Oncology phase I trial design and conduct: time for a change - MDICT Guidelines 2022.

In 2021, the Food and Drug Administration Oncology Center of Excellence announced Project Optimus focusing on dose optimization for oncology drugs. The Methodology for the Development of Innovative Cancer Therapies (MDICT) Taskforce met to review and discuss the optimization of dosage for oncology trials and to develop a practical guide for oncology phase I trials. Defining a single recommended phase II dose based on toxicity may define doses that are neither the most effective nor the best tolerated. MDICT recommendations address the need for robust non-clinical data which are needed to inform trial design, as well as an expert team including statisticians and pharmacologists. The protocol must be flexible and adaptive, with clear definition of all endpoints. Health authorities should be consulted early and regularly. Strategies such as randomization, intrapatient dose escalation, and real-world eligibility criteria are encouraged whereas serial tumor sampling is discouraged in the absence of a strong rationale and appropriately validated assay. Endpoints should include consideration of all longitudinal toxicity. The phase I dose escalation trial should define the recommended dose range for later testing in randomized phase II trials, rather than a single recommended phase II dose, and consider scenarios where different populations may require different dosages. The adoption of these recommendations will improve dosage selection in early clinical trials of new anticancer treatments and ultimately, outcomes for patients.

Reparación laparoscópica de una hernia lumbar de tipo Grynfelt-Lesshaft: caso clínico / Laparoscopic repair of Grynfelt-Lesshaft lumbar hernia: case report

Introducción: La hernia lumbar es un tipo muy infrecuente de hernia de la pared abdominal con un reducido número de casos publicados. Puede producirse a través de dos triángulos anatómicos: uno superior o triángulo de Grynfelt-Lesshaft y uno inferior o triángulo de Petit. Presentación del caso: Presentamos el caso de una mujer de 64 años con una tumoración blanda y reductible en la región posterolateral izquierda de la pared abdominal. La tomografía computarizada confirmó la existencia de una hernia lumbar a través del triángulo superior o Grynfelt-Lesshaft. Fue intervenida mediante un abordaje laparoscópico transabdominal en el que tras la reducción del contenido herniario (tejido graso) se colocó una malla de doble capa en posición intraperitoneal. Fue dada de alta a las 24 horas de la intervención sin observarse complicaciones inmediatas. Discusión: Se trata de un tipo muy infrecuente de hernia de la pared por lo que su diagnóstico requiere una alta sospecha clínica y a menudo una confirmación radiológica mediante tomografía computarizada. Conclusiones: La reparación de la hernia lumbar está indicada para evitar posibles complicaciones y puede realizarse tanto por vía abierta como laparoscópica, debiendo incluir la colocación de material prótesico en forma de malla para reducir el riesgo de recidiva.

Introduction: Lumbar hernia is a very rare type of abdominal wall hernia with a small number of published cases. It can occur through two anatomical triangles: an upper one or Grynfelt-Lesshaft triangle and a lower one or Petit triangle. Case presentation: We present the case of a 64-year-old woman with a soft and reducible tumor in the left posterolateral region of the abdominal wall. Computerized tomography confirmed the existence of a lumbar hernia through the superior triangle or Grynfelt-Lesshaft triangle. Patient was operated through a transabdominal laparoscopic approach in which after reduction of hernial content (fatty tissue) a double-layer mesh was placed in an intraperitoneal position. She was discharged 24 hours after the intervention and no immediate complications were observed. Discussion: Lumbar hernia is a very rare type of abdominal wall hernia and its diagnosis requires high clinical suspicion and often radiological confirmation by computerized tomography. Conclusion: Lumbar hernia repair is indicated to avoid possible complications and can be performed with an open or laparoscopic approach. Repair should include a mesh to reduce the risk of recurrence.

Dosage of anti-PD-1 monoclonal antibodies: a cardinal open question.

Discovery and clinical development of monoclonal antibodies with the ability to interfere in the regulation of the immune response have significantly changed the landscape of oncology in recent years. Among the active agents licensed by the regulatory agencies, nivolumab and pembrolizumab are paradigmatic as the most relevant ones according to the magnitude of available data derived from the extensive preclinical and clinical experience. Although in both cases the respective data sheets indicate well-defined dosage regimens, a review of the literature permits to verify the existence of many issues still unresolved about dosing the two agents, so it must be considered an open question of potentially important consequences, in which to work to improve the effectiveness and efficiency of use.

Consensus of the Spanish society of laboratory medicine and the Spanish society of medical oncology on the methodology and criteria for evaluation of circulating tumour markers in breast cancer.

The measurement of circulating tumour markers (TMs) for the diagnosis or monitoring of breast cancer has sometimes been considered of limited utility. In addition to the overinterpretation of irrelevant changes in marker levels, the characteristics of the patient, the disease or other pathologies that can modify them are often not considered in their evaluation. On the other hand, there are recent data on the relationship of TMs with molecular subtypes and on their prognostic value, the knowledge of which may improve their clinical utility. This consensus article arises from a collaboration between the Spanish Society of Laboratory Medicine (SEQCML) and the Spanish Society of Medical Oncology (SEOM). It aims to improve the use and interpretation of circulating TMs in breast cancer. The text summarizes the current knowledge and available evidence on the subject and proposes a series of recommendations mainly focussed on the indication, the frequency of testing and the factors that should be considered for correctly interpreting changes in the levels of TMs.

Clinical and pathologic features of patients with non-epithelial ovarian cancer: retrospective analysis of a single institution 15-year experience.

PURPOSE: Non-epithelial ovarian cancers (NEOCs) are rare diseases. Despite their overall good prognosis, the best management and current prognostic factors remain unclear. The objective of our study was to assess the clinical and pathological features of NEOC patients treated in our institution in the last 15 years and to explore risk factors for relapse and survival. METHODS/PATIENTS: All patients with a pathological diagnosis of NEOC referred to the medical oncology department at Hospital Universitario Virgen del Rocio between 1999 and 2014 were included. Demographics, tumor characteristics, treatment procedures, and clinical follow-up were retrospectively collected. Risk factors for disease-free survival (DFS) and overall survival (OS) were assessed. RESULTS: Fifty-seven patients were included, 33 (58 %) had a sex cord-stromal tumor (SCST) and 24 (42 %) had a germ-cell tumor (GCT). Median age, non-conservative surgery rates and DFS were lower in the GCT cohort; however, salvage chemotherapy led to a high proportion of complete responses in this group translating into a 90 % 3-year OS rate in both NEOC subtypes. The only identified risk factors statistically significant were stage and tumour relapse that associated, respectively, with DFS (HR = 8.84; 95 % CI 1.85-42) and OS (HR = 11.02; 95 % CI 1.76-68.7). CONCLUSIONS: Despite their rarity, NEOCs remain a highly curable group of neoplasm. In our series, a more conservative treatment approach in ovarian GCTs revealed comparable OS outcomes to SCST. No new risk factors that would help in patient stratification were identified.

Description of high rates of unapparent and simultaneous multiple dengue virus infection in a Colombian jungle settlement.

Dengue disease statistics is mainly based on consulting patients with febrile illness, but misdiagnosed and asymptomatic cases are important to measure dengue epidemiology in endemic areas. The main objective of this work was to determine the prevalence of IgM and IgG antibodies or NS1 antigen and viral RNA in a group of healthy volunteers from an isolated village in Colombian Chocó rain forest. It found 51.7% of virologically PCR confirmed asymptomatic cases, despite low IgM seroprevalence. It was confirmed that all four serotypes are in the circulation and in 17.2% of individuals it detected natural coinfections of two or three different serotypes simultaneously. This is the first report in Colombia evaluating viremia in asymptomatic volunteers. These findings pose a big concern about the transmission of dengue virus by asymptomatic individuals because they can spread the virus without take appropriate control measures.

Surface Study of Lithium-Air Battery Oxygen Cathodes in Different Solvent-Electrolyte pairs.

The O2/Li2O2 electrode reaction has been studied on low surface area Au electrodes in three solvent-electrolyte pairs (0.1 M LiPF6/DMSO, LiPF6/ACN, and LiBF4/ACN) using an electrochemical cell coupled to UHV XPS spectrometer, EQCM, AFM, and DEMS. The XPS spectra of the surfaces after treatment at selected electrode potentials for the O2 reduction and reoxidation of the surface show the presence of C and S from solvent decomposition and of F and P from electrolyte decomposition. Furthermore, Li 1s and O 1s peaks due to Li2O2 and decomposition products such as carbonate, organics, LiF, high oxidation sulfur, and phosphorus compounds were also observed. Using ACN instead of DMSO results in less solvent decomposition, whereas using LiBF4 results in less electrolyte decomposition. XPS, AFM, and EQCM show that O2 reduction products removal only takes place at very high overpotentials. In agreement with XPS which shows removal of carbonate surface species, DEMS confirms evolution of CO2 and consumption of O2 at 4.5 V, but LiF cannot be removed completely in a round trip of the Li-O2 battery cathode.

Selective electrocatalytic hydrogenation using palladium nanoparticles electrochemically formed in layer-by-layer multilayer films.

Sequential adsorption of PdCl4(2-) within weak polyelectrolyte layer-by-layer (LbL) self-assembled multilayer films with further electrochemical reduction to yield Pd(0) nanoparticles (Pd-NPs) has been demonstrated. The electrocatalytic hydrogenation (ECH) of model molecules such as acetophenone and benzophenone on Pd-NPs of different sizes (6 to 35 nm) and bulk Pd crystal surface in hydroalcoholic acid solution has been investigated. Distribution of reaction products (secondary alcohols and alkanes) and faradaic yield was systematically investigated. While the polyelectrolyte multilayers act as nanoreactors by confining PdCl4(2-) ions and preventing the formation of large crystals, their presence also alters the hydrogenation reaction and therefore heat treated surfaces showed only the effect of nanocrystal size on the reaction selectivity and faradaic yield.

Electrochemistry of Os(2,2'-bpy)2ClPyCH2NHCOPh tethered to Au electrodes by S-Au and C-Au junctions.

Osmium pyridine-bipyridine redox centers have been tethered to Au electrodes by chemical modification through Au-S and Au-C bonds respectively. 4-Mercapto benzoic acid and the reduction product of the aryl diazonium salt of 4-amino benzoic acid were reacted on Au surfaces, with further post-functionalization by chemical reaction of the osmium complex amino-pyridine derivative with the surface carboxylates. The resulting modified Au surfaces were characterized by polarization modulated infrared reflection absorption spectroscopy (PM-IRRAS), scanning tunneling microscopy (STM), X-ray photoelectron spectroscopy (XPS), resonant raman spectroscopy and cyclic voltammetry.

Pathology of striped dolphins (Stenella coeruleoalba) infected with Brucella ceti.

Seventeen striped dolphins (Stenella coeruleoalba) displaying swimming disorders compatible with neurological syndromes were investigated for Brucella infection. Sixteen dolphins had meningoencephalomyelitis. Serum antibody against Brucella antigen was detected in all 14 animals tested and Brucella ceti was isolated from eight out of nine animals. Brucella antigen was detected in the brain by immunofluorescence, but not by immunohistochemical labelling. By contrast, Brucella antigen was demonstrated by immunohistochemistry in the trophoblast of animals with severe placentitis and in the mitral valve of animals with myocarditis. The microscopical lesions observed in the tissues of the infected dolphins were similar to those of chronic brucellosis in man. The severity of brucellosis in S. coeruleoalba indicates that this dolphin species is highly susceptible to infection by B. ceti.

Extracting kinetic parameters for homogeneous [Os(bpy)2ClPyCOOH]+ mediated enzyme reactions from cyclic voltammetry and simulations.

The homogeneous reaction between glucose oxidase and osmium bipyridine-pyridine carboxylic acid in the presence of glucose has been studied in detail by cyclic voltammetry and digital simulation. Combination of the analytical equations that describe the dependence of the amperometric response on enzyme, substrate and co-substrate concentrations for the limiting cases with digital simulation of the coupled enzyme reaction diffusion problem allows us to extract kinetic parameters for the substrate-enzyme reaction: K(MS)=10.8 mM, k(cat)=254 s(-1) and for the redox mediator-enzyme reaction, k=2.2x10(5) M(-1) s(-1). The accurate determination of the kinetic parameters at low substrate concentrations (<7 mM) is limited by depletion of the substrate close to the electrode surface. At high substrate concentrations (>20 mM) inactivation of the reduced form of glucose oxidase in the bulk solution must be taken into account in the analysis of the results.

Wired-enzyme core-shell Au nanoparticle biosensor.

We report a fully integrated core-shell nanoparticle system responsive to glucose. The system is comprised of self-assembled glucose oxidase and an osmium molecular wire on core-shell Au nanoparticles. Characterization of the functional nanoparticles by spectroscopy, quartz crystal microbalance and electrochemical techniques has shown that the catalytically active shell has a structure as designed and all components are active in the self-assembled multilayer shell. Furthermore, amperometric reagentless detection of glucose and contactless photonic biosensing by the Os(II) resonant Raman signal have been demonstrated. The enzymatic reduction of FAD by glucose and further reduction of the Raman silent Os(III) by FADH 2 yields a characteristic enzyme-substrate calibration curve in the millimolar range. Furthermore, coupling of electronic resonant Raman of the osmium complex with the SERS amplification by Au NPs plasmon resonance has been demonstrated which leads to an extra enhancement of the biosensor signal. We present a proof of concept extending the work done with planar surfaces to core-shell NPs as an advance in the design of glucose-responsive chemistry detected by SERS-like methods.

Relaxation and Simplex mathematical algorithms applied to the study of steady-state electrochemical responses of immobilized enzyme biosensors: Comparison with experiments.

A description of the implementation of the relaxation method with automatic mesh point allocation for immobilized enzyme electrodes is presented. The advantages of this method for the solution of coupled reaction-diffusion problems are discussed. The relaxation numerical simulation technique is combined with the Simplex fitting algorithm to extract kinetic parameters from experimental data. The results of the simulations are compared to experimental data from self-assembled multilayered electrodes comprised of glucose oxidase (GOx) and an Os modified redox mediator and found to be in excellent agreement.

Molecular biology of testicular germ cell tumors.

Testicular germ cell tumors (TCGT) comprise a heterogeneous group of neoplasms, although all of them are originated from common precursors related to germ cell lineage. Understanding of normal development of germinal cells is essential to define new markers for diagnosis, prognostic subgroups and targeted therapies. Recent advances related to cytogenetic and molecular features have established the role of immunohistochemistry of c-kit, OCT-3/4 and determination of gain of chromosome 12 in the daily workup of premalignant lesions and invasive tumors. This review summarizes the current knowledge in the field of molecular biology of TGCT.

Oxidation-reduction dynamics in layer-by-layer self-assembled redox polyelectrolyte multilayer modified electrodes.

The oxidation-reduction dynamics of layer-by-layer (LbL) self-assembled redox polyelectrolyte multilayer films on electrodes has been studied by cyclic voltammetry, chrono-amperometry, electrochemical quartz crystal microbalance (EQCM), ellipsometry, and Fourier transform reflection-absorption infrared spectroscopy (FT-IRRAS). Thin layer electrochemistry with fast electron transfer at the underlying metal-film interface and charge propagation by electron hopping between adjacent redox sites in the finite thin film has been observed. An almost ideal cyclic voltammetry for a fixed number of redox sites in the thin surface film suggests that the multilayer can be fully oxidized and reduced in the time scale of the experiment (RT/vF > or = 0.05 sec). The electron hopping diffusion coefficient 3 x 10(-10) cm2 s(-1) was obtained from the chronoamperometric current transient and the ellipsometric thickness. Both cyclic voltammetry and potential step yield a surface osmium bipyridyl redox concentration of gamma Os = 4 x 10(-10) mol x cm(-2) for (PAH-Os)5(PVS)4 film. Exchange of ions and solvent occur simultaneously to the charge injection as revealed by the EQCM mass change and the ellipsometric thickness change. From the end-to-end mass-to-charge linear relationship, the molar mass of the ionic and neutral species exchanged largely exceeds the molar mass of any ions or solvent which suggests an important flux of solvent during redox switching. An initial "break in" effect is observed for the first oxidation-reduction cycles when a newly self-assembled film equilibrates with the electrolyte as charge is injected during the electrochemical perturbation.

SERS in PAH-Os and gold nanoparticle self-assembled multilayers.

We present a detailed structural and surface-enhanced Raman scattering (SERS) study of poly(allylamine) modified with Os(byp)2ClPyCHO (PAH-Os) and gold nanoparticles self-assembled multilayers [PAH-Os+(Au-nanoparticlesPAH-Os)n, n=1 and 5]. Atomic force microscopy and variable-angle spectroscopic ellipsometry measurements indicate that the first nanoparticle layer grows homogenously by partially covering the substrate without clustering. Analyzing the sample thickness and roughness we infer that the growth process advances thereafter by filling with nanoparticles the interstitial spaces between the previously adsorbed nanoparticles. After five immersion steps the multilayers reach a more compact structure. The interaction between plasmons of near-gold nanoparticles provides a new optical absorption around 650 nm which, in addition, allows a more effective SERS process in that spectral region than at the single-plasmon resonance (approximately 530 nm). We compare the electronic resonance Raman and SERS amplification mechanisms in these self-assembled multilayers analyzing Raman resonance scans and Raman intensity micromaps. As a function of nanoparticle coverage we observe large changes in the Raman intensity scans, with maxima that shift from the electronic transitions, to the plasmon resonance, and finally to the coupled-plasmon absorption. The Raman micromaps, on the other hand, evidence huge intensity inhomogeneities which we relate to "hot spots." Numerical discrete dipole approximation calculations including the interaction between gold nanoparticles are presented, providing a qualitative model for the coupled-plasmon absorption and redshifted Raman hot spots in these samples.

Resonant Raman spectroscopy of PAH--Os self-assembled multilayers.

We present a resonant Raman scattering study of (PAH--Os/PVS)n and (PAH--Os/GOx)m self-assembled multilayers (n=1-11 and m=1-3). These Os polymer multilayers can be used in electrodes as efficient molecular wires for biomolecular recognition. The Raman intensity dependence on the number of self-assembly cycles provides information on the deposition process. The spectra are identical to that observed for PAH--Os in aqueous solution, indicating that the PAH--Os metal complex structure is conserved in the multilayers. We observe at approximately 500 nm incoming and outgoing Raman resonances of osmium and bipyridine vibrational modes. These resonances are associated to the metal-to-ligand charge transfer (MLCT) transition. We study the evolution of these Raman modes as a function of the Os oxidation state during in situ electrochemistry. During the oxidation process, Os(II)-->Os(III), the Raman resonance related to the MLCT disappears and the bipyridine related modes harden by approximately 10 cm(-1). These results are correlated with optical transmission measurements which show the disappearance of the visible region absorption when the Os complex is oxidized. We also find partial quenching of the Raman mode intensity after in situ voltamperometric cycles which demonstrates the existence of photo-electro-chemical processes.

Characterization of self-assembled redox polymer and antibody molecules on thiolated gold electrodes.

Multilayer immobilization of antibody and redox polymer molecules on a gold electrode was achieved, as a strategy for the potential development of an amperometric immunosensor. The step-by-step assembly of antibiotin IgG on Os(bpy)(2)ClPyCH(2)NH poly(allylamine) redox polymer (PAH-Os) adsorbed on thiolated gold electrodes was proved by quartz crystal microbalance (QCM) and atomic force microscopy (AFM) experiments, confirming the electrochemical evidence. The increase of redox charge during the layer-by-layer deposition demonstrated that charge propagation within the layers is feasible. The multilayer structure proved to be effective for the molecular recognition of horseradish peroxidase-biotin conjugate (HRP-biotin), as confirmed by the QCM measurements and the electrocatalytic reduction current obtained upon H(2)O(2) addition. The catalytic current resulting from PAH-Os mediation was shown to increase with the number of assembled layers. Furthermore, the inventory of IgG molecules on the supramolecular self-assembled structure and the specific and non-specific binding of HRP-biotin conjugate were confirmed by the QCM transient studies, giving information on the kinetics of IgG deposition and HRP-biotin conjugate binding to the IgG.

The transcriptome of adult female Anopheles darlingi salivary glands.

Anopheles (Nyssorhynchus) darlingi is an important malaria vector in South and Central America; however, little is known about molecular aspects of its biology. Genomic and proteomic analyses were performed on the salivary gland products of Anopheles darlingi. A total of 593 randomly selected, salivary gland-derived cDNAs were sequenced and assembled based on their similarities into 288 clusters. The putative translated proteins were classified into three categories: (S) secretory products, (H) housekeeping products and (U) products with unknown cell location and function. Ninety-three clusters encode putative secreted proteins and several of them, such as an anophelin, a thrombin inhibitor, apyrases and several new members of the D7 protein family, were identified as molecules involved in haematophagy. Sugar-feeding related enzymes (alpha-glucosidases and alpha-amylase) also were found among the secreted salivary products. Ninety-nine clusters encode housekeeping proteins associated with energy metabolism, protein synthesis, signal transduction and other cellular functions. Ninety-seven clusters encode proteins with no similarity with known proteins. Comparison of the sequence divergence of the S and H categories of proteins of An. darlingi and An. gambiae revealed that the salivary proteins are less conserved than the housekeeping proteins, and therefore are changing at a faster evolutionary rate. Tabular and supplementary material containing the cDNA sequences and annotations are available at http://www.ncbi.nlm.nih.gov/projects/Mosquito/A_darlingi_sialome/

Determination of photodegradation and ozonation by products of linear alkylbenzene sulfonates by liquid chromatography and ion chromatography under controlled laboratory experiments.

A Suntest solar simulator with arc xenon lamp was used to irradiate pure linear alkylbenzene sulfonates (LAS) standard and some commercial LAS solutions. The ozonation treatment was carried out in a pilot plant air-lift type reactor. Kinetic degradation curves were obtained showing an apparent first order reaction in both cases. Extraction and preconcentration of samples was carried out by off-line SPE using polymeric an RP-18 cartridges with recoveries varying from 77 to 93% for the LAS compounds. For LC chromatographic elution of LAS and degradation products an ion pair based on 5mM triethylamine and 5nM acetic acid had to the acetonitrile-water or methanol-water mobile phases. Fluorescence detection was achieved at 225 and 295nm as excitation and emission radiation wavelength, respectively. Degradation by products were identified by liquid chromatography electrospray mass spectrometry detection (LC-ESI-MS). Ion chromatography (IC) was used to analyze refractory species such as oxalate, formate and acetate ions which were present in the treated solution even after 3h of ozone treatment. The LAS mixture was almost totally degraded in less than 20min using O(3)/H(2)O(2), the reaction being faster than in the case of catalyzed photodecomposition. TOC removal reached 84% after 3h of ozonation process.