bluuebunny/crossref_metadata_2025 huggingface dataset:
The informal curriculum of family medicine – what does it entail and how is it taught to residents? A systematic review
Authors: Rothlind Erica , Fors Uno , Salminen Helena , Wändell Per , Ekblad Solvig
Published: March 2020

Background

The informal curriculum is a seemingly well-explored concept in the realm of medical education. However, it is a concept with multiple definitions and the term “the hidden curriculum” is often used interchangeably. In short, they both refer to the implicit learning taking place outside the formal curriculum, encompassing both a trickling down effect of organizational values and attitudes passed on by a mentor or colleague. While the informal curriculum is a recurrent theme in medical education literature; it is seldom discussed in Family Medicine. As the informal curriculum is likely to be highly influential in the forming of future family practitioners, our aim was to explore the area further, with respect to the following: which elements of the informal curriculum are applicable in a Family Medicine context and what educational interventions for Family Medicine residents, visualizing the various educational elements of it, have been performed?

Methods

We conducted a systematic review comprising iterative literature searches and a narrative synthesis of the results.

Results

Twenty articles, published between 2000 and 2019, were included in the analysis which resulted in three partly interrelated themes comprising the informal curriculum in Family Medicine: gaining cultural competence, achieving medical professionalism and dealing with uncertainty. The themes on cultural competence and uncertainty seemed to be more contextual than professionalism, the latter being discussed in relation to the informal curriculum across other medical disciplines as well. Formalized training for Family Medicine residents in aspects of the informal curriculum appeared to be lacking, and in general, the quality of the few interventional studies found was low.

Conclusions

Important aspects of being a family practitioner, such as cultural competence and dealing with uncertainty, are learned through a context-dependent informal curriculum. In order to ensure a more uniform base for all residents and to reduce the impact of the individual supervisor’s preferences, complementary formalized training would be beneficial. However, to date there are too few studies published to conclude how to best teach the informal curriculum.

Trial registration

The systematic review was registered with Prospero; registration number CRD42018104819.
Pneumocystis pneumonia occurrence and prophylaxis duration in kidney transplant recipients according to perioperative treatment with rituximab
Authors: Kim Young Hoon , Kim Jee Yeon , Kim Dong Hyun , Ko Youngmin , Choi Ji Yoon , Shin Sung , Jung Joo Hee , Park Su-Kil , Kim Sung-Han , Kwon Hyunwook , Han Duck Jong
Published: March 2020

Background

Pneumocystis pneumonia (PCP) is a life-threatening fungal infection that can occur in kidney transplantation (KT) recipients. A growing number of KT recipients are receiving perioperative treatment with rituximab, which is associated with prolonged B-cell depletion and possible risk of PCP occurrence; however, the optimal prophylaxis duration according to rituximab treatment is yet unknown. We compared the occurrence of PCP and the duration of prophylaxis in KT recipients according to rituximab treatment.

Methods

We retrospectively analyzed 2110 patients who underwent KT between January 2009 and December 2016, who were divided into non-Rituximab group (n = 1588, 75.3%) and rituximab group (n = 522, 24.7%).

Results

In the rituximab group, the estimated number needed to treat (NNT) for prophylaxis prolongation from 6 to 12 months was 29.0 with a relative risk reduction of 90.0%. In the non-rituximab group, the estimated NNT value was 133.3 and the relative risk reduction was 66.4%. Rituximab treatment (hazard ratio (HR) = 3.09; P <  0.01) and acute rejection (HR = 2.19; P = 0.03) were significant risk factors for PCP in multivariate analysis.

Conclusions

Our results suggest that maintaining PCP prophylaxis for 12 months may be beneficial in KT recipients treated with rituximab for desensitization or acute rejection treatment.
Outcomes in acute kidney injury in noncritically ill patients lately referred to nephrologist in a developing country: a comparison of AKIN and KDIGO criteria
Authors: Nascimento Ginivaldo Victor Ribeiro do , Silva Marcela do Nascimento , Carvalho Neto Juarez Duarte de , Feitosa Filho Ludgero Ribeiro , Antão Jessica Duarte
Published: March 2020

Background

In low-middle-income countries (LMICs), data regarding acute kidney injury (AKI) are scarce. AKI patients experience delayed diagnosis. This study aimed to evaluate whether delayed nephrologist consultation (NC) affected outcomes of AKI patients and compare Acute Kidney Injury Network (AKIN) and Kidney Disease: Improving Global Outcomes (KDIGO).

Methods

An observational, retrospective study was conducted in a tertiary public hospital in an LMIC.

Results

Overall, 103 AKI patients were analysed. In-hospital mortality was 61.16%, and dialysis was required in 38.83%. NC took place after 48 h in 68.93% of the patients. Mean time for NC was 5.22 ± 4.30 days. At NC, serum creatinine was 4.48 (±3.40) mg/dL and blood urea nitrogen was 68.21 (± 35.02) mg/dL. The AKIN and KDIGO stage stratifications were identical; KDIGO stage 3 was seen in 58.25% of the patients. The group with NC >  4 days had a mortality rate of 74.46% and the group with NC ≤ 4 days had a mortality rate of 50% (p = 0.011). Multivariate analysis showed that haemodialysis was independently associated with mortality. NC >  4 days was associated with death [odds ratio 2.66 (95% confidence interval, 1.36–4.35), p = 0.001]. Logistic regression showed an OR of 1.20 (95% CI, 1.05–1.37) (p = 0.008) for each day of delayed NC.

Conclusion

Delayed NC was associated with mortality even after adjustments, as was haemodialysis, though marginally. In AKI patients with NC > 4 days, there was a high prevalence of KDIGO stage 3, and AKIN and KDIGO criteria were identical.
Validation of the Chinese version of the Amsterdam Preoperative Anxiety and Information Scale (APAIS)
Authors: Wu Hao , Zhao Xin , Chu Shuaishuai , Xu Fangxia , Song Jia , Ma Zhengliang , Gu Xiaoping
Published: March 2020

Background

Preoperative anxiety is an unpleasant state of tension that may impact patients’ post-operative pain and satisfaction. The level of preoperative anxiety should be routinely identified. The Amsterdam Preoperative Anxiety and Information Scale (APAIS) is a self-reported questionnaire that is used to quickly assess preoperative anxiety and information needs with good psychometric properties.

Objectives

To validate the Chinese version of the Amsterdam Preoperative Anxiety and Information Scale (APAIS) and to explore coping strategies used by patients in dealing with surgery and anesthetic.

Methods

The cross-cultural validation of APAIS involved the translation of a Chinese version of APAIS and an investigation of its psychometric properties and clinical applicability. Forward-back translation and a pilot study were performed to produce a Chinese adaptation of APAIS. The inpatients of the orthopedic, otolaryngology, and general surgery department scheduled for general anesthesia surgery were enrolled to complete psychometric testing. The reliability was assessed using Cronbach’s alpha. Exploratory factor analysis and confirmatory factor analysis were calculated to assess construct validity. The criteria validity was analyzed using the correlation between APAIS and State-trait anxiety inventory-state (STAI-S) and Visual analogue scale-anxiety (VAS-A). Coping styles were evaluated using the Medical Coping Modes Questionnaire (MCMQ) score that covered three domains: confrontation, avoidance, and resignation. The impact of different coping styles on patients’ anxiety was explored.

Results

A total of 204 valid questionnaires were collected the day before surgery. Cronbach’s alpha coefficients were 0.862 for the anxiety scale and 0.830 for the information scale. Exploratory factor analysis with oblique rotation revealed two factors that explained 76.45% of the total variances. A confirmatory factor analysis showed a two-factor model with an adequate model fit (root mean square error of approximation: 0.073, goodness-of-fit: 0.966). The APAIS anxiety score significantly correlated with STAI-S (r = 0.717,P < 0.01) and VAS-A (r = 0.720,P < 0.01). For the three coping strategies, preoperative anxiety had a low correlation with confrontation (r = 0.33,P < 0.01) and resignation (r = 0.22,P < 0.05).

Conclusions

The Chinese version of APAIS is a valid and reliable instrument for assessing preoperative anxiety. Use of this measurement tool for Chinese patients is feasible and shows promising results.
Response to: Simpson’s Paradox is suppression, but Lord’s Paradox is neither: clarification of and correction to Tu, Gunnell, and Gilthorpe (2008) by Nickerson CA & Brown NJL (https://doi.org/10.1186/1742-7622-5-2)
Authors: Gilthorpe Mark S. , Tu Yu-Kang
Published: March 2020

We commend Nickerson and Brown on their insightful exposition of the mathematical algebra behind Simpson’s paradox, suppression and Lord’s paradox; we also acknowledge there can be differences in how Lord’s paradox is approached analytically, compared to Simpson’s paradox and suppression, though not in every example of Lord’s paradox. Furthermore, Simpson’s paradox, suppression and Lord’s paradox ask the same contextual questions, seeking to understand if statistical adjustment is valid and meaningful, identifying which analytical option is correct. In our exposition of this, we focus on the perspective of context, which must invoke causal thinking. From a causal thinking perspective, Simpson’s paradox, suppression and Lord’s paradox present very similar analytical challenges.
Systematic analysis of ovarian cancer platinum-resistance mechanisms via text mining
Authors: Li Haixia , Li Jinghua , Gao Wanli , Zhen Cheng , Feng Limin
Published: March 2020

Background

Platinum resistance is an important cause of clinical recurrence and death for ovarian cancer. This study tries to systematically explore the molecular mechanisms for platinum resistance in ovarian cancer and identify regulatory genes and pathways via text mining and other methods.

Methods

Genes in abstracts of associated literatures were identified. Gene ontology and protein-protein interaction (PPI) network analysis were performed. Then co-occurrence between genes and ovarian cancer subtypes were carried out followed by cluster analysis.

Results

Genes with highest frequencies are mostly involved in DNA repair, apoptosis, metal transport and drug detoxification, which are closely related to platinum resistance. Gene ontology analysis confirms this result. Some proteins such as TP53, HSP90, ESR1, AKT1, BRCA1, EGFR and CTNNB1 work as hub nodes in PPI network. According to cluster analysis, specific genes were highlighted in each subtype of ovarian cancer, indicating that various subtypes may have different resistance mechanisms respectively.

Conclusions

Platinum resistance in ovarian cancer involves complicated signaling pathways and different subtypes may have specific mechanisms. Text mining, combined with other bio-information methods, is an effective way for systematic analysis.
Smarcad1 mediates microbiota-induced inflammation in mouse and coordinates gene expression in the intestinal epithelium
Authors: Kazakevych Juri , Denizot Jérémy , Liebert Anke , Portovedo Mariana , Mosavie Mia , Jain Payal , Stellato Claudia , Fraser Claire , Corrêa Renan Oliveira , Célestine Marina , Mattiuz Raphaël , Okkenhaug Hanneke , Miller J. Ross , Vinolo Marco Aurélio Ramirez , Veldhoen Marc , Varga-Weisz Patrick
Published: March 2020

Background

How intestinal epithelial cells interact with the microbiota and how this is regulated at the gene expression level are critical questions. Smarcad1 is a conserved chromatin remodeling factor with a poorly understood tissue function. As this factor is highly expressed in the stem and proliferative zones of the intestinal epithelium, we explore its role in this tissue.

Results

Specific deletion of Smarcad1 in the mouse intestinal epithelium leads to colitis resistance and substantial changes in gene expression, including a striking increase of expression of several genes linked to innate immunity. Absence of Smarcad1 leads to changes in chromatin accessibility and significant changes in histone H3K9me3 over many sites, including genes that are differentially regulated upon Smarcad1 deletion. We identify candidate members of the gut microbiome that elicit a Smarcad1-dependent colitis response, including members of the poorly understood TM7 phylum.

Conclusions

Our study sheds light onto the role of the chromatin remodeling machinery in intestinal epithelial cells in the colitis response and shows how a highly conserved chromatin remodeling factor has a distinct role in anti-microbial defense. This work highlights the importance of the intestinal epithelium in the colitis response and the potential of microbial species as pharmacological and probiotic targets in the context of inflammatory diseases.
GtxA is a virulence factor that promotes a Th2-like response during Gallibacterium anatis infection in laying hens
Authors: Tang Bo , Pors Susanne E. , Kristensen Bodil M. , Skjerning Ragnhild Bager J. , Olsen Rikke H. , Bojesen Anders M.
Published: March 2020

GtxA, a leukotoxic RTX-toxin, has been proposed a main virulence factor of Gallibacterium anatis. To evaluate the impact of GtxA during infection, we experimentally infected laying hens with a G. anatis wild-type (WT) strain and its isogenic gtxA deletion mutant (ΔgtxA), respectively, and monitored the birds during a 6 day period. Birds inoculated with ΔgtxA had significantly reduced gross lesions and microscopic changes compared to the birds inoculated with the WT strain. To assess the host response further, we quantified the expression of pro-inflammatory cytokines and apoptosis genes by RT-qPCR. In the ovarian tissue, the expression levels of IL-4 and TNF-α were significantly lower in the ΔgtxA group compared to the WT group, while IL-6 and IL-10 levels appeared similar in the two groups. In the spleen tissue of ΔgtxA infected chickens, IL-4 expression was also lower compared to the WT infected chickens. The results indicated that GtxA plays a key role in an acute cytokine-mediated Th2-like response against G. anatis infection in the ovary tissue. The pro-inflammatory response in the ovary tissue of birds inoculated with ΔgtxA mutant was thus significantly lower than the wild-type response. This was, at least partly, supported by the apoptosis gene expression levels, which were significantly higher in the ΔgtxA mutant compared to the wild-type infected chickens. In conclusion, GtxA clearly plays an important role in the pathogenesis of G. anatis infections in laying hens. Further investigations into the specific factors regulating the host response is however needed to provide a more complete understanding of the bacteria-host interaction.
The role of poly(ADP-ribose) polymerase inhibitors in the treatment of cancer and methods to overcome resistance: a review
Authors: Patel Mausam , Nowsheen Somaira , Maraboyina Sanjay , Xia Fen
Published: March 2020

Poly(ADP-ribose) polymerase (PARP) inhibitors represent one of the successful novel approaches to targeted cancer treatment. Indeed, the US Food and Drug Administration (FDA) has recently approved PARP inhibitors for the treatment of breast and ovarian cancers. Despite the proven efficacy of these agents, certain challenges remain with their use. Among the most important are primary and secondary resistance. Here, we review the mechanism of action of PARP inhibitors and their ability to exploit certain inherent deficiencies among malignant cells to improve cell killing, with a focus on deficiencies in homologous recombination among cells with BRCA1 and BRCA2 mutations. Moreover, we discuss the different mechanisms of resistance including development of secondary resistance and strategies to overcome them. Finally, we discuss the limitations of novel therapeutic interventions and possible future studies to exploit biochemical pathways in order to improve therapeutic efficacy of PARP inhibitors.
RapidAIM: a culture- and metaproteomics-based Rapid Assay of Individual Microbiome responses to drugs
Authors: Li Leyuan , Ning Zhibin , Zhang Xu , Mayne Janice , Cheng Kai , Stintzi Alain , Figeys Daniel
Published: March 2020

Background

Human-targeted drugs may exert off-target effects or can be repurposed to modulate the gut microbiota. However, our understanding of such effects is limited due to a lack of rapid and scalable assay to comprehensively assess microbiome responses to drugs. Drugs and other compounds can drastically change the overall abundance, taxonomic composition, and functions of a gut microbiome.

Results

Here, we developed an approach to screen compounds against individual microbiomes in vitro, using metaproteomics to both measure absolute bacterial abundances and to functionally profile the microbiome. Our approach was evaluated by testing 43 compounds (including 4 antibiotics) against 5 individual microbiomes. The method generated technically highly reproducible readouts, including changes of overall microbiome abundance, microbiome composition, and functional pathways. Results show that besides the antibiotics, the compounds berberine and ibuprofen inhibited the accumulation of biomass during in vitro growth of the microbiota. By comparing genus and species level-biomass contributions, selective antibacterial-like activities were found with 35 of the 39 non-antibiotic compounds. Seven of the compounds led to a global alteration of the metaproteome, with apparent compound-specific patterns of functional responses. The taxonomic distributions of altered proteins varied among drugs, i.e., different drugs affect functions of different members of the microbiome. We also showed that bacterial function can shift in response to drugs without a change in the abundance of the bacteria.

Conclusions

Current drug-microbiome interaction studies largely focus on relative microbiome composition and microbial drug metabolism. In contrast, our workflow enables multiple insights into microbiome absolute abundance and functional responses to drugs. The workflow is robust, reproducible, and quantitative and is scalable for personalized high-throughput drug screening applications.
How to tell the difference between a model and a digital twin
Authors: Wright Louise , Davidson Stuart
Published: March 2020

“When I use a word, it means whatever I want it to mean”: Humpty Dumpty in Alice’s Adventures Through The Looking Glass, Lewis Carroll. “Digital twin” is currently a term applied in a wide variety of ways. Some differences are variations from sector to sector, but definitions within a sector can also vary significantly. Within engineering, claims are made regarding the benefits of using digital twinning for design, optimisation, process control, virtual testing, predictive maintenance, and lifetime estimation. In many of its usages, the distinction between a model and a digital twin is not made clear. The danger of this variety and vagueness is that a poor or inconsistent definition and explanation of a digital twin may lead people to reject it as just hype, so that once the hype and the inevitable backlash are over the final level of interest and use (the “plateau of productivity”) may fall well below the maximum potential of the technology. The basic components of a digital twin (essentially a model and some data) are generally comparatively mature and well-understood. Many of the aspects of using data in models are similarly well-understood, from long experience in model validation and verification and from development of boundary, initial and loading conditions from measured values. However, many interesting open questions exist, some connected with the volume and speed of data, some connected with reliability and uncertainty, and some to do with dynamic model updating. In this paper we highlight the essential differences between a model and a digital twin, outline some of the key benefits of using digital twins, and suggest directions for further research to fully exploit the potential of the approach.
Geolocator study reveals east African migration route of Central European Common Terns
Authors: Kralj Jelena , Martinović Miloš , Jurinović Luka , Szinai Péter , Sütő Szandra , Preiszner Bálint
Published: March 2020

Background

The majority of European Common Terns (Sterna hirundo) migrate south along the western coast of Europe and Africa, while birds from eastern regions are known to cross the Mediterranean Sea from east to west or migrate along the eastern African coast. The migration route of north European terns wintering along the coast of western Africa was already described using geolocator data, while knowledge about movements of the European inland populations is based only on relatively scarce recoveries of ringed birds.

Methods

We used light-level geolocators in inland Common Tern colonies in Hungary and Croatia to study their migration route and to identify wintering areas along with stopover sites. Results revealed by geolocators were compared with recoveries of ringed birds.

Results

All tracked birds used the east African migration route with autumn stopovers at Lower Nile and in the southern part of the Red Sea, and short spring stopover in Israel. Terns wintered along Kenyan coasts and in the southern Mozambique Channel. Autumn migration lasted four times longer than spring migration.

Conclusions

This is the first geolocator study that describes the east African migration route of the Common Tern. Important stopover sites were identified. More studies of inland populations are needed to better elucidate tern winter movements.
Accuracy of static computer-assisted implant placement in anterior and posterior sites by clinicians new to implant dentistry: in vitro comparison of fully guided, pilot-guided, and freehand protocols
Authors: Abduo Jaafar , Lau Douglas
Published: March 2020

Background

One of the challenges encountered by clinicians new to implant dentistry is the determination and controlling of implant location. This study compared the accuracy of fully guided (FG) and pilot-guided (PG) static computer-assisted implant placement (sCAIP) protocols against the conventional freehand (FH) protocol for placing single anterior and posterior implants by recently introduced clinicians to implant dentistry.

Material and methods

Ten clinicians new to implant dentistry inserted one anterior (central incisor) and one posterior (first molar) implants per protocol in training maxillary models. The FG protocol involved drilling and implant placement through the guide, while the PG protocol controlled the pilot drilling only. The FH implant placement was completed without the aid of any guide. A total of 30 models were used, and 60 implants were inserted. The implant vertical, horizontal neck, horizontal apex, and angle deviations from planned positions were calculated.

Results

The FG protocol provided the most accurate implant placement in relation to horizontal neck (0.47 mm–0.52 mm), horizontal apex (0.71 mm–0.74 mm), and angle deviations (2.42o–2.61o). The vertical deviation was not significantly different among the different protocols. The PG protocol was generally similar to the FH protocol with a horizontal neck deviation of 1.01 mm–1.14 mm, horizontal apex deviation of 1.02 mm–1.35 mm, and angle deviation of 4.65o–7.79o. The FG protocol showed similarity in the accuracy of the anterior and posterior implants. There was a tendency for inferior accuracy for posterior implants compared with anterior implants for the PG and FH protocols.

Conclusions

In the hands of recently introduced clinicians to implant dentistry, it appears that the accuracy of the FG protocol was superior to the other protocols and was not influenced by the position of the implants. The PG and FH protocols showed inferior accuracy for posterior implants compared with anterior implants.
Effect of different shielding conditions on the stability of Cisplatin
Authors: Abe Tomoya , Matsumoto Daigo , Nakayama Toshiaki , Shimazaki Yukinari , Sagara Atsunobu , Kanehira Dan , Azechi Takuya , Sato Fumiaki , Sakai Hiroyasu , Yumoto Tetsuro , Kamei Junzo
Published: March 2020

Background

Because cisplatin (CDDP) decreases upon light exposure, it is necessary to prevent such exposure during administration. However, the shielding conditions employed are not uniform. Therefore, in this study, we examined the shielding effects of four shading covers, which are commonly used to ensure the stability of CDDP in clinical settings.

Methods

Four shielding conditions, along with a control, were tested under a 1000-Lux white fluorescent lamp at room temperature: aluminum foil (Al), brown shading cover (BSC), yellow shading cover (YSC), milky-white anti-exposure cover (MAC), and no shading cover (NSC). Under each shielding condition, the relationship between the wavelength and transmittance was monitored in the range of 200–800 nm. CDDP was diluted to three concentration levels: 50, 100, and 250 μg/mL. Furthermore, the amount of remaining CDDP and the pH in the solutions were measured for 120 h.

Results

We found that BSC, YSC, and MAC conditions allowed various levels of transmittance; however, Al could not completely transmit light at all wavelengths. Moreover, we showed that the CDDP decreased under MAC and NSC conditions in a time-dependent manner, whereas this decrease was prevented under Al, BSC, and YSC conditions till 120 h. We also demonstrated increases in pH under MAC and NSC conditions in a time-dependent manner, which was prevented under Al, BSC, and YSC conditions till 120 h. Similar results were observed for all three CDDP concentration levels. The results also indicated the approximate relationship between the amount of remaining CDDP and the pH increase.

Conclusions

Considering the opacity of each cover, our results suggest that BSC and YSC are useful and effective for minimizing CDDP degradation in clinical settings. Our results also indicate the alternatives for preparing, storing, and administering CDDP in clinical facilities, making the treatment schedule more flexible. Cumulatively, these findings indicate that the use of the appropriate shading covers, such as BSC or YSC, prevents the decrease in CDDP under fluorescent lighting, potentially contributing to achieving its full therapeutic effect.
A challenging case of Mesenchymal Chondrosarcoma involving the thyroid and special considerations for diagnosis
Authors: Nachawi Noura , Lew Madelyn , Konopka Kristine , Sandouk Zahrae
Published: March 2020

Background

Thyroid ultrasound is usually used to risk-stratify incidental thyroid nodules. Nodules with high risk sonographic features for malignancy are evaluated by fine-needle aspiration. The role of core needle biopsy for thyroid nodules is limited to cases where the fine needle aspiration is inconclusive.

Case presentation

We describe a rare case of mesenchymal chondrosarcoma of the thyroid gland with uncertain primary origin. Thyroid ultrasound showed right sided large, solid, hypoechoic nodule with calcifications and peripheral vascularity and unremarkable isthmus and left thyroid lobe. Fine needle aspiration of the right nodule suggested lymphocytic thyroiditis. The sonographic findings contradicted the typical bilateral clinical and sonographic picture of lymphocytic thyroiditis. A core needle biopsy showed mesenchymal chondrosarcoma.

Conclusion

This case highlights the importance of correlating pathologic diagnosis with sonographic findings, the appropriate utilization of fine needle aspiration and core needle biopsy to evaluate thyroid nodules and the rare incidence of mesenchymal chondrosarcoma involving the thyroid.
Recent progress in the development of advanced biofuel 5-ethoxymethylfurfural
Authors: Chen Binglin , Yan Guihua , Chen Gaofeng , Feng Yunchao , Zeng Xianhai , Sun Yong , Tang Xing , Lei Tingzhou , Lin Lu
Published: March 2020

Biomass-derived 5-ethoxymethylfurfural (EMF) with excellent energy density and satisfactory combustion performance holds great promise to meet the growing demands for transportation fuels and fuel additives to a certain extent. In this review, we summarized the relative merits of the EMF preparation from different feedstocks, such as platform chemicals, biomass sugars and lignocellulosic biomass. Advances for EMF synthesis over homogeneous (i.e. inorganic acids and soluble metal salts), heterogeneous catalysts (i.e. zeolites, heteropolyacid-based hybrids, sulfonic acid-functionalized catalysts, and others) or mixed-acid catalysts were performed as well. Additionally, the emerging development for the EMF production was also evaluated in terms of the different solvents system (i.e. single-phase solvents, biphasic solvents, ionic liquids, and deep eutectic solvents). It is concluded with current challenges and prospects for advanced biofuel EMF preparation in the future.
Masitinib mesylate in imatinib-resistant advanced GIST: A randomized phase II trial.
Authors: Adenis Antoine , Le Cesne Axel , Bui Nguyen Binh , Bouche Olivier , Domont Julien , Ray-Coquard Isabelle , Penel Nicolas , Blesius Aurore , Montestruc Francois , Moussy Alain , Hermine Olivier , Blay Jean-Yves
Published: March 2020

10007

Background: Masitinib is an oral tyrosine kinase inhibitor with greater in vitro activity and selectivity than imatinib against wild-type and juxtamembrane mutations of KIT (Dubreuil, 2009, PLoSONE). This trial studied efficacy and safety of masitinib at 12 mg/kg/day and sunitinib at 50 mg/day for the treatment of imatinib-resistant GIST. Methods: Patients with inoperable, locally advanced or metastatic GIST and showing disease progression while treated with imatinib 400 mg/day received either masitinib or sunitinib until progression. Primary endpoint was PFS evaluated with RECIST with OS as a secondary endpoint. Based upon an 80% power to detect with a Fleming design a median PFS ≥3 months (alpha 10%, unilateral), a population of 44 patients (22 per arm) was required. Stratification was applied based on mutation status. Results: 44 patients (exon 11 [66%], exon 9 [11%], wild-type or other [5%], not done at baseline [18%]) were randomized into masitinib (n=23) or sunitinib (n=21) treatment-arms from 9 centers between 02/2009 and 09/2011. After a median follow-up of 14 months, median PFS was 3.9 months (95%CI [2.6;8.1]) for masitinib vs 3.8 months [1.9;11] for sunitinib. Of those patients progressing under masitinib, 88% received sunitinib in third line. Median OS was not reached (NR) (95%CI [21;NR]) for masitinib vs 15 months [9.4;22] for sunitinib. The 18-month and 24-month OS rates for masitinib vs sunitinib were 79% (95%CI [53;92]) vs 20% [1.5;55], and 53% (95%CI [9.5;84]) vs 0%, respectively. Similar results were seen in the exon 11 subpopulation with median OS for masitinib NR (95%CI [NR;NR]) vs 15 months [9.6;22] for sunitinib. The safety profile of masitinib was better than sunitinib with a lower occurrence of severe related adverse events (AEs) (17% vs 52%) and related AEs leading to discontinuation (0% vs 9.5%). In masitinib treated patients, nausea, diarrhea and asthenia were the most common related AEs. Conclusions: Although PFS curves looked similar, this study apparently showed a longer survival in the masitinib treatment-arm with a better safety profile than sunitinib. Masitinib may potentially offer patients a new active compound for advanced GIST in the second-line setting.
Is CTNNB1 mutational analysis predictive for progression in patients with sporadic desmoid tumors primarily observed?
Authors: Colombo Chiara , Miceli Rosalba , Domont Julien , Perrone Federica , Fiore Marco , Le Cesne Axel , Le Pechoux Cécile , Gronchi Alessandro , Bonvalot Sylvie
Published: March 2020

10016

Background: Recently, a wait and see (W&S) approach has been proposed for patients affected by desmoid tumor (DT). Specific CTNNB1 mutation has been correlated with higher risk of recurrence after surgical resection. Aim of this study was to evaluate the correlation between CTNNB1 mutation type and time to progression in patients primarily observed (TTP). Methods: We included all consecutive patients:(1) primarily observed at the Fondazione IRCSS Istituto Nazionale Tumori (Milano, Italy) or Institut Gustave Roussy (Paris, France) for primary sporadic DTs (2) with available FFPE preserved tissue for CTNNB1 mutational analysis, (3) with measurable disease and adequate follow-up. TTP from date of diagnosis to date of radiological (PRO-R) or symptomatic (PRO-S) progression were conducted by Kaplan-Meier method and log-rank test to compare strata. Results: A total of 79 patients (August 2002- July 2011) were included (81% female, 19% male); median age was 34 (IQ, 10-77); sites distribution: abdominal/chest wall (75%), extremity (21%), intra-abdominal (4%). CTNNB1 mutations were observed in 76% of DT samples: 41A (48%), 45F (25%), 45P (2%); 24% were WT. Median follow-up was 19 mo (IQ, 11-28). Thirty-six patients experienced progression (86% PRO-R, 14% PRO-S): 41A (47%), 45F (55%), 45P (100%), WT (26%). An inferior TTP at 36 months was observed in mutated patients vs WT, while no difference was detected for specific subtype mutated patients (WT 68%, 45F 24%, 41/45P 35%, p= 0.045). A variety of different treatments including surgery, hormonal therapy, chemotherapy, antiCOX2 or persistent W&S approach were proposed at progression. Forty-two patients did not receive any treatment. Conclusions: A clear trend towards a lower risk of progression was observed in WT patients, but no difference between specific mutated patients (45F vs 41/45P) was observed. Prospective studies to eventually clarify the potential role of CTNNB1 as prognostic tool in tailoring desmoids treatment are presently underway.
Gemcitabine/docetaxel for metastatic or locally advanced soft tissue sarcoma: A retrospective single-center experience.
Authors: Egerer Gerlinde , Wuchter Patrick , Dietrich Sascha , Schmier Johann Wilhelm , Ho Anthony D , Schmitt Thomas
Published: March 2020

10040

Background: Soft tissue sarcoma (STS) represent a group of rare malignant tumors. Survival for patients with disseminated disease is dismal. Gemcitabine/docetaxel (GD) is a commonly used systemic 2°-line regime in this setting. Methods: Here we report on our single center experience of GD (G 900 mg/m² or 675 mg/m² d1+8 and D 100 mg/m² d8) in STS. Patients were retrospectively analysed. Restaging according to RECIST criteria of primary tumor site and metastases was performed every 3 cycles or on clinical progression. Progression-free (PFS) and overall survival (OS) were estimated using the method of Kaplan and Meier. Results: Between 2005 and 2011, 34 STS patients (male=20, female=14, median age 59 years [range 32-75]) were treated with GD at our institution. Histological subtypes comprised leiomyo- (n=13), lipo- (n=7), pleomorphic- (n=6), rhabdomyo- (n=3), synovial sarcoma (n=2), and other subtypes (n=3) with tumor grades being G1 (n=1), G2 (n=9) and G3 (n=24). Primary tumor sites included extremities (n=19), abdomen/retroperitoneum (n=10), trunk (n=3), and others (n=2). Metastases were found in lung (n=26), soft tissue/solid organs (n=12), bone (n=8) and lymph nodes (n=5). Patients had received no (n=2), 1 (n=22), 2 (n=9) or 3 (n=1) previous lines of CTX. A total number of 158 cycles was administered with a median number of 6 cycles (range 1-6) per patient. Best response by RECIST criteria after 3 cycles of treatment was PR (n=2, 6%). Disease stabilisation (SD) was achieved in further 22 subjects, resulting in a clinical benefit rate (CBR) of 70%. Median PFS and OS for the whole population were 7.7 and 15.3 months, respectively. PFS at 6 months was 62%. Patients responding to therapy had a significantly longer median PFS with 8.6 months (p <0.0001; HR 33.1) and OS with 22.5 months (p<0.0001; HR 20.2). Major toxicities included hand-foot syndrome (n=10), febrile neutropenia (n=7), mucositis (n=7), oedema (n=5), hematological toxicity (n=4) and polyneuropathy (n=3), leading to dose reductions in 10 patients. Conclusions: GD is an active regimen in STS with tolerable side effects. CBR was 70% after 3 cycles. Patients achieving at least SD had a significantly prolonged PFS and OS.
Delay in diagnosis and treatment of soft tissue sarcomas (STS): Causes of late intervention and their role in prognosis—A prospective, multidisciplinary group study.
Authors: Comandone Alessandro , Berno Elisa , Boglione Antonella , Oliva Cristiano , Ingui' Manuela , Linari Alessandra , Giubellino Elena , Gino Giancarlo , Brach del Prever Elena Maria , Faletti Carlo , Piana Raimondo , Turbiglio Marco , Monasterolo Gabriella , Pochettino Paolo , Dal Canton Orietta , Chiado' Cutin Simona , Bergnolo Paola
Published: March 2020

10055

Background: STS are 1% of malignant tumors in adults. Rarity, heterogeneity in presentation, low expertise in primary care physicians (PCP) or in general hospitals, organisation problems in specialized centers may cause a delay in both diagnosis and treatment. Aim of this study is to acknowledge the barriers to optimal care and the consequences of the delay on prognosis. Methods: Patients with STS of the extremities, trunk, retroperitoneum treated and followed from 1999 to 2011 by the same multidisciplinary group were included. Time and pattern of symptoms onset, anatomic site, tumor volume, patients’ age, gender and home, interval between diagnosis and surgical treatment or neoadjuvant chemotherapy; time to start adjuvant RT or CT were considered in a univariate - multivariate analysis. Results: 449 adult patient (53% F, 47% M, median age 55 years) were followed for a median time of 116.38 months. 65.7% of STS were at the extremities, 17.6% retroperitoneal, 16.7% at the trunk wall. Median volume at diagnosis was 8 cm for trunk and extremities; 15 cm for retroperitoneum. Commonest histologies: liposarcoma. 18.2%; leiomyo 16.8%; mixofibro 13.6%. Increasing mass, pain, and abdominal disconfort were the main revealing signs of diseases. Median time of delay were: from onset of symptom to first medical visit 68 days for trunk and extremities, 82 for retroperitoneum; 104 days from symptoms to histological diagnosis; 129 days from symptoms to start of therapy. Time to surgery after definitive diagnosis was 12 days in extremities and 21 in abdomen. Adjuvant CT started 22 days after surgery for extremities, 25 in trunk, 35 in retroperitoneum. RT initiated after 78 days. Longer delay in treatment lead to worse prognosis: MS 89.95 months if delay was > 3 months; 190.40 months if wait was < 3 months (p 0.007). Conclusions: Low self consciousness of the patient; misdiagnosis or inadequate approach in general hospitals; late referral to specialized centres are 75% of the cause of wasted time. Organization problems at the referral Centre concur for 25% of delay. Guidelines implementation and educational programme among general population and PCP are necessary.
Preclinical study of trabectedin (TR) and poly(ADP-ribose)polymerase 1 (PARP-1) inhibitor combination in soft tissue sarcoma (STS).
Authors: Pignochino Ymera , Capozzi Federica , Dell' Aglio Carmine , Basiricò Marco , Tarraran Loredana , D'Ambrosio Lorenzo , Galizia Danilo , Palesandro Erica , Gammaitoni Loretta , Sangiolo Dario , Benassi Maria Serena , Aglietta Massimo , Grignani Giovanni
Published: March 2020

10066

Background: TR is an alkylating agent approved in Europe for the treatment of advanced STS as second/third line therapy. TR binds to the minor groove of DNA and interferes with gene transcription and nucleotide excision repair mechanism, inducing DNA double strand breaks (DSBs), and S/G2 cell cycle arrest. There is a strong clinical interest to increase TR activity combining it with other anti-cancer drugs. PARP-1 inhibitors disable DNA base-excision repair mechanism causing the accumulation of DSBs and look like a reasonable TR partner to be explored. We focused our in vitro studies on the effects of the combination of TR with the PARP-1 inhibitor Olaparib (OL). Methods: We explored the activity of TR-OL combination against a panel of different histotypes of STS cell lines, evaluating cell viability after 72h treatment with escalating doses of TR (0-2 nM), OL (0-20 µM), and their constant combination. Following colony formation, cell cycle, apoptosis (annexin V+/PI+) and DNA damage (phospho-histone H2AX - Ser139) were checked. Results: The TR-OL combination strongly affects STS cell viability, showing synergism (Combination Index < 1, based on Chou–Talalay method) on 8 out of 13 cell lines tested. We observed a strong synergism, as a massive reduction of colony growth (402.91, MES-SA, and DMR-SN-8.4.98 lines) induced by the combination if compared with each single agent (78% vs. ~27% : p<0.05). OL potentiates the S/G2 cell-cycle arrest caused by TR at 48h (Control= 29%, TR= 33.4%, OL= 31.5%, TR-OL= 80.9%), and induces a strong increase of the apoptotic cells at 72h (Control= 17.4%, TR= 28.3%, OL= 33.5%, TR-OL= 56.8%). Furthermore, the TR-OL synergism on DNA damage is confirmed by a significant increase of the DSBs marker (Control= 8.7%, TR= 59.5%, OL= 23.8%, TR-OL= 76.5%). Conclusions: These results validate the biological rationale to combine TR and PARP-1 inhibitors in STS and suggest assessing this drug combination in the clinical setting.
Neoadjuvant chemotherapy for adult soft tissue sarcomas: A phase II trial.
Authors: Aguiar Samuel , Ferreira Fabio Oliveira , Batista Ranyell Spencer Sobreira , Bressan Alexsander Kurowa , Mello Celso Lopes , Lopes Ademar
Published: March 2020

10069

Background: Treatment of soft tissue sarcomas (STS) is characterized by high rates of local control, but poor overall survival because of distant relapses and high rates of wound complications, when preoperative radiation is used. The objective of this study was to test the effectiveness of a protocol with neoadjuvant chemotherapy for STS. Methods: A phase II single-arm prospective trial was carried out. Only adult patients with high grade extremity lesions and tumors deep and larger than 5 cm were included. A total of four cycles of chemotherapy was administered pre-operatively. The chemotherapeutic regimen was: ifosfamide – total of 9.0 g/m2 per cycle, infused in 2 hours from Day 1 to Day 5 (1.8 mg/m2/day). Half of the equivalent dose of mesna was infused 15 min pre-ifosfamide and 4 hours post-ifosfamide. Doxorubicin – total of 60mg/m2 per cycle, was infused in bolus on Day 1. Filgrastima 300 mcg, SC, was administered after the last dose of chemotherapy for 5 days. Radiation was given after surgery. Toxicity was classified by the NIH Toxicity Criteria and response was determined by the RECIST criteria. The others endpoints were the amputation and the wound-related complication rates. Results: Between January, 2005 and May, 2011, 42 patients were included. 21(50%) patients have completed the 4 cycles. Nineteen patients (45.2%) have grade 3 or 4 toxicity, and one (2.3%) death related to treatment had occurred. Between severe complications, febrile neutropenia was the most frequent. By using the RECIST criteria, we observed 10(24.5%) cases of progression, 24(58.5%) cases of stable disease, and 7(17%) partial responses. No complete clinical or radiological response was observed. In the pathological analysis of the surgical specimens, 4(9.7%) cases showed no residual disease (complete pathological response), and a total of 6 (14.6%) showed ≤ 5% of viable residual cells. The amputation rate was 4.8% (2 cases) and complications related to the wound were observed in 9 patients (21.9%). Conclusions: The protocol showed a good rate of objective and pathological response, low rate of complications related to the operative wound, and maintained an acceptable amputation rate. On the other hand, we observed high rate of progression, by RECIST criteria.
Pharmacokinetics of escalated dose of imatinib in patients with advanced gastrointestinal stromal tumors.
Authors: Yoo Changhoon , Ryu Min-Hee , Ryoo Baek-Yeol , Park Inkeun , Beck Mo Youl , Kang Yoon-Koo
Published: March 2020

10085

Background: Although escalated dose (ED, 800 mg daily) of imatinib (IM) is one of important options in resistant gastrointestinal stromal tumors (GIST) on standard dose (SD, 400mg daily), there has been lack of pharmacokinetic data at ED. We therefore explore the potential relationship between IM plasma trough level (Cmin), and clinical outcomes or toxicities in patients treated with ED. Methods: Between 2008 and 2011, steady-state IM Cmin was measured in 66 patients with GIST who received ED of IM using liquid chromatography-tandem mass spectrometry. Percent change from IM Cmin at SD was calculated in 43 patients that both SD and ED IM Cmin were measured. The association with efficacy and toxicity was analyzed with grouping patients into quartiles according to IM Cmin at ED and percent change. Results: Median age was 59 years (range, 36–77) and 40 patients were male. KIT exon 11 and 9 mutation was detected in 32 and 18 patients, respectively. At ED, partial response was achieved in 4 patients (6%) and stable disease was in 32 patients (48%). The median progression-free survival was 4.2 months (95% CI, 1.8-6.6) and overall survival was 38.5 months (95% CI, 7.6-69.3). The mean (± standard deviation) IM Cmin at ED was 3552 (± 1540) ng/mL. IM Cmin was significantly increased after dose escalation (p <0.001), and mean percent change from IM Cmin at SD was 162% (± 100). Body surface area (p=0.01), hemoglobin (p=0.001), and neutrophil count (p=0.006) were significant covariates for IM Cmin at ED in multivariate analysis. The group of quartiles of IM Cmin at ED and percent change was not associated with response and survival outcomes. However, grade 3-4 hematologic or grade 2-4 non-hematologic toxicity was observed in 9% (1/11) of patients in the lowest percent change quartile (Q1, <90%) compared with 56% (18/32) in Q2 to Q4 (p=0.012), although absolute values were not associated with toxicity. Conclusions: In GIST patients treated with ED of IM, IM Cmin was not associated with response and survival. Clinically significant toxicity following dose escalation was correlated with percent change of IM Cmin, rather than absolute values. Monitoring of IM Cmin might help to predict or manage ED of IM induced toxicity.