bluuebunny/crossref_metadata_2025 huggingface dataset:
Long-term efficacy and safety of subcutaneous C1-inhibitor in women with hereditary angioedema: subgroup analysis from an open-label extension of a phase 3 trial
Authors: Levy Donald S. , Farkas Henriette , Riedl Marc A. , Hsu Florence Ida , Brooks Joel P. , Cicardi Marco , Feuersenger Henrike , Pragst Ingo , Reshef Avner
Published: February 2020

Background

Women with hereditary angioedema due to C1-inhibitor deficiency (HAE-C1INH) experience more frequent and severe angioedema attacks compared with men. Fluctuations in female sex hormones can influence HAE attack frequency and severity. Subcutaneous C1-INH (C1-INH [SC]) is indicated as routine prophylaxis to prevent HAE attacks. In this post hoc subgroup analysis, we evaluated the efficacy and safety of C1-INH (SC) in female subjects with HAE-C1INH enrolled in an open-label extension of the pivotal phase III COMPACT trial.

Methods

In this multicenter, randomized, parallel-arm trial, eligible subjects (age ≥ 6 years with ≥ 4 attacks over 2 consecutive months) received C1-INH (SC) 40 IU/kg or 60 IU/kg twice weekly for 52 to 140 weeks. Analyses of efficacy endpoints were performed for all female subjects and those of childbearing age (age ≥ 15 to ≤ 45 years), including subjects who became pregnant during the evaluation period.

Results

Overall, 91% (69/76) of female subjects were classified as responders (≥ 50% reduction in HAE attacks relative to the pre-study period); 82% experienced < 1 attack/4 weeks. The median number of attacks/month was 0.10, with 96% median reduction in attacks relative to the pre-study period. Results were similar in the subgroup of subjects of childbearing age. Four women who became pregnant during the trial and were exposed to C1-INH (SC) during the first trimester delivered healthy babies with no congenital abnormalities.

Conclusions

C1-INH (SC) prophylaxis was safe and effective in women with HAE-C1INH, including those of childbearing age. Four women exposed to C1-INH (SC) during the first trimester had uneventful pregnancies and delivered healthy babies.

Trial registration Clinicaltrials.gov identifier NCT02316353 (Registered December 10, 2014); https://clinicaltrials.gov/ct2/show/NCT02316353.
Stancu type q-Bernstein operators with shifted knots
Authors: Mursaleen M. , Qasim Mohd , Khan Asif , Abbas Zaheer
Published: February 2020

In the present paper, Stancu type generalizations of theq-analog of Lupaş Bernstein operators with shifted knots are introduced. Some approximation results and rate of convergence for these operators are investigated. A Voronovskaja type theorem and local approximation results for the mentioned operators are studied. The extra parametersγ,δ,q,aandbprovide more flexibility for approximation.
Recent advances in control technologies for non-point source pollution with nitrogen and phosphorous from agricultural runoff: current practices and future prospects
Authors: Xia Yinfeng , Zhang Ming , Tsang Daniel C. W. , Geng Nan , Lu Debao , Zhu Lifang , Igalavithana Avanthi Deshani , Dissanayake Pavani Dulanja , Rinklebe Jörg , Yang Xiao , Ok Yong Sik
Published: February 2020

Eutrophication of natural water is a universal problem. Nitrogen (N) and phosphorus (P) from agricultural runoff are the main sources of nutrient input, provided that emissions from industrial point sources (IPS) are under control. Therefore, it is of great environmental importance to reduce pollution associated with agricultural runoff as a means of regulating eutrophication levels in natural water. Numerous methods proposed for treating agricultural runoff can be classified into three categories: source control, process control, and end treatment. In this review, major technologies for N and P control from agricultural runoff are summarized along with discussion of newly proposed technologies such as biochar biomimetics and microbial catalyst. Because agricultural runoff (from farmlands to receiving waters) is a complicated pollution process, it is difficult to regulate the nutrients discharged via such process. This review will thus offer a comprehensive understanding on the overall process of agricultural runoff and eutrophication to help establish control strategies against highly complicated agricultural non-point sources.
Identification of pAKT as a pharmacodynamic marker for MER kinase in human melanoma G361 cells
Authors: Chen Yaoyu , Favata Margaret , Pusey Michelle , Li Jun , Lo Yvonne , Ye Min , Wynn Richard , Wang Xiaozhao , Yao Wenqing , Chen Yingnan
Published: February 2020

Background

The MER signaling pathway represents an attractive therapeutic target for human cancers. Growth arrest–specific protein 6 (GAS6)–induced MER phosphorylation is often unstable and difficult to detect without pervanadate pretreatment in human cancer cells, posing a challenge for the development of selective MER kinase inhibitors. Here, we identified phosphorylated AKT (pAKT) as a specific pharmacodynamic marker for MER kinase inhibitors in human melanoma G361 cells.

Methods

The expression of MER, TYRO3, and AXL were profiled among multiple human cancer cells. To determine whether they play a role in the activation of pAKT, MER and TYRO3 were selectively depleted by small, interfering RNA knockdown. In addition, using AKT phosphorylation as a readout, a high-throughput cell-based assay was established in G361 cells for evaluation of the potency of potential inhibitors of MER pathway activation.

Results

We demonstrated that high levels of MER and TYRO3, but not AXL, were expressed in G361 cells. In these cells, pAKT was induced by GAS6 treatment, which could be reversed by AXL/MER inhibitors. We showed that GAS6-induced pAKT is only dependent on MER kinase, but not TYRO3, in G361 cells. Furthermore, we observed a correlation in potency between inhibition of pAKT in G361 cells and pMER in MER-overexpressing Ba/F3 cells by these inhibitors.

Conclusions

In summary, we have demonstrated that GAS6-induced pAKT is a possible pharmacodynamic marker for the inhibition of MER kinase, and we have successfully developed a cell-based functional assay for screening small-molecule inhibitors of MER kinase for potential therapeutic utility in treating GAS6/MER-deregulated human cancers.
Characterization of structural failures founded on soils in Panyam and some parts of Mangu, Central Nigeria
Authors: Igwe Ogbonnaya , Umbugadu Allu Augustine
Published: February 2020

Structural failure of buildings, roads, and other infrastructures has led to the loss of lives and monumental damage to the economy. In developing countries such as Nigeria, the failures are always attributed to the nature/type of soils in the area without considering other factors. With the increase in civil engineering constructions and the scramble for a limited portion of competent soils for such constructions, land, therefore, is becoming man’s most priced commodity for agriculture, residential and industrial purposes. No works of such have been done in the area, it is, therefore, imperative to study the cause(s) to prevent further loss of lives and the negative effects of such on the economy. The study was carried out at Panyam and some surrounding localities on latitudes N9021′ and N9026′ and longitudes 9011′E and 9016′E an area of 72 km2. A total of forty samples were collected out of which twenty were selected for swelling potentials determination due to their cohesive nature within the 1.5 m depth. To characterize the swelling of the soils, inferential testing methods; direct method comprising Liquid Limit and Plasticity Index with values ranging from 30% – 70% and 10% – 27% respectively, and the indirect method (Free Swell Index, FSI) whose values range from 9.1% – 90% were used. Most of the soils analyzed based on the geotechnical standards were categorized relatively safe for civil infrastructure. Structural studies employed the direct measurements of surface structures to get the orientations of structures measured. Landsat image and Total Magnetic Intensity (TMI) map of the area was acquired from the Nigerian Geological Survey Agency (NGSA) for subsurface structural analysis. The RTP-TMI (reduce to pole) grid data of the area were processed to improve magnetic anomalies associated with edges of surface/near-surface geological structures using the MAGMAP two-dimensional fast fourier transform (2D-FFT) filters package in Oasis Montaj v7.2 software. Geophysical studies using aeromagnetic data at a near-surface depth of 40 m and fractures measured on the surface both revealed a major trend in the NNE – SSW. It was observed that structures constructed across the major trend suffered little to moderate damage while those constructed along the major fractures trend suffered severe damage. It was concluded that both soils and fractures played individual roles in the collapse of infrastructure in the area.
Study of the anti-inflammatory effect of the combined extract BNO 1016 in a leukotriene-dependent in vivo inflammation model
Authors: Zupanets Igor A. , Shebeko Sergii K. , Popovych Vasyl I. , Zimin Stanislav M.
Published: February 2020

A significant role in the pathogenesis of rhinosinusitis is played by an inflammatory reaction in the maxillary sinuses of the nasal cavity. Leukotrienes are the most powerful mediators of inflammation, especially at the early stages. The effect of combined dry extract BNO 1016 could be useful for the inhibition of the inflammation in rhinosinusitis. Thus, it appears reasonable to study the anti-inflammatory activity of the combined dry extract BNO 1016.

Materials and methods

The tested drug is the combined dry extract BNO 1016 produced by “Bionorica SE”. The reference drug is Ibuprofen. Leukotriene inflammation was induced by subplantar injection of zymozan into the right hind paw of male and female Wistar rats. Volumes of the resulting edema were measured and levels of anti-inflammatory activity together with mean effective dose (ED50) were calculated.

Results

The highest anti-inflammatory activity was observed at a dose level of 500 mg/kg of BNO 1016 during all time-points of the experiment and reached 65.2% 2 h after induction of inflammation. The anti-inflammatory activity of BNO 1016 at 500 mg/kg was credibly higher than that of Ibuprofen at all time-points of the experiment. Based on the data obtained from this leukotriene-dependent inflammation experiment the mean effective dose (ED50) for anti-inflammatory activity of dry combined extract BNO 1016 was calculated with help of Probit analysis.

Conclusion

The combined dry extract BNO 1016 shows a high level of anti-inflammatory activity in leukotriene-dependent inflammation which is very promising for the improvement of the treatment of patients. However, additional preclinical and clinical research on this drug should be carried out.
Biomaterials in orthopaedics: the past and future with immune modulation
Authors: Im Gun-Il
Published: February 2020

Abstracts

Orthopaedics owes its current status of advanced care to the development of biomaterial science more than any other clinical medical specialty. The purpose of this brief review is to introduce the history and present status of biomaterials in orthopaedic field and cast a perspective on the future use of biomaterials to treat musculoskeletal disorders with particular emphasis on immune modulation. While the biomaterials in orthopaedics started from inert materials to replace the function and structure of hard tissue such as bone and cartilage, regenerative medicine will play a greater role in preventing the traumatic loss of tissues, as well as in the earlier stages of diseases. The understanding and modulation of immune response to biomaterials will further lead to the better incorporation of implants into host tissue or the near-perfect regeneration of host tissue.
Comparison between Erigo tilt-table exercise and conventional physiotherapy exercises in acute stroke patients: a randomized trial
Authors: Kumar Suraj , Yadav Ramakant , Aafreen
Published: February 2020

Background

Stroke is a common, serious, and disabling health-care problem throughout the world. Although great advances have been made in acute stroke management, the most of post-stroke care to reduce a patient’s dependency relies on rehabilitation.

Purpose

To compare the effectiveness of exercises using an Erigo tilt-table and conventional physiotherapy in the rehabilitation of acute stroke patients.

Methods

A total of 110 acute stroke patients (age 51.08 ± 7.48 years, 8.69 ± 4.62 days after stroke) were assigned randomly into two groups, 55 in each for 30 days of conventional physiotherapy (Group A) or Erigo tilt-table (Group B) rehabilitation. The National Institutes of Health Stroke Scale (NIHSS), Mini-Mental Scale Examination (MMSE), Modified Ashworth Scale were used to measure muscle tone, quality of life (QOL) and muscle strength (MMT), Affected upper (UE) and lower limb (LE) outcomes were assessed at baseline (day 0), after day 30 of the intervention and on 90th day of follow up. Repeated measures ANOVA followed by a Bonferroni post-hoc test and independent Student’s t-test were used for statistical analysis to evaluate the improvement in outcome variables within and between the groups.

Results

Both the treatments were effective. Notably, Group B patients showed a significant improvement in both QOL (p < 0.001) and lower limb strength (p = 0.030) at day 90 and muscle tone (p = 0.011) at day 30 compared to Group A.

Conclusion

Both the groups improved with time but the Erigo tilt-table group experienced greater improvement in QOL, NIHSS and muscle strength of the lower limb. Thus, Erigo tilt-table can be used for early rehabilitation of acute hemiplegic patients and improving their quality of life and motor system, resulting in better functional performances.
Coagulation assessment with thromboelastography during abdominal endovascular aneurysm repair in a patient with hemophilia A
Authors: Sato Kazuki , Katori Nobuyuki , Suga Yoshifumi , Kiyama Shuya , Uezono Shoichi
Published: February 2020

Background

As both APTT and APTT-based coagulation method cannot distinguish heparin effect from intrinsic coagulation factor deficiency, we implemented thromboelastography (TEG) for the coagulation assessment in a patient with hemophilia A undergoing an endovascular surgery with heparinization.

Case presentation

A 68-year-old male with hemophilia A underwent endovascular aortic repair for abdominal aortic aneurism. TEG results showed recovery of coagulation time (R) in both kaolin assay (CK) and kaolin-heparinase assay (CKH) after factor VIII replacement before heparinization. Against our expectations, R-CKH was slightly prolonged (9.0 min) during heparinization. After the administration of protamine sulfate, R in both assays showed similar values within the normal ranges.

Conclusions

The combination of CK and CKH assays could be useful to estimate factor VIII (FVIII) level when heparin concentration is low or without heparin; however, caution should be necessary for estimation of FVIII level by TEG under the effect of medium- or high-dose heparin.
Ultrasound-guided interventions with augmented reality in situ visualisation: a proof-of-mechanism phantom study
Authors: Farshad-Amacker Nadja A. , Bay Till , Rosskopf Andrea B. , Spirig José M. , Wanivenhaus Florian , Pfirrmann Christian W. A. , Farshad Mazda
Published: February 2020

Background

Ultrasound (US) images are currently displayed on monitors, and their understanding needs good orientation skills. Direct overlay of US images onto the according anatomy is possible with augmented reality (AR) technologies. Our purpose was to explore the performance of US-guided needle placement with and without AR in situ US viewing.

Methods

Three untrained operators and two experienced radiologists performed 200 US-guided punctures: 100 with and 100 without AR in situ US. The punctures were performed in two different phantoms, a leg phantom with soft tissue lesions and a vessel phantom. Time to puncture and number of needle passes were recorded for each puncture. Data are reported as median [range] according to their non-normal distribution.

Results

AR in situ US resulted in reduced time (median [range], 13 s [3–101] versus 14 s [3–220]) and number of needle passes (median [range], 1 [1–4] versus 1 [1–8]) compared to the conventional technique. The initial gap in performance of untrained versus experienced operators with the conventional US (time, 21.5 s [3–220] versus 10.5 s [3–94] and needle passes 1 [1–8] versus 1 [1, 2]) was reduced to 12.5 s [3–101] versus 13 s [3–100] and 1 [1–4] versus 1 [1–4] when using AR in situ US, respectively.

Conclusion

AR in situ US could be a potential breakthrough in US applications by simplifying operator’s spatial orientation and reducing experience-based differences in performance of US-guided interventions. Further studies are needed to confirm these preliminary phantom results.
Are apprenticeships business cycle proof?
Authors: Lüthi Samuel , Wolter Stefan C.
Published: February 2020

Although there is evidence that apprenticeship training can ease the transition of youth into the labour market and thereby alleviate youth unemployment, many policymakers fear that firms will reduce the number of apprenticeship positions during economic crises, thus exacerbating the problem of youth unemployment. Using recent panel data of Swiss cantons and dynamic regression models, we examine the relationship between newly created apprenticeships and the business cycle. The empirical results suggest that economic shocks induce a pro-cyclical, moderate response in the apprenticeship market, both immediately and in subsequent years.
Restricting lepidopteran herbivory through trap cropping and bird perches in Egyptian clover (Trifolium alexandrinum L.)
Authors: Kumar Ravinder , Cheema Harpreet Kaur
Published: February 2020

The Egyptian clover L. is a winter season leguminous forage that supports a great diversity of insect pest populations in the Northern Indian Plains. In the context of evolving non-chemical approach for pest control, different trap crops viz. marigold,Tagetes erecta: chickpea,Cicer arietinumL.; and sunflower,Helianthus annuus, were planted as border rows around the clover plots to trap lepidopteran larvae. The push and pull strategy was further augmented by the help of neem seed kernel extract (NSKE) 3% spray on the main crop. Services of insectivorous birds were utilized through T-shaped bird perches for feeding on lepidopteran larvae. The lowest larval population ofHelicoverpa armigera(2.29 individuals/m row length) was recorded in the plots with the trap crops such as marigold and bird perches, and those that received neem insecticidal sprays which indicated the decrease of larval population due to the repellant action of neem gave (75.8%) a reduction in larval population than the sole cropped plots, followed by chickpea (2.58 larvae; 72.8%) reduction in larval population and sunflower (3.53 larvae; 63%). Sunflower recorded the highest number ofH.armigerapopulation, at flowering stage of berseem which depicted the suitability of sunflower for the attractiveness of low number of the larvae (2.75 larvae/m row length) on berseem. The plots with berseem as a sole crop without any control measure exhibited significantly highH.armigeralarvae (12.95 larvae per meter row length). The fecundity of pod borer on different trap crops revealed the highest fecundity population (7.25 larvae) ofHelicoverpaon either chickpea or sunflower as trap crops. During the vegetative phase of berseem and the flowering stage of marigold and sunflower, these were recorded as favorable hosts. The highest green fodder yield (GFY; 1115 q/ha) was recorded in plots sown with marigold as the trap crop and with bird perches and in plots that received NSKE sprays as compared to sole cropped plots (700 q/ha). The data on seed yield also revealed superiority of berseem plots with sunflower, as a trap crop, and also a high parasitization by parasitoids.
Effect of autologous platelet-rich plasma transfusion in the treatment of infertile women with thin endometrium and its implications in IVF cycles: a literature review
Authors: Samy Ahmed , Abbas Ahmed M. , Elmoursi Ahmed , Elsayed Mohamed , Hussein Reda S.
Published: February 2020

Background

Thin endometrium could be a major contributing factor in decreasing pregnancy rates with in-vitro fertilization. Several treatments have been studied in patients with thin endometrium, like hormonal therapy by GnRH-agonist and estrogen. Additionally, vasoactive measures like aspirin, a mix of pentoxifylline, vitamin E, l-arginine, sildenafil, and intrauterine infusion of a growth factor such as G-CSF, and the recent application of regenerative medicine were reported in previous trials.

Main body of the abstract

We discuss here a new modality for thin endometrium treatment using platelet-rich plasma (PRP) administered as an intrauterine infusion. The purpose of this review is to evaluate the effectiveness of PRP in cases of infertility. All relevant articles addressing the use of PRP, published from January 2000 to September 2018, were reviewed and analyzed. The studies published on the PRP treatment model for thin endometrium in the gynecology field were mainly case series, pilot studies, or case reports.

Conclusion

In the current review, we found that the local administration of PRP is significantly effective in increasing pregnancy rates of infertile women with thin endometrium < 6 mm.
The value of CESM in the evaluation of intraductal breast papilloma: a comparative study with DCE-MRI
Authors: Hegazy Rania , Adel Lamia , Yasin Rabab
Published: February 2020

Background

The purpose of this study was to assess the accuracy of contrast-enhanced spectral mammography (CESM) as compared to dynamic contrast-enhanced MRI (DCE-MRI) in the evaluation of intraductal breast papilloma with histopathological correlation. This study is a retrospective study done on 45 consecutive patients. Their ages ranged between 36 and 70 years with a mean age of 51.1 ± 8.7. All of them were suspected to have intraductal papilloma on full-field digital mammography (FFDM), 3D automated breast ultrasound (3D-ABUS), and 2D handheld ultrasound (2DHHUS). CESM and DCE-MRI were done for all patients. The data were collected, tabulated, statistically analyzed using an IBM personal computer with Statistical Package of Social Science (SPSS).

Results

There were 37 histopathology proven papillomas either by US-guided core needle biopsy, surgical biopsy following wire localization or fine-needle aspiration cytology (FNAC). Lesions are divided into three subgroups according to size. When the size of lesion > 10 mm MRI sensitivity and specificity is 100% and 66.7%, that of CESM is 90.1% and 0% respectively. In lesions sized 5–10 mm Sensitivity and specificity of MRI is 100% and 58% respectively and those of CESM are 63.6% and 50% respectively. Lesions less than 5mm MRI sensitivity and specificity is 100% and 0%, that of CESM was 0% and 100% respectively.

Conclusion

DCE-MRI has a significantly higher sensitivity than CESM for the diagnosis of intraductal papilloma whatever the size of the lesion, especially when the size is less than 5 mm.
The value of dynamic contrast-enhanced MRI in the diagnosis and management of triple-negative breast cancer
Authors: Azzam Heba , Kamal Rasha , El-Assaly Hany , Omer Liza
Published: February 2020

Background

Breast cancer is undoubtedly the world’s most frequent cancer among women. Triple-negative breast cancer (TNBC) is a subtype of breast cancer that does not express estrogen, progesterone, or human epidermal growth factor receptors, yet its imaging is considered a challenge to radiologists having imprecise features.

In this study, we aimed at defining the MRI characteristics of triple-negative breast cancer to validate its impact on management.

Results

Most of the TNBCs in this study showed malignant pattern kinetic curves (types II and III), 87/104 (83.7%), and P value 0.673 (not significant), and regarding the type of lesion enhancement, 104/172 cases (60.5%) showed mass enhancement compared to 52/172 (30.2%) non-mass enhancement and 16/172 (9.3%) focus enhancement, P value 0.185 (not significant). As for the internal enhancement pattern of mass lesions, rim internal enhancement was predominant in TNBC mass lesions, 48/104 (46.2%), as well as intratumoral bright signal intensity on T2-weighted images, 108/172 (62.8%), P value 0.001 (highly significant).

Conclusion

Triple-negative breast cancers (TNBC) are larger, better defined, and more necrotic than conventional cancers. On MRI, necrosis yields high T2-weighted signal intensity.
Role of dexmedetomidine infusion after coronary artery bypass grafting
Authors: Hamouda Tamer , Ismail Mohamed , Ibrahim Tamer Hamed , Ewila Hesham , Elmahrouk Ahmed
Published: February 2020

Background

Postoperative pain has negative consequences on patients’ outcomes after cardiac surgery. Routine management with opioid and or non-steroidal anti-inflammatory medications has several disadvantages. Dexmedetomidine is a selective α2 agonist used for sedation and analgesia. The use of dexmedetomidine for postoperative pain management and decreasing delirium and agitation in cardiac surgery patients is a matter of debate. Our objective was to determine the role of an early administration of dexmedetomidine in decreasing opioid use post-cardiac surgery and its effects on the quality of postoperative recovery.

Results

Medical records of 120 patients admitted to the cardiac surgery intensive care unit (CSICU) after coronary artery bypass grafting (CABG) in two cardiac centers between December 2015 and December 2016 were reviewed. Patients were divided into two groups. Group A included 55 patients who received dexmedetomidine in a dose of 0.2–0.4 mcg/kg/h on admission to CSICU, and group B included 65 patients who did not receive dexmedetomidine. The primary outcome was the pain score immediately after extubation, and the secondary outcomes included post-extubation sedation and pain scores for 12 h.

There were significant decrease of the pain scores in dexmedetomidine group that continues through the 3rd, 6th, 8th, and 12th hour readings after surgery with mean modified Ramsay scores 0.1 ± 0.0, 0.89 ± 2.05, 0.35 ± 0.1, and 0.12 ± 1.1 respectively compared to 0.46 ± 1.15, 3.46 ± 2.93, 0.98 ± 1.90, and 0.12 ± 1.1 in group B (p < 0.001), significant decrease in cumulative morphine received (p < 0.001, OR = 909, 95% CI 0.05–0.19), favorable reduction in heart rate in dexmedetomidine group (80 ± 1.9 b/min) compared to 96 ± 8.8 b/min in the other group (p = 0.017), and smoother recovery from general anesthesia.

Conclusion

Administration of dexmedetomidine in the early postoperative period can be safe. It may reduce the use of opioids, has sedative, analgesic, and sympatholytic effects that could play a useful role during the management of coronary artery bypass patients, and may improve postoperative recovery.
Correction to: Synthesis and biological evaluation of some 4-aminoquinoline derivatives as potential antitubercular agents
Authors: Alegaon Shankar , Kashniyal Kamlesh , Kuncolienkar Sanket , Kavalapure Rohini , Salve Preeti , Palled Mahesh , Suryawanshi Shailendra , Jalalpure Sunil
Published: February 2020

Following publication of the original article [1], the authors reported an error in one of the authors’ names.
Scoop: Multicenter phase I/II trial of BBI608 and pembrolizumab in patients with metastatic colorectal cancer (EPOC1503).
Authors: Hara Hiroki , Kawazoe Akihito , Kuboki Yasutoshi , Komatsu Yoshito , Nishina Tomohiro , Shinozaki Eiji , Yuki Satoshi , Takahashi Koji , Mikamoto Yuichi , Hirano Nami , Nomura Shogo , Togashi Yosuke , Nishikawa Hiroyoshi , Sato Akihiro , Ohtsu Atsushi , Yoshino Takayuki
Published: February 2020

107

Background: The anti–PD-1 antibody pembrolizumab (P) provides response rates of 28-57% in patients (pts) with MSI-H metastatic colorectal cancer (mCRC) vs 0% in those with non-MSI-H cancers. STAT3 has been previously reported as a potential key driver of immune evasion. This study investigates efficacy and safety for the combination of BBI608 (napabucasin), which blocks phosphorylated STAT3 and downregulates IDO1 and PD-L1, with P, in pts with mCRC. BBI608 480 mg BID with P was determined as the recommended phase II dose in phase I. Methods: Phase II included Cohorts A (MSI-H) and B (non-MSI-H). Pts with mCRC not responding to or intolerant of standard chemotherapies were enrolled. The primary endpoint was immune-related objective response rate (irORR), according to irRECIST. The sample size for Cohort A (10 pts) was derived in an exploratory manner. In Cohort B, assuming null and alternative hypotheses of irORR = 5% and 20% led to an estimated required sample size of 40 pts, with a 1-sided alpha of 5% and power of 90%. Genomic profiles and the consensus molecular subtypes (CMS) of colorectal cancer were determined by whole exome sequencing and RNA sequencing as previously described. Results: From Feb/2017 to Jun/2018, 10 pts were enrolled in Cohort A and 40 in Cohort B. The irORR was 50% (5 of 10 pts) in Cohort A and 10% (95% CI 2.8 to 23.7) (4 of 40 pts) in Cohort B. Of evaluable 19 pts for CMS classification in Cohort B, CMS1, CMS2, CMS3, and CMS4 were detected in 3, 6, 4, and 6 cases, respectively. The irORR was 33% (1 of 3 pts), 0% (0 of 6 pts), 25% (1 of 4 pts), 33% (2 of 6 pts) in CMS1, CMS2, CMS3, and CMS4, respectively. One CMS3 patient with partial response had POLE mutation, while 1 CMS1 and 2 CMS4 pts with partial response did not. The most common grade 3 or higher treatment-related adverse events included fever (10%) in Cohort A, and diarrhea (5%) and appetite loss (7.5%) in Cohort B, without unexpected safety signals. No treatment-related deaths occurred. Conclusions: BBI608 with P showed encouraging anti-tumor activity with acceptable toxicity for non-MSI-H mCRC pts as well as MSI-H mCRC pts. Impact of CMS on the efficacies of this combination warrants further investigation in the additional cohort of this study. Clinical trial information: NCT02851004.
Nivolumab plus low-dose ipilimumab as first-line therapy in microsatellite instability-high/DNA mismatch repair deficient metastatic colorectal cancer: Clinical update.
Authors: Lenz Heinz-Josef , Lonardi Sara , Zagonel Vittorina , Van Cutsem Eric , Limon M. Luisa , Wong Ka Yeung Mark , Hendlisz Alain , Aglietta Massimo , Garcia-Alfonso Pilar , Neyns Bart , Spallanzani Andrea , Cardin Dana Backlund , Dragovich Tomislav , Shah Usman , Atasoy Ajlan , Ledeine Jean-Marie , Overman Michael J.
Published: February 2020

11

Background: In the phase 2 CheckMate 142 trial, nivolumab plus low-dose ipilimumab provided robust and durable clinical benefit and was well tolerated as first-line therapy for microsatellite instability-high/DNA mismatch repair deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC) (Lenz et al. Ann Oncol 2018;29:LBA18). Longer follow-up data will be presented. Methods: Patients with MSI-H/dMMR mCRC and no prior treatment for metastatic disease received nivolumab 3 mg/kg every 2 weeks plus low-dose ipilimumab 1 mg/kg every 6 weeks until disease progression or discontinuation. The primary endpoint was investigator-assessed objective response rate (ORR). Results: For all 45 patients (median follow-up was 13.8 months), ORR was 60% (95% CI 44.3–74.3). Responses were consistent with the overall population across subgroups including age, Eastern Cooperative Oncology Group (ECOG) performance status, prior adjuvant/neoadjuvant therapy, and mutation status (Table). Seven patients (16%) had grade 3–4 treatment-related adverse events; 3 (7%) had any grade treatment-related adverse events leading to discontinuation. Updated response, survival, and safety data after a longer follow-up (median 19.9 months) will be presented. Conclusions: Nivolumab plus low-dose ipilimumab demonstrated robust and durable clinical benefit and was well tolerated. Evaluated subgroups had responses consistent with the overall population. Nivolumab plus low-dose ipilimumab may represent a new first-line treatment option for patients with MSI-H/dMMR mCRC. Clinical trial information: NCT02060188.

[Table: see text]
A phase Ib/II study of the anti-CD47 antibody magrolimab with cetuximab in solid tumor and colorectal cancer patients.
Authors: Fisher George A. , Lakhani Nehal J. , Eng Cathy , Hecht J. Randolph , Bendell Johanna C. , Philip Philip Agop , O'Dwyer Peter J. , Johnson Benny , Kardosh Adel , Ippolito Tina M , Wang Yan V. , Agoram Balaji , Volkmer Jens-Peter , Maute Roy , Chico Isagani , Chao Mark , Takimoto Chris H.M. , Patnaik Amita
Published: February 2020

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Background: Magrolimab (M, Hu5F9-G4) is an antibody targeting CD47, a macrophage “don’t eat me” signal that demonstrates preclinical synergy with cetuximab (C) in refractory KRAS wild type (KRASwt) and KRAS mutant (KRASm) colorectal (CRC) tumors. Methods: Phase (Ph) 1 doses of M+C were escalated in solid tumor patients (pts) and Ph 2 efficacy was explored in previously treated KRASwt and KRASm CRC patients. Day 1 priming with 1 mg/kg of M was used to mitigate on-target anemia followed by maintenance doses ranging from 10 to 45 mg/kg in combination with C. Ph 2 pts were treated with 30 or 45 mg/kg of M and 400/250 mg/m2 of C. Results: In 78 treated pts (32 Ph 1 and 46 Ph 2), the median age was 59 years (range 19-82), and median prior therapies was 5 (range 1-14). No maximum tolerated dose was reached. Treatment-related adverse events (TRAEs) of any Grade (G) included dermatitis acneiform 36%, dry skin 33%, fatigue 32%, infusion reactions 31%, headache 30%, diarrhea 23%, nausea 23%, chills 23%, and anemia 22%. There were no fatal TRAEs and 3/78 (4%) discontinued M treatment due to any adverse events. In the combined Ph 1+2 study, 2 of 30 evaluable KRASwt CRC pts had confirmed PRs for 7.0 and 12.5 months (mo), for a 6.7% objective response rate (ORR). Both had prior C treatment. The median progression-free survival (mPFS) and median overall survival (mOS) was 3.6 mo (95%CI 1.8-5.4) and 10.1 mo (95%CI: 6.9-14.4), respectively. In 40 evaluable KRASm pts, there were no responses but 45% had stable disease (SD) and the mPFS and mOS were 1.9 mo (95%CI: 1.8-3.5) and 10.4 mo (95%CI: 5.7-16.4), respectively. In 28 KRASm pts who were TAS102/regorafenib naïve, preliminary mOS was 12.4 mo (95%CI: 5.9-not reached) which is longer than that reported for historical controls. Tumor biopsies showed treatment-related increases in macrophage immune cell infiltrates in SD pts, and baseline T cell infiltration was associated with longer OS. Pharmacokinetic profiles will be presented. Conclusions: M+C is a novel, well-tolerated combination immunotherapeutic treatment regimen. Responses were observed in two previously treated CRC pts and survival is encouraging in KRASm pts. Funded by Forty Seven and California Institute for Regenerative Medicine. Clinical trial information: NCT02953782.
Optimizing FOLFIRINOX tolerability in patients with colorectal cancer through dosing irinotecan in the morning for men and in the afternoon for women.
Authors: Levi Francis , Ballesta Annabelle , Karaboué Abdoulaye , Huang Qi , Focan C. N. J. , Chollet Philippe , Bouchahda Mohamed , Adam Rene , Garufi Carlo , Innominato Pasquale
Published: February 2020

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Background: Irinotecan (IRI) toxicity was worse in female (F) than in male (M) patients (pts) on FOLFIRI for metastatic colorectal cancer (MCC). This finding could reflect different optimal administration timing of IRI in M and F pts along the 24 hours. IRI pharmacology is regulated by the circadian clock, and its least toxic daily time (LTT) occurred ~6 hours later in F as compared to M mice. The relevance of sex for the LTT of IRI is addressed here using data from an international randomized trial, whose primary endpoint was not met for all the 193 pts with MCC (EORTC 05011). Methods: 130 M and 63 F were randomized to receive chronomodulated IRI (180 mg/m2 over 6-h, with peak delivery in the morning (at 5:00 or 9:00), in the afternoon (at 13:00 or 17:00) or at night (at 21:00 or 01:00) on day (d) 1, followed by fixed-time chronomodulated oxaliplatin-5-fluorouracil-leucovorin for 4 d. Triplet combination was given q3 weeks as 1st or 2nd line, without prophylactic G-CSF. The relevance of IRI timing for main toxicities was determined separately in M and F, using Cosinor and Fisher Exact tests. Results: Baseline characteristics of M or F pts did not differ significantly according to IRI timing group. Main worse grade 3-4 toxicities per pt after 6 courses were diarrhea (M, 40.2%; F, 51.9%) neutropenia (M, 12.6%; F, 18.4%), fatigue (M, 13.4%; F, 17.3%) and anorexia (M, 8.2%; F, 9.6%). These toxicities were reduced following IRI delivery in the morning for M, but in the afternoon for F, with statistically significant rhythms (p < 0.05 from cosinor) and sex*timing interactions (Fischer Exact, diarrhea, p = 0.023; neutropenia, p = 0.015; fatigue, p = 0.062; anorexia, p = 0.032). IRI timing was most critical for F, with Grade 3-4 toxicities ranging from 55.2% of the pts (morning) to 29.4% (afternoon) for diarrhea, and from 25.9% (morning) to 0% (afternoon) for neutropenia. IRI timing did not significantly influence efficacy. Conclusions: The present study results supports the administration of irinotecan in the morning for M and in the afternoon for F in order to minimize adverse events of triplet chemotherapy without impairing efficacy. Prospective trials testing sex specific timing issues are warranted. Clinical trial information: 05011.
Negative impact of cachexia during chemotherapy on survival as first-line chemotherapy for metastatic colorectal cancer.
Authors: Nozawa Kazuki , Masuishi Toshiki , Kumanishi Ryosuke , Nakazawa Taiko , Ogata Takatsugu , Matsubara Yuki , Kato Kyoko , Narita Yukiya , Honda Kazunori , Bando Hideaki , Kadowaki Shigenori , Andoh Masashi , Tajika Masahiro , Muro Kei ,   Department of Clinical Oncology, Aichi Cancer Center Hospital
Published: February 2020

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Background: Sarcopenia and muscle loss during chemotherapy (Cx) have a poor prognosis in metastatic colorectal cancer (mCRC). It is unclear whether cachexia during Cx has a survival impact. Methods: mCRC patients (pts) receiving first-line Cx at a single institution between Jan 2010 and Jun 2018 were retrospectively evaluated. Pts receiving doublet Cx with bevacizumab or anti-EGFR agents, ECOG Performance Status (PS) 0–2, and abdominal computed tomography (CT) before and after initiating first-line Cx at least once were included and classified pts into those with (cachexia group) or without (non-cachexia group) cachexia. The skeletal muscle index (SMI) was calculated from the CT cross-section area at L3 divided by the length squared. Muscle loss was defined as a < 5% reduction in the SMI. The association between muscle loss and cachexia during Cx, time to treatment failure (TTF) and overall survival (OS) was determined by univariate and multivariate analysis including muscle loss, primary tumor location, ECOG PS, number of metastatic sites, ALP, WBC, LDH, KRAS status, and BRAF status as independent variables. Results: Of 562 included pts, 185 were eligible and 69 (37%) experienced cachexia. Differences in all patient characteristics such as muscle loss, ECOG PS 2, KRAS mutant, and BRAF mutant (28%, 8%, 32%, and 10% with cachexia group and 27%, 3%, 32%, and 8% with non-cachexia group) were not significant. Median follow-up was 26.8 months. Muscle loss was not associated with TTF (13.3 vs. 15.5 months, HR = 1.05; 95% CI: 0.76–1.45, p = 0.76). OS was shorter (24.4 vs. 29.9 months, HR = 1.23; 95% CI: 0.86–1.76, p = 0.25), but the difference was not significant in univariate and multivariate analysis. However, cachexia group presented significantly shorter TTF [median TTF 11.9 vs. 16.9 m; HR 1.52, 95% CI: 1.12-2.07, p < 0.01; adjusted HR (aHR) 1.53, 95% CI: 1.12-2.11, p < 0.01] and shorter OS (median OS 21.4 vs. 34.1 m; HR 1.81, 95% CI: 1.29-2.55, p < 0.01; aHR 1.97, 95% CI: 1.38-2.81, p < 0.01) than non-cachexia group. Conclusions: Cachexia during Cx may have a negative impact on survival in pts with mCRC.
Continued cetuximab in second-line treatment for patients with unresectable metastatic wild-type KRAS, NRAS, and BRAF colorectal cancer after disease progression during first-line cetuximab-based therapy.
Authors: Liu Ying , Wang Feng , Ma Ning , Xu Shuning , Qiao Lei , Li Ke , Kuang Gaizhen , Li Danyang , Liu Yangyang , Xiong Yanyan , Sun Mingming
Published: February 2020

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Background: Cetuximab plus chemotherapy is a first-line treatment option for metastatic RAS wild type colorectal cancer patients. Currently, no data are available on continuing cetuximab or changing bevacizumab as second-line therapy beyond first-line cetuximab-based chemotherapy. Methods: Patients (aged ≥18 years) with metastatic, histologically and genetically confirmed wild-type KRAS, NRAS and BRAF colorectal cancer progressing after first-line cetuximab plus chemotherapy were randomly assigned (1:1 ratio) to second-line chemotherapy with cetuximab (arm A) or with bevacizumab (arm B) 2·5 mg/kg per week equivalently. The choice between oxaliplatin-based or irinotecan-based second-line chemotherapy depended on the first-line regimen (switch of chemotherapy). The primary endpoints were progression-free survival (PFS) and objective response rate (ORR). The second endpoint was overall survival (OS). Results: 77 Patients (from July 1, 2016 to Sept 20, 2019, 77) were randomized (41 in arm A and 36 in arm B). ORR was 29.3% and 19.4% in Arm A and Arm B ( p= 0.31). PFS was 7.2 months (95% CI 5.2–9.2) for Arm A and 5.9 months (95% CI 5.1–6.7) for Arm B ( p= 0.677). OS was 18.5 months (95% CI 15.1–21.8) for Arm A and 17.5 months (95% CI 15.4–19·7) for Arm B ( p= 0.444). Patients with ECOG PS 0 had significantly longer PFS and OS than ECOG PS 1 in second-line therapy whether cetuximab or bevacizumab combined with chemotherapy. ECOG 0 group vs ECOG 1 group, PFS was 8.7 months vs 4.6 months (p = 0.00) and OS was 21.2 months vs 12.3 months (p = 0.00). Moreover, ETS may predict efficacy of second-line continued cetuximab. The most frequently grade 3–4 adverse events in both arms were neutropenia (19.4% VS 16.7%), diarrhea (7.5% vs 11.1%), and nausea(10% vs 13.9%). Conclusions: Continuing cetuximab or changing bevacizumab plus standard second-line chemotherapy in patients with metastatic wild-type KRAS, NRAS and BRAF colorectal cancer after first-line cetuximab plus chemotherapy have similar clinical benefits. ECOG score is an independent predictor of prognosis and second-line treatment efficacy for colorectal cancer.
Association of sarcopenia and myosteatosis with the systemic inflammatory response and tumor stage in patients undergoing surgery for colorectal cancer (CRC).
Authors: Abbass Tanvir , Dolan Ross , McSorley Stephen Thomas , Horgan Paul G. , McMillan Donald C.
Published: February 2020

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Background: There is now good evidence that sarcopenia and myosteatosis, measured as low skeletal muscle index (SMI) and low skeletal muscle density (SMD) from CT scans, are associated with poor survival in patients undergoing surgery for CRC. However, this is not clear whether this is as a result of tumour burden or chronic inflammation. Methods: The relationship between tumour stage, systemic inflammatory response using modified Glasgow prognostic score (mGPS), neutrophil lymphocyte ratio (NLR) and sarcopenia and myosteatosis using defined SMI/SMD was examined in 840 patients undergoing CRC resection from a prospectively maintained database. Results: The majority of patients were > 65 years of age (64.5%), male (55%) and did not have sarcopenia (51%) but had myosteatosis (65%). In those patients with a mGPS = 0 (n = 617), mGPS = 1 (n = 99), mGPS = 2 (n = 124), TNM stage of 0-I, II and III was not associated with sarcopenia (p = 0.260, p = 0.869 and p = 0.458 respectively) or myosteatosis (p = 0.136, p = 0.879 and p = 0.06 respectively). In those patients with TNM stage of 0-I (n = 202), stage II (n = 346) and stage III (n = 292), mGPS (0,1,2) was significantly associated with sarcopenia (p = 0.329, p = 0.001 and p = 0.002 respectively) and myosteatosis (p = 0.329, p < 0.001 and p = 0.001 respectively). In patients with TNM stage of 0-I, stage II and stage III, NLR was significantly associated with sarcopenia (p = 0.492, p = 0.299 and 0.027 respectively) and myosteatosis (p = 0.870, p = 0.012 and p = 0.019 respectively). Conclusions: Compared with tumour burden, the systemic inflammatory response (particularly mGPS) appears to have a greater influence on the development of sarcopenia and myosteatosis. These results have implications for the treatment of sarcopenia and myosteatosis in patients undergoing surgery for CRC.
Immunomodulatory effects of tumor treating fields (TTFields) on colon cancer models.
Authors: Voloshin Tali , Kaynan Noa , Davidi Shiri , Porat Yaara , Shteingauz Anna , Munster Mijal , Schneiderman Rosa S , Tempel-Brami Catherine , Zeevi Einav , Gotlib Karnit , Cahal Shay , Giladi Moshe , Kirson Eilon D. , Weinberg Uri , Kinzel Adrian , Palti Yoram
Published: February 2020

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Background: Tumor Treating Fields (TTFields) are clinically approved in glioblastoma and malignant pleural mesothelioma as an anti-mitotic treatment modality delivered via noninvasive application of low intensity (1-3 V/cm), intermediate frequency (100-500 kHz), alternating electric fields. We evaluated whether TTFields (150 kHz) induced colon cancer cell death can be perceived as immunogenic and suitable for combination with anti-programmed cell death protein 1 (anti-PD-1; immune checkpoint inhibitor) therapy. Methods: Murine colorectal carcinoma cells (CT-26) were treated with TTFields using the inovitro system. Immunogenic cell death was evaluated by assessing changes in the levels of calreticulin (CRT) on the surface of treated cells, phosphorylation of eukaryotic translation initiation factor alpha (eIF2α), and secretion of ATP and high-mobility group box 1 (HMGB1). For in-vivo studies, CT-26 cells were subcutaneously implanted in BALB/c mice. The mice were treated with TTFields (150 kHz), anti-PD-1 (200 μg/mouse), or a combination of the 2 modalities. Tumor volume was monitored and flow cytometry analyses performed for phenotypic characterization of infiltrating immune cells. Results: We demonstrate that cancer cell death under TTFields application exhibited release of HMGB1, ATP secretion from cells, and ER stress leading to CRT translocation to the cell surface, all of which are signs of immunogenic cell death. The combined treatment of colon tumor-bearing mice with TTFields plus anti-PD-1 led to a significant decrease in tumor volume compared to anti-PD-1 alone or to the control group. Significant increases in CD45+ tumor infiltrating cells were observed in the TTFields plus anti-PD-1 group. We demonstrate significant increases in both CD8 and CD4 T-cells in tumors treated with combination therapy, and in CD8 in tumors treated with anti-PD-1 alone. Conclusions: Our results establish the potential of TTFields therapy to induce immunogenic cell death. We also demonstrate efficacy of concurrent application of TTFields and anti PD-1 therapy in mouse cancer models. These data suggest that TTFields plus anti-PD-1 combination treatment may achieve tumor control by further enhancing anti-tumor immunity.