Impact of intensified chemotherapy in metastatic pancreatic ductal adenocarcinoma (PDAC) in clinical routine in Europe

Background

Pancreatic ductal adenocarcinoma (PDAC) is associated with poor prognosis. Gemcitabine is the standard chemotherapy for patients with metastatic pancreatic adenocarcinoma (MPA). Randomized clinical trials evaluating intensified chemotherapies including FOLFIRINOX and nab-paclitaxel plus gemcitabine (NAB+GEM) have shown improvement in survival. Here, we have evaluated the efficacy of intensified chemotherapy versus gemcitabine monotherapy in real-life settings across Europe.

SAPHO syndrome presenting as widespread bony metastatic disease of unknown origin

SAPHO (synovitis, acne, pustulosis, hyperostosis and osteitis) syndrome represents an inflammatory spectrum ranging from an osteitis through to a spondyloarthropathy which may or may not be associated with dermatological manifestations. We present the case of a 52-year-old female who presented with non-specific back pain. Radiological imaging showed mixed lytic and sclerotic lesions of her lumbar spine and pelvis consistent with bony metastatic disease. She underwent CT-guided biopsy that confirmed histological findings in keeping with non-bacterial osteitis/chronic recurrent multifocal osteomyelitis. This case report and review of the literature highlights the importance of the SAPHO syndrome and its treatment.     

Critical review on the chemical reduction of nitroaniline

Conversion of nitroaniline (NA), a highly toxic pollutant that has been released into aquatic systems due to unmanaged industrial development in recent years, into the less harmful or a useful counterpart is the need of the hour. Various methods for its conversion and removal have been explored. Owing to its nominal features of advanced effectiveness, the chemical reduction of 4-NA using various different nanocatalytic systems is one such approach that has attracted tremendous interest over the past few years. The academic literature has been confined to case studies involving silver (Ag) and gold (Au) nanoparticles, as these are the two most widely used materials for the synthesis of nanocatalytic assemblies. Focus has also been given to sodium borohydride (NaBH₄), which is used as a reductant during the chemical reduction of NA. This systematic review summarizes the fundamentals associated with the catalytic degradation of 4-NA, and presents a comprehensive and critical study of the latest modifications used in the synthesis of these catalytic systems. In addition, the kinetics, mechanisms, thermodynamics, as well as the future directions required for understanding this model reaction, have been provided in this particular study.

Schematic illustration of catalytic reduction of 4-NA in the presence of nanocatalysts and a reducing agent.     

Localized deferoxamine injection augments vascularity and improves bony union in pathologic fracture healing after radiotherapy

BackgroundMedically based efforts and alternative treatment strategies to prevent or remediate the corrosive effects of radiotherapy on pathologic fracture healing have failed to produce clear and convincing evidence of success. Establishing an effective pharmacologic option to prevent or treat the development of non-unions in this setting could have immense therapeutic potential. Experimental studies have shown that deferoxamine (DFO), an iron-chelating agent, bolsters vascularity and subsequently enhances normal fracture healing when injected locally into a fracture callus in long bone animal models. Since radiotherapy is known to impede angiogenesis, we hypothesized that the pharmacologic addition of DFO would serve to mitigate the effects of radiotherapy on new vessel formation in vitro and in vivo.Materials and MethodsIn vitro investigation of angiogenesis was conducted utilizing HUVEC cells in Matrigel. Endothelial tubule formation assays were divided into four groups: Control, Radiated, Radiated + Low-Dose DFO and Radiated + High-Dose DFO. Tubule formation was quantified microscopically and video recorded for the four groups simultaneously during the experiment. In vivo, three groups of Sprague–Dawley rats underwent external fixator placement and fracture osteotomy of the left mandible. Two groups received pre-operative fractionated radiotherapy, and one of these groups was treated with DFO after fracture repair. After 40 days, the animals were perfused and imaged with micro-CT to calculate vascular radiomorphometrics.ResultsIn vitro, endothelial tubule formation assays demonstrated that DFO mitigated the deleterious effects of radiation on angiogenesis. Further, high-dose DFO cultures appeared to organize within 2 h of incubation and achieved a robust network that was visibly superior to all other experimental groups in an accelerated fashion. In vivo, animals subjected to a human equivalent dose of radiotherapy (HEDR) and left mandibular fracture demonstrated quantifiably diminished μCT metrics of vascular density, as well as a 75% incidence of associated non-unions. The addition of DFO in this setting markedly improved vascularity as demonstrated with 3D angiographic modeling. In addition, we observed an increased incidence of bony unions in the DFO treated group when compared to radiated fractures without treatment (67% vs. 25% respectively).ConclusionOur data suggest that selectively targeting angiogenesis with localized DFO injections is sufficient to remediate the associated severe vascular diminution resulting from a HEDR. Perhaps the most consequential and clinically relevant finding was the ability to reduce the incidence of non-unions in a model where fracture healing was not routinely observed.     

Development and validation of a short-form, rapid estimate of adult literacy in medicine

BACKGROUND: Although prior studies used the 66-item Rapid Estimate of Adult Literacy in Medicine (REALM instrument) for literacy assessment, researchers may require a shorter, validated instrument when designing interventions for clinical contexts. OBJECTIVE: To develop and validate a very brief literacy assessment tool, the REALM-Short Form (REALM-SF). PATIENTS: The model development, validation, and field testing validation samples included 1336, 164, and 50 patients, respectively. SETTING: General medicine and subspecialty clinics and medicine inpatient wards. DESIGN: For development and validation samples, indicator variables for REALM instrument items were evaluated as potential predictors of REALM instrument score by stepwise multiple regression analysis with subsequent bootstrap and confirmatory factor analysis of selected items. Pearson correlations compared REALM-SF and REALM instrument scores and kappa analyses compared grade level assignments. For the field testing validation sample, Pearson correlations compared Wide Range Achievement Test and REALM-SF scores. RESULTS: The REALM-SF included 7 items with stable model coefficients and 1 underlying linear factor. REALM-SF and REALM instrument scores were highly correlated in development (r = 0.95, P < 0.001) and validation (r = 0.94, P < 0.001) samples. There was excellent agreement between REALM-SF and REALM instrument grade-level assignments when dichotomized at the 6th grade (development: 97% agreement, K = 0.88, P < 0.001; validation: 88% agreement, K = 0.75, P < 0.001) and 8th grade levels (development: 94% agreement, K = 0.78, P < 0.001; validation: 84% agreement, K = 0.67, P < 0.001). REALM-SF and Wide Range Achievement Test scores were highly correlated (r = 0.83, P < 0.001) in field testing validation. CONCLUSIONS: The REALM-SF provides researchers a brief, validated instrument for assessing patient literacy in diverse research settings.     

Gap Junction Mediated Intercellular Metabolite Transfer in the Cochlea Is Compromised in Connexin30 Null Mice

Connexin26 (Cx26) and connexin30 (Cx30) are two major protein subunits that co-assemble to form gap junctions (GJs) in the cochlea. Mutations in either one of them are the major cause of non-syndromic prelingual deafness in humans. Because the mechanisms of cochlear pathogenesis caused by Cx mutations are unclear, we investigated effects of Cx30 null mutation on GJ-mediated ionic and metabolic coupling in the cochlea of mice. A novel flattened cochlear preparation was used to directly assess intercellular coupling in the sensory epithelium of the cochlea. Double-electrode patch clamp recordings revealed that the absence of Cx30 did not significantly change GJ conductance among the cochlear supporting cells. The preserved electrical coupling is consistent with immunolabeling data showing extensive Cx26 GJs in the cochlea of the mutant mice. In contrast, dye diffusion assays showed that the rate and extent of intercellular transfer of multiple fluorescent dyes (including a non-metabolizable D-glucose analogue, 2-NBDG) among cochlear supporting cells were severely reduced in Cx30 null mice. Since the sensory epithelium in the cochlea is an avascular organ, GJ-facilitated intercellular transfer of nutrient and signaling molecules may play essential roles in cellular homeostasis. To test this possibility, NBDG was used as a tracer to study the contribution of GJs in transporting glucose into the cochlear sensory epithelium when delivered systemically. NBDG uptake in cochlear supporting cells was significantly reduced in Cx30 null mice. The decrease was also observed with GJ blockers or glucose competition, supporting the specificity of our tests. These data indicate that GJs facilitate efficient uptake of glucose in the supporting cells. This study provides the first direct experimental evidence showing that the transfer of metabolically-important molecules in cochlear supporting cells is dependent on the normal function of GJs, thereby suggesting a novel pathogenesis process in the cochlea for Cx-mutation-linked deafness.