Discordance between central versus local response assessments in neuroendocrine tumor (NET) patients (pts) enrolled in A021202.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 361-361
Author(s):  
Susan Michelle Geyer ◽  
Michelle R. Mahoney ◽  
Timothy R. Asmis ◽  
Nathan Hall ◽  
Sanja Karovic ◽  
...  
Keyword(s):  
Real Time ◽  
Study Drug ◽  
Progression Free Survival ◽  
Disease Spread ◽  
Kappa Statistics ◽  
Primary Tumor Site ◽  
Randomized Phase Ii ◽  
High Prevalence ◽  
Serial Images ◽  
High Degree

361 Background: Assessment of tumor response in extrapancreatic NETs with metastases can be very challenging. Previous studies suggest a high degree of discordance between local and central imaging reviews, which has implications for clinical practice and trial design. Methods: Serial images archived from a randomized phase II trial (A021202) of pazopanib vs placebo in progressive non-pancreatic NETs were evaluated by central review, with real-time review conducted at the time of locally interpreted progressive disease (PD). The primary endpoint of the trial was progression-free survival (PFS) by central review. Discordances between central (Alliance Imaging Core Laboratory) and local (investigator-reported) reviews were assessed. Scan-level and pt-level results across both treatment arms were evaluated. Kappa tests were used to test concordance based on source of review. Results: 151 pts had a total of 724 scans with response adjudication by both local and central RECIST review. Discordance was observed in both directions. Overall, 20% of scans (143/724) had discordant classifications. The most common discordances were: stable disease (SD) on local vs. PD on central review (82/143=57%), and PD on local vs. SD on central review (32/143=22%). On a pt level, 78 of 151 pts (52%) had discordant reviews; 8 had >1 type of discordance. Overall, 30% of pts (N=45) had a determination of PD on central review, but SD or better on local review, potentially resulting in excessive exposure to therapy. In contrast, 20% (N=30) were classified as PD on local read but SD or better on real-time central review (which did not necessarily translate into an abbreviated course of treatment). Cohen’s kappa statistics revealed only moderate concordance between local and central reviewers both at the scan (K=0.48, 95% CI: 0.42 – 0.55) and pt (K=0.41, 95% CI: 0.32 – 0.5) levels, with no significant influence by treatment arm, primary tumor site, tumor functionality, histology, differentiation or primary disease spread. Conclusions: Discordance was observed in both directions, where 30% of pts were potentially kept on study drug too long (based on central read), and 20% would have been taken off study treatment early for local PD were it not for real-time central review. Although this bidirectional discordance did not affect the overall findings of the PFS outcome between arms in the trial, these analyses highlight the high prevalence of discordance, the potential to negatively influence treatment duration in both directions, and the need for more straightforward methods of assessing treatment response in carcinoid. Support: U10CA180821, U10CA180882, U24CA196171; NETRF Investigator Award; https://acknowledgments.alliancefound.org Clinical trial information: NCT01841736.

Efficacy and safety of CetuGEX in recurrent/metastatic squamous cell carcinoma of the head and neck (RM-HNSCC): Results from the randomized phase II RESGEX study.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 59-59 ◽  
Author(s):  
Ulrich Keilholz ◽  
Andrzej Kawecki ◽  
Andreas Dietz ◽  
Bogdan Zurawski ◽  
Michael Schenker ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Primary Endpoint ◽  
Single Agent ◽  
Objective Response ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Primary Tumor Site ◽  
Randomized Phase Ii ◽  
Secondary Endpoints ◽  
Epidermal Growth

59 Background: Standard treatment for RM-HNSCC is a combination of cisplatin (P), 5-FU (F), and the epidermal growth factor receptor (EGFR) blocking monoclonal antibody cetuximab. CetuGEX is a new monoclonal antibody sharing the identical EGFR-binding domain with cetuximab, but a modified Fc part by a proprietary glycosylation method to optimize antibody dependent cellular cytotoxicity (ADCC). Methods: Patients with RM-HNSCC without relevant comorbidities were randomized to receive up to 6 cycles of P 100 mg/m2, F 4 x 1000 mg/m2/24hrs and CetuGEX vs. cetuximab. Initial dose of cetuximab was 400mg/m2, followed by weekly 250 mg/m2. CetuGEX was given as 990 mg, followed by weekly 720 mg. After end of combination treatment, patients received single agent antibody maintenance until disease progression or intolerable toxicity. Stratification factors included FcγRIIIa status, primary tumor site, EGFR pretreatment vs. naïve, and recurrent vs. metastatic disease. Primary endpoint was progression-free survival (PFS) by immune related response criteria (irRC). Secondary endpoints included objective response rate (ORR), clinical benefit rate (CBR) and overall survival (OS) as well as safety and QoL. Results: During Jan 2014 and Feb 2016, 240 patients were accrued in 34 European centers, of which 123 received cetuximab and 117 CetuGEX. The median follow-up was 15 month until May 2017. No difference was observed for the primary endpoint of PFS by irRC [median 27.7 (CetuGEX) and 26.4 (cetuximab) weeks; HR 1.003; 95%-CI 0.738 – 1.363; p = 0.98]. No advantage of CetuGEX over cetuximab was observed for all other secondary efficacy endpoints and subgroup analyses by stratification factors. Infusion related reactions (IRR) were higher for CetuGEX (38.8%) than for cetuximab (5.7%) (Pearson chi2= 37.08; p < 0.0001), but without sequelae. Conclusions: The RESGEX study is the first head-to-head comparison of an ADCC-optimized to a conventional EGFR-directed antibody. The study failed to show superior efficacy of CetuGEX over cetuximab. Both compounds appear to have the same efficacy and a similar safety profile. Glycosylation changes in the Fc part induced more IRRs. Clinical trial information: NCT02052960.

Randomized phase II CTEP study of MK2206 versus everolimus in VEGF inhibitor refractory renal cell carcinoma patients.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 4517-4517 ◽  
Author(s):  
Eric Jonasch ◽  
Paul Gettys Corn ◽  
Lance C. Pagliaro ◽  
Primo Lara ◽  
Xuemei Wang ◽  
...  
Keyword(s):  
Phase Ii ◽  
Study Drug ◽  
Progression Free Survival ◽  
Pi3k Pathway ◽  
P Value ◽  
Vegf Inhibitor ◽  
Anti Vegf ◽  
Randomized Phase Ii ◽  
Secondary Endpoints ◽  
Grade 3

4517 Background: Up-regulation of the phosphoinositide-3 phosphate kinase (PI3K) pathway is associated with poorer prognosis in pts with advanced RCC. We hypothesized that optimal blockade of AKT in pts refractory to anti-VEGF therapy eliminates key drivers of tumor growth and proangiogenic signaling, and will prolong progression-free survival (PFS). We tested whether MK-2206, a selective allosteric inhibitor of AKT, will yield superior PFS to everolimus in anti-VEGF therapy refractory RCC pts. Methods: Eligible pts with metastatic RCC who progressed on an anti-VEGF agent were randomized (2:1 ratio) to receive MK2206 or everolimus. Up to two prior therapies allowed. Primary endpoint was PFS. The study had 80% power to detect a 67% increase in PFS with MK2206 over everolimus (8.2 vs. 4.9 mo) with a 1-sided log-rank at alpha= 0.10. One interim futility analysis was planned. Secondary endpoints: safety, overall survival, & response rate. Tumor tissue was collected in correlative analyses. Results: A total of 43 patients were accrued; 42 were evaluable for efficacy. Demographics: Male, 77%;White, 81%; median age 62 (range 41-83). MK2206 was held in 3 pts due to grade 3 rash; 1 came off study for rash. No everolimus pt discontinued study drug due to AEs. 30 events had occurred at first futility analysis. The 1-sided log-rank p-value for rejecting null hypothesis was 0.979, exceeding p-value boundary of 0.6413 for stopping trial. Median PFS for MK2206 was 3.65 mo (95%CI 1.77-5.52) and 7.43 mo for everolimus (95%CI 1.84-13.27). Two out of 29 MK2206 pts demonstrated dramatic response with greater than 50% disease regression and PFS of 8 months and 6 months (ongoing). Conclusions: Monotherapy with MK2206 was not superior to everolimus in this randomized, phase II study. However, dramatic response to MK2206 was seen in a subset of patients. Planned translational studies to allow genotype-phenotype correlations may help explain this observation. Clinical trial information: NCT01239342.

ANTICYTOKINE ACTIVITY OF THE PROTOZOA BLASTOCYSTIS SPP

2020 ◽  
pp. 44-48
Author(s):  
Bugero N.V. ◽  
Ilyina N.A. ◽  
Aleksandrova S.M.
Keyword(s):  
Gastrointestinal Tract ◽  
Gastrointestinal Diseases ◽  
Control Group ◽  
Ulcer Disease ◽  
Cytokine Balance ◽  
High Prevalence ◽  
Blastocystis Spp ◽  
High Level ◽  
Eukaryotic Organisms ◽  
High Degree

In addition to the classical pathogens, which are well understood and well identified, new pathogens with the potential to spread epidemiologically are being identified. Some of these little-known organisms are the simplest Blastocystis spp. blastocystostosis. The clinical significance of Blastocystis spp. and its pathogenicity are still under discussion. This parasite belongs to a group of single-celled eukaryotic organisms living in the colon of the human intestine. Blastocystis spp. is known to be found both in people with reduced immune status and in individuals without any clinical manifestation. It has been established that a sufficiently high degree of invasiveness is observed in persons with gastrointestinal tract diseases, dermatosis, allergic reactions, in patients with carriers of the human immunodeficiency virus, etc. Possessing persistence factors, protozoa blastocysts contribute to the inactivation of host defensive mechanisms, providing a stable anthogonistic effect. In recent years, many works have been devoted to the characteristics of the persistent properties of Blastocystis spr., however, individual properties of blastocysts, in particular, anticytokine activity (ACA), have not yet been studied. In this regard, the work studied the anticytokine activity of microorganisms isolated from healthy subjects and patients with gastrointestinal tract diseases. A high prevalence of the studied characteristic in the subjects was shown. The expression of anticytokine activity in the obtained isolates of blastocysts was the highest in the group of persons with gastric ulcer disease, which decreased in the order of duodenal ulcer, chronic cholecystitis, chronic gastritis, etc. The data obtained in this work on the high level of ACA expression in blastocyst isolates obtained from individuals with gastrointestinal diseases as compared with the control group enables to conclude that their exometabolites may influence the local cytokine balance [1], which supports the inflammatory process.

scholarly journals The case for tracking misinformation the way we track disease

2021 ◽  
Vol 8 (1) ◽  
pp. 205395172110138
Author(s):  
Erika Bonnevie ◽  
Jennifer Sittig ◽  
Joe Smyser
Keyword(s):  
Public Health ◽  
Real Time ◽  
Supervised Machine Learning ◽  
Disease Spread ◽  
The Public ◽  
Monitoring Tools ◽  
Core Function ◽  
Public Health Organizations ◽  
Front Line Workers ◽  
Media Data

While public health organizations can detect disease spread, few can monitor and respond to real-time misinformation. Misinformation risks the public’s health, the credibility of institutions, and the safety of experts and front-line workers. Big Data, and specifically publicly available media data, can play a significant role in understanding and responding to misinformation. The Public Good Projects uses supervised machine learning to aggregate and code millions of conversations relating to vaccines and the COVID-19 pandemic broadly, in real-time. Public health researchers supervise this process daily, and provide insights to practitioners across a range of disciplines. Through this work, we have gleaned three lessons to address misinformation. (1) Sources of vaccine misinformation are known; there is a need to operationalize learnings and engage the pro-vaccination majority in debunking vaccine-related misinformation. (2) Existing systems can identify and track threats against health experts and institutions, which have been subject to unprecedented harassment. This supports their safety and helps prevent the further erosion of trust in public institutions. (3) Responses to misinformation should draw from cross-sector crisis management best practices and address coordination gaps. Real-time monitoring and addressing misinformation should be a core function of public health, and public health should be a core use case for data scientists developing monitoring tools. The tools to accomplish these tasks are available; it remains up to us to prioritize them.

scholarly journals Porcine Gammaherpesviruses in Italian Commercial Swine Population: Frequent but Harmless

Pathogens ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 47
Author(s):  
Giovanni Franzo ◽  
Michele Drigo ◽  
Matteo Legnardi ◽  
Laura Grassi ◽  
Maria Luisa Menandro ◽  
...  
Keyword(s):  
Real Time ◽  
Real Time Pcr ◽  
Clinical Signs ◽  
Northern Italy ◽  
Porcine Circovirus ◽  
Swine Industry ◽  
Positive Interaction ◽  
High Prevalence ◽  
Swine Population ◽  
Clinical Conditions

Differently from alpha- and betaherpesviruses affecting swine, interest in the recently discovered Suid gammaherpesvirus 3, Suid gammaherpesvirus 4, and Suid gammaherpesvirus 5, also known as porcine lymphotropic herpesviruses (PLHV-1, PLHV-2, and PLHV-3), has largely focused on their role as potential zoonotic agents in cases of xenotransplantation. However, their role as primary pathogens of swine or as co-factors for other lymphotropic infections has essentially been neglected. The present study aims at filling this gap, evaluating the association between PLHVs infection and different clinical conditions and/or porcine circovirus (PCV) co-infection. One hundred seventy-six samples were obtained from different animals located in a high-density pig area of Northern Italy in the period 2017–2020. The presence of PLHVs and PCVs was tested and quantified by specific real-time PCR: PLHVs were widespread among pigs (PLHV-1, PLHV-2, and PLHV-3 prevalence was 28.97%, 10.79%, and 4.54%, respectively) and detected in all considered tissues and clinical conditions. Frequent co-infections were also observed among PLHVs and with PCVs, although a significant association was not detected with the exception of a positive interaction between PLHV-1 and PLHV-3, and a negative one between PLHV-2 and PCV-2. Significantly, no association between PLHVs, alone or in co-infection, emerged with any of the considered clinical signs, their frequency being comparable between healthy and diseased animals. Based on these pieces of evidence and despite their high prevalence, PLHVs’ relevance for the swine industry appears negligible, either as primary pathogens or as predisposing factors for circovirus-induced diseases.

scholarly journals Identification of effective spreaders in contact networks using dynamical influence

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Ruaridh A. Clark ◽  
Malcolm Macdonald
Keyword(s):  
Disease Transmission ◽  
Average Rate ◽  
Laplacian Matrix ◽  
Disease Spread ◽  
Eigenvector Centrality ◽  
Contact Networks ◽  
Human Contact ◽  
Spread Dynamics ◽  
Definition Of ◽  
High Degree

AbstractContact networks provide insights on disease spread due to the duration of close proximity interactions. For systems governed by consensus dynamics, network structure is key to optimising the spread of information. For disease spread over contact networks, the structure would be expected to be similarly influential. However, metrics that are essentially agnostic to the network’s structure, such as weighted degree (strength) centrality and its variants, perform near-optimally in selecting effective spreaders. These degree-based metrics outperform eigenvector centrality, despite disease spread over a network being a random walk process. This paper improves eigenvector-based spreader selection by introducing the non-linear relationship between contact time and the probability of disease transmission into the assessment of network dynamics. This approximation of disease spread dynamics is achieved by altering the Laplacian matrix, which in turn highlights why nodes with a high degree are such influential disease spreaders. From this approach, a trichotomy emerges on the definition of an effective spreader where, for susceptible-infected simulations, eigenvector-based selections can either optimise the initial rate of infection, the average rate of infection, or produce the fastest time to full infection of the network. Simulated and real-world human contact networks are examined, with insights also drawn on the effective adaptation of ant colony contact networks to reduce pathogen spread and protect the queen ant.

Prognostic Relevance of Celiac Lymph Node Involvement in Ovarian Cancer

2014 ◽  
Vol 24 (1) ◽  
pp. 48-53 ◽  
Author(s):  
Alejandra Martínez ◽  
Cristophe Pomel ◽  
Thomas Filleron ◽  
Marjolein De Cuypere ◽  
Eliane Mery ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Overall Survival ◽  
Lymph Node ◽  
Oncologic Outcome ◽  
Progression Free Survival ◽  
Disease Spread ◽  
Short Term ◽  
Free Survival ◽  
Increased Risk

ObjectiveThe aim of the study was to report on the oncologic outcome of the disease spread to celiac lymph nodes (CLNs) in advanced-stage ovarian cancer patients.MethodsAll patients who had CLN resection as part of their cytoreductive surgery for epithelial ovarian, fallopian, or primary peritoneal cancer were identified. Patient demographic data with particular emphasis on operative records to detail the extent and distribution of the disease spread, lymphadenectomy procedures, pathologic data, and follow-up data were included.ResultsThe median follow-up was 26.3 months. The median overall survival values in the group with positive CLNs and in the group with negative CLNs were 26.9 months and 40.04 months, respectively. The median progression-free survival values in the group with metastatic CLNs and in the group with negative CLNs were 8.8 months and 20.24 months, respectively (P = 0.053). Positive CLNs were associated with progression during or within 6 months after the completion of chemotherapy (P = 0.0044). Tumor burden and extensive disease distribution were significantly associated with poor progression-free survival, short-term progression, and overall survival. In multivariate analysis, only the CLN status was independently associated with short-term progression.ConclusionsDisease in the CLN is a marker of disease severity, which is associated to a high-risk group of patients with presumed adverse tumor biology, increased risk of lymph node progression, and worst oncologic outcome.

To Determine the Degree of Agreement between Ki67 and Histopathology to Differentiate between Hydatidiform Mole

2021 ◽  
Vol 15 (10) ◽  
pp. 2619-2621
Author(s):  
Mariya Manzoor ◽  
Haseeb Ahmed Khan ◽  
Sabiha Riaz ◽  
Imrana Tanvir ◽  
Atiya Batool Gardezi ◽  
...  
Keyword(s):  
Hydatidiform Mole ◽  
P Value ◽  
Kappa Statistics ◽  
Cross Sectional Survey ◽  
Ki 67 ◽  
Cross Sectional ◽  
Histopathologic Diagnosis ◽  
Hematoxylin And Eosin ◽  
High Degree ◽  
Gross Examination

Aim: To determine the degree of agreement between Ki67 and histopathology to differentiate between hydatidiform mole and hydropic abortus. Methods: Descriptive, Cross Sectional Survey was conducted in the Department of Pathology, Fatima Memorial Hospital, Lahore during 6 months (May 11, 2016 to Nov 11, 2016). Using non-probability consecutive sampling, 105 cases were included in this study as per the inclusion and exclusion criteria. 10% buffered formalin was used to fix the sepecimens. Gross examination and staining with Hematoxylin and Eosin was done. The cases were diagnosed by a histopathologist. IHC staining Ki67 was performed, assessed by histopathologist and the data was recorded on the proforma. Results: The mean age was 27.79±5.81 years with minimum and maximum ages of 18 years and 42 years respectively. The histopathological findings showed hydatidiform mole in 41 (39%) women and hydropic abortus in 64(61%) women. The Ki67 was reported to be >25 in 41(39%) patients and less than or equal to 25 in 64(61%) patients. The agreement of differentiation in the two types for histopathology and Ki67 was found in 101(96.2%) patients. Kappa statistics showed 92% (p-value= 0.000) strength of agreement between histopathology and Ki67. Conclusion: There is high degree of agreement between Ki67 and histopathology for differentiation of hydatidiform mole and hydropic abortus. So Ki67 can be used as an adjacent in histopathologic diagnosis of hydatidiform mole in difficult cases. MeSh words: Hydatidiform Mole, Immunohistochemistry, Ki-67 Antigen

scholarly journals Novel multiplex real-time PCR assays reveal a high prevalence of diarrhoeagenic Escherichia coli pathotypes in healthy and diarrhoeal children in the South of Vietnam

2020 ◽  
Author(s):  
Vu Thuy Duong ◽  
Le Thi Phuong Tu ◽  
Ha Thanh Tuyen ◽  
Le Thi Quynh Nhi ◽  
James I Campbell ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Real Time ◽  
Real Time Pcr ◽  
Clinical Samples ◽  
Middle Income ◽  
Middle Income Countries ◽  
Virulence Markers ◽  
Low Middle Income Countries ◽  
High Prevalence ◽  
Pcr Assays

Abstract BackgroundDiarrhoeagenic Escherichia coli (DEC) infections are common in children in low-middle income countries (LMICs). However, detecting the various DEC pathotypes is complex as they cannot be differentiated by classical microbiology. We developed four multiplex real-time PCR assays were to detect virulence markers of six DEC pathotypes; specificity was tested using DEC controls and other enteric pathogens. PCR amplicons from the six E. coli pathotypes were purified and amplified to be used to optimize PCR reactions and to calculate reproducibility. After validation, these assays were applied to clinical samples from healthy and diarrhoeal Vietnamese children and associated with clinical data. ResultsThe multiplex real-time PCRs were found to be reproducible, and specific. At least one DEC variant was detected in 34.7% (978/2,815) of the faecal samples from diarrhoeal children; EAEC, EIEC and atypical EPEC were most frequent Notably, 41.2% (205/498) of samples from non-diarrhoeal children was positive with a DEC pathotype. In this population, only EIEC, which was detected in 34.3% (99/289) of diarrhoeal samples vs. 0.8% (4/498) non-diarrhoeal samples (p<0.001), was significantly associated with diarrhoea. Multiplex real-time PCR when applied to clinical samples is an efficient and high-throughput approach to DEC pathotypes. ConclusionsThis approach revealed high carriage rates of DEC pathotypes among Vietnamese children. We describe a novel diagnostic approach for DEC, which provides baseline data for future surveillance studies assessing DEC burden in LMICs.

scholarly journals Randomized Phase II Study of SOX+B-mab Versus SOX+C-mab in Patients With Previously Untreated Recurrent Advanced Colorectal Cancer With Wild-Type KRAS (MCSGO-1107 Study)

2021 ◽  
Author(s):  
Yujiro Nishizawa ◽  
Naotsugu Haraguchi ◽  
Hirotoshi Kim ◽  
Yoshihito Ide ◽  
Ken Nakata ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Phase Ii ◽  
Progression Free Survival ◽  
Efficacy And Safety ◽  
Wild Type ◽  
Open Label ◽  
Randomized Phase Ii ◽  
Early Tumor ◽  
Patient Prognosis ◽  
Clinical Trials Registry

Abstract Background: Although chemotherapy for metastatic colorectal cancer (mCRC) has improved, the standard chemotherapy regimens for patients with RAS wild-type mCRC remain debated.Methods: This randomized phase II, open-label, multicenter study compared the efficacy and safety of S-1 and oxaliplatin (SOX)+bevacizumab (B-mab) with SOX+cetuximab (C-mab) in patients with previously untreated recurrent advanced CRC with wild-type KRAS. Between February 2012 and October 2016, 45 patients were enrolled.Results: Overall response rates were 59.1% and 43.5% (p=0.29) and disease control rates were 90.9% and 91.3% (p=0.96) in the SOX+B-mab and SOX+C-mab groups, respectively. Median overall survival (OS) was 25.3 and 15.5 months (HR=0.607, p=0.167) and median progression-free survival (PFS) were 11.7 and 5.5 months (HR=0.558, p=0.077) in the SOX+B-mab and SOX+C-mab groups, respectively. The OS and PFS of patients with early tumor shrinkage (ETS) were not significantly different in the SOX+B-mab group. However, they were significantly better when ETS was ≥20 in the SOX+C-mab group (p=0.032 and p=0.003, respectively).Conclusions: The efficacy and safety of SOX+B-mab and SOX+C-mab for wild-type KRAS recurrent advanced CRC as first-line chemotherapy were almost the same. Consideration of the treatment strategy based on ETS may improve patient prognosis, especially in patients receiving the SOX+C-mab regimen.Trial registration: UMIN Clinical Trials Registry (UMIN000006706)Date of registration: NOV/11/2011URL of trial registry record:https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000007920

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