bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical outcome of pediatric Hodgkin’s disease in upper Egypt
Authors: Ebeid E. N. , Zaghloul M. , Khairy M.
Published: March 2020

9035

Background: To assess clinical outcome of chemotherapy and involved field radiotherapy in all stages of pediatric Hodgkin’s Disease in rural areas of Egypt treated at Menya oncology centre which is located 300km south the capital. Methods: Between April 2000 and November 2005, 27 previously untreated patients were investigated, treated and analyzed for remission and survival. Results: There were 21 males and 6 girls with a median age of 11 years, 29.6% were less than 10 years, 70.3% had advanced stage disease (IIB-IV), bulky mediastinal mass in 19 cases spleen involvement in 6 cases, bone marrow aspirate was free in all cases, bone marrow biopsy was not done. patients with stage I and IIA received 2 courses of EOPA (etopsid, vincristine, prednisone and doxorubicin), patients with stage IIb and IIIa received 2 courses of EOPA and 2 courses of ECOP (etopsid, cyclophophamide, vincristine and prednisone), while patients with stage IIIb and IV received 2courses of EOPA and 4 courses of ECOP, All patients received involved field radiotherapy according to stage. Complete remission was achieved in 96.2%. Progressive disease in 1 (3.7%) which required change line of therapy. Out of the 27 patients 3 (11.1%) have relapsed (17, 22 and 25 months) post completion of chemotherapy and were treated with another line of chemotherapy. The 2 years DFS was 90.9% with 95% of CI (73%-100%). Treatment was given outpatient, with no supportive therapy or toxic deaths and no secondary malignancy from etopsid Conclusions: This regimen provides high rate of durable remission in rural areas of Egypt with limited resources (drugs availability and supportive measures).

No significant financial relationships to disclose.
Identification of candidate tumor related genes using comprehensive gene expression analysis of neuroblastic tumors
Authors: Mora J. , Lavarino C. , Domenech G. , Rios J. , Gerald W. , De Torres C. , Cheung N.
Published: March 2020

9051

Background: Neuroblastic tumors (NBTs) represent a heterogeneous and relatively well defined spectrum of neoplastic diseases. We performed gene expression analysis to molecularly characterize the distinct clinicobiological subtypes of NBTs. Methods: Gene expression analysis of 106 NBTs (10 ganglioneuromas, 10 stage 4s, 29 loco-regional (stages 1, 2, 3), and 57 stage 4) and 12 neuroblastoma cell lines was performed using Affymetrix Genechip Human Genome U95 Set Arrays. Differential expression between predefined groups of biological and clinical relevance was determined by differences >3 standard deviations between the means for groups, step-down permutation and false discovery rate methods. Results: Gene expression analysis of clinically defined groups including stage 4 infants versus children, metastatic versus non metastatic, and stroma poor loco-regional versus stage 4, revealed that many differentially expressed genes mapped to chromosomal regions with well described recurrent abnormalities in NBTs (chromosomes 1, 11, 17, 19 and X). Pairwise comparison analysis of biologically defined groups, including triploid versus diploid/tetraploid NBTs, identified significantly discriminating genes that map to the same chromosomal regions. Gene expression analysis of MYCN-amplified versus MYCN non amplified NBTs, confirmed a functional overrepresentation for genes involved in protein biosynthesis. Conclusions: Gene expression profile analysis of clinically and biologically relevant subgroups of NBTs revealed differential expression of genes at specific chromosomal regions known to have strong association between genetic alterations and NBT clinical features. The identification of altered expression helps to define critical chromosomal regions and identify tumor related candidate genes within each region.

No significant financial relationships to disclose.
Gliomatosis Cerebri: A pediatric case series and review of the literature
Authors: Armstrong G. T. , Phillips P. C. , Rorke-Adams L. B. , Judkins A. , Localio A. R. , Fisher M. J.
Published: March 2020

9056

Background: Gliomatosis Cerebri (GC) is a rare and universally fatal glial neoplasm of the central nervous system. Although over 160 cases have been reported in the medical literature, the largest pediatric case series published to date includes only three patients. We describe the largest cohort to date of children with GC and explore relationships between potential prognostic factors, treatment, and survival. Methods: Imaging, pathologic, and outcome information were reviewed for this case series of thirteen patients diagnosed with GC and treated at the Children’s Hospital of Philadelphia (CHOP) between 1982 and 2005. All patients had GC confirmed by biopsy. Twelve patients were treated with cranial irradiation; eight of these received adjuvant chemotherapy as well. A single patient under one year of age was treated with chemotherapy alone. A review of the literature identified 51 reported cases of GC in the pediatric population. Results: The progression free survival (PFS) in the CHOP cohort was 13% (range: 1.5–22.5 months) and the overall survival rate (OS) was 64% (range: 6.5–27 months) at 2 years. Time to progression was significantly prolonged for those with no evidence of tumor enhancement on initial imaging (p = .03). OS was significantly shorter for patients who presented in the first decade of life (p = .04). When survival data from patients reported in the literature are combined with the CHOP cohort, treatment significantly prolonged OS (p = .003). Conclusions: Outcome in pediatric patients with GC is extremely poor, however treatment prolongs OS. Age less that 10 years and enhancement on MRI at diagnosis may be risk factors for shorter survival.

No significant financial relationships to disclose.
Results of chemotherapy (CT) based protocol for treatment of retinoblastoma (RB)
Authors: Goyal L. , Banavali S. , Bhagwat R. , Arora B. , Muckaden M. , Laskar S. , Padhye B. , Nicholson A. , Kurkure P. , Parikh P.
Published: March 2020

9068

Background: One the main reasons for delayed presentation of children with RB in India is non acceptance of enucleation. CT is being increasingly utilized as primary treatment of RB to reduce the tumor volume and thus avoid enucleation and/or external beam radiation (EBRT) in early stage disease and reduce the risk of relapse in advanced stage disease. Methods: This retrospective (from 1996 to 2001) study involved 62 Patients (pts) (30 were bilateral) who received CT consisting of monthly cycles of carboplatin, etoposide, vincristine and cyclophosphomide. Pts with stage I disease, were started on CT alone, whereas most of the other pts were also started on concurrent EBRT (50Gy). Where indicated, pts also received local therapy, usually cryotherapy & EBRT. Eyes which did not show response or had stable disease, were advised enucleation. Results: Majority of pts had Reese-Ellsworth groups IV-V (74.1%). 17 pts had Stg I, 22 Stg II, 17 Stg III & 6 Stg IV disease (St Jude’s). All pts received CT (median 12 cycles). Out of 92 eyes only 79 were evaluable (13 were already enucleated).The response rate was 73.2% (51.8% CR or near CR); 12.9% had progressive disease. 47 Pts (74%) received RT. Only 23 pts received focal treatment (Cryotherapy 15, laser 3, combination 5). Vision was present in 38 eyes (48.1%) at presentation. 26 eyes (68.4%) were finally saved with useful vision. 20 pts had recurrence. 18 have died (17 died of disease, 1 treatment related sepsis). In those following up in the clinic, survival is 77% for stage I; 78.5% for stage II; 41.6% for stage III. All stage IV pts have died except 1 with nodal disease. Conclusions: CT has a role in the management of RB, however unless it is coupled with good focal therapy the results are poor as shown here. Also longer follow-ups are required because of late recurrences. This data highlights that in developing countries the social reasons complicate patient treatment & compliance. Further efforts are needed to spread awareness of this disease so that patients are diagnosed and treated in earlier stages so as to improve the outcomes.

No significant financial relationships to disclose.
Sunitinib (SU) response in imatinib-resistant (IM-R) GIST correlates with KIT and PDGFRA mutation status
Authors: Heinrich M. C. , Maki R. G. , Corless C. L. , Antonescu C. R. , Fletcher J. A. , Fletcher C. D. , Huang X. , Baum C. M. , Demetri G. D.
Published: March 2020

9502

Background: IM resistance in advanced GIST represents a major clinical problem. SU (SU11248) is an oral multitargeted tyrosine kinase inhibitor with antitumor and antiangiogenic activities related to KIT, PDGFRs, VEGFRs, RET and FLT3 inhibition. SU has demonstrated efficacy in clinical trials of pts with IM-R GIST. Methods: This study examined the relationship between tumor kinase genotypes and SU clinical activity in 97 pts with metastatic IM-R GIST treated as part of a phase I/II trial. Tumors were imaged by CT or MRI for RECIST-defined response assessment. Tumor specimens were obtained prior to (n=76) and following (n=64) IM therapy and analyzed for primary or secondary KIT and PDGFRA mutations, respectively. Results: Clinical benefit (CB; defined as PR or SD >6 months) with SU was observed for all major molecular GIST subtypes: KIT exon 11 (42 pts, CB 36%), KIT exon 9 (19 pts, CB 42%), PDGFRA (4 pts, CB 25%), no KIT or PDGFRA mutation (wild-type [WT]; 9 pts, CB 56%). Notably, the PR rate for GISTS with primary KIT exon 9 mutations was 37%, vs 5% for KIT exon 11 mutations (P=0.003). PFS and OS were significantly longer for pts with either a primary KIT exon 9 mutation or WT KIT/PDGFRA compared with pts with a KIT exon 11 mutation (exon 9 vs 11: PFS P=0.0007, OS P=0.005; WT vs exon 11: PFS P=0.03, OS P=0.01). Secondary KIT mutations (in exons 13, 14, 17 or 18) were found in 62% of GISTs with a primary KIT exon 11 mutation, but only in 16% with a primary KIT exon 9 mutation (P=0.002). No secondary mutations were found in GISTs lacking a primary KIT/PDGFRA mutation. Biochemical profiling of secondary kinase mutations revealed in-vitro sensitivity of KIT exon 13 and 14 mutations to SU, while secondary KIT exon 17 and 18 mutations were resistant to SU in vitro. These in-vitro results were consistent with clinical results: CB was observed in 65% of pts with secondary KIT mutations in exon 13 or 14 and in only 9% of pts with secondary KIT exon 17 or 18 mutations (P=0.006). Conclusions: Our findings suggest that, similar to prior results observed using imatinib, CB of SU following failure of IM treatment is significantly influenced by both primary and secondary mutations in the predominant pathogenic kinase, the uncontrolled activity of which is a critical etiologic factor for GIST.

[Table: see text]
Sirolimus reduced tumor-related morbidity and resulted in biochemical and radiographic response in patients with progressive sarcoma
Authors: Schuetze S. M. , Baker L. H. , Maki R. G.
Published: March 2020

9503

Background: Chemotherapy options for palliative treatment of advanced sarcomas are limited and studies are underway to identify new classes of active agents. Second generation inhibitors of the mammalian target of rapamycin (mTOR) are being tested in phase II trials. Objective responses of sarcomas to the mTOR inhibitor AP23573 have been reported. Sirolimus (rapamycin) is a macrocyclic triene antibiotic that inhibits activation of S6 kinase, the cdk2/cyclinE complex and phosphorylation of retinoblastoma protein and causes cell cycle arrest in G1-S phase. Methods: We report the cases of four (out of 20) patients (pts) with progressive, metastatic sarcoma failing 2–6 chemotherapies treated with sirolimus and followed for clinical benefit. Sirolimus was self-administered daily with (n=2) or without (n=2) daily oral cyclophosphamide 200 mg every other week. Patients were followed in clinic for disease and toxicity assessments every 2 weeks. Molecular analysis of mTOR targets will be performed. Results: Patients with MFH, leiomyosarcoma, angiosarcoma and osteosarcoma were treated using 4–8 mg sirolimus daily for a median of 16 weeks (range 8–28 wks). Three pts were symptomatic from disease and had reduced performance status prior to treatment. All 3 pts had subjective improvement in tumor-related symptoms and 2 had improvement in performance status. LDH and bilirubin fell from 1,712 u/L and 5.6 mg/dl to 388 u/L and 1.1 mg/dl, respectively, in the pt with angiosarcoma during 3 months of sirolimus and cyclophosphamide. Alkaline phosphatase fell from 791 u/L to 120 u/L in the pt with osteosarcoma over 6 weeks of simolimus and cyclophosphamide. Three pts had minor radiographic improvement in tumor and remain on treatment. One pt has died of disease progression. Treatment was well tolerated. Conclusions: Sirolimus treatment was associated with improvement in tumor-related symptoms, performance status and biochemical markers of disease activity and inhibited tumor growth in pts with advanced sarcoma failing multiple prior therapies. Phase I studies of sirolimus in advanced cancer are underway at the University of Chicago. Formal study of sirolimus in advanced sarcoma is contemplated.

No significant financial relationships to disclose.
Response of gastrointestinal stromal tumors (GISTs) to imatinib by Choi criteria and response evaluation criteria in solid tumors (RECIST) as surrogates for survival and time to progression
Authors: Benjamin R. S. , Choi H. , Macapinlac H. A. , Burgess M. A. , Patel S. R. , Chen L. L. , Podoloff D. A. , Chuslip C.
Published: March 2020

9506

Background: Recent studies have demonstrated that RECIST is insensitive in evaluating GIST’s treated with imatinib. We have demonstrated in a small group of patients that a good response by Choi Criteria, i.e., a 10% decrease in unidimensional tumor size or a 15% decrease in tumor density on contrast-enhanced CT, correlated well with good response by PET (Proc. ASCO 22:819, 2003) and was more predictive of time to tumor progression (TTP) than response by RECIST (CTOS 2004). The aim of this study was to validate the correlation with disease-specific survival (DSS) and TTP with follow-up updated to 5-years. Methods: We evaluated 98 patients treated with imatinib for recurrent or metastatic GIST at our institution from December 2000 to September 2001 by RECIST and Choi criteria. All patients had pre-treatment and initial 2-monthly follow-up CT’s. DSS and TTP were analyzed by response category. Results: There were 28 (48%) good responders by RECIST and 30 (52%) poor responders. There were 49 (84%) good responders by Choi criteria, and 9 (16%) poor responders. Patients with good response by Choi criteria on CT at 8 weeks after treatment had significantly improved DSS (P = 0.04) in contrast to those with complete or partial response at any time by RECIST (P = 0.45). Similarly, TTP was significantly correlated with Choi response group (P = 0.01) but not with response group by RECIST (P = 0.74). Conclusions: Choi response criteria, incorporating tumor density and using small changes in tumor size on CT, are more sensitive and more accurate than RECIST in assessing the response of GISTs to imatinib mesylate and should be routinely incorporated into future studies of GIST therapy. Good response is detected earlier by Choi criteria and is a valid surrogate for DSS and TTP. We should desist using RECIST, at least in GIST. (Supported in part by NCI contracts U01-CA70172–01 and N01-CM-17003)

[Table: see text]
Consequences of different approaches to local treatment of Ewing’s sarcoma within an international randomised controlled trial: Analysis of EICESS-92
Authors: Whelan J. , McTiernan A. , Weston C. , Douglas C. , Grimer R. , Cassoni A. , Paulussen M. , Jurgens H. , Craft A. , Lewis I.
Published: March 2020

9533

Background: Two national clinical trial groups (NCTG 1 and 2) together undertook a randomised trial (EICESS-92) which addressed chemotherapy treatment options for Ewing’s sarcoma (ES). No significant differences were found in analysis of the randomised trial questions. A significantly greater use of surgery, with or without radiotherapy, to achieve local tumour control was noted in NCTG 1. The influence on overall outcome was investigated. Methods: Univariate and multivariate analysis of the trial data set was undertaken. Patient characteristics, recognised prognostic factors for ES and treatment factors were all examined. Results: In total, 647 patients (pts) were randomised (NCTG 1: 437 pts; NCTG 2: 210 pts). There were no differences between groups in patient characteristics, disease factors or in chemotherapy received. Surgery of the primary tumour (74.6% v 51%) and pre-operative radiotherapy (44.6% v 2.9%) were more commonly used by NCTG1. Radiotherapy alone was more commonly used by NCTG 2 (39% v 19.5%). Five year overall survival (OS) for the whole cohort was 62.1% (95%CI: 58.3 to 66.0). Five year OS was 66.5% (95% CI 62.0–71.1) for NCTG 1 and 54.3% (95% CI 47.3–61.4) for NCTG 2 (p=0.009). OS was best for those selected for surgery alone and worst for those treated with radiotherapy alone (p <0.001). OS was equivalent between groups for each modality of local treatment. Local recurrence rates for NCTG1 were 7.1% vs. 21.4% for NCGT2. Conclusions: Unexpected differences in OS can occur between patient cohorts recruited by study groups co-operating in international randomised trials. Higher rates of local recurrence and poorer survival were seen in NCTG 2. Failure to select or deliver appropriate local treatment modalities for ES may compromise chances of cure.

No significant financial relationships to disclose.
Gene expression profiles classifies the responsiveness of human osteosarcoma to doxorubicin, cisplatin and ifosfamide
Authors: Bruheim S. , Xi Y. , Nakajima G. , Ju J. , Fodstad O.
Published: March 2020

9534

Background: Despite the increased survival rates of osteosarcoma patients attributed to adjuvant chemotherapy, at least one third of the patients still succumb to their disease. Furthermore, ultra-aggressive combination chemotherapy is associated with considerable acute and long term toxicity. This is of particular concern in patients who may be cured by a simpler and less toxic regimens or do not have micrometastatic disease. Hence, further improvements in the management of osteosarcoma seemingly depend on diagnostic and prognostic tools that may allow for a more risk adapted and individualized treatment. Methods: We have used GE Uniset Human 20K microarrays to obtain gene expression profiles from a panel of ten unique human osteosarcoma xenografts. For each of the three drugs doxorubicin, cisplatin or ifosfamide the xenografts were grouped according to their response to chemotherapy, resistant, weakly sensitive or sensitive. For each individual drug, a one-way ANOVA test with a Benjamini and Hochberg multiple test correction allowing a false discovery rate of 5% (doxorubicin, cisplatin) or 2% (ifosfamide) was used to identify genes with significantly differential expression. In addition a 2-fold cut off was applied to exclude smaller but yet significant differences. Results: For doxorubicin and cisplatin, respectively 59 and 120 genes met these criteria. The expression levels of 25 genes overlapped between these two groups. For ifosfamide, 148 genes were selected, for 5 of them the expression overlapped with cisplatin sensitivity related genes. In the lists, genes involved in mediating and regulating apoptosis were abundant, such as regulators of TGF signaling, ubiquitin mediated protein degradation and members of the immediate early response protein family. Several genes which products interact with components of the cytoskeleton were also identified. Conclusion: We have used a unique strategy to screen for potential chemosensitivity markers by utilizing xenografts as training sets.

No significant financial relationships to disclose.
Dynamic contrast-enhanced Doppler ultrasound (DCE-US) is a useful radiological assessment to early predict the outcome of patients with gastrointestinal stromal tumors (GIST) treated with imatinib (IM)
Authors: Lamuraglia M. , Le Cesne A. , Chami L. , Bonvalot S. , Terrier P. , Tursz T. , Roche A. , Lassau N.
Published: March 2020

9539

Background: DCE-US combined with perfusion software VRI (Vascular Recognition Imaging) and contrast agent injection (Sonovue-Bracco) is a simple and reproductible imaging technique that allows an early and accurate evaluation of IM activity in GIST patients (Lassau et al, ASCO 2004). The objective of this study was to correlate the results observed with DCE-US with the outcome of c-Kit-positive GIST pts treated with IM and to early detect secondary resistance to IM. Methods: 36 pts with advanced GIST were prospectively included in a monocentric imaging trial. DCE-US was performed before IM administration (d0) on days 1, 7, 14, 60, and then every 3 months up to 33 months. The percentage of contrast uptake was evaluated on each tumor target by two radiologists and results were compared to PFS. Results: A total of 371 examinations were performed. At d7, the good responders (GR: 25 pts) and poor responders (PR: 11 pts) presented a statistically significant difference in contrast uptake of DCE-US (p=0.004). There was no significant difference between the 2 groups in tumor volume modification (WHO and RECIST criteria at 2 months). After a median follow-up of 510 days, the median PFS of GR an PR were 602 days and 252 days respectively. A resumption of contrast uptake, before any increase in tumor volume was depicted 6 months before any modification of CT-scan in 7 patients. Conclusion: DCE-US is a new functional non invasive imaging technique that allows: 1) to predict after d7 the PFS 2) an early evaluation of secondary resistance to IM.

No significant financial relationships to disclose.
Molecular profiling of malignant peritoneal mesothelioma identifies the ubiquitin-proteasome pathway as a therapeutic target in poor prognosis tumors
Authors: Antonini Cappellini G. , Borczuk A. , Kim H. , Hesdorffer M. , Taub R. , Powell C.
Published: March 2020

9549

Background: Malignant peritoneal mesothelioma (MPM) is an aggressive neoplasm derived from cells lining serosal membranes. The characteristics of the epithelial (E) type MPM are distinct from those of the biphasic and sarcomatous (BS) type tumors. The goal of our study was to examine the molecular basis for this distinction. Methods: We used global molecular profiling with DNA microarrays to identify pathways associated with histologic subtype of 16 MPM tumor specimens acquired from patients entered into pilot multimodality protocols at our Institution. We performed immunohistochemistry on a tissue microarray and quantitative-real time PCR to validate the microarray results. Results: We performed average linkage agglomerative hierarchical clustering using microdissected MPM specimens and normal peritoneal tissue. The tumors segregated into two clades associated with histological subtype, which were distinct from the controls. 476 genes were differentially expressed between E and BS histologic classes (P < .001, with permutation test P value of .001). To identify biologically important differentially expressed genes and pathways, we examined the functional annotation of mesothelioma histologic subtype classifiers using the Pathway Comparison tool of BRB-Array. Among the differentially expressed categories was the ubiquitin-proteasome (UP) pathway, which was upregulated in BS tumors. Cytoxicity experiments by MTS assay indicated that, by the computation of combination indexes of activity, cells derived from BS tumors were exquisitely sensitive to sequential combination regimens containing the proteasome inhibitor (PI) bortezomib and oxaliplatin. The mechanism of this synergistic response, which was not detected in cells of E tumor origin, was apoptosis. Conclusions: Together, our results identify the ubiquitin-proteasome pathway as a biomarker of poor prognosis biphasic and sarcomatous malignant peritoneal mesothelioma tumors and suggest that proteasome inhibitors could increase the effectiveness of cytotoxic chemotherapy in this subset of patients.

No significant financial relationships to disclose.
Pediatric-type sarcomas in adult patients: Age is an independent prognostic factor in IRS group I/II
Authors: Uhm J. E. , Park J. O. , Lee J. , Park B. B. , Ahn J. S. , Ahn M. J. , Park Y. S. , Lim H. Y. , Im Y. H. , Kang W. K. , Park K.
Published: March 2020

9552

Backgrounds: A number of pediatric sarcomas occur in adults, including Ewing’s sarcoma (EWS)/primitive neuroectodermal tumor (PNET) and rhabdomyosarcoma (RMS). However, these are rare in adult patients (pts) and differ from typical adult sarcomas in that they are generally considered as systemic disease. There is debate as to whether adults do worse than pediatric pts with the same stage of disease. This study was performed to investigate whether various clinical parameters such as tumor size, primary site, age at diagnosis and response to chemotherapy predict the outcome. Methods: 74 consecutive cases of previously untreated pts over 18 years who were diagnosed with EWS/PNET, RMS, and desmoplastic small round cell tumor (SRCT) between 1995 and 2005, were identified from the database at the Samsung Medical Center. Among them, 64 pts were reviewed retrospectively and 10 pts who were lost to follow up were excluded. All pts were treated by a multimodality therapeutic approach, including surgery, chemotherapy, and radiotherapy, based on the ongoing protocols at the time of diagnosis. Results: The median age of the patients was 28 years (range, 18 - 74 years) and the majority (62.5%) of patients was male. There were 35 (54.6%) cases of EWS/PNET, 25 (39.1%) of RMS and 4 (6.3%) of desmoplastic SRCT. 29 pts (45.3%) had metastatic disease and 42 pts (65.6%) were Intergroup RMS Study (IRS) groups III/IV at diagnosis. Median overall survival was 41.5 months (95% CI, 16.1–66.9 months) and 5 years-survival rates was 38.7% (95% CI, 26.7–50.6%) in all pts. In univariate analysis, age (p=0.015), IRS group (p=0.0007) and tumor size (p=0.044) were correlated with better survival. However, multivariate analysis showed that independent variables for better survival were age (p=0.017) and IRS group (p=0.016). In subset analysis, significant statistical correlation between age and overall survival was observed in pts with IRS group I/II. Notably, pts younger than 30 years showed favorable outcome. Conclusions: In this study, age at diagnosis and IRS group reflecting tumor burden were important prognostic factors. Therefore, it is necessary that adult pts with pediatric sarcomas should be included in pediatric protocols, whenever feasible, to provide proper management for the rare disease.

No significant financial relationships to disclose.
Liposomal anthracyclines and ifosfamide in the first line treatment of advanced soft tissue sarcomas: A two cohort phase II study
Authors: Siehl J. M. , Thiel E. , Schmittel A. , Hütter G. , Keilholz U.
Published: March 2020

9563

Objectives: The current first line standard chemotherapy for advanced soft-tissue sarcomas is the combination of doxorubicine and ifosfamide. Liposomal encapsulation is a strategy pursued to reduce toxicity and improve tumor uptake. There are so far only limited systematic data regarding the efficacy of liposomal anthracyclines in advanced soft-tissue sarcomas. We have previously reported on a phase II study with liposomal daunorubicine (L-Dauno) with ifosfamide, named IDx1. Here we report on an additional cohort of the phase II study using liposomal doxorubicine (L-Doxo). Methods: In a single-arm two cohort phase II study 55 patients with advanced soft-tissue sarcoma had received first line a maximum of 6 cycles (median 2 cycles) of ifosphamide (5 g/m2) and in cohort 1 L-Dauno (100 mg/m2, 40 patients) or in cohort 2 the approximate equivalent of L-Doxo (75 mg/m2, 15 patients). Cycles were repeated every 4 weeks in absence of disease progression. Primary study endpoint was response rate. Results: The overall response rate was 25% (n = 14). In the L-Dauno group the results were as follows: CR 3% (n = 1), PR 29% (n = 10), SD 17% (n = 6), PD 37% (n = 13), NED or intermittent death 14% (n = 5), and in the L-Doxo group: PR 20% (n =3), SD 26% (n =4) and PD 53% (n = 8). Interestingly, all three liposarcoma patients (two in the L-Dauno group, one in the L-Doxo group) responded, whereas liposarcoma usually carries a poor response rate. For both combinations toxicity was similarly tolerable with short episodes of hematotoxicity (leucocyte nadir on day 9, platelet nadir on day 11), 11 febrile episodes, no grade 3 or 4 mucositis, no cardiac toxicity and 5 episodes of grade 2 acute ifosfamide-related CNS-toxicity. Based on the hematotoxicity kinetics, three weekly regimens appear feasible. Conclusion: The combination of liposomal anthracyclines and ifosfamide is a safe and effective first line regimen in the treatment for advanced soft tissue sarcoma. Further evaluation in a randomized trial will be pursued. The unexpected high responsiveness of liposarcoma warrants further phase II investigation. 1Siehl JM et al. Cancer 2005.

No significant financial relationships to disclose.
The mechanism of human angiosarcoma drug resistance
Authors: Ravi V. , Henry D. , Chen S. , Wong M. K.
Published: March 2020

9567

Background: Angiosarcoma (AS) is a malignant neoplasm of endothelial cells. AS has an extremely poor outcome since it can metastasize widely and rapidly becomes chemoresistant. Understanding the mechanism of this resistance is important not only because of the critical need for new therapeutic strategies in sarcoma, but also since it sheds light on important pathways in endothelial growth that may help understand tumor angiogenesis. Methods/Results: We have established and characterized stable pre-chemotherapy (named B8) and chemotherapy-resistant (named D3) angiosarcoma cell lines from an individual patient with primary (non radiated) breast angiosarcoma prior to initiation of chemotherapy and later after development of resistance to adriamycin, ifosfamide, gemcitabine, docetaxel, paclitaxel, interferon, thalidomide and bevacizumab. D3 cells differ dramatically from B8s in morphology and function. Prechemotherapy B8 cells assume a polygonal morphology reminiscent of native endothelial cells, the D3 cells throw out long processes that span several cell lengths, and do not appear to contact-inhibit. Migration and invasion assays confirm the highly motile nature of these cells. Although it is not surprising that the D3 cells were doxorubicin resistant, we found that unlike the B8 cells, the D3 cells actively transcribe VEGF. In keeping with this, D3 cells are relatively more sensitive to growth inhibition by the anti-VEGF drug bevacizumab than chemonaïve B8 cells. Conclusion: These studies reveal two avenues to target chemoresistant human angiosarcoma; via agents affecting cell migration and those agents that target the VEGF pathway.

No significant financial relationships to disclose.
Aromatase inhibitors (AI) are highly effective in uterine sarcomas (US) expressing estrogen receptors
Authors: Fayette J. , Ray-Coquard I. , Bompas E. , Zufferey L. , Tabone-Eglinger S. , Ranchère D. , Thiesse P. , Méeus P. , Sunyach M. , Blay J.
Published: March 2020

9576

Background: US frequently recur despite adequate locoregional treatments. Estrogen (ER) and progesterone (PR) receptors are expressed by 43–88% of US, mostly in endometrial stromal sarcomas (ESS) without correlation with survival. Whether hormonal treatment may be useful in estrogenreceptor (ER) expressing connective tumors of the uterus and pelvis is not known. Here, we report on the clinical antitumor effect of aromatase inhibitors (AI) in patients with US. Methods: Since september 2002, 8 menopaused women relapsing uterine leiomyosarcoma, ESS or intravascular leiomyomatosis, (all of grade 1 or 2 in WHO grading) were treated with AI (letrozole, n=5 or anastrozole, n=3). Median age was 62 (41–84), 7/8 expressed ER and 8/8 progesterone (PgR). Progression free, overall survival, and response to AI in evaluable patients were analyzed. Results: After a median follow-up of 16.5 months [1–38], 6 patients are currently non progressive under treatment by AI, without toxicity. All 8 (100%) evaluable patients experienced tumor control with 2 complete response -CR- (1 after lung surgery 25+, 38+), 2 PR (21 and 17+) and 4 stabilizations -SD- (15 months and at 1+, 3+ and 9+ months). Time to response was 3, 5 and 6 months respectively. Two patients progressed after 15 and 21 months; 3 patients are currently treated after 17+, 25+ and 38+ months. At 2 years. Median survival was not reached. 2 years DFS is 60% currently. Conclusions: AI enables prolonged progression free survival in uterine sarcoma expressing hormonal receptors. A prospective study for treatment of relapses and later in adjuvant setting is needed in these rare diseases.

No significant financial relationships to disclose.
Defining intracellular signaling targets in soft tissue sarcoma (STS) using immunohistochemical staining (IHC)
Authors: Forman D. A. , Scarlato M. , Brown R. E. , Amadio C. , Friedman E. L. , Berman S. , Robertson G. , Mosca P. , Nair S. G.
Published: March 2020

9577

Background: Pathologic events pertaining to the intracellular cell signaling pathway are now being recognized to be directly or indirectly responsible for oncogenic transformation in a variety of malignancies. Many drugs are now available which can block key steps of these signaling pathways. We sought to use IHC stains of previously stored sarcoma specimens to determine if expression of potential molecular targets (mTOR, p 70 S6 Kinase, ERK1/2, NF Kappa B) is present. Methods: Using tumor registry data, our three most common adult STS histopathologic subtypes were identified, and paraffin embedded tissue blocks representing these histologies were retrieved. Each block was reviewed for tissue adequacy. The blocks were cut and then stained with the aforementioned phosphorylated IHC stains (Cell Signal Technologies). Slides were graded on intensity of stain uptake (0–3+) and percentage of cells staining. A particular IHC stain was considered positive if 10% or more cells were stained 1+ or greater in intensity. Results: Seventeen Malignant Fibrous Histiocytomas (MFH), 20 Leiomyosarcomas (LMS) and 7 Liposarcomas were stained for the presence of p-mTOR, p-p70S6 Kinase, p ERK1/2, and p-NF Kappa B. Data for NF Kappa B will be presented at the meeting. The results are summarized in the table below. Conclusions: Pathways involving ERK appear to be active in more frequently diagnosed Sarcomas. Slightly more than half of the MFHs we studied expressed phosphorylated ERK1/2. Further exploration of this pathway, as well as mTOR, as potential targets of therapeutic intervention is indicated in STS.

[Table: see text]

No significant financial relationships to disclose.
The Influence of Hemorrhagic Shock on the Disposition and Effects of Intravenous Anesthetics: A Narrative Review
Authors: Egan Ezekiel D. , Johnson Ken B.
Published: March 2020

The need to reduce the dose of intravenous anesthetic in the setting of hemorrhagic shock is a well-established clinical dogma. Considered collectively,; the body of information concerning the behavior of intravenous anesthetics during hemorrhagic shock, drawn from animal and human data, confirms that clinical dogma and informs the rational selection and administration of intravenous anesthetics in the setting of hemorrhagic shock. The physiologic changes during hemorrhagic shock can alter pharmacokinetics and pharmacodynamics of intravenous anesthetics. Decreased size of the central compartment and central clearance caused by shock physiology lead to an altered dose-concentration relationship. For most agents and adjuncts, shock leads to substantially higher concentrations and increased effect. The notable exception is etomidate, which has relatively unchanged pharmacokinetics during shock. Increased concentrations lead to increased primary effect as well as increased side effects, notably cardiovascular effects. Pharmacokinetic changes are essentially reversed for all agents by fluid resuscitation. Propofol is unique among agents in that, in addition to the pharmacokinetic changes, it exhibits increased potency during shock. The pharmacodynamic changes of propofol persist despite fluid resuscitation. The persistence of these pharmacodynamic changes during shock is unlikely to be due to increased endogenous opiates, but is most likely due to increased fraction of unbound propofol. The stage of shock also appears to influence the pharmacologic changes. The changes are more rapid and pronounced as shock physiology progresses to the uncompensated stage. Although scant, human data corroborate the findings of animal studies. Both the animal and human data inform the rational selection and administration of intravenous anesthetics in the setting of hemorrhagic shock. The well-entrenched clinical dogma that etomidate is a preferred induction agent in patients experiencing hemorrhagic shock is firmly supported by the evidence. Propofol is a poor choice for induction or maintenance of anesthesia in severely bleeding patients, even with resuscitation; this can include emergent trauma cases or scheduled cases that routinely have mild or moderate blood loss.
Zika virus non-structural protein NS4A restricts eye growth inDrosophilathrough regulation of JAK/STAT signaling
Authors: Harsh Sneh , Fu Yulong , Kenney Eric , Han Zhe , Eleftherianos Ioannis
Published: March 2020

To gain a comprehensive view of the changes in host gene expression underlying Zika virus (ZIKV) pathogenesis, we performed whole-genome mRNAseq of ZIKV infected Drosophila adult flies. RNA-seq analysis revealed that ZIKV infection alters several and diverse biological processes including stress, locomotion, lipid metabolism, imaginal disc morphogenesis and regulation of JAK/STAT signaling, To explore the interaction between ZIKV infection and JAK/STAT signaling regulation, we generated genetic constructs overexpressing ZIKV-specific non-structural proteins NS2A, NS2B, NS4A and NS4B. We find that ectopic expression of non-structural proteins in the developing Drosophila eye significantly restricts growth of the larval and adult eye and correlates with a considerable repression of the in vivo JAK/STAT reporter, 10XStat92E-GFP. At the cellular level, eye growth defects are associated with reduced rate of proliferation without affecting the overall rate of apoptosis. In addition, ZIKV NS4A genetically interacts with the JAK/STAT signaling components; co-expression of NS4A along with dominant negative form of domeless or StatRNAi results in aggravated reduction in eye size while co-expression of NS4A in HopTuml mutant background partially rescues the Hop-induced eye overgrowth phenotype. The function of ZIKV NS4A in regulating growth is maintained in the wing, where ZIKV NS4A overexpression in the pouch domain results in reduced growth linked with diminished expression of Notch targets, Wingless and Cut and the Notch reporter, NRE-GFP. Thus, our study provides evidence that ZIKV infection in Drosophila results in restricted growth of the developing eye and wing, wherein eye phenotype is induced through regulation of JAK/STAT signaling while restricted wing growth is through regulation of Notch signaling. The interaction of ZIKV non-structural proteins with the conserved host signaling pathways further advance our understanding of ZIKV-induced pathogenesis.
Cofilin regulates axon growth and branching of Drosophila γ-neurons
Authors: Sudarsanam Sriram , Yaniv Shiri , Meltzer Hagar , Schuldiner Oren
Published: March 2020

The mechanisms that control intrinsic axon growth potential, and thus axon regeneration following injury, are not well understood. Developmental axon regrowth of Drosophila mushroom body γ-neurons during neuronal remodeling offers a unique opportunity to study the molecular mechanisms controlling intrinsic growth potential. Motivated by the recently uncovered developmental expression atlas of γ-neurons, we here focus on the role of the actin-severing protein cofilin during axon regrowth. We show that Twinstar (Tsr), the fly cofilin, is a crucial regulator of both axon growth and branching during developmental remodeling of γ-neurons. tsr mutant axons demonstrate growth defects both in vivo and in vitro, and also exhibit actin-rich filopodial-like structures at failed branch points in vivo. Our data is inconsistent with Tsr being important for increasing G-actin availability. Furthermore, analysis of microtubule localization suggests that Tsr is required for microtubule infiltration into the axon tips and branch points. Taken together, we show that Tsr promotes axon growth and branching, likely by clearing F-actin to facilitate protrusion of microtubules.
MEDIDAS PROVISÓRIAS APÓS A EC 32/2001: UM DIAGNÓSTICO JURÍDICO DA REGULAÇÃO SOCIAL NO BRASIL
Authors: Vasconcelos Fabio , Sganzerla Rogerio Barros , Cunha Brenda , Amaral Thiago Bottino do
Published: March 2020

Este estudo tem como objetivo identificar diversos padrões existentes dentro do processo legislativo com a edição de Medidas Provisórias a partir da Emenda Constitucional nº 32/2001 e os seus impactos dentro do ordenamento jurídico brasileiro. A análise se refere ao período posterior à edição da EC nº 32/2001, quando o Congresso Nacional procurou disciplinar o uso desse instrumento, sob o argumento de que o excesso de MPVs retirava prerrogativas do Legislativo. Partindo da metodologia adotada por Figueiredo e Limongi no período 19881995, verificamos que, após 2009, há um aumento na edição de Medidas Provisórias que tratavam de temas sociais. Até a EC nº 32/2001, elas representavam cerca de 19%. Após essa data, passou a representar 33%. As análises das MPVs da área social indicaram que os temas mais frequentes foram trabalho e emprego (9,35%), política energética (8,24%) e educação (8,02%). Além disso, os dados demonstram que as alterações únicas (cria, altera ou revoga) de trechos de leis apresentam frequência de 55%, enquanto mudanças múltiplas no ordenamento jurídico brasileiro chegam a 45%.
Hard, Harder, and the Hardest Problem: The Society of Cognitive Selves
Authors: Rayudu Posina Venkata
Published: March 2020

The hard problem of consciousness is explicating how moving matter becomes thinking matter. Harder yet is the problem of spelling out the mutual determinations of individual experiences and the experiencing self. Determining how the collective social consciousness influences and is influenced by the individual selves constituting the society is the hardest problem. Drawing parallels between individual cognition and the collective knowing of mathematical science, here we present a conceptualization of the cognitive dimension of the self. Our abstraction of the relations between the physical world, biological brain, mind, intuition, consciousness, cognitive self, and the society can facilitate the construction of the conceptual repertoire required for an explicit science of the self within human society.
Estado nutricional en adultos de población rural en un cantón de la sierra ecuatoriana
Authors: Romero Viamonte Katherine , Sánchez Martínez Belkis , Vega Falcón Vladimir , Salvent Tames Adrian
Published: March 2020

Introducción: La desnutrición es un problema de salud en el mundo, y la Sierra ecuatoriana es una región bastante afectada por dicha situación. En esta investigación, se evaluó el estado nutricional de la población adulta no hospitalizada de un cantón de dicha zona. Materiales y métodos: se realizó un estudio observacional, descriptivo, de corte transversal en una muestra de 115 pacientes adultos del cantón Cevallos, en la región Sierra del Ecuador durante el periodo de abril a septiembre del 2016. Para determinar el estado nutricional, se utilizó el cálculo del índice de masa corporal. Las enfermedades asociadas se determinaron a partir de la anamnesis de cada uno de los pacientes. Todos los resultados fueron evaluados mediante la determinación de valores porcentuales y se utilizó el coeficiente de correlación de Pearson para determinar la relación entre estado nutricional y enfermedades asociadas. Resultados: el 82.61 % de los pacientes estaban desnutridos. El 69.56 % presentaba enfermedades asociadas a un predominio de hipertensión arterial (41.84 %), diabetes mellitus (21.44 %) y cardiopatía isquémica (18.37 %). La correlación desnutrición-enfermedades asociadas fue prácticamente nula. Conclusiones: conocer el estado de salud de la población de los adultos pertenecientes al cantón Cevallos, permitió crear los espacios necesarios para garantizar atención médica en el desarrollo de las actividades de la población, así como diseñar un programa de charlas educativas para los beneficiarios.
Implementación del Convenio Marco de la Organización Mundial de la Salud para el Control del Tabaco y la Prevención del Cáncer en Colombia
Authors: Tellez Neira Luis Miguel , Romero-Torres Sandra , Calderón Cortés Maria Isabel
Published: March 2020

Introducción: el tabaquismo es un problema global. Un problema tan importante que hizo que la Organización Mundial de la Salud liderara el Convenio Marco Para el Control del Tabaco, del cual son parte la gran mayoría de países del mundo. En ese contexto, Colombia ha realizado varias acciones para reducir la prevalencia del tabaquismo; estas acciones están enmarcadas en el Plan Decenal para el Control del Cáncer 2012-2021. Desarrollo: se analizó la implementación de las acciones planteadas por el Plan Decenal para el Control del Cáncer y su correlación con el Convenio Marco de la Organización Mundial de la Salud, bajo la implementación del Plan de Medidas mpower. Conclusiones: Colombia ha implementado varias estrategias para el control del tabaco, enmarcadas en el Plan Decenal para el Control del Cáncer. Entre estas estrategias, se encuentra un sistema de vigilancia del consumo de tabaco, políticas de control, espacios cien por ciento libres de humo de tabaco, el Programa para la Cesación del Consumo de Tabaco y Atención del Tabaquismo, advertencias sanitarias moderadas, campañas de comunicación, prohibición completa de publicidad, promoción y patrocinio, así como un aumento de los impuestos al tabaco. A pesar de estas implementaciones, el reto actual es intervenir aquellas medidas en las que menos se ha trabajado o que han tenido menor resultado para lograr que el control del tabaquismo sea más efectivo; también es necesario hacer frente al uso de cigarrillos electrónicos. Las medidas descritas deberían implementarse sin la interferencia de la industria tabacalera.
Being bullied as a midwifery student: does age matter?
Authors: Capper Tanya , Muurlink Olav , Williamson Moira
Published: March 2020

Clinical placement is a compulsory component of midwifery education and a time when some midwifery students become targets of workplace bullying. An anonymous, online qualitative survey was used to collect data from two contrasting groups of purposively recruited UK and Australian midwifery students that responded to a call for experiences of bullying while on clinical placement. Participants in group were either aged between 18–21 years (n=20) or over 43 years of age (n=20). The data collected from each group was thematically analysed and compared. While younger midwifery students have an additional power disadvantage compared to their older counterparts, the pattern of bullying experience between the two groups was remarkably similar. Younger students however, experience more verbal and overt forms, and are more likely to respond passively to the experience. Results are discussed in terms of impact on individual welfare and the viability of the profession.