimidazoles, imidazothiazoles, and macrocyclic lactones. The relentless development of drug resistance has severely limited the usefulness of such drugs and the search for a new class of compounds - preferably with a different mode of action - is an important endeavor. Marcfortine A (1), a metabolite of Penicillium roqueforti, is structurally related to paraherquamide A (2), originally isolated from Penicillium paraherquei. Chemically the two compounds differ only in one ring, in marcfortine A, ring G is six-membered and carries no substituents, while in paraherquamide A, ring G is fivemembered with methyl and hydroxyl substituents at C14. Paraherquamide A (2) is superior to marcfortine A as a nematocide. 2-Desoxoparaherquamide A (PNU-141962, 53) has excellent nematocidal activity, a superior safely profile, and is the first semi-synthetic member of this totally new class of nematocides that is a legitimate candidate for development. This review describes the chemistry, efficacy and mode of action of PNU-141962.

To compare the hematopoietic recovery and the clinical outcome after high dose chemotherapy and peripheral blood stem cell (PBSC) transplant between patients who received recombinant granulocyte colony-stimulating factor (G-CSF) starting on day 0 and those who received it starting on day +7.Thirty-five consecutive patients received high dose chemotherapy with ifosfamide, etoposide and carboplatin (ICE) and autologous PBSC transplant. PBSC mobilization was achieved with G-CSF. In 19 transplants done in 1994, G-CSF was started on day 0 and in 16 procedures done in 1995, G-CSF was started on day +7. In both groups G-CSF was given until the absolute neutrophil count was 1 x 10(9)/L.The median number of days to reach an absolute neutrophil count0.1 x 10(9)/L, was 11 in the patients who started the G-CSF on day 0 and 11 days in the patients with delayed administration of G-CSF and to reach0.5 x 10(9)/L 14 days and 13 respectively. The median number of days to reach a platelet count20 x 10(9)/L was 14 and 13. Comparison of early vs. delayed administration of G-CSF did not show any significant differences regarding the time to achieve platelet independence, number of days with fever, median days of hospital stay, number of red cell or platelet transfusions.Starting G-CSF on day +7 after high dose ICE chemotherapy and autologous transplant of PBSC is as effective in restoring the hematopoietic function as is starting its administration on day 0.

The type A allatostatins (ASTs) are a group of insect peptides with a common C-terminal motif F/YXFGL-NH2. ASTs control visceral muscle contractions and, indirectly, insect larval development, sexual maturation and reproduction by inhibiting juvenile hormone release from the corpus allatum. The existence of at least four putative type A Drosophila melanogaster (fruit fly) ASTs (called drostatins or DSTs) has been predicted from the sequence of a recently cloned DST preprohormone [1]. SRPYSFGL-NH2, (DST-3), the only DST isolated from Drosophila so far, activated the first cloned Drosophila type A DST GPCR (DAR-1) [2]. A newly cloned orphan Drosophila GPCR, which shares 47% overall and 60% transmembrane region sequence identity with DAR-1, was classified as a second putative Drosophila type A DST receptor (DAR-2) [3]. Although activation of DAR-2 by DSTs has been postulated [3], no experimental evidence for that has been reported to date. In this study, we transiently expressed both DAR-1 and DAR-2 in CHO cells and used a GTPγS and a Ca+2 mobilization assay for pharmacological receptor evaluation.

Secretion of gelatinases A (MMP-2) and B (MMP-9) from 21 tumoral explants of squamous cell carcinoma (SCC) and five samples of normal mucosa of the oral cavity is demonstrated here. The explants were cultured into fetal bovine serum- and phenol red-deprived medium for 48 hours. The gelatinases secreted into the medium were revealed and quantified by zymography and densitometry, respectively. The results showed high medians of the 66 kDa forms of gelatinase A in tumoral explants, in comparison to normal explants: 31.0 vs 5.9 densitometric units (DU) (p0.01). There was also a relatioship between clinical response to neo-adjuvant chemotherapy and low activity of 66 kDa form of gelatinase A, as well as 84 kDa and 92 kDa forms of gelatinase B. The median of gelatinolysis of the inactive form of gelatinase A (72 kDa form) was higher in those patients who exhibited a complete response to neo-adjuvant chemotherapy. We conclude that gelatinase A is a useful and objective tool to evaluate the response to chemotherapy and the aggressiveness of carcinomas of the oral cavity.

Oral etoposide administration is a suitable alternative to the intravenous route; therefore, commercial capsules have been developed. Before these capsules were available in Mexico, we studied drug bioavailability after oral administration of the intravenous etoposide solution (IVES).Eight adult cancer patients received a 50-mg oral etoposide dose as IVES and blood samples were collected over a period of 24 h. Plasma etoposide concentration was determined by high-performance liquid chromatography, plasma concentration against time curves were constructed, and bioavailability parameters were calculated.Oral IVES yielded an adequate bioavailability profile because Cmax was 2.38 +/- 0.30 micrograms/mL, AUC was 12.87 +/- 2.02 micrograms/mL and half-life was 6.72 +/- 0.97 h.Considering that the pharmacokinetic aim is to maintain plasma concentrations between 0.5 and 1.0 microgram/mL for several hours while avoiding high concentrations, i.e., of 10 micrograms/mL or higher, oral administration of 50-mg etoposide as IVES appears to be a suitable dosing option. In addition, oral IVES is considerably less expensive than intravenous administration in terms of both drug presentation and administration.

Following our discovery of the strong binding of thiadiazole 1 to the AF-2 neuropeptide receptor of gastrointestinal nematodes (e.g., Ascaris suum), we prepared two series of analogs. Only the series containing the thiadiazole ring had potencies comparable to that of compound 1. Analog 50 exhibited an apparent potency in the AF-2 binding assay 300 times that of compound 1.

The first tumor marker (TM) described in Oncology was the Bence-Jones protein in 1847 in patients with multiple myeloma. However, it was not until the early 60s that the first useful TM in gastrointestinal (GI) cancer was recognized, alpha fetoprotein. The development of TM has achieved enormous progress over the last years and its definition includes not only tumor products but elements inherent to the tumor such as oncogenes. A review is presented of the most important TM in GI tumors according to anatomic location. Emphasis is made in colon cancer and the clinical usefulness of carcinoembryonic antigen throughout the different stages in the management of such patients.

Improved survival in osteosarcoma patients treated with Adjuvant chemotherapy was reported since the early 70s [1, 2]. However it was strongly disputed [3] and it was not until the 80s, after the results of randomized clinical trials [4, 5] that Adjuvant chemotherapy became widely accepted. As chemotherapy has improved the cure rate, further steps have been taken in the management of these patients, such as limb-salvage surgery with preoperative chemotherapy [6]. Up to 100 % necrosis can be found in the surgical specimen and for such patients, disease free survival is significantly longer than for those with an initial poor response to chemotherapy [7, 8]. Nevertheless, it has not been demonstrated that Neo-Adjuvant chemotherapy has a survival advantage over adjuvant treated patients. Various active agents have been utilized but there is not a standard regimen [1, 2, 4–8]. Among the combinations utilized, systemic Doxorubicin and intra-arterial Cisplatin have yielded a 76 % 3-year disease-free survival [8]. At our institution in 1988 we began utilizing i.v. adjuvant Doxorubicin and Cisplatin and in 1989 conservative surgery.

Most patients with metastatic NSGCTT have an excellent prognosis due to the effectiveness of Cisplatin based chemotherapy. This has permitted to hold treat­ ment in stage I patients to only those who relapse. Orchiectomy alone will cure 60-80 lifo of the patients, avoiding unnecessary morbidity in more than half of the patients. Surveillance results published in the english literature come from centers in industrialized countries were follow-up of patients is easier and better [1, 3]. In Mexico there is some reluctance against the surveillance poli­ cy, arguing that follow-up is very poor and that it would represent a high risk to the patient. Compliance is certainly a problem in our country, but a RPLND should not be considered a substitute for a potential poor follow-up. Another option for stage I NSGCTT has been Adjuvant chemotherapy for high risk patients such as those with vascular invasion [4]. This alternative overtreats some patients, adding unnecessary toxicity. And at our institution due to finan­ cial reasons we limit the administration of chemotherapy in patients with NSGCTT only to those with metastatic disease. In July 1985 we decided to submit to surveillance all patients with stage I NSGCTT and give additional treatment only at relapse. Patients and methods

Seminoma is highly radio-sensitive. Patients with low-volume disease have an excellent prognosis. But as tumor volume increases, the relapse rate can be as high as 80 %. CT in advanced disease is effective [1, 2] and there are even regimens with low myelosuppression or neurotoxicity [1, 3].

856 Background: Despite the progress in the treatment of breast cancer, patients with visceral metastatic disease have a poor prognosis. Nevertheless, BC with LM have a median survival of 14 months without prior therapy and a better outcome when they have no other site of metastases (Zinser et al. JCO 1987;5:773–82). We describe a 5-year experience at our institution. Patients and Treatment: Between 01/95–12/99 187 BCLM were identified with histologically confirmed diagnosis of breast cancer and measurable hepatic disease by imaging studies. Results: Mean age 48 year (26–86). PS-1 (WHO): 70%, initial stage: I-IIIB 56% IV 44%. Postmenopausal 59%. Liver as only site of metastases in 7%, two sites 44% and ≥3 49%. Therapy prior to LM: 126 (67%) anthracycline based chemotherapy, XRT 76 (40%) and tamoxifen 103 (55%). Five patients with LM received no further therapy. Treatment for LM was: anthracycline based chemotherapy in 173 (95%), taxanes 3%, other 2%. One case was treated with surgical resection plus chemo...

A finite element procedure is presented for the solution of the Navier-Stokes equations, adopting a segregated velocity-pressure formulation. The procedure is based on the derivation of an approximate pressure equation, which allows the uncoupling of pressure and velocity solutions. This equation is derived from the discretized continuity equation by considering the relationships established between velocity and pressure in the discretized momentum equations. The numerical performance of the proposed method is demonstrated by investigating several examples. The results are compared with finite difference predictions.

The results of boundary-layer calculations are reported for wall flows with different levels of free-stream turbulence, severe longitudinal acceleration and a step change in surface heat transfer. A one-equation turbulence model was used in finite-difference calculations which extended through the low-Reynolds-number region adjacent to the wall. The model failed to predict relaminarisation due to acceleration but in the other flows considered the agreement with experiment was good.

A complete finite element model of enclosed turbulent diffusion flames is presented. A velocity-pressure formulation is preferred in the analysis. A mixed interpolation is employed for the velocity and pressure. In the solution of the Navier-Stokes equations, a segregated formulation is adopted, where the pressure discretization equation is obtained directly from the finite element discretized continuity equation considering the relationships established between the velocity and pressure in the finite element discretized momentum equations. The state of turbulence is defined by a k-∈ model of turbulence. Near solid boundaries, a wall-functions approach is employed. The combustion rates are estimated by the eddy dissipation concept. The expensive direct treatment of the integrodifferential equations of radiation is avoided by employing the moment method, which allows the derivation of an approximate elliptic differential equation for the radiation intensity. The proposed finite element model is verified by investigating several examples. The results are compared with experiments and finite difference predictions.

The finite element method is applied to turbulent confined flow problems adopting a primitive-variables formulation. The turbulence state is defined by a k - e model of turbulence. The argument is presented that the velocity components as well as k and e should be interpolated linearly. Near solid boundaries a wall-functions method is employed. A new and effective way of estimating the wall shear stress in the application of this method is proposed. The model is verified by investigating several examples. The results are compared with experiments and finite difference predictions.

The turbulent flow field in large utility boiler furnaces is strongly affected hy heat release from combustion and by the heat extracted from the furnace through the boiler tube walls. To describe and predict these effects with reasonable engineering accuracy, a mathematical model termed COMpac has been developed at the University of Stuttgart. The series of codes is based on a finite difference solution of the turbulence-modelled Navier-Stokes equations in axisymmetric and in fully three-dimensonal coordinates. Radiative heat transfer is presently predicted using flux method approximatians. A simplified mechanism of pulverized coal combustion is described in a Eulerian framework for both the gaseous and particulate phase. In the present work, validation studies are reported and discussed. The combustion model has been tested for single enclosed flames where detailed measurements were available. Prediction results for three-dimensional furnace flows are compared with velocity data from an isother...

Formation and reduction of nitrogen oxide from fuel-bound nitrogen in pulverized coal flames strongly depends on combustion conditions. From experimental investigations it is known that important parameters envolved are residence times, temperature distributions and the availability of reducing flame zones. While these effects can be directly studied in laboratory scale experiments, problems arise in practical applications where these parameters are generally unknown. Mathematical flame models offer a possibility to predict the turbulent flow field and local flame conditions at least to some engineering accuracy.