bluuebunny/crossref_metadata_2025 huggingface dataset:
Prospective evaluation of stress in patients with newly diagnosed glioblastoma and in a close partner (TOGETHER-study).
Authors: Conen Katrin Lisa , Schüpbach Regula , Handschin Barbara , Zwahlen Diana , Voss Martin , Eisele Günter , Rentsch Katharina , Beyrau Ralf , Vogt Deborah R , Katan Mira , Weller Michael , Steinbach Joachim Peter , Hess Viviane
Published: September 2018

e13524

Background: Diagnosis and treatment of glioblastoma (GBM), the most common and aggressive malignant brain tumor in adults, impose profound chronic distress on patients and their partners. In order to assess how distress in patients and partners affects GBM outcome, we describe in a first step the level of distress – both biological and psychological – in patients and partners before and during standard radiochemotherapy -as measured by different assessment tools. Methods: Stress, measured by salivary cortisol levels (diurnal cortisol slope (DCS), cortisol awakening response (CAR)), copeptin serum level and distress thermometer (DT), perceived stress scale (PSS), anxiety/depression (HADS) and quality of life (FACT-G) was assessed prospectively in all patients with newly diagnosed GBM and their partners at 3 participating centers. The baseline measurements (T1), reported here, were taken immediately before start of standard first-line radiochemotherapy. Further follow-up is ongoing. The TOGETHER-Study with the primary aim to describe the impact of distress and exercise behavior on progression-free survival in GBM in patients and in a close partner was closed prematurely due to poor recruitment. Results: 12 patients and 11 partners were included. Pts were newly diagnosed with histologically confirmed GBM and immediately prior to starting radiochemotherapy with temozolomide. Age of pts in years (median = 62.5, range = 34-70), partners (median = 58, range = 47-79); sex (pts = all male/ partners = all female). Conclusions: Results from our small cohort lead to the hypothesis, that shortly after diagnosis and before start of radiochemotherapy partners of GBM patients seem to be more distressed than patients themselves -as assessed by DT and CAR. Clinical trial information: NCT02129335. [Table: see text]
Galectin-1 (Gal-1) expression as a prognostic factor in patients with newly diagnosed glioblastoma (GB) treated with Stupp regimen (GLIOCAT study).
Authors: Vilarino Noelia , Martinez-Bosch Neus , Balana Carmen , Alameda Francesc , Estival Anna , Pineda Estela , del Barco Sonia , Gil Gil Miguel J. , Mesia Carlos , Gallego Oscar , Carrato Cristina , Ribalta Teresa , Vidal Sarro Noemi , Balana Natalia , Velarde Jose Maria , Navarro Pilar , Martinez-Garcia Maria
Published: September 2018

e13526

Background: Gal-1 is a β-galactoside binding protein that plays an important role in cancer, promoting cell invasion, proliferation, migration, angiogenesis and evasion of the immune response. Gal-1 is involved in glioma progression and is related to tumor grade and poor clinical outcome. Gal-1 has been implicated in resistance to chemotherapy and as a potential mediator of resistance to anti-VEGF therapy. The aim of our study was to evaluate the prognostic significance of Gal-1 in a homogenous cohort of GB patients and to analyze its potential predictive value of response to bevacizumab at recurrence. Methods: A substudy of GLIOCAT, a multicenter study of newly diagnosed GB patients treated with standard Stupp regimen (previously reported). GLIOCAT enrolled 432 patients between 2005-2014. Tissue was available from 243 cases, from which a tissue microarray (TMA) was constructed. Gal-1 expression in tissue from initial surgery was analyzed by immunohistochemistry. Results were evaluated by three reviewers and quantified by H-score. Expression levels were correlated with clinical outcome, known GB prognostic factors and response to bevacizumab. Results: We defined a cut off for Gal-1 H-Score of >60 (cytoplasm) and >25 (nucleus). HighcytoplasmicGal-1 expression significantly correlated with worse OS and with a trend for shorter PFS. In the multivariate analysis KPS, age, MGMT methylation status and, extent of resection but not Gal-1 expression were independent prognostic factors for survival. Of 92 patients who received bevacizumab at recurrence, only 54 were included in the TMA, and only 1 had low Gal-1 expression. We couldn’t find any relationship with OS or PFS in this population. Conclusions: Gal-1 expression may represent a prognostic factor for GB patients treated with standard therapy. [Table: see text]
Relative thrombocytosis following chemoradiation of patients with glioblastoma to predict survival.
Authors: Boonyawan Keeratikarn , Yang Jie , Long Lihong , Wang Qianghu , Ezhilarasan Ravesanker , Alessandra Audia , Hess Kenneth R. , Alfaro Kristin , De Groot John Frederick , Bhat Krishna , Sulman Erik P.
Published: September 2018

e13527

Background: Thrombocytosis is associated with poor survival in several malignancies and is both triggered by and promoting of tumor growth. We hypothesized that an increase in circulating platelets following standard temozolamide (TMZ) CRT and/or adjuvant TMZ would predict for decreased survival in patients with glioblastoma (GBM). Methods: We reviewed data of 122 patients with newly diagnosed, pathological-proven GBM from 2007 to 2016 with documented complete blood counts before the start of CRT, after CRT, before adjuvant TMZ, and after a minimum 2 cycles of adjuvant TMZ. The association between changes in blood count levels and patient survival was analyzed by log-rank test. Multivariate analysis was performed using known prognostic co-variates, including MGMT methylation, patient age, and performance status (PS). Results: The mean change in platelets before and after CRT was -46 k/µl (range -387 to 179 k/µl) and before and after adjuvant TMZ was -25 k/µl (range -408 to 143 k/µl). As a reference, the mean change in lymphocytes was -5.7 k/µl (range -0.7 to 1.3 k/µl) and -0.0 k/µl (range -1.6 to 0.9 k/µl) for CRT and adjuvant TMZ, respectively. Patients were dichotomized based on the relative change in platelets and lymphocytes from baseline (≤30% increase, “low”, n = 101 vs > 30% increase, “high”, n = 12). The median survival of low patients vs. high patients was 30 vs 13 months (p = 0.006). Potential confounders, such as infection or thrombosis, were not associated with the high group. However, no significant survival difference was observed between groups based on platelet changes during adjuvant TMZ. Similarly, changes in lymphocyte counts were not significantly prognostic. In multivariate analysis, extent of resection, MGMT status, PS and the increase in platelets after CRT were significantly associated with survival (HR for platelets 4.0, 95% CI 1.6-10.1). Conclusions: Increased platelet counts after CRT predict for poor survival in patients with GBM. The effect is platelet specific and does not reflect general bone marrow changes, as lymphocyte changes were not significantly prognostic. These results suggest a potential interaction between platelets and tumor aggressiveness.
Phase 1 single-center, dose escalation study of D2C7-IT administered intratumorally via convection-enhanced delivery for adult patients with recurrent malignant glioma.
Authors: Randazzo Dina , Desjardins Annick , Chandramohan Vidyalakshmi , Sampson John H. , Peters Katherine B. , Vlahovic Gordana , Threatt Stevie , Herndon James Emmett , Boulton Susan , Lally-Goss Denise , Healy Patrick , Lipp Eric S , Friedman Allan H. , Bigner Darell D.
Published: September 2018

e13532

Background: D2C7 immunotoxin (D2C7-IT) is a dual-specific recombinant immunotoxin consisting of EGFR-wt and EGFRvIII monoclonal antibodies with a genetically engineered Pseudomonas exotoxin, PE-38KDEL. The primary objective is to determine the maximum tolerated dose of D2C7-IT when delivered intratumorally by convection enhanced delivery (CED). Methods: Inclusion criteria includes subjects with a single, recurrent supratentorial WHO grade III or IV glioma, KPS ≥ 70 and a washout of chemotherapy, bevacizumab or study drug of ≥ 4 weeks. Prior to administration of D2C7-IT, recurrent tumor must be confirmed by histopathology. A minimum of 2 subjects are accrued by dose level. Results: Currently, 23 subjects have been treated (16 male, 7 female) with a median age of 54 years. Out of 9 dose levels, 2 subjects have been treated at every dose except for 4 at dose level 3 (120 ng/ml) and 5 at dose 6 (405ng/ml). Adverse events possibly, probably or definitely related to D2C7-IT are mostly grade 1 or 2 events consisting of, but not limited to: intracranial hemorrhage (n = 1), stroke (n = 2), headache (n = 15), seizure (n = 5), confusion (n = 4), paresthesia (n = 4), dysarthria (n = 1), dysphasia (n = 4), visual disturbances (n = 7), fatigue (n = 4), gait disturbance (n = 2), elevated transaminases (n = 5), decreased platelets (n = 3), decreased neutrophil count (n = 1), nausea (n = 3), vomiting (n = 1), and thromboembolic event (n = 1). There was 1 dose limiting toxicity (grade 4 seizure at dose level 3), 2 grade 3 headaches and 1 grade 3 elevated ALT. 14 subjects are still alive with 6 remaining on study. So far, the longest survival time from infusion is 18.2+ months. Conclusions: D2C7-IT infusion via CED is safe with encouraging results. This dose escalation Phase I study is ongoing and will set the stage for the Phase II trial. Clinical trial information: NCT02303678.
In situ expression of hypoxia inducible factor 2-alpha in gliomas.
Authors: Renfrow Jaclyn , Mott Ryan , Huang Yue , Wong Tai , Lesser Glenn Jay , Debinski Waldemar , Strowd Roy E.
Published: September 2018

e13534

Background: Hypoxia, a driver of malignancy, is fundamental to glioblastoma (GBM). Of the hypoxia inducible transcription factors (HIFs), HIF-2a is expressed in GBM tumor cells, responds to prolonged hypoxia, and is a prime candidate for HIF therapeutic targeting. PT2385 is a novel, orally available, first-in-class, HIF-2a inhibitor with a brain:plasma ratio of 0.9 in rats. To establish HIF-2a as a therapeutic target in GBM, in situ expression needs to be described. Methods: Twenty-two paraffin-embedded gliomas (grade II-IV) underwent immunohistochemistry for HIF-2a. After rehydration, a hot Tris EDTA pH 9.0 solution retrieved epitopes, non-specific sites were blocked, and HIF-2a antibody (Santa Cruz, sc-13596) was added. A horseradish peroxidase detection system identified staining. Representative samples were digitally scanned. Localization and quantification of HIF-2a was independently verified by a neuropathologist. Patient survival and molecular genetics were retrospectively collected with Institutional Review Board approval. Results: HIF-2a expression was not detected in the 4 Grade II and 2 Grade III gliomas.Of the 16 GBMs, HIF-2a was expressed in 13 specimens (81%) - highly in 7 ( > 10% cells positive), intermediate in 6 ( < 10% cells positive), and minimally in 3. Recurrent disease stained highly for HIF-2a. Staining was specific to tumor cells and occasionally monocytic cells, clustering in perivascular and perinecrotic regions. Amongst the 16 GBMs, median patient age and survival was 58 and 13.9 months. The two longest survivors harbored positive prognostic genetics (six-year survival with a 1p/19q co-deletion and ten-year survival with MGMT gene methylation). Twelve of 16 patients received chemoradiation. Survival was not correlated with HIF-2a. Conclusions: This first in situ description of HIF-2a demonstrates expression is absent in low-grade gliomas, present in the majority of GBMs, and high in recurrent GBMs. HIF-2a abundance varies with clustering in perivascular and perinecrotic niches. Survival did not appear to be correlated with HIF-2a in this small cohort though well-known prognostic genetic mutations and treatment heterogeneity limit firm conclusions. Preclinical studies with PT2385 are in progress.
Effects of cranial irradiation on dendritic spine complexity in the rat hippocampus and to induce memory decline.
Authors: Ji Shengjun
Published: September 2018

e13545

Background: Cognitive deficit was the most serious complication of cranial irradiation in brain metastatic carcinoma. However, the underlying mechanisms remain obscure. Dendrites are the anatomic bases of synaptic contact and action potential propagation. Alterations of dendritic architecture may contribute to radiation-induced memory dysfunction. Methods: 21-day-old Sprague-Dawley rats received 10Gy cranial irradiation. 1 and 3 months later, Morris Water Maze, Fear Conditioning test and novel object recognition were used to test the memory function. Golgi staining was used to assess changes in dendritic spine density and morphology. Moreover, cytoskeletal proteins PSD-95 were analyzed with Western blot. Results: Our data showed that 10Gy cranial irradiation induced significant decline in the spatial memory and memory retention of rats and accompanied the morphological changes in dendritic spines. The result revealed significant reductions in spine density at 1 month (40.58%) and 3 months (28.92%) in the DG. In CA1 basal dendrites, irradiation resulted in a significant reduction (33.29%) in spine density only at 1month postirradiation. Compared to control, mushroom spines reduced at 1 month (7.17%, 10.01%) and 3 months (9.29%, 11.94%) post irradiation in DG and CA1 basal dendrites, respectively. Also, we found PSD-95 depletion coincided in time with alteration in dendritic spines. Conclusions: These data suggest that cranial irradiation decreased the dendritic spine density and mushroom spines, which may be associated with radiation-induced memory dysfunction. Acknowledgment: This study was supported by the National Natural Science Foundation of China 81402517 and the Suzhou Science and Technology Project SYS201651.
Spectrochemical analysis highlights similarities in adenocarcinomas irrespective of primary tissue origins.
Authors: Bury Danielle , Faust Guy , Paraskevaidi Maria , Dawson Timothy P , Martin Francis L.
Published: September 2018

e13551

Background: Identification of primary tissue origin of brain metastases can be histopathologically challenging. Initial diagnosis of malignancy can be provided on intraoperative tissue smears; however, it requires formal histopathological examination along with immunohistochemistry to reach a final diagnosis. On occasion this will still fail to determine primary origin. This study aims to demonstrate if Raman spectroscopy is able to determine primary tissue origin of brain metastasis of three common primary tumours. Methods: Formalin fixed paraffin embedded tissue from twenty brain metastasis comprising colorectal adenocarcinomas ( n= 7), lung adenocarcinomas ( n= 7) and melanomas ( n= 6) were obtained from the Brain Tumour NorthWest tissue bank. Sections (10-μm thick) were placed onto glass slides covered in aluminium foil and de-waxed prior to spectral acquisition. 25 spectra per section were collected at random, using a 785 nm laser at 1200 g mm-1grating with an acquisition time of 30 sec. Computational analysis within a MatLab environment was then conducted. Results: Following PCA-LDC analysis, classification accuracy of the three groups was; colorectal adenocarcinoma 71.3%, lung adenocarcinoma 71% and melanoma 70%. A one-way ANOVA showed statistically significant differences between the three groups, p = 0.0014. On combining adenocarcinoma groups accuracy increased to 87.8%, whilst melanoma fell to 68.9%. A student’s t-test confirmed statistical significance between the two groups, p < 0.0001. Conclusions: Raman spectroscopy can classify different tumours by type, though sensitivity and specificity is diminished if used to classify primary tissue origin of adenocarcinomas. Therefore for clinical use, such new tools may aid the clinician to determine tumour type intra-operatively but classic histopathology is still required for tissue origin confirmation. Such technologies may provide a useful adjunct to more conventional approaches; for instance, decreasing the number of immunohistochemical stains required to determine tissue origin. These results also suggest strong similarities between adenocarcinomas of different primary origins.
Computational exploration of mechanistic determinants of antibody drug-conjugate pharmacokinetics using quantitative systems pharmacology modeling strategies.
Authors: Burke John M , Wilkins Anna Katharina , Matteson Andrew , Gruenbaum Lore , Apgar Josh F
Published: September 2018

e14000

Background: The pharmacokinetics of antibody drug conjugate (ADC) therapeutics typically show a discrepancy between the PK of total antibody (conjugated and unconjugated antibody) and that of conjugated antibody, carrying one or more payload molecules This discrepancy is often attributed to deconjugation (Kamath, 2014), however recent evidence suggests that the underlying mechanisms may be more complex. Methods: This work employs a computational quantitative systems pharmacology (QSP) approach to understand the impact of drug antibody ratio (DAR) and the resulting changes in molecular properties on overall PK and relative payload disposition as observed in preclinical and clinical studies. Results: Using QSP approaches, the model (1) describes the kinetics of individual DAR species and agrees well with typical ADC PK, individual DAR PK, and average DAR measurements in vivo; (2), quantitatively describes the trade-off between higher DAR and lower exposure; consequently, we predict that ADC2 is half as potent as ADC4 and ADC8, which are equipotent; (3) longer mAb half-life reduces payload delivery after multiple doses; and (4) ADC half-life affects the percent of payload delivered through different mechanisms. Conclusions: A QSP model describing mechanism is a useful tool to translate and understand PK from preclinical species to human, by acting as a central repository of data, knowledge, and hypotheses. It provided a rational basis to generate testable hypotheses and provide early insights into complex ADC PK data and established the benefit of using computational models to design novel ADCs and to optimize the discovery and development of existing ADCs.
Midcavitary Tako-Tsubo syndrome in cancer patients.
Authors: Ionescu Dana , Stone Danielle , Stone James , Durand Jean-Bernard , Lopez-Mattei Juan , Iliescu Gloria , Karimzad Kaveh , Iliescu Cezar
Published: September 2018

e14011

Background:Variants of the classic Tako-tsubo syndrome or stress induced cardiomyopathy (SC) includes mid ventricular or basal left ventricular wall motion abnormalities. Midcavitary dyskinesia and ballooning is considered a unique presentation, and there is no published data showing midcavitary involvement in cancer patients. Methods: All cancer patients who fulfilled the diagnostic criteria for SC at MD Anderson Cancer Center over a 6–year period were included in the study. We selected and retrospectively reviewed the medical records of 8 patients who had midcavitary SC. Clinical presentation, ECG, laboratory data, transthoracic echocardiogram and left ventriculography results were reviewed. Results: Out of30 cancer patients who fulfilled the diagnostic criteria for SC, 8 patients (26.7%) (4 females, 4 men, mean age 57.37 yo) had midcavitary SC. 62,5 % patients were diagnosed with a solid malignancy. Trigger factors for midcavitary SC were: systemic infection (3 patients with neutropenia), emotional stress (2 patients), chemotherapy (1 patient undergoing treatment with Ibrutinib), and surgical interventions (3 patients). Clinical presentation included chest pain (37.5%), shortness of breath (50%) and non specific symptoms (12.5%). T wave inversion was the most common electrocardiographic presentation (37.5 %), followed by ST elevation (25 %). All patients had changes of the cardiac biomarkers (BNP mean 2224. 4 pg/dl, TN I mean 2. 8 ng/dl, CK-MB mean 14 ng/dl) and significant LV dysfunction (LVEF < 50%). All patients underwent coronary angiography which showed no obstructive CAD; left ventriculography identified basilar and apical hyperkinesis and midventricular hypokinesia. Cancer therapy was interrupted; aspirin and beta blockers were initiated in all patients. The most common complications of midcavitary SC were: respiratory failure requiring intubation (37, 5%), pulmonary edema (25%), and hypotension (25%). No cardiac deaths were registered. None of the patients experienced recurrence of SC. Conclusions: Mid cavitary SC remains a rare entity, and raises further questions about the causal association between the mid cavitary involvement and cancer, and its impact on cancer therapy and overall survival in this cohort of patients.
Fluoropyrimidine-associated myocardial toxicity as a global metabolic effect compared to vascular spasm and visibility on FDG PET scanning.
Authors: Dean Andrew Peter , Higgs Domenic , Robins Peter , Stobie Paul , Craven Philip , Daly Ciara , Carija Samantha
Published: September 2018

e14013

Background: Myocardial toxicity from fluoropyrimidines is a rare but potentially serious side effect, estimated by some as occurring in up to 9%. Coronary spasm has been suggested as the underlying mechanism, despite a lack of supporting evidence and other toxicity mechanisms have been proposed. Matsubara described Krebs cycle dysfunction in the presence of 5FU with depletion of high energy phosphate compounds in rodent myocardial tissue with ECG changes. Following a chance discovery of abnormal myocardial FDG uptake on a PET scan shortly after presenting with presumed 5FU cardiac toxicity (angina, ST elevation, troponin rise; normal coronary vessels on imaging), we prospectively evaluated all instances of angina occurring during 5FU infusion with coronary artery imaging and FDG PET scan. Methods: We identified 5 patients who experienced angina during 5FU therapy. They were investigated for coronary ischaemia and also underwent PET scanning to assess myocardial FDG uptake. Data was collected from patient records, and subsequent cardiac investigations. Results: In all 5 cases, PET scan demonstrated markedly abnormal FDG uptake throughout the myocardium, with the ventricular blood pool demonstrating more FDG activity than myocardium. No significant underlying coronary artery disease was identified. All 5 patients had previous PET scans with normal myocardial FDG uptake. Conclusions: We identified a consistent pattern of abnormal FDG uptake throughout the myocardium for all scanned patients with chest pain following administration of 5FU. This was not restricted to a single arterial territory. There were no typical ECG changes of spasm. Obstructive coronary disease was excluded with angiographic imaging or myocardial perfusion scanning. The FDG PET scans suggest global myocardial metabolic change, supporting the notion of 5FU being a direct myocardial toxin inhibiting myocardial glucose utilization. The myocardium may then be dependent on fatty acid metabolism, posing additional risk to patients on low fat diets. Our data provides new insight into the mechanism of 5-FU myocardial toxicity and further prospective assessment using PET is warranted.
Cardiac safety profile of patients receiving high cumulative doses of pegylated-liposomal doxorubicin (PLD): Use of left ventricular ejection fraction (EF).
Authors: Skubitz Keith M. , Blaes Anne Hudson , Konety Suma , Francis Gary S.
Published: September 2018

e14016

Background: The use of doxorubicin (D) is limited by cardiotoxicity. Cumulative dose is an important risk factor for D-induced heart failure (D-HF). Retrospective studies found a ~7.5% incidence of clinical HF at a cumulative dose of 550 mg/m2, and prospective trials have found even higher rates. The administration of D by continuous intravenous infusion (CIVI) has less cardiotoxicity than when given by bolus administration. Pegylated-liposomal doxorubicin (PLD) has a longer half-life in blood, and may have lower cardiotoxicity. Limiting D use based on ejection fraction (EF) is commonly performed. Despite the wide use of EF to monitor D-HF, evidence for its utility to predict D-HF is limited, and monitoring adds cost. There is even less information regarding large cumulative doses of PLD and its effect on D-HF and EF. We examined the incidence of D-HF in patients who received a large cumulative dose of D as PLD, and its relation to EF and HF. Methods: A retrospective chart review of patients who received a large cumulative dose of PLD, sometimes following previous free D, was performed. Results: Definite clinical D-HF was not observed in 53 patients who received a cumulative D dose (free + PLD) of > 450 mg/m2, 46 of whom received > 500 mg/m2, 26 > 700 mg/m2, 14 > 1000 mg/m2, and 5 > 1400 mg/m2. The EF varied greatly over time in some patients in the absence of symptoms or signs of HF and was not a reliable predictor of the development of heart failure. Conclusions: The findings provide further evidence for the low risk of D-HF with PLD. Although this study is subject to the usual limits of a retrospective study, the doses received and long-term follow-up are noteworthy. While the determination of EF is commonly used to monitor D cardiotoxicity, it has many limitations. Serial monitoring of EF during treatment may not be helpful, at least in the case of PLD and CIVI-D in adults. Indeed, given the lack of prognostic clarity regarding modest EF changes, regular measurement of EF may sometimes inappropriately limit patient access to this useful drug. These findings may not apply to children or other liposomal formulations, such as non-pegylated formulations.
Examining the adherence to CONSORT guidelines and the reporting of the enrollment process in clinical oncology randomized controlled trials: A review of trials published between 2013 and 2015.
Authors: Audet Sophie , Doyle Catherine , Lemieux Christopher , Lemieux Julie
Published: September 2018

e14026

Background: Due to eligibility criteria, most, if not all, randomized controlled trials (RCTs) exclude patients at the outset, before randomization. Understanding which patients are excluded is important to evaluate the external validity of the results. The proportion of trials that report the entire flow diagram of patient enrollment, in accordance with the CONSORT 2010 statement, is unknown. Failure to do so makes it more difficult to discuss the generalizability of the trial findings. Methods: We performed the systematic retrieval and analysis of all phases II and III RCTs published in paper form between 2013 and 2015, in four high impact factor journals, in the field of clinical oncology. Our main objective was to determine the proportion of trials that report the number of patients assessed for eligibility before randomization. We further aimed to identify the variables that affect this reporting as well as the reasons for patient exclusion, to calculate the recruitment fraction and the number needed to screen and to determine the proportion of trials that include a discussion on the generalizability of the trial findings. Results: 462 RCTs were reviewed. Among them, 426 (92.2%) included the flow diagram in the article and 224 (48.5%) reported the number of patients assessed for eligibility. This proportion varied significantly between the journals studied, but it did not increase over time. A total of 116 (25.1%) included a discussion of generalizability. Among the trials that reported the entire enrollment process, the reason for patient exclusion could not be found in 50 (22.3%). Conclusions: There is still room for improvement in the reporting of the determinants of external validity in clinical oncology RCTs. Increasing the reporting of the enrollment process could help clinicians and health policy makers establish to whom the results of a trial apply.
Phase I clinical trials in oncology: A review of the old and a look at the new.
Authors: Fellman Bryan M. , Hess Kenneth R.
Published: September 2018

e14030

Background: In Phase I oncology trials the primary goal is to assess dose limiting toxicities (DLT) and estimate the maximum tolerated dose (MTD). The classical 3+3 design is still used in greater than 90% of studies. We review the classical 3+3 design and two new model-based designs: Bayesian Optimal Interval (BOIN) design and the recently updated modified toxicity probability interval (mTPI-2) design. These designs are easy to implement like the 3+3 using a simple table to guide dose escalation/de-escalation. As opposed to the 3+3 design, these designs can target a DLT rate well above or below the standard 33% target. In general, an expansion cohort is added to 3+3 designs to verify safety and get an early efficacy signal. In the 3+3 expansion cohort it is unclear how to proceed if excessive toxicity is observed; whereas, with BOIN and mTPI-2, expansion can be built in with toxicity monitoring and MTD updating. Methods: We carefully explain how computer simulations can be used to evaluate phase I designs and present results from simulations comparing the designs under several true dose toxicity curves. Results: We show that BOIN and mTPI-2 have better performance than the 3+3. These new designs select the true MTD at a much higher rate and treat a higher percentage of patients at the MTD. The new designs generally tend to allocate fewer patients to high toxicity doses and fewer patients to low toxicity doses, thus ensuring high ethical standards. Unlike older Bayesian designs (e.g., modified continual reassessment method), the newer designs do not require a statistician to update the model during the course of the trial. Readily available, free software make these designs simple to implement. Conclusions: We recommend the use of the new model-based designs over the classical 3+3 design.
Risk assessment based on the Risk Index for Serious Adverse Events (SAEs) in phase I trials.
Authors: Koganemaru Shigehiro , Kuboki Yasutoshi , Shitara Kohei , Nomura Shogo , Harano Kenichi , Takahashi Hideaki , Kogawa Takahiro , Naito Yoichi , Sakai Takahiro , Kimura Yukie , Yoh Kiyotaka , Doi Toshihiko
Published: September 2018

e14032

Background: Although patients (pts) in phase I trials may have expectations about their chance to benefit, they sometimes experience serious adverse events (SAEs). These events impact on their quality of life negatively as well as their clinical management and survival, if once occurred, regardless of timing of occurrence or relation to study drugs. Therefore, paying close attention for pts who are more likely to experience SAEs may be required; however, little is known about which clinical features are related to SAEs in phase I trials. The aim of this study is to construct a risk index for SAEs prediction. Methods: We collected medical records of 418 pts with solid tumor who participated in phase I trials for the first time and were treated at our hospital from January 2011 to December 2015. The time to first SAE (TTS), defined as the time from registration to first SAE, was analyzed. Stepwise Cox regression model was applied to screen out the factors to build a risk index. Internal validation was performed using a bootstrap procedure. Results: Four hundred and seven pts were analyzed for building a risk index. Median age was 63 years (range 22-81). Predominant primary tumor site was gastrointestinal cancer (65.1%), followed by lung cancer (8.4%) and genitourinary cancer (5.7%). A total of 251 pts (61.7%) were treated with small molecule compounds, while 136 pts (33.4%) were treated with antibody therapy including immune therapy. A total of 101 pts (24.8%) experienced SAEs included 18 events related to study drugs. Four independent risk factors (use of antibody therapy, 60 < age < 70, higher serum albumin concentration and lower serum alkaline phosphatase concentration), identified by stepwise Cox regression model, were combined into simple ternary risk index that stratified pts into low- (n = 93), intermediate- (n = 175) and high-risk group (n = 139). Hazard ratios for high-risk and intermediate-risk relative to low-risk group and their 95% confidence intervals were 5.25 (2.64-10.42; high-risk) and 2.00 (0.99-4.07; intermediate-risk). Conclusions: Risk assessment based on the risk index for SAEs may be useful for patient management in phase I trials. Further research is needed to validate this risk index.
Global trends in phase I trials: Changes in cancer types of enrolled patients in 1991-2015.
Authors: Itahashi Kota , Shimizu Toshio , Koyama Takafumi , Kondo Shunsuke , Fujiwara Yutaka , Yamamoto Noboru
Published: September 2018

e14037

Background: Detailed information on cancer types of enrolled patients in phase I oncology trials is scarce. Global distribution, time-dependent change, and regional differences were evaluated. Methods: A systematic search of the PubMed database was performed and all single-agent phase I clinical trials permitting enrollment of all-comer patients (i.e. patients with any type of solid tumor) published between Jan 1991 and Dec 2015 were included. The trials expected to enroll specific patient populations were excluded per the criteria developed for this study. Results: A total of 10,596 articles were reviewed by three researchers. We identified 866 eligible clinical trials, which enrolled a total of 28,751 patients with advanced solid tumors. The extracted trials were performed mainly in North America (55.5%), Europe (27.8%), and Asia (10.5%). Colorectal (n = 7,483; 26.0%) and lung (n = 3,211; 11.2%) cancers were the most prevalent solid tumors, followed by sarcoma (n = 1,739, 6.0%), breast cancer (n = 1,625, 5.7%), and renal cancer (n = 1,547, 5.4%). The proportion of patients with either colorectal or lung cancer tended to decrease with time: 28.0% and 16.3% in 1991-1995; 31.9% and 12.4% in 1996-2000; 27.1% and 10.8% in 2001-2005; 23.9% and 10.7% in 2006-2010; and 23.4% and 9.9% in 2011-2015. In the same years, the proportion of trials, in which patients with either of these two cancers accounted for ≥50% of the total number of patients in each trial, also decreased: 33 of 67 trials (33/67) (49.3%), 59/142 (41.5%), 62/223 (27.8%), 38/189 (20.1%), and 40/245 (16.3%), respectively. This tendency was consistent in the three main regions. Instead, the proportion of patients with various types of cancer increased, leading to diversification of enrolled patients in phase I trials. Conclusions: The distribution of cancer types among enrolled patients in all-comer phase I trials has changed. Patients with common forms of cancer, whose general condition is likely to be deteriorated after many lines of standard chemotherapy or other approved drugs, tend to not participate in these trials. Diversification of enrolled patients will increase the chances of assessing the preliminary efficacy of new treatments against various types of cancer.
Clinical features and outcomes of reversible posterior encephalopathy syndrome following bevacizumab treatment.
Authors: Iwamoto Mitsuhiko , Inoue Shiori , Kawaguchi Kanako , Terasawa Risa , Fujioka Hiroya , Kimura Kosei , Uchiyama Kazuhisa
Published: September 2018

e14045

Background: Reversible posterior leukoenchephalopathy syndrome (RPLS), also known as Posterior reversible encephalopathy syndrome (PRES) is a distinct clinicoradiological entity characterized by a constellation of clinical features, and a potentially devastating complication of bevacizumab treatment. Methods: Patients were identified from the published literature using ‘PubMed’ databases using the terms ‘bevacizumab’ or , ‘RPLS’ and ‘RPES’ from 2006 to 2016, who developed RPLS features within 3 weeks of bevacizumab treatment, who had brain imaging findings of focal vasogenic edema and radiologic proof of reversibility Results: A total of 22 cases of RPLS following the administration of bevacizumab have been reported. The mean age of these patients was 50 years (range 34–74 years), 6 of whom were male and 14 female. Headaches ( n = 11), seizures ( n = 10), visual disturbances ( n = 9) and nausea and vomiting ( n = 8) were the common presenting symptoms. In a majority of patients, an increase in blood pressure from their baseline values was observed during their hospitalization. RPLS occurred in 3 patients who received bevacizumab as monotherapy and the rest had received bevacizumab in combination with other chemotherapeutic agents (oxaliplatin, n = 8; fluorouracil, n = 6; leucovorin, n = 5; gemcitabine, n = 3; paclitaxel, n = 3; capecitabine, n = 3; doxorubicin, n = 2; carboplatin, n = 2; and irinotecan, n = 1). In 20 out of 22 patients, PRES resolved following withdrawal of bevacizumab and strict control of blood pressure. 3 patients also received prednisolone and mannitol as part of their treatment for RPLS. However, 2 out of 22 patients could not recover from severe coma, and died. Conclusions: A high level of suspicion for RPLS is advisable in patients who develop headache, seizures, visual disturbances, during bevacizumab treatment, either as monotherapy or in combination with other chemotherapeutic agents. These data support the need for close vigilance of neurological features and blood pressure monitoring of patients undergoing bevacizumab treatment. Prompt withdrawal of bevacizumab and blood pressure control appear to portend favorable outcomes in these patients.
Factors and conditions affecting the antitumor effect of magnetite nanoparticles in the experiments in vivo.
Authors: Zhukova Galina Vitalyevna , Shikhlyarova Alla Ivanovna , Barteneva Tatiana Albertovna , Bragina Marina Igorevna , Shirnina Elena Alekseevna , Polozhentsev Oleg Evgenevich , Kurkina Tatiana Anatolevna
Published: September 2018

e14051

Background: Independent antitumor effects of magnetite nanoparticles (NPs) in animals, up to complete regression of large tumors, have been demonstrated. Factors and conditions that contribute to the appearance and enhancement of such effects are an important issue. Our purpose was to study the dependence of antitumor effects of magnetite NPs on characteristics of animals, ways of preparation and injection of NPs and weak magnetic fields (WMF). Methods: The experiment included 380 white outbred rats with transplantable sarcoma 45 (S45), Pliss lymphosarcoma (PL) and Heren carcinoma (HC) and 230 С57Black/6 mice with B16 melanoma. The animals received 6-8 1.25-35.4 mg/kg peritumoral or intraperitoneal injections of a water-based magnetite NP ferrofluid (FF) diluted with saline solution. WMF parameters were: 0.03-9 Hz frequency, 0.7-3.2 mT induction, exposure on the head. Dynamics of tumor sizes, histological changes and FF characteristics after the dilution with saline (X-ray absorption spectroscopy analysis) were evaluated. Results: An effective single dose in S45 female rats with peritumoral injections was higher than in males (35.4 and 17.7 mg/kg, respectively). Female rats with HC were sensitive to small NP doses (1.25 mg/kg) in intraperitoneal (but not peritumoral) injections (regression in > 30%). Peritumoral injections of small NP doses were most effective in PL males, while a number of experiments did not show benefits of small NP doses for mice. NP solution storage led to its lower effect due to the oxidation of Fe +2 to Fe +3, and even FF dilution ex tempora decreased the effect as SS pH changed to 7.4. WMF was able to enhance the effect of NPs by up to 1.5 times but not in intraperitoneal injections. Conclusions: Antitumoral effects of NPs depended on species of animals and their gender, tumor types, doses and methods of NP injections, storage time of diluted FF prior to its injection, saline pH, and WMF. WMF effects were different depending on NP injection methods.
Systemic effects of cAMP in chemotherapy for Heren’s carcinoma.
Authors: Shikhlyarova Alla Ivanovna , Frantsiyants Elena Mikhaylovna , Zhukova Galina Vitalyevna , Cheryarina Natalia D. , Barteneva Tatiana Albertovna , Protasova Tatiana P. , Shirnina Elena Alekseevna , Kurkina Tatiana Anatolevna , Bragina Marina Igorevna
Published: September 2018

e14052

Background: Along with tumor itself, mechanisms of regulation of homeostasis are the target for tumor progression inhibition. The brain, various organs and tumor have different resources of energetic and metabolic substrates. Involvement of cyclic adenosine monophosphate (cAMP) into intimate mechanisms of proliferation, hormonal and energetic homeostasis indicates the possibility to use this factor in chemotherapy of tumors to improve the resistance of the organism. The purpose of the study was to analyze levels of endogenous cAMP in tumor and in organs as a criterium of systemic body response to chemotherapy with cAMP application. Methods: The study included 56 male Wistar rats with Heren’s carcinoma receiving peritumoral injections of cyclophosphan (CP) 50 mcg/kg (Baxter Oncology GmbH, Germany) alone and in combination with cAMP (Sigma-Aldrich, USA), P.O. at a concentration of 0.01%. cAMP levels in homogenates of organs and tumors were measured by immunoradiometric assay (Immunotech, Czech Republic) using Arian radiometer (Vitaco, Russia). Data were processed using Statistica 6. Results: cAMP levels in growing tumors in rats without treatment (the control) were maximal (7.03±1.5 nmol/L). CP injections alone during inhibition of carcinoma growth allowed the reduction of tumor cAMP level by 3.3 times. Combination of CP and cAMP resulted in tumor regression, and endogenous cAMP levels in tumor decreased by 10 times compared with the control. Similar dynamics of cAMP reductions was noted in the adrenal glands. The lungs, thymus, lymph nodes and especially the testes and the brain, on the contrary, showed accumulation of cAMP to the normal levels and higher. Conclusions: The range of cAMP levels in organs and tumors of rats receiving combination of CP and cAMP demonstrated the development of adaptive and regenerative processes in organs responsible for the neuroendocrine regulation, suppression of stimulation of stress-realizing systems and metabolic support of the processes of increasing non-specific antitumor resistance along with inhibited proliferative activity of tumors.
Hemorrhagic and thrombotic events in oncology patients treated with antiangiogenic therapy: Impact of study design on the results assessed by meta-analysis.
Authors: Trone Jane-Chloe , Chapelle Céline , Ollier Edouard , Bertoletti Laurent , Cucherat Michel , Mismetti Patrick , Magné Nicolas , Laporte Silvy
Published: September 2018

e14058

Background: Antiangiogenic (AA) therapies emerge as a new cornerstone for cancer treatment, but carry their own particular risk profile. Several previous meta-analyses have showed increasing risk of bleeding and paradoxically thrombosis in cancer patients receiving antiangiogenic. The aim of the meta-analysis is to investigate the impact of studies design (open or double blind (DB)), on the incidence and the occurrence of bleeding, venous thrombotic events (VTE) and arterial thrombotic events (ATE) in cancer patients treated by AA therapies. Methods: We searched Medline, Cochrane, ClinicalTrial databases, meeting abstracts of the American Society of Clinical Oncology and the European Society of Medical Oncology for relevant clinical trials. We included prospective phase II and III clinical trials that randomly assigned patients with solid cancer to AA therapy or control. Statistical analyses were conducted to calculate the summary incidence, ORs, and 95% CIs, using random-effects or fixed-effects models based on the heterogeneity of included studies. Results: A total of 166 trials (72,024 patients) were included. For bleeding events, comparison on AA treatment versus control yielded an OR of 2.41 (95% CI 2.07 to 2.71; p < 0.001) with an exaggeration of treatment effects by 68% (95% CI, 33 to 113) in open-label studies compared with DB trials. Concerning VTE, an OR of 1.18 (95% CI 1.04 to 1.35; p = 0.0115) was noted, with a significant enhancement of 53% (95% CI, 19 to 96) of treatment side effects with open trials compared with DB trials. AA don’t increase significantly the frequency of VTE when considering only DB trials. For ATE, an OR of 1.59 (95% CI 1.30 to 1.94; p < 0.001) was observed, associated with a significant exaggeration of 65% (95% CI, 13 to 143) with open trials compared with DB trials. Conclusions: The present meta-analysis showed a significant interaction of study design for the tolerance assessment in the AA therapies in cancers. The increasing risk of hemorrhagic events, VTE and ATE appear to have been overestimated in the previous meta-analyses. In the future, meta-analyses should be restricted to DB trials for analysis of toxicity profile.
SMK/SM88 toxicity, efficacy, and patient reported outcomes in metastatic pancreas cancer.
Authors: Hoffman Steve , Stega Jeanetta , Del Priore Giuseppe , Rothman John
Published: September 2018

e14060

Background: SMK/SM-88 is a combination of novel tyrosine isomer ( TI) and 3 low dose repurposed agents that are generally recognized as safe for typical use. Its mechanism of action is based on the Warburg effect. It has previously been reported to have clinical benefit with little toxicity in a variety of cancers (J. Clin. Oncol. 2013 31: e22095). We now report on a subset of subjects with pancreas cancer. Methods: Retrospective chart review. Results: Subjects received all four SMK/SM-88 components orally and subcutaneously, consisting of a proprietary altered TI, CYP3a4 inducer, mTOR inhibitor and mitochondrial oxidative stress catalyst, five days per week for a period of six weeks (1 cycle). A total of 11 pancreatic cancers cases were identified. The average age was 63.2 (44-81), 36.4% (4/11) were female. Prior treatment included surgery only (n = 3); chemo only (n = 4); multi-modality therapy (n = 2) and unknown or none (n = 2). Duration on study regimen was 3-57 weeks (mean = 28.5). Clinical benefits documented for all subjects included: 1-3 points improvement in ECOG performance status; 1-5 point mean improvement on EORTC questionnaire (scale 1-7); weight gain (1-5 lbs.); and reduction in pain levels (1-9 points/10 scale) with cessation of all analgesics by the end of cycle 1 in 36% (4/11). Overall reduction in tumor size was seen in 27.3% (3/11) including one CR with PFS of at least 6 months duration, and 2 PRs with one known PFS of 15wks. 72.7% (8/11) had stable disease for 6-61wks. One patient had an overall survival of 23.3 months with no further treatment, and one had an overall survival of 43.2 months. All subjects developed hyperpigmentation. Overall, all subjects tolerated the SMK/SM-88 compounds well. No serious or unexpected adverse events related to the agent have been reported. Conclusions: SMK/SM-88 is a promising treatment for metastatic pancreatic cancer with no significant toxicity. Additional studies are on going in other cancers and confirmatory pancreas investigations are planned.