bluuebunny/crossref_metadata_2025 huggingface dataset:
Influence of tumor site on cognitive deficits in children with cerebellar tumors at diagnosis
Authors: Riccardi R. , Peruzzi L. , Iuvone L. , Colosimo C. , Tamburrini G. , Massimi L. , Caldarelli M. , Lazzareschi I. , Ridola V. , Di Giannatale A. , Di Rocco C.
Published: March 2020

9045

Background: Children with cerebellar tumor are at risk for cognitive deficits (CD) depending on surgery and radiotherapy. Only few studies analyze the role of tumor itself in mental functioning (Ellenberg et al., ‘87). Data about neuropsychological organization before any treatment are essential to understand the effect of tumor and have a baseline for analyzing the negative impact of the different treatments in the CD. Aim of this study is to prospectively analyze cognitive functions before treatment in patients (pts) with cerebellar tumors. Methods: Twenty-five pts with cerebellar tumor were assessed at diagnosis.Children with previous and severe neurological disturbances neurological were excluded. Intelligence quotient (IQ) and sectorial cognitive abilities (memory, attention, language, visuospatial and executive functions) were evaluated. Neurological examination (BUSPAR) and magnetic resonance imaging (MRI) were performed in the same period of cognitive assessment. Neurological deficits were classified as major, mild or absent in relation with the results of BUSPAR. Results: Twenty pts were selected; males/females: 12/8; age: 7.6 years (range: 18 m-14.8 y); histhology: pilocytic astrocytoma (9 pts), medulloblastoma (9), ependymoma (1) and atypical teratoid-rabdoid (1); tumor location: right cerebellar hemisphere (4), left (4), vermal (12); neurological examination: major neurological signs (2 pts), mild (10), absent (6); hydrocephalus: 50% of pts. Three pts had IQ values below the average level, although mean IQ values were normal (mean: 99.6; range: 78–118). Sixteen/20 pts had selective CD mainly involving working memory, executive functions, attention, and visual motor integration. Language processing was defective in 6 pts (2/4 right-sides lesions, 4/12 vermal lesion). Conclusions: Sectorial CD are present before treatment in about 80% of pts, mainly related to the location of tumor. Preliminar data suggest a correlation between specific sites inside cerebellum and selective CD, with language problems mainly in right hemispheric tumor. Complex cognitive impairment was present in 15% of pts before treatment. These data will represent the baseline for further analysis about the impact of treatment on cognitive outcome.

No significant financial relationships to disclose.
Risk factors for low bone mineral density (BMD) in pediatric sarcoma survivors
Authors: Ahn H. , Kaste S. C. , Liu T. , Billups C. A. , Hudson M. M. , Spunt S. L.
Published: March 2020

9059

Background: The incidence of and risk factors for low BMD in patients treated for sarcoma in childhood is unknown. Methods: Retrospective medical record review of 99 patients with pediatric sarcoma diagnosed between 12/82 and 2/03 who had undergone QCT evaluation more than 1 year after completion of treatment. Low BMD was defined as >1.5 standard deviations below the mean. A Z-test was used to assess whether BMD was lower in our patient population than in the normal reference population. Logistic regression was used to examine factors predictive of low BMD. Risk factors analyzed included demographic variables, tumor features, treatment exposures, endocrine/renal dysfunction, and health habits. Results: Twenty-six of the 99 sarcoma survivors (26%) had low BMD. The mean (−0.8) and median (−0.75) QCT Z-scores were significantly lower than those of the normal reference population (mean and median = 0, p<0.0001). Factors associated with lower BMD included young age at sarcoma diagnosis (p=0.044) or at QCT measurement (p=0.001), greater weight at diagnosis (p=0.045), non-lower extremity tumor site (p=0.023), higher cumulative cyclophosphamide dose (p=0.007), smaller size at QCT measurement [height (p=0.018), weight (p=0.012)], and low serum creatinine [at diagnosis (p=0.033), at QCT measurement (p=0.014)]. Gender, race, ifosfamide/methotrexate/etoposide exposure, radiotherapy, endocrinopathy, and health habits were not predictive of low BMD. Conclusions: Survivors of childhood sarcoma are at high risk for low BMD. Risk factors include young age, non-lower extremity tumor site, and high cumulative cyclophosphamide exposure. Prospective studies are needed to confirm these risk factors, and to guide implementation of effective screening guidelines and therapeutic measures.

No significant financial relationships to disclose.
Large volume peripheral blood progenitor cell (PBPC) harvest in 27 pediatric solid tumor patients weighing less than 20 Kg
Authors: Fernández Sasso D. , López O. , García Lombardi M. , Chantada G. , Figueroa M. , Diez B. , Dengra C. , Koziner B.
Published: March 2020

9061

While PBPC collection has become a safe and common procedure in adults, fewer reports exist about its efficacy and safety in low weight pediatric patients. PBPC harvest might be difficult in this patient population and extracorporeal separator line priming with red blood cells is usually required to improve hemodynamic stability and effectiveness of the collection. We present our experience in 27 children (11 females, 16 males) weighing less than 20 kg and autografted between May 2001 and December 2005. Median age and weight at the time of apheresis were 2.7 years (0.7 to 8) and 14.3 kg (9.7 to 20), respectively. Diagnosis were neuroblastoma in 15, brain tumor in 10, and others in 2. Harvest of PBPC started after mobilization with G-CSF 10 ug/kg/day SC for 4 days. A double lumen (Arrow 7Fr) central venous catheter was surgically placed under sedation in the OR. Collections were performed using a COBE Spectra separator primed with irradiated, white cell-depleted and CMV-negative packed red cells. A median of 2 (1 to 7) procedures were performed, resulting in the harvest of 12.9 (3.6–33.1) × 108/kg mononuclear cells and 4.98 (2.33–12.69) × 106/kg CD34 (+) cells. The apheresis were performed in the presence of the parents and did not require sedation. Only 1 patient had as side-effect perioral paresthesias with normal serum calcium. No patient had vasovagal reactions. A median platelet count reduction of 66% was observed, comparing pre and post apheresis values. All patients completed the procedure with a median of 71.800 platelets (25.000 to 152.000) and a median hemoglobin of 10.8 g/dl (8.2 to13.6). All children were successfully transplanted with myeloid engraftment (ANC >500 × 109/L) at a median of 11 days (9 to 14) and independence from platelet transfusions (> 20,000x × 109/L) at a median of 17 days (8 to 39) after PBPC infusion. Median of hospitalization days was 23 (18 to 42). We conclude that PBPC harvesting using large volume continuous flow cell separation was safe, even in this low-weight pediatric population. This procedure shortens the total number of apheresis, providing an adequate number of CD34 + cells, resulting in satisfactory hematological recovery and duration of hospitalization.

No significant financial relationships to disclose.
Metastases outside the abdomen (MOA) are associated with initial high tumor burden (TB) in gastrointestinal stromal tumors (GIST)
Authors: Aliberti S. , Grignani G. , Allione P. , Rota-Scalabrini D. , Carnevale-Schianca F. , Bucci A. , Caravelli D. , Galla A. , Ferraris R. , Aglietta M.
Published: March 2020

9546

Background: In GIST MOA are rare events (8–10%) with a prognostic and predictive impact (JCO 2005;23:5795). To stage GIST, NCCN recommends either CT or abdominal MRI + chest imaging, suggesting PET scan only if early response assessment is needed. Therefore, MOA may be missed by standard work up. We evaluated if TB (largest tumor diameter > 12 centimetres) at diagnosis was associated to a higher incidence of MOA. Methods: From 01/02 to 12/05, 66 pts affected by GIST were either treated or followed-up at our hospital. Routine initial work up consisted in: chest CT + CT or MRI abdominal scan. Pet scan was performed if: uncertainties after standard imaging, to monitor “neoadjuvant” therapy or within clinical trials. Identified MOA if unique, would be considered for fine needle biopsy whilst multiple MOA would be monitored by most appropriate imaging technique. Results: Twenty-three pts (34%) had TB between 13 and 31 centimetres. At diagnosis 10 pts (15%) had MOA located in: lung (7 pts), bone (2 pts) subcutaneous tissue (1 pts). In this unfavourable group 9 pts (14%) were affected by tumors larger than 12 cm. Pts without MOA were 56 (85%) of whom 14 (21%) had TB. The association between initial TB and MOA was statistically significant (p<0.001). Conclusions: In this small series, high tumor burden is positively correlated to MOA. If these data should be confirmed, initial diagnostic work up could usefully include both chest CT and PET scan in abdominal mass beyond 12 centimetres wide. A precocious recognition of MOA would allow to better control therapeutic response and to better identify high-risk patients.

No significant financial relationships to disclose.
Surgical interventions for focal progression of gastrointestinal stromal tumors under imatinib therapy
Authors: Nishida T. , Hasegawa J. , Nishitani A. , Takahashi T. , Kanda T. , Hatakeyama K.
Published: March 2020

9548

Background: Although Imatinib has shown high activity oin advanced gastrointestinal stromal tumors (GIST), secondary resistance appears as focal or systemic progressions during chronic therapy. At present, there are limited therapeutic options for Imatinib-resistant GIST. This retrospective study examines the safety and short-term outcomes of surgical interventions for focal progressions under Imatinib. Patients and Methods: Between Jan. 2002 and May 2005, 16 patients (pts) with focal progressions of secondarily-resistant GIST (Male:Female, 12:4; median age, 61 years) underwent surgical interventions including resection (N=13), radiofrequency ablation (RFA) (n=2), and their combination (n=1). Doses of Imatinib were 400 (n=10) or 600 (n=6) mg/day. Results: Postoperative complications including liver abscess (n=1), minor bile leak (n=1), wound infection (n=1) and transient ileus (n=1) were occurred to 4 patients, who recovered from them within a few weeks. There was no in-hospital deaths. Median time to progression (TTP) was 5.5 months. Only one patient died of the of disease, 16 months after the resection, and the remaining 15 pts are alive, with a median follow-up of 13 months. Pts with total eradication of resistant lesions (n=7) had longer TTP than those with incomplete (n=9) (p<0.05). Total eradication could be performed in patients with a smaller number (P=0.014) and size (P=0.018) of resistant lesions. Overall survival after Imatinib therapy was 100% at 1 year and 93% at 3 years, with a median follow-up of 39 months. Conclusions: These data suggest that surgical interventions for focal progressions of secondarily-resistant GIST under Imatinib may be safe and that total eradication of resistant lesions may result in a survival benefits under conditions of limited treatment modality.

No significant financial relationships to disclose.
Terminal phase in patients (pts) with advanced sarcomas: A perspective study for a better assistance
Authors: Comandone A. , Oliva C. , Boglione A. , Garetto F. , Bergnolo P. , Dal Canton O. , Chiado Cutin S. , Pochettino P. , Gino G. , Brach Del Prever E.
Published: March 2020

9551

Background: Sarcoma are rare tumors, with an incidence <1% of all neoplasms. Very few data are available on the clinical and psychological needs of the pts in terminal phase of these diseases. In terminal phase the goal is no more cure or prolongation of life, but the control of symptoms related to the disease progression. Methods: As a specialized interdisciplinary group we have started to treat the pts afflicted from soft tissue and bone sarcomas since 1994. We have recorded in a perspective study the problems of the terminal pts from 1998 until 2005. We have followed 178 pts with sarcomas in terminal phase for at least 3 months: 95 males and 83 females, median age 57 years, median PS 50 Karnofsky. Histologically 143 had soft tissue sarcomas, 28 osteosarcomas, 7 Ewing sarcomas. Extremities were the origin of the disease in 33.7% of the cases, abdomen in 29.2%, trunk in 21.9% and other sites in 15.2%. Site of recorded metastases: lung 48.3%, liver 18.5%, bone 15.7%, brain 7.9%, nodes 4.5%. Inoperable primary tumors or local relapse 30.9%. Results: During the last part (1 months) of their lives the pts complained with: pain 78.7%, dyspnoea 48.9%, anxiety 16.9%, gastrointestinal obstruction 24.7%, anorexia 51.1%, bleeding 7.9%. 57.3% of these pts died at home, 42.7% at the hospital. To control pain, dyspnoea and the other symptoms radiotherapy (43%), supportive care (100%) and palliative chemotherapy (36%) were used. Psycological support was offered to the majority of pts (63.5%) as well as physical rehabilitation (56.8%). Conclusions: Supportive care of pts with advanced sarcomas is an underestimated aspect in clinical oncology. We have demonstrated that these pts have specific needs, on some aspects, different from those of the pts afflicted from the most common cancers. A complex, multidisciplinary approach is necessary in order to improve the assistance and quality of life of these pts.

No significant financial relationships to disclose.
Assessment of trabectedin (T) induced liver toxicity with correlation to liver morphology in a phase I study of T + pegylated liposomal doxorubicin (PLD)
Authors: Yver A. , Cohen R. , Williams D. , Von Mehren M.
Published: March 2020

9568

Background: T (ET-743) is a first-in-class compound that binds the minor groove of DNA. T has activity in soft tissue sarcoma and ovarian cancers with predictable, transient, non-cumulative and reversible hepatic toxicity, compatible with long term treatment. The combination of T and doxorubicin had preclinical synergistic activity. This study tested T + PLD in advanced malignancies. Methods: Eligibility included normal cardiac and liver functions, prior doxorubicin exposure <250 mg/m2. PLD 30 mg/m2 was administered iv 1-hour followed by 1 of 6 T doses (0.4 -1.3 mg/m2) iv 3 hours q 21 days. In select subjects (4 at pre/post cycle 1, 4 under long term treatment -cycle 14, 20, 30 and 30), liver biopsies were done with expert independent review. Results: Six dose levels of T were evaluated in 30 subjects. The DLTs were 1 grade 3 AST and 2 grade 4 ALT elevations seen at T 1.3 mg/m2. Grade 3–4 toxicities were: ALT elevation (4%), neutropenia (3%), hand-foot syndrome (2%), AST elevation (1%) and nausea/vomiting (1%). Liver biopsies were obtained from 8 subjects (1 in 0.6, 7 in 1.1 mg/m2 T dose cohorts), age 45–78 years, with sarcoma (4), and ovarian (2), uterine (1), and head and neck (1) cancers. T and PLD mean drug exposure for these subjects was 15 (2–36) and 12 (2–24) cycles, respectively. Mean total doses for T and PLD were 23.2 (3.4–39) and 597 (94–1296) mg, respectively. Findings included NASH (nonalcoholic steatohepatitis), severity ranging from minimal steatosis to moderate steatosis with fibrosis. Pre/post treatment biopsies showed no change in NASH pre/post in 3 cases, one subject had minimal post-treatment steatosis. No mitochondrial abnormalities or stellate cell activation were observed. Review concluded no evidence of persistent liver pathological abnormalities attributable to T. Conclusions: The MTD of T is 1.1 mg/m2 with 30 mg/m2 PLD q 21 days, and is well tolerated when both drugs are administered at near full therapeutic doses for prolonged periods. Liver biopsies did not demonstrate clinically relevant hepatic tissue toxicity. As reported previously, this is an active regimen which is being further evaluated in an ongoing Phase III study in relapsed ovarian cancer.

[Table: see text]
The role of adjuvant radiotherapy after marginal excision for local control of extremity and truncal soft tissue sarcoma
Authors: Kim Y. B. , Shin K. H. , Kim G. E. , Han S. B. , Roh J. K. , Suh C. O.
Published: March 2020

9573

Background: Adjuvant radiotherapy (RT) has been shown to improve local control (LC) in patients with extremity and truncal soft tissue sarcoma (STS). The purpose of this study was to analyze how much RT promoted LC in patients with marginally excised STS compared with patients with widely excised STS. Methods: Two hundred and thirty-two patients with STS (173 extremity cases and 59 trunk cases) who had received conserving surgery were divided into 3 groups according to marginal status and the addition of RT; (1) wide excision alone (n = 56, Group A), (2) wide excision plus RT (n = 64, Group B) and (3) marginal excision plus RT (n = 112, Group C). LC, overall survival, and morbidity rates were retrospectively compared among 3 groups. Results: There were no differences in age, gender, pathologic type, and tumor site among three groups, but Group A had the higher incidence of small-sized tumor and low grade tumor than other groups. Thirty-eight patients experienced local failures (LF) after completion of treatment. Group C had similar incidence of LF compared with Group B (Group A; 4%, Group B; 21%, and Group C; 19%). Overall 5-year and 10-year LC rates were 80% and 70%, and there were no significant differences between Group B and Group C in 10-year LC rate (Group A; 84%, Group B; 65%, and Group C; 68%). Tumor grade and tumor site were found to be significant predictors of LF. Group C had lower 10-year overall actuarial survival rate compared with Group B (Group A; 85%, Group B; 78%, and Group C; 69%). This was associated with significantly different incidence of distant failure (Group A; 11%, Group B; 16%, and Group C; 29%, p=0.008). Seven patients suffered from wound dehiscence, and 1 patient from bone necrosis. The incidence of Grade 3–4 late complication was higher in Group B than Group A and Group C (Group A; 0%, Group B; 9.3%, and Group C; 1.7%, p=0.03). Conclusions: Our data indicate that RT seems to promote LC in patients with positive or close margin up to that of patients with wide margin in extremity and truncal STS. We suggest that conserving surgery and RT for patients with marginal STS should be the alternative choice rather than aggressive surgery for better LC without deteriorating limb-function or causing serious complication.

No significant financial relationships to disclose.
Multimodality treatment in retroperitoneal sarcoma
Authors: Minea L. N. , Anghel R. , Stanculeanu D. , Georgescu T. , Bacinschi X. , Tarlea A. , Oprea L. , Negrei C. , Barna M. , Gheta C.
Published: March 2020

9579

Background: Soft tissue sarcomas account for less than 1% of all malignancies; 10% of them arise in the retroperitoneal tissues. Surgical resection is considered as the most important treatment but it is often difficult to perform because of late presentation, anatomical conditions and invasion of adjacent structures. Adjuvant treatments have limited efficacy. Methods: We evaluate two year survival rate and safety profile of multimodal treatment in retroperitoneal sarcomas. Between Jan 1999 - Dec 2003, 37 patients with retroperitoneal sarcomas were treated in our institution. Median age 48.2 years (range 20 - 70), sex ratio M:F - 15:22, PS ECOG 0:1:2 - 25:8:4, tumor grading G1:G2:G3 - 8:14:15. Surgery was performed in 34 cases (29 complete resection, 5 partial resection) and 3 patients were only biopsied. All the patients received adjuvant radiochemotherapy and 4 more chemotherapy cycles thereafter. The chemotherapy regimen consisted of Ifosfamide 1,500 mg/sqm/day day 1–5 with mesna uroprotection and Epirubicin 50 mg/sqm day 1, repeated on days 29–33 during RT. They received external beam RT up to 45 - 50 Gy, conventional fractionation. The Ifosfamide and Epirubicin doses were increased at 1,800 mg/sqm and 75 mg/sqm respectively after chemoradiotherapy if no grade 3–4 toxicities occurred. Results: The overall 2 year survival rate was 70.27%. The 2 year survival rate was 100% - 71.43% - and 53.33% for G1, G2 and G3 tumors respectively; the figures are 82.75% - 40% and 0% for complete resection, partial resection and diagnostic biopsy respectively. All patients received the intended treatment. There were only 8 cycle delays for grade 3 toxicities. 6 patients had grade 3–4 hematological toxicities and 4 patients had grade 3–4 digestive toxicities. Retroperitoneal fibrosis occurred in 3 cases. Conclusions: This combined modality treatment can be successfully delivered. We have no major toxicities. We obtained similar results as cited in the literature. Better results could be obtained with newer radiation techniques (conformal RT or IMRT).

No significant financial relationships to disclose.
BCIRG 007: Randomized phase III trial of trastuzumab plus docetaxel with or without carboplatin first line in HER2 positive metastatic breast cancer (MBC)
Authors: Forbes J. F. , Pienkowski T. , Valero V. , Eiermann W. , Von Minckwitz G. , Martin M. , Smylie M. , Crown J. M. , Noel N. , Pegram M.
Published: March 2020

LBA516

Background: Based on preclinical synergism between docetaxel (T), carboplatin (C) and trastuzumab (H), BCIRG conducted a phase III trial for women with HER2+ MBC to evaluate efficacy and safety of H in combination with T or TC. Methods: 263 patients (pts) with HER2 FISH+ MBC were randomized to TH, (H with T 100 mg/m2) or TCH, (H with T 75 mg/m2 and C AUC=6). Chemo was given q3 wks for 8 cycles with wkly H at 2 mg/kg (loading dose of 4 mg/kg), followed by H q3 wks at 6 mg/kg until progression. Pts were stratified by centre and prior (neo) adjuvant taxane chemotherapy. Primary endpoint was TTP with 80% power (0.05 significance) to detect a 50% improvement in median TTP between the 2 arms. Secondary endpoints include overall survival, response rate, duration of response (DR), clinical benefit (CB) and safety. Results: 131 pts were treated in each arm. Pt characteristics were well balanced in both groups. Importantly, only 52% of pts received C at the protocol specified dose (RDI > 0.9). Efficacy analysis was conducted at 204 events. There was no significant difference between TH and TCH in median TTP (11.1 vs 10.4 mos, p = 0.57), ORR (73% in both arms), DR (10.7 vs 9.4 mos) and CB (67% in both arms). The most common gr 3/4 toxicities were: infection (44% vs 30%), neutropenic infection (22% vs 12%), thrombocytopenia (2% vs 15%), febrile neutropenia (12% vs 13%) asthenia (5% vs 12%), anemia (5% vs 11%), and diarrhea (2% vs 9%). Two pts died (1.5%) due to sepsis in TCH. Absolute LVEF decline > 15% were seen in 5.5% vs 6.7% of pts. One pt (0.8%) had a symptomatic CHF in TH arm Conclusions: The already effective TH regimen does not benefit from the addition of C, when the T dose in TH is 100 mg/m2 and 75 mg/m2 in TCH, in women with HER2+ MBC.

No significant financial relationships to disclose.
Docetaxel (T) given concurrently with or sequentially to anthracycline-based (A) adjuvant therapy (adjRx) for patients (pts) with node-positive (N+) breast cancer (BrCa), in comparison with non-T adjRx: First results of the BIG 2–98 Trial at 5 years median follow-up (MFU)
Authors: Crown J. P. , Francis P. , Di Leo A. , Buyse M. , Balil A. , Anderson M. , Nordenskjöld B. , Jakesz R. , Gutierrez J. , Piccart M.
Published: March 2020

LBA519

Background: The activity of T in metastatic BrCa mandated evaluation as adjRx. We compared the efficacy of T with, or after A, both followed by CMF (cyclophosphamide/ methotrexate/ 5-fluorouracil), versus non-T adjRx. Methods: Random assignment trial in resected N+ pts, 18–70 yrs, stratified by: center, 1–3 vs >3 nodes and age <50 vs ≥50. The treatment arms were (mg/m2, intravenously unless otherwise stated): Ia: A 75 q 3 weeks × 4 ⋄ CMF ×3 (oral C 100 day 1–14, F 600 + M 40 d 1+8; q 28 days). Arm Ib; AC 60/600 × 4⋄CMF × 3. Arm II: A75 × 3 ⋄T100 ×3 ⋄CMF ×3. Arm III: AT 50/75 ×4 ⋄ CMF × 3. Pts subsequently received hormono-(receptor+), and radiotherapy per local guidelines. Randomization was in the ratio (1:1:2:2). The trial was designed to have 80% power to detect a 78% hazard ratio (HR) for relapse in II+III v I, with final analysis at 1215, and interim at 405 and 810 events. The primary comparison between the II+III and I would be done at a one-tailed significance level of 0.025. Secondary comparisons of II vs Ia and III vs Ib would be done using a closed testing procedure at a one-tailed significance level of 0.025. The 95% confidence limits of the HR of III v II would be calculated. Due to a low relapse rate, the plan was amended with main analysis after 810 events or 5 years MFU. Results: 2887 pts were enrolled (6/1998–6/2001). Characteristics were well-balanced, 46% had >3N+. Grade 3/4 toxicity occurred in 22.9, 24.7, 35.3 and 28.6 % of pts in Ia, Ib, II and III respectively. At 62.2 months MFU (3/2006), 732 pts (25%) had events. Planned event-free survival (EFS) comparisons were: Conclusion: In this study, the HR for T v non-T adjRx was of borderline significance. There were possibly important differences related to schedule, sequential but not concurrent appearing superior to non-T adjRx. Overall survival analysis will require longer follow-up. Translational studies are underway.

[Table: see text] [Table: see text]
Volatile Anesthetic Sevoflurane Attenuates Toll-Like Receptor 1/2 Activation
Authors: Mitsui Yusuke , Hou Lifei , Huang Xiayi , Odegard Kirsten C. , Pereira Luis M. , Yuki Koichi
Published: March 2020

BACKGROUND:

Although immunomodulatory effects of anesthetics have been increasingly recognized, their underlying molecular mechanisms are not completely understood. Toll-like receptors (TLRs) are one of the major receptors to recognize invading pathogens and danger signals from damaged host tissues to initiate immune responses. Among the TLR family, TLR2 and TLR4 recognize a wide range of ligands and are considered to be important players in perioperative pathophysiology. Based on our recent finding that volatile anesthetics modulate TLR4 function, we tested our hypothesis that they would also modulate TLR2 function.

METHODS:

The effect of anesthetics isoflurane, sevoflurane, propofol, and dexmedetomidine on TLR2 activation was examined by reporter assays. An anesthetic that affected the activation was subjected to in silico rigid docking simulation on TLR2. To test our prediction that sevoflurane and a TLR1/TLR2 ligand Pam3CSK4 would compete for the same pocket of TLR2, we performed Pam3CSK4 competitive binding assay to TLR2 using HEK cells stably transfected with TLR2 (HEK-TLR2) with or without sevoflurane. We examined the effect of different anesthetics on the functions of human neutrophils stimulated with TLR2 ligands. Kruskal–Wallis test and Mann–Whitney U test were used for statistical analysis.

RESULTS:

We observed that the attenuation of TLR1/TLR2 activation was seen on sevoflurane exposure but not on isoflurane, propofol, or dexmedetomidine exposure. The attenuation of TLR2/TLR6 activation was not seen in any of the anesthetics tested. The rigid docking simulation predicted that sevoflurane and Pam3CSK4 bound to the same pocket of TLR1/TLR2 complex. The binding of Pam3CSK4 to HEK-TLR2 cells was impaired in the presence of sevoflurane, indicating that sevoflurane and Pam3CSK4 competed for the pocket, as predicted in silico. The stimulation of neutrophils with Pam3CSK4 induced L-selection shedding but did not affect phagocytosis and reactive oxygen species production. L-selectin shedding from neutrophils was attenuated only by sevoflurane, consistent with the result of our reporter assays.

CONCLUSIONS:

We found that TLR1/TLR2 activation was attenuated by sevoflurane, but we found no evidence for attenuation by isoflurane, propofol, or dexmedetomidine at clinically relevant concentrations. Our structural analysis and competition assay supported that sevoflurane directly bound to TLR2 at the interphase of the TLR1/TLR2 complex. Sevoflurane attenuated neutrophil L-selectin shedding, an important step for neutrophil migration.
Using machine learning techniques to develop risk prediction models to predict graft failure following kidney transplantation: protocol for a retrospective cohort study
Authors: Senanayake Sameera , Barnett Adrian , Graves Nicholas , Healy Helen , Baboolal Keshwar , Kularatna Sanjeewa
Published: March 2020

Background:A mechanism to predict graft failure before the actual kidney transplantation occurs is crucial to clinical management of chronic kidney disease patients.  Several kidney graft outcome prediction models, developed using machine learning methods, are available in the literature.  However, most of those models used small datasets and none of the machine learning-based prediction models available in the medical literature modelled time-to-event (survival) information, but instead used the binary outcome of failure or not. The objective of this study is to develop two separate machine learning-based predictive models to predict graft failure following live and deceased donor kidney transplant, using time-to-event data in a large national dataset from Australia.  

Methods:The dataset provided by the Australia and New Zealand Dialysis and Transplant Registry will be used for the analysis. This retrospective dataset contains the cohort of patients who underwent a kidney transplant in Australia from January 1st, 2007, to December 31st, 2017. This included 3,758 live donor transplants and 7,365 deceased donor transplants. Three machine learning methods (survival tree, random survival forest and survival support vector machine) and one traditional regression method, Cox proportional regression, will be used to develop the two predictive models (for live donor and deceased donor transplants). The best predictive model will be selected based on the model’s performance.

Discussion:This protocol describes the development of two separate machine learning-based predictive models to predict graft failure following live and deceased donor kidney transplant, using a large national dataset from Australia. Furthermore, these two models will be the most comprehensive kidney graft failure predictive models that have used survival data to model using machine learning techniques. Thus, these models are expected to provide valuable insight into the complex interactions between graft failure and donor and recipient characteristics.
Findings of a feasibility study of pre-operative pulmonary rehabilitation to reduce post-operative pulmonary complications in people with chronic obstructive pulmonary disease scheduled for major abdominal surgery
Authors: Marlow Lucy L. , Lee Angeline H.Y. , Hedley Emma , Grocott Michael P. , Steiner Michael C. , Young J. Duncan , Rahman Najib M. , Snowden Christopher P. , Pattinson Kyle T.S.
Published: March 2020

Background: Patients with chronic obstructive pulmonary disease (COPD) are at increased risk of complications and death following surgery. Pulmonary complications are particularly prominent.  Pulmonary rehabilitation is a course of physical exercise and education that helps people with COPD manage their condition.  Although proven to improve health outcomes in patients with stable COPD, it has never been formally tested as a pre-surgical intervention in patients scheduled for non-cardiothoracic surgery.  If a beneficial effect were to be demonstrated, pulmonary rehabilitation for pre-surgical patients with COPD might be rapidly implemented across the National Health Service, as pulmonary rehabilitation courses are already well established across much of the United Kingdom (UK).

Methods: We performed a feasibility study to test study procedures and barriers to identification and recruitment to a randomised controlled trial testing whether pulmonary rehabilitation, delivered before major abdominal surgery in a population of people with COPD, would reduce the incidence of post-operative pulmonary complications.  This study was run in two UK centres (Oxford and Newcastle upon Tyne).

Results:  We determined that a full randomised controlled trial would not be feasible, due to failure to identify and recruit participants.  We identified an unmet need to identify more effectively patients with COPD earlier in the surgical pathway.  Service evaluations suggested that barriers to identification and recruitment would likely be the same across other UK hospitals.

Conclusions:  Although pulmonary rehabilitation is a potentially beneficial intervention to prevent post-operative pulmonary complications, a randomised controlled trial is unlikely to recruit sufficient participants to answer our study question conclusively at the present time, when spirometry is not automatically conducted in all patients planned for surgery.  As pulmonary rehabilitation is a recommended treatment for all people with COPD, alternative study methods combined with earlier identification of candidate patients in the surgical pathway should be considered.

Trial registration: ISRCTN29696295, 31/08/2017
Genomic and protein structure modelling analysis depicts the origin and pathogenicity of 2019-nCoV, a new coronavirus which caused a pneumonia outbreak in Wuhan, China
Authors: Dong Ning , Yang Xuemei , Ye Lianwei , Chen Kaichao , Chan Edward Wai-Chi , Chen Sheng
Published: March 2020

Background: A pandemic outbreak caused by a novel coronavirus, 2019-nCoV, has originated from Wuhan, China and spread to many countries around the world. The outbreak has led to around 45 thousand cases and over one thousand death so far.

Methods: Phylogenetic analysis and sequence alignment were used to align the whole genome sequence of 2019-nCoV with other over 200 sequences of coronaviruses to predict the origin of this novel virus. In addition, protein modeling and analysis were performed to access the potential binding of the spike protein of 2019-nCoV with human cell receptor, angiotensin-converting enzyme 2 (ACE2).

Results: Detailed genomic and structure-based analysis of a new coronavirus, namely 2019-nCoV, showed that the new virus is a new type of bat coronavirus and is genetically fairly distant from the human SARS coronavirus. Structure analysis of the spike (S) protein of this new virus showed that its S protein only binds much weaker to the ACE2 receptor on human cells whereas the human SARS coronavirus exhibits strongly affinity to the ACE receptor.

Conclusions: These findings suggest that the new virus should theoretically not be able to cause very serious human infection when compared to human SARS virus. However, the lower pathogenicity of this new virus may lead to longer incubation time and better adaption to human, which may favor its efficient transmission in human. These data are important to guide design of infection control policy and inform the public on the nature of threat imposed by 2019-nCov. Most importantly, using the analysis platform that we have developed, we should be able to predict whether the new mutations could lead to the increase of infectivity of the mutated virus in a very short time.
An Analysis of the Falsification Criterion of Karl Popper: A Critical Review
Authors: Mitra Suddhachit
Published: March 2020

Karl Popper identified ‘falsifiability’ as the criterion in demarcating science from non-science. The method of induction, which uses the (debated) principle of uniformity of nature, was rejected by Popper. He instead suggested that a scientific theory cannot be ‘verifiable’ but only ‘falsifiable’; one counter-example to the claims made by the theory would falsify it. The paper conducts a survey of the extant literature to understand the concept, the methodology as suggested by Popper to operationalize the concept, and possible limitations, both conceptual and methodological. The extant literature points out inherent ambiguities in the Popperian concept of falsifiabilty. One recurring theme is that Popper, the deductivist, uses the much critiqued inductivistic method among his methodological suite.
Risk Factors for Cervical Cancer and Papanicolaou Test in Marginalized Adolescents in Bogotá, Colombia
Authors: Sarmiento Medina María Inés , Puerto de Amaya Miryam
Published: March 2020

Introduction: Cervical cancer is rare in young women, so screening in women under 21 years is not recommended. However, early and intense exposure to risk factors could increase the likelihood of early pre-neoplastic lesions. Currently, particular social conditions in adolescents can favor exposure, generate changes in lifestyles, and affect their immediate and future health. This work describes the frequency of risk factors and Pap results in adolescents of a child protection center. Materials and Methods: This paper presents a retrospective cross-sectional study that measured the frequency of exposure to risk factors for cervical cancer and Pap results of 889 adolescents exposed to critical social conditions. It used information from the cytology report files made between 2011 and 2016. Results: Normal Pap smear was found in 85 % of the cases. The risk factors had a very high prevalence, especially the early age of onset of sexual relations with 75 % before age 14, the number of sexual partners with more than one in 66.7 %, no use of a condom 95 % and high cigarette consumption. Discussion: The frequency of pre-malignant cervical lesions was very low; however, in women under 21 years old with premature and intense exposure to risk factors, an early-onset conservative screening accompanied by gynecological consultation for prevention, diagnosis, or treatment can be considered. The marginalized adolescent’s social problem requires interdisciplinary and intersectoral management.
A new approach to managing follow-up patients with sino-nasal disorders: the rhinology panel
Authors: Abushaala Abdulaziz , Sargent Helen , McLean Jennifer , Grech-Marguerat Deborah , Khalil Hisham
Published: March 2020

Background/aims

There is a growing backlog of patients with sino-nasal disorders waiting for a follow-up appointment. This study aimed to identify rhinology patients on the outpatient follow-up list who could be removed from the waiting list for a face to face follow-up appointment and instead either given a phone consultation by a clinical nurse specialist or discharged from the service.

Methods

The clinical records of patients on the waiting list for a follow-up appointment at a nasal disorders clinic were reviewed by a panel comprising a consultant rhinologist, a rhinology fellow, a specialist registrar and two nurse specialists.

Results

A total of 300 clinical records of patients on the follow-up list of the Rhinology clinic were identified, of which 253 were found to have a sino-nasal disorder. Of these, 137 patients (54%) were discharged from the rhinology face to face follow-up clinics, while 116 patients (46%) were given face to face review appointments.

Conclusions

A multi-professional rhinology review panel is an effective way of managing the waiting list of an outpatient rhinology clinic and providing nurse-led telephone consultations could decrease the strain on resources while maintaining patient safety.
Time to make healthcare professions more accessible to women with children
Authors: Archibong Uduak , McIntosh Bryan , Donaghy Louise
Published: March 2020

In response to a recent report published by the Royal College of Nursing, Bryan McIntosh, Uduak Archibong and Louise Donaghy discuss the impact of motherhood, part-time hours and career breaks on the cultural perceptions and experiences of female healthcare professionals.
From handover to takeover: should we consider a new conceptual model of communication?
Authors: Spranzi Francesca , Norton Christine
Published: March 2020

Objective

This service evaluation aimed to collect data on clinical handover on labour ward and compare them with the local guideline.

Design and methods

This service evaluation was structured in four stages, each using a different design and research methods.

Setting

The study was undertaken between September 2013 and August 2014 in a maternity unit in a large NHS teaching hospital in London, UK.

Findings and conclusion

Communication breakdown is widely considered to be a significant factor contributing to poor patient outcomes, with handover being a major risk point. The discrepancy between the local guideline and current clinical practice reinforces the belief that urgent action is needed to improve clinical handover on labour ward. The results of this service evaluation suggest that a drastic overhaul of the communication model during handover should be considered, ie from handover to takeover, and that the mnemonic SBAR may not be fit-for-purpose in maternity care and should be replaced with a different format that reflects the chronological flow of clinical events.
Wavelength selection and measurement error theoretical analysis on ground-based coherent differential absorption lidar using 1.53  µm wavelength for simultaneous vertical profiling of water vapor density and wind speed: publisher’s note
Authors: Imaki Masaharu , Hirosawa Kenichi , Yanagisawa Takayuki , Kameyama Shumpei , Kuze Hiroaki
Published: March 2020

This publisher’s note amends the title in Appl. Opt.
59, 2238 (2020).APOPAI0003-693510.1364/AO.384675
Effect of cone spectral topography on chromatic detection sensitivity
Authors: Neitz Alexandra , Jiang Xiaoyun , Kuchenbecker James A. , Domdei Niklas , Harmening Wolf , Yan Hongyi , Yeonan-Kim Jihyun , Patterson Sara S. , Neitz Maureen , Neitz Jay , Coates Daniel R. , Sabesan Ramkumar
Published: March 2020

The spatial and spectral topography of the cone mosaic set the limits for detection and discrimination of chromatic sinewave gratings. Here, we sought to compare the spatial characteristics of mechanisms mediating hue perception against those mediating chromatic detection in individuals with known spectral topography and with optical aberrations removed with adaptive optics. Chromatic detection sensitivity in general exceeded previous measurements and decreased monotonically for increasingly skewed cone spectral compositions. The spatial grain of hue perception was significantly coarser than chromatic detection, consistent with separate neural mechanisms for color vision operating at different spatial scales.
VIPR: vectorial implementation of phase retrieval for fast and accurate microscopic pixel-wise pupil estimation
Authors: Ferdman Boris , Nehme Elias , Weiss Lucien E. , Orange Reut , Alalouf Onit , Shechtman Yoav
Published: March 2020

In microscopy, proper modeling of the image formation has a substantial effect on the precision and accuracy in localization experiments and facilitates the correction of aberrations in adaptive optics experiments. The observed images are subject to polarization effects, refractive index variations, and system specific constraints. Previously reported techniques have addressed these challenges by using complicated calibration samples, computationally heavy numerical algorithms, and various mathematical simplifications. In this work, we present a phase retrieval approach based on an analytical derivation of the vectorial diffraction model. Our method produces an accurate estimate of the system’s phase information, without any prior knowledge about the aberrations, in under a minute.
Vortex soliton molecule in a fiber laser
Authors: Wang Yue-E , Wu Han , Tan Yan-Jie , Ma Qi-Chang , Hong Wei-Yi , Cui Hu , Luo Zhi-Chao , Xu Wen-Cheng , Luo Ai-Ping
Published: March 2020

We report the generation of vortex soliton molecules (VSMs) in a passively mode-locked fiber laser based on a mode selective coupler (MSC). ±1-order VSMs with variable numbers of molecules are observed. By adjusting the polarization state of the light in the cavity, we further demonstrate the process in which one VSM splits to multiple. During this process, the number of the solitons inside the VSM also varies and their separation gradually increases while the spectral modulation being unobservable, and vice versa. The obtained results have potential applications in fields of optical communications, especially in information coding.
Optical beam shift as a vectorial pointer of curved-path geodesics: an evolution-operator perspective
Authors: Zheltikov Aleksei
Published: March 2020

When set to travel along a curved path, e.g., in a bending-waveguide setting, an optical beam tends to re-adjust its position, shifting away from the center of path curvature. This shift is highly sensitive to the spatial profile of the refractive index, providing a vectorial pointer for curved-path geodesics and bending-induced optical tunneling. An evolution-operator analysis of this effect extends an analogy with a time-evolution-operator treatment of quantum dynamics and suggests the routes whereby the ability of an optical beam to sense curved-path geodesics can be understood in terms of the pertinent evolution operators, path integrals, and imaginary-time/path theorems.
Transforming terahertz plasmonics within subwavelength hole arrays into enhanced terahertz mission via Smith-Purcell effect
Authors: Yu Zijia , Liu Yucheng , Liu Weihao
Published: March 2020

We illustrate the transformation of terahertz plasmonics within an array of rectangular sub-wavelength holes (RSHs) into coherent and enhanced terahertz emission via Smith-Purcell effect. The radiative plasmonic modes within each RSH of the array are successively excited by an free-electron beam, which then generate coherent radiation by constructive interference. Compared with the case without taking plasmonics into consideration, the radiation field intensity is enhanced by more than an order of magnitude, affording a promising way of developing high-power terahertz radiation. We perform detailed analysis of the plasmonic modes within the RSH by using the dielectric waveguide theory, and the results are verified by numerical simulations. The influences of the RSH parameters on the radiation properties are revealed and discussed.
Light reflection and transmission in planar lattices of cold atoms
Authors: Yoo Sung-Mi , Javanainen Juha
Published: March 2020

Manipulation of light using atoms plays a fundamental and important role in emerging technologies such as integrated photonics, information storage, and quantum sensors. Specifically, there have been intense theoretical efforts involving large samples of cold neutral atoms for coherent control of light. Here we present a theoretical scheme that enables efficient computation of collective optical responses of mono- and bi-layer planar square lattices of dense, cold two-level atoms using classical electrodynamics of coupled dipoles in the limit of low laser intensity. The steady-state transmissivity and reflectivity are obtained at a field point far away from the atomic lattices in the regime with no Bragg reflection. While our earlier method was based on exact solution of the electrodynamics for a small-scale lattice, here we calculate the dipole moments assuming that they are the same at all lattice sites, as for an infinite lattice. Atomic lattices with effectively over one hundred times more sites than in our earlier exact computations can then be simulated numerically with fewer computational resources. We have implemented an automatic selection of the number of sites under the given convergence criteria. We compare the numerical results from both computational schemes. We also find similarities and differences of a stack of two atomic lattices from a two-atom sample. Such aspects may be exploited to engineer a stack for potential applications.