Cell wall dynamics: novel tools and research questions.

Years ago, a classic textbook would define plant cell walls based on passive features. For instance, a sort of plant exoskeleton of invariable polysaccharide composition, and probably painted in green. However, currently, this view has been expanded to consider plant cell walls as active, heterogeneous, and dynamic structures with a high degree of complexity. However, what do we mean when we refer to a cell wall as a dynamic structure? How can we investigate the different implications of this dynamism? While the first question has been the subject of several recent publications, defining the ideal strategies and tools needed to address the second question has proven to be challenging due to the myriad of techniques available. In this review, we will describe the capacities of several methodologies to study cell wall composition, structure, and other aspects developed or optimized in recent years. Keeping in mind cell wall dynamism and plasticity, the advantages of performing long-term non-invasive live-imaging methods will be emphasized. We specifically focus on techniques developed for Arabidopsis thaliana primary cell walls, but the techniques could be applied to both secondary cell walls and other plant species. We believe this toolset will help researchers in expanding knowledge of these dynamic/evolving structures.

Activation of caspase-3/7, an apoptotic-related marker, during incubation and cryopreservation of alpaca (Vicugna pacos) spermatozoa.

Caspases are crucial mediators of programmed cell death (apoptosis). Apoptosis can occur in spermatozoa during spermatogenesis or epididymal transit, as well as in ejaculated spermatozoa. A high proportion of apoptotic sperm would be a poor indicator of the freezability of a raw seminal sample. Alpaca spermatozoa are notoriously difficult to freeze successfully. Therefore, the objectives of this study were to study caspase activation during incubation (37°C) of fresh alpaca spermatozoa, as well as before and after cryopreservation, to gain some insight into the mechanisms behind the vulnerability of alpaca spermatozoa. Eleven sperm samples were incubated for 4 h at 37°C (Study 1), and 23 samples were frozen using an automated system (Study 2). Caspase-3/7 activation was assessed at 0,1,2,3, and 4 h in samples incubated at 37°C (Study 1); and before/after cryopreservation (Study 2) using CellEvent™ Caspase 3/7 Green Detection Reagent and flow cytometry. The proportions of alpaca spermatozoa with caspase-3/7 activated increased (p < 0.05) after 3-4 h of incubation at 37°C; however, caspase activation was similar before and after cryopreservation (36.2 ± 11.2% vs. 36.6 ± 33.7%, p > 0.05). The high standard deviation found after freezing could be explained by the existence of two subpopulations: one subpopulation where caspase-3/7 activation decreased during cryopreservation (from 36.6 ± 9.1% to 1.5 ± 2.2%), and the other subpopulation where caspase-3/7 activation increased after cryopreservation (from 37.7 ± 13.0% to 64.3 ± 16.7%). In conclusion, after 3-4 h of incubation, caspase-3/7 activation increased in fresh alpaca sperm, whereas cryopreservation affects alpaca sperm samples in different ways.

Cell wall integrity regulation across plant species.

Plant cell walls are highly dynamic and chemically complex structures surrounding all plant cells. They provide structural support, protection from both abiotic and biotic stress as well as ensure containment of turgor. Recently evidence has accumulated that a dedicated mechanism exists in plants, which is monitoring the functional integrity of cell walls and initiates adaptive responses to maintain integrity in case it is impaired during growth, development or exposure to biotic and abiotic stress. The available evidence indicates that detection of impairment involves mechano-perception, while reactive oxygen species and phytohormone-based signaling processes play key roles in translating signals generated and regulating adaptive responses. More recently it has also become obvious that the mechanisms mediating cell wall integrity maintenance and pattern triggered immunity are interacting with each other to modulate the adaptive responses to biotic stress and cell wall integrity impairment. Here we will review initially our current knowledge regarding the mode of action of the maintenance mechanism, discuss mechanisms mediating responses to biotic stresses and highlight how both mechanisms may modulate adaptive responses. This first part will be focused on Arabidopsis thaliana since most of the relevant knowledge derives from this model organism. We will then proceed to provide perspective to what extent the relevant molecular mechanisms are conserved in other plant species and close by discussing current knowledge of the transcriptional machinery responsible for controlling the adaptive responses using selected examples.

The Elongator complex regulates hypocotyl growth in darkness and during photomorphogenesis.

The Elongator complex (hereafter Elongator) promotes RNA polymerase II-mediated transcript elongation through epigenetic activities such as histone acetylation. Elongator regulates growth, development, immune response and sensitivity to drought and abscisic acid. We demonstrate that elo mutants exhibit defective hypocotyl elongation but have a normal apical hook in darkness and are hyposensitive to light during photomorphogenesis. These elo phenotypes are supported by transcriptome changes, including downregulation of circadian clock components, positive regulators of skoto- or photomorphogenesis, hormonal pathways and cell wall biogenesis-related factors. The downregulated genes LHY, HFR1 and HYH are selectively targeted by Elongator for histone H3K14 acetylation in darkness. The role of Elongator in early seedling development in darkness and light is supported by hypocotyl phenotypes of mutants defective in components of the gene network regulated by Elongator, and by double mutants between elo and mutants in light or darkness signaling components. A model is proposed in which Elongator represses the plant immune response and promotes hypocotyl elongation and photomorphogenesis via transcriptional control of positive photomorphogenesis regulators and a growth-regulatory network that converges on genes involved in cell wall biogenesis and hormone signaling.This article has an associated First Person interview with the first author of the paper.

Effects of malnutrition on treatment-related morbidity and survival of children with cancer in Nicaragua.

BACKGROUND: Most children with cancer live in resource-limited countries where malnutrition is often prevalent. We identified the relationship between malnutrition and treatment-related morbidity (TRM), abandonment of therapy, and survival of children with cancer in Nicaragua to better inform targeted nutritional interventions. PROCEDURE: We conducted a retrospective review of patients aged 6 months to 18 years with newly diagnosed acute lymphoblastic leukemia, acute myeloid leukemia (AML), Wilms tumor, Hodgkin lymphoma, or Burkitt lymphoma (BL) who were treated between January 1, 2004, and December 31, 2007 at Children's Hospital Manuel de Jesus Rivera in Managua, Nicaragua. Statistical analysis examined the relations among nutritional status and cancer type, risk category, TRM, and event-free survival (EFS). RESULTS: Sixty-seven percent of patients (189/282) were malnourished at diagnosis. Malnutrition was highest among patients with Wilms tumor (85.7%), BL (75%), and AML (74.3%). A total of 92.2% of patients (225/244) experienced morbidity during the first 90 days. Malnutrition was associated with severe infection (P = 0.033). Severely malnourished patients had ≥grade 3 TRM on more days (P = 0.023) and were more likely to experience severe TRM on >50% of days (P = 0.032; OR, 3.27 [95% CI, 1.05-10.16]). Malnourished patients had inferior median EFS (2.25 vs. 5.58 years; P = 0.049), and abandoned therapy more frequently (P = 0.015). CONCLUSIONS: In Nicaragua, pediatric oncology patients with malnutrition at diagnosis experienced increased TRM, abandoned therapy more frequently, and had inferior EFS. Standardized nutritional evaluation of patients with newly diagnosed cancer and targeted provision of nutritional support are essential to decrease TRM and improve outcomes.

ent-Labdane Diterpenoids from the Aerial Parts of Eupatorium obtusissmum.

Six new ent-labdane diterpenoids, uasdlabdanes A-F (1-6), were isolated from the aerial parts of Eupatorium obtusissmum. The new structures were elucidated through spectroscopic and spectrometric data analyses. The absolute configurations of compounds 1 and 2 were established by X-ray crystallography, and those of 3-6, by comparison of experimental and calculated electronic circular dichroism spectra. The antiproliferative activity of the compounds was studied in a panel of six representative human solid tumor cell lines and showed GI50 values ranging from 19 to >100 µM.

Metastatic Ovarian Tumor Masquerading as Atypical Pneumonia.

Krukenberg tumor is a malignancy in the ovary from a primary lesion in the gastrointestinal tract and a metastatic signet ring cell adenocarcinoma to the ovary. Stomach is the most common primary site, but other organs can serve as a primary site. The lymphatic system is the most likely route for metastasis. CA 125 levels can be used for screening for early detection of ovarian metastasis as well as for monitoring the course of disease. The prognosis of Krukenberg tumor is poor and no curative treatment is currently available.

Chelation-Based Route to Aluminum-Free Layered Transition Metal Carbides (MXenes).

MXenes are of much interest because of their electrochemical, electronic, and surface chemical properties that arise from their structure and stoichiometry. The integrity and the nature of the terminal groups on the basal planes of MXene sheets depend strongly on the method used to etch the parent MAX (M = transition metal, A = Al, X = C, N, B) compound. Aluminum removal typically involves a high concentration of aqueous HF, HCl/LiF mixtures, or fluoride solutions of strong acids. HF etching is problematic because it leaves insoluble AlF3 in the product, degrades the crystallinity of the nanosheets, and results in the termination of the basal planes with F, O, or OH groups. Here, we demonstrate the use of HF at a low concentration in tandem with a chelating agent, N,N'-dihydroxyoctanediamide (suberohydroxamic acid), to selectively etch the archetypical MAX compound Ti3AlC2 at room temperature. X-ray absorption spectroscopy (XAS) of the etched materials shows that the carbide nature of bonding in the parent MAX structure is retained in the MXene layers. The stability of the MXene in aqueous suspensions is also significantly improved relative to MXene products made by etching in concentrated HF solutions.

Metastatic extra-abdominal presentation of gastrointestinal stromal tumors in a young Hispanic male: a case presentation and literature review.

This article presents the medical history and management of a 44-year-old Hispanic male with metastatic extra-abdominal gastrointestinal stromal tumor including a literature review on this rare clinical presentation.

Molecular Characterization and Prospective Evaluation of Pathologic Response and Outcomes with Neoadjuvant Therapy in Metaplastic Triple-Negative Breast Cancer.

PURPOSE: Metaplastic breast cancer (MpBC) is a rare subtype of breast cancer that is commonly triple-negative and poorly responsive to neoadjuvant therapy in retrospective studies. EXPERIMENTAL DESIGN: To better define clinical outcomes and correlates of response, we analyzed the rate of pathologic complete response (pCR) to neoadjuvant therapy, survival outcomes, and genomic and transcriptomic profiles of the pretreatment tumors in a prospective clinical trial (NCT02276443). A total of 211 patients with triple-negative breast cancer (TNBC), including 39 with MpBC, received doxorubicin-cyclophosphamide-based neoadjuvant therapy. RESULTS: Although not meeting the threshold for statistical significance, patients with MpBCs were less likely to experience a pCR (23% vs. 40%; P = 0.07), had shorter event-free survival (29.4 vs. 32.2 months, P = 0.15), metastasis-free survival (30.3 vs. 32.4 months, P = 0.22); and overall survival (32.6 vs. 34.3 months, P = 0.21). This heterogeneity is mirrored in the molecular profiling. Mutations in PI3KCA (23% vs. 9%, P = 0.07) and its pathway (41% vs. 18%, P = 0.02) were frequently observed and enriched in MpBCs. The gene expression profiles of each histologically defined subtype were distinguishable and characterized by distinctive gene signatures. Among nonmetaplastic (non-Mp) TNBCs, 10% possessed a metaplastic-like gene expression signature and had pCR rates and survival outcomes similar to MpBC. CONCLUSIONS: Further investigations will determine if metaplastic-like tumors should be treated more similarly to MpBC in the clinic. The 23% pCR rate in this study suggests that patients with MpBC should be considered for NAT. To improve this rate, a pathway analysis predicted enrichment of histone deacetylase (HDAC) and RTK/MAPK pathways in MpBC, which may serve as new targetable vulnerabilities.

Primary angiosarcoma of the breast in a pre-menopausal woman.

This case report describes the clinical presentation, imaging findings and pathologic features of a rare aggressive breast tumor in a pre-menopausal woman, namely primary angiosarcoma. Recognition of this extremely rare entity is needed to make an early diagnosis, institute early therapy and eventually improve patient's survival.

Alexithymia and Insecure Attachment among Male Intimate Partner Violence Aggressors in the Dominican Republic.

The complexity of intimate partner violence and the impossibility of understanding it from single factors have been studied from different biological, psychological, and socio-cultural factors. A cross-sectional study was conducted on 187 men involved in legal proceedings for problems of violence in their intimate partner relationships in the Dominican Republic in order to explore whether insecure attachment represents a risk factor for alexithymia in men with violent behaviors. The attachment style was determinate by the Casullo and Fernández-Liporace Attachment Styles Scale, and alexithymia was assayed using the Latin American Consensual Toronto Alexithymia Scale (LAC TAS-20), a modification of the Toronto Alexithymia Scale (TAS-20). Chi-square test and multiple binary logistic regression analysis were performed to explore the phenomena of alexithymia and attachment styles in the context of a confinement center for male intimate partner offenders in the Dominican Republic. The results showed that insecure attachment represents a risk factor for alexithymia, being highest for avoidant attachment in the population studied. The results also highlight the influence of other factors such as education and maternal-familial relationships as a factor risk for alexithymia.

Development of emulgels formulated with sweet fennel oil and rhamsan gum, a biological macromolecule produced by Sphingomonas.

In this work, a current application of rhamsan gum, a biological macromolecule which belongs to the sphingans group, as an efficient stabilizer of emulsions and emulgels is investigated. The main objective of this investigation was 1) to study the influence of glycerol and sweet fennel oil concentration on microfluidized emulsion properties; and 2) to develop stable emulgels stabilized with rhamsan gum. The emulsions and emulgels were characterized by droplet size, rheological properties, physical stability and microstructure. An analysis by surface response methodology of the results obtained revealed that essential oil concentration was the most determining factor affecting emulsion mean droplet sizes and rheological properties. An optimal emulsion with minimum d4,3 was obtained for the sample formulated with 10 wt% sweet fennel oil and 0 wt% glycerol. However, all of these emulsions suffered destabilization by creaming. The results of the rheological characterization of emulsions formulated with the biological macromolecule showed that the addition of 0.2 wt% of rhamsan gum allows an emulgel with enhanced physical stability to be obtained. Thus, we provide valuable information concerning the use of rhamsan gum as emulsion stabilizer and the development of stable emulsions and emulgels for use in the food industry.

Laparoscopic hepp couinaud for the treatment of caroli's disease: a case report / Hepp Couinaud laparoscópica para el tratamiento de la enfermedad de Caroli: reporte de caso

Caroli disease is a rare congenital disorder characterized by dilatation of intrahepatic bile ducts. The treatment could correspond to hepatic resection for localized disease. This paper describes a case of Caroli's disease in a 60 years old female patient, who presented jaundice and diffuse abdominal pain. Further examinations suggested the diagnosis of Caroli disease associated with cholestatic syndrome. We decided to perform a Hepp Couinaud biliodigestive bypass by video laparoscopy with Roux-en-Y reconstruction. There were no immediate complications and no longterm complications after 6 months of follow-up. The VLP biliodigestive bypass in patients with associated cholestatic syndromes should be considered a treatment prior to a more aggressive approach.

La enfermedad de Caroli es un raro trastorno congénito que consiste en una dilatación de las vías biliares intrahepáticas. Su tratamiento definitivo debe consistir en resección hepática por la enfermedad localizada. Este artículo describe un caso de enfermedad de Caroli en una paciente de sexo femenino de 60 años de edad, quien presentó ictericia y dolor abdominal difuso. Exámenes posteriores sugirieron el diagnóstico de enfermedad de Caroli asociada con síndrome colestásico. Los médicos decidieron realizar un bypass biliodigestivo de Hepp Couinaud mediante videolaparoscopia con reconstrucción en Y de Roux. No hubo complicaciones inmediatas ni complicaciones a largo plazo después de 6 meses de seguimiento. El bypass biliodigestivo VLP en pacientes con síndromes colestásicos asociados debe considerarse un tratamiento previo a un abordaje más agresivo.

Costo de los accidentes de moto en menores de 19 años atendidos en un hospital de referencia

Introducción: Los accidentes de tránsito constituyen un grave problema de salud pública, sin embargo, su impacto socioeconómico no se conoce en el Paraguay. Objetivos: determinar el impacto socioeconómico de los accidentes de moto en <19 años en el año 2016. Materiales y Métodos: estudio descriptivo, observacional, retrospectivo. Se incluyeron todos los pacientes ≤19 años que acudieron al Hospital de Trauma (HT) con antecedente de accidente de moto en el año 2016. Los datos y los costos fueron obtenidos de la base de datos del Dpto. de Estadísticas y del Dpto. de Ingresos del HT, respectivamente. Resultados: se incluyeron 700 pacientes que acudieron al HT por accidente de moto. La edad media de los pacientes fue de 15,6 ± 4.33 años. El 78% (546/700) era de sexo masculino. De los accidentados 450 (64,2%) era conductor y 250 (35,7%) acompañante. La media de edad de los conductores fue de 17 ± 4,3 años (rango 11 - 19 años) y de los acompañantes 12,3 ± 4,4 (rango <1 - 19 años). Entre los conductores solo el 50.4% (227/450) tenía la edad reglamentaria para obtener licencia de conducir. Solo el 7,7% (54/695) de los accidentados usaba casco al momento del accidente. Requirió hospitalización por 2 o más días el 89,2% (625/700) de los pacientes, de los cuales el 7.6% requirió ser hospitalizado en UCIP. La media de días de hospitalización en sala y UCIP fue de 11.04 días (DS 14,85 días) y 16.57 (DS 23 días). El 25,1% (176/700) tuvo algún grado de discapacidad o secuela y el 5,4% (38/700) falleció. Los costos directos por hospitalización por día en sala y en UCIP fueron de 275,4 y 737,2 $, respectivamente. Los costos directos por accidentes de moto en el año 2016 fue de 2.587.179,2$. Los años de vida potencialmente perdidos (AVPP) en el año 2016, fueron de 2159 años. Conclusiones: El impacto socioeconómico de los accidentes de motos, representa un costo social extremo derivado de una causa de muerte que podría prevenirse.

Introduction: Traffic accidents are a serious public health problem, however, their socio-economic impact has not been described in Paraguay. Objectives: to determine the socioeconomic impact of motorcycle accidents in victims <19 years of age in 2016. Materials and Methods: this was a descriptive, observational, retrospective study. All patients aged ≤19 years who were admitted to the Trauma Hospital (TH) with a history of a motorcycle accident in 2016 were included. The data and costs were obtained from the Statistics Department and the Admissions Department of the TH. Results: 700 patients were included, all of whom were admitted to the TH due to a motorcycle accident. The average age of the patients was 15.6 ± 4.33 years. 78% (546/700) were male. Of those injured, 450 (64.2%) were drivers and 250 (35.7%) were passengers. The average age of the drivers was 17 ± 4.3 years (range 11-19 years) and that of the passengers was 12.3 ± 4.4 years (range <1-19 years). Among the drivers, only 50.4% (227/450) were of the legal age to obtain a driver's license. Only 7.7% (54/695) of the victims wore a helmet at the time of the accident. 89.2% (625/700) of patients required hospitalization stays of 2 or more days of length, of which 7.6% required PICU admission. The mean number of regular ward hospitalization days and PICU days were 11.04 days (SD 14.85 days) and 16.57 days (SD 23 days), respectively. 25.1% (176/700) had some degree of disability or long-term effects and 5.4% (38/700) died. The direct costs per hospitalization per day in the ward and in the PICU were US$ 275.4 and 737.2, respectively. The direct costs for motorcycle accidents in 2016 was US$ 2,587,179.2. The years of potential life lost (YPLL) in 2016 were 2159 years. Conclusions: The socioeconomic impact of motorcycle accidents represents an extremely high social cost, stemming from a preventable cause of death.

One-dimensional silver nanostructures on single-wall carbon nanotubes.

We report the synthesis and characterization of one-dimensional silver nanostructures using single-wall carbon nanotubes (SWCNT) as a template material. Transmission electron microscopy and scanning tunneling microscopy are consistent with the formation of a one-dimensional array of silver particles on SWCNT. We observe evidence for the excitation of the longitudinal silver plasmon mode in the optical absorption spectra of Ag-SWCNT dispersions, even in the lowest silver concentrations employed. The results indicate that silver deposits on SWCNT may be candidates for light-to-energy conversion through the coupling of the electric field excited in arrays of plasmonic particles.

Signal transduction proteins in tumors from Puerto Rican and Caucasian gastric adenocarcinoma patients: expression differences with potential for specific targeted therapies.

Overexpression of the HER2/NEU gene is associated with aggressive behavior and poor prognosis in breast cancer, making the Her2/neu protein a directed-therapy target. Tumors of two Puerto Rican (PR) patients overexpressed Her2/neu and resulting partial clinical responses motivated us to compare Her2/neu expression in PR (n = 101) and Caucasian non-Hispanic (n = 95) patients. Immunohistochemistry of tumors showed overexpression of p-Stat3, Cyclin D1, and Her2/neu, compared to non-neoplastic mucosa. Her2/neu and EGF-R protein levels were statistically significantly different with higher levels of both proteins in the PR group. Importantly, Her2/neu expression was strong and diffuse in tumors with signet-ring morphology, while other histo-pathological subtypes showed higher intra-tumoral Her2/neu heterogeneity than typically observed in breast cancer. Targeted therapies in gastric cancer directed at EGF-R and Hers-2/neu pathways warrant further investigation. These therapies may be especially effective in PR patients and in patients with signet-ring cell morphologies with a dismal prognosis.

Protocol-based treatment for children with cancer in low income countries in Latin America: a report on the recent meetings of the Monza International School of Pediatric Hematology/Oncology (MISPHO)--part II.

Pediatric cancer programs in low-income countries (LIC) can improve outcomes. However, treatment must be tailored to the patient's living conditions and the availability of supportive care. In some cases, a more intense regimen will decrease survival since the increase in death from toxicity may exceed any decrease in relapse. Attempts to practice evidence-based pediatric oncology are thwarted by the lack of evidence derived from local experience in LIC to determine optimal therapy. This report summarizes treatment regimens used by pediatric oncologists from 15 countries of the Caribbean, Central and South America who participate in the Monza International School of Pediatric Hematology/Oncology (MISPHO). Patients with hepatoblastoma, Wilms tumor, and histiocytosis treated on unmodified published protocols had outcomes comparable to those in high-income countries (HIC). Those with rhabdomyosarcoma, osteosarcoma, Hodgkin lymphoma, and acute myeloid leukemia treated with unmodified regimens had event-free survival estimates 10%-20% lower than those reported in HIC due to higher rates of toxic death, abandonment of therapy, and relapse. Treatment of retinoblastoma is complicated by advanced stages and extraocular disease at diagnosis; improved outcomes depend on education of pediatricians and the public to recognize early signs of this disease. Use of unmodified protocols for Burkitt lymphoma and acute lymphoblastic leukemia have been associated with unacceptable toxicity in LIC, so MISPHO centers have modified published regimens by giving lower doses of methotrexate and reducing use of anthracyclines. Despite the use of all-trans-retinoic acid during induction for acute promyelocytic leukemia, the incidence of fatal hemorrhage remains unacceptably high.

Phase II study of intravenous TZT-1027 in patients with advanced or metastatic soft-tissue sarcomas with prior exposure to anthracycline-based chemotherapy.

BACKGROUND: TZT-1027, a novel chemotherapeutic agent, is derived from dolastatin 10, and blocks cells during G2/M-phase by interfering with microtubule assembly and stability. TZT-1027 has exhibited potential cytotoxic activity in several human cancer cell lines (in vitro) and also demonstrated antitumor activity in human xenografts (in vivo). In addition, Phase I clinical investigations suggested activity in STS (soft-tissue sarcoma). METHODS: Eligible patients were those who had histologic evidence of locally advanced or metastatic STS and who had received 1 prior treatment regimen with an anthracycline-based chemotherapy for metastatic disease. Subjects received intravenous infusions of TZT-1027 over 1 hour on Day 1 and Day 8 of each 21-day treatment course. Efficacy was evaluated per Response Evaluation Criteria in Solid Tumors (RECIST) criteria. RESULTS: Twenty-nine patients were enrolled and 28 patients received at least 1 course of study drug and were eligible for efficacy and safety evaluation. The median age of the patients was 48 years (range, 23-73 years) and the median baseline Eastern Cooperative Oncology Group (ECOG) performance status was 1 (range, 0-2). A total of 67 courses (range, 1-9 courses; median, 2 courses) of TZT-1027 were administered. No patient in the study demonstrated an objective response to treatment. Of 6 patients (21.4%) who experienced disease stabilization, 1 continued to have stable disease for 9.3 months. The median time to tumor progression was 44 days (95% confidence interval [95% CI], 43.0-54.0) and the median survival was 178 days (95% CI, 134.0-317.0). The most commonly reported toxicities were neutropenia, fatigue, and constipation. CONCLUSIONS: TZT-1027 was found to be safe and well tolerated, and the hematologic toxicities observed were consistent with preclinical toxicology and Phase I study findings. No confirmed responses were seen in the current study.

A phase II clinical and pharmacokinetic study of intravenous exatecan mesylate (DX-8951f) in patients with untreated metastatic gastric cancer.

PURPOSE: To determine the anti-tumor activity DX-8951f when administered as a 30-minute infusion daily for 5 days every 3 weeks to patients with previously untreated metastatic gastric cancer, and to evaluate toxicities and pharmacokinetics (PK) of DX-8951f in this patient population. PATIENTS AND METHODS: Forty-one patients were enrolled. All had previously untreated metastatic gastric cancer. DX-8951f was administered until disease progression or unacceptable toxicity. Responses were assessed after every 2 courses using RECIST criteria. RESULTS: Thirty-nine patients were evaluable. Two patients achieved a partial response (PR) and 18 achieved stable disease (SD), including five patients with unconfirmed PR. A total of 141 courses of therapy were delivered (median 3, range 1-10). The most common drug-related toxicity was neutropenia. Non-hematologic toxicities were mostly mild to moderate; the most common were nausea, vomiting and anorexia. Plasma concentrations of DX-8951 (the anhydrous form of DX-8951f) were well described using a linear 2-compartment PK model. All concentrations and dose events were simultaneously modeled and explained by the population PK model. There was no evidence of non-linearity in the elimination PK, auto-inhibition or induction of DX-8951 clearance over the five days of administration. CONCLUSIONS: DX-8951f had modest activity against metastatic gastric cancer and its PK was dose-proportional. The toxicity profile was predictable and manageable. Further development of this agent is warranted.