Pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) is strongly associated with favorable outcome. We examined the utility of serial circulating tumor DNA (ctDNA) testing for ...predicting pCR and risk of metastatic recurrence.
Cell-free DNA (cfDNA) was isolated from 291 plasma samples of 84 high-risk early breast cancer patients treated in the neoadjuvant I-SPY 2 TRIAL with standard NAC alone or combined with MK-2206 (AKT inhibitor) treatment. Blood was collected at pretreatment (T0), 3 weeks after initiation of paclitaxel (T1), between paclitaxel and anthracycline regimens (T2), or prior to surgery (T3). A personalized ctDNA test was designed to detect up to 16 patient-specific mutations (from whole-exome sequencing of pretreatment tumor) in cfDNA by ultra-deep sequencing. The median follow-up time for survival analysis was 4.8 years.
At T0, 61 of 84 (73%) patients were ctDNA positive, which decreased over time (T1: 35%; T2: 14%; and T3: 9%). Patients who remained ctDNA positive at T1 were significantly more likely to have residual disease after NAC (83% non-pCR) compared with those who cleared ctDNA (52% non-pCR; odds ratio 4.33, P = 0.012). After NAC, all patients who achieved pCR were ctDNA negative (n = 17, 100%). For those who did not achieve pCR (n = 43), ctDNA-positive patients (14%) had a significantly increased risk of metastatic recurrence hazard ratio (HR) 10.4; 95% confidence interval (CI) 2.3-46.6; interestingly, patients who did not achieve pCR but were ctDNA negative (86%) had excellent outcome, similar to those who achieved pCR (HR 1.4; 95% CI 0.15-13.5).
Lack of ctDNA clearance was a significant predictor of poor response and metastatic recurrence, while clearance was associated with improved survival even in patients who did not achieve pCR. Personalized monitoring of ctDNA during NAC of high-risk early breast cancer may aid in real-time assessment of treatment response and help fine-tune pCR as a surrogate endpoint of survival.
•Lack of ctDNA clearance early during NAC portends poor response.•Detectable ctDNA during NAC is associated with poor outcomes.•Failure to clear ctDNA after NAC is associated with inferior distant disease-free recurrence survival.•Clearance of ctDNA is associated with improved survival even in patients who did not achieve pCR.
Difference in pathologic complete response (pCR) rate after neoadjuvant chemotherapy does not capture the impact of treatment on downstaging of residual cancer in the experimental arm. We developed a ...method to compare the entire distribution of residual cancer burden (RCB) values between clinical trial arms to better quantify the differences in cytotoxic efficacy of treatments.
The Treatment Efficacy Score (TES) reflects the area between the weighted cumulative distribution functions of RCB values from two trial arms. TES is based on a modified Kolmogorov–Smirnov test with added weight function to capture the importance of high RCB values and uses the area under the difference between two distribution functions as a statistical metric. The higher the TES the greater the shift to lower RCB values in the experimental arm. We developed TES from the durvalumab + olaparib arm (n = 72) and corresponding controls (n = 282) of the I-SPY2 trial. The 11 other experimental arms and control cohorts (n = 947) were used as validation sets to assess the performance of TES. We compared TES to Kolmogorov–Smirnov, Mann–Whitney, and Fisher’s exact tests to identify trial arms with higher cytotoxic efficacy and assessed associations with trial arm level survival differences. Significance was assessed with a permutation test.
In the validation set, TES identified arms with a higher pCR rate but was more accurate to identify regimens as less effective if treatment did not reduce the frequency of high RCB values, even if the pCR rate improved. The correlation between TES and survival was higher than the correlation between the pCR rate difference and survival.
TES quantifies the difference between the entire distribution of pathologic responses observed in trial arms and could serve as a better early surrogate to predict trial arm level survival differences than pCR rate difference alone.
•We developed a statistical tool to compare two RCB distributions giving a single metric named Treatment Efficacy Score (TES).•TES identifies a regimen with a higher pCR rate and also captures the downstaging effects of treatment on residual cancer.•TES correlates with event-free and distant recurrence-free survival better than pCR rate difference.•TES could serve as a better early surrogate for trial arm level survival than pCR rate difference.•We created a free web tool (http://dssoftware.aei.polsl.pl/TES/TES/) to plot RCB distributions and calculate TES statistic.
Biomarkers of transplant tolerance would enhance the safety and feasibility of clinical tolerance trials and potentially facilitate management of patients receiving immunosuppression. To this end, we ...examined blood from spontaneously tolerant renal transplant recipients and patients enrolled in two interventional tolerance trials using flow cytometry and gene expression profiling. Using a previously reported tolerant cohort as well as newly identified tolerant patients, we confirmed our previous finding that tolerance was associated with increased expression of B cell–associated genes relative to immunosuppressed patients. This was not accounted for merely by an increase in total B cell numbers, but was associated with the increased frequencies of transitional and naïve B cells. Moreover, serial measurements of gene expression demonstrated that this pattern persisted over several years, although patients receiving immunosuppression also displayed an increase in the two most dominant tolerance‐related B cell genes, IGKV1D‐13 and IGLL‐1, over time. Importantly, patients rendered tolerant via induction of transient mixed chimerism, and those weaned to minimal immunosuppression, showed similar increases in IGKV1D‐13 as did spontaneously tolerant individuals. Collectively, these findings support the notion that alterations in B cells may be a common theme for tolerant kidney transplant recipients, and that it is a useful monitoring tool in prospective trials.
The authors associate a B cell‐focused signature of tolerance previously identified in spontaneously tolerant renal allograft recipients with an increase in transitional and naïve B cells, persistence over time, and presence in patients rendered tolerant via transient mixed chimerism. See editorial from Feng and Fairchild on page 2793.
An in vivo digestibility trial was conducted to evaluate the digestibility of six forages. These were selected indigenous browse species and groundnut haulms in Lawra and Jirapa Districts of the ...Upper West Region of Ghana. Groundnut haulms served as a control due to its known good digestibility in small ruminants. Thirty West African Dwarf (WAD) young castrated billy goats with a mean age of 8 months were used. The average live body weight was 8.9 ± 0.1 kg. The animals were randomly assigned to the six treatments and replicated five times in a completely randomized design. They were confined in metabolism cages. The adaptation period was 3 weeks after which data was taken for 10 days. The treatments were the leaves and tiny twigs of T1
Annona senegalensis
, T2
Ficus gnaphalocarpa
, T3
Pericopsis laxiflora
, T4
Pterocarpus erinaceus
, T5
Afzelia africana
, and T6 (control)
Arachis hypogaea
. Feed intake, faecal matter and urine output were measured. The results indicated that dry matter (DM) contents of the feedstuffs were less than 50% but crude protein (CP) contents were higher than the minimum required for sustaining ruminants. Neutral and acid detergent fibre contents were high, and
F. gnaphalocarpa
, in particular, contained a higher level of phosphorus (P). The amounts of feed intakes were typical of most fodder species with the exception of
P. laxiflora
and
P. erinaceus
, which were lower (
P
< 0.05). The apparent digestibility values were also typical of most fodder species but the digestibility of
A. africana
fibre appeared to be lower. Nitrogen retention was positive for all test species with the exception of
P. laxiflora
, which was negative. Mortality was recorded in animals on
P. laxiflora
, and the rate was high.
Pericopsis laxiflora
leaves, even though morphologically similar to the leaves of
P. erinaceus
, were not a suitable fodder.
Ficus gnaphalocarpa
appeared to be the overall best fodder species in terms of nutrient uptake.
The article "In vivo digestibility of six selected fodder species by goats in northern Ghana," written by F. K. Avornyo et al., was originally published electronically on the publisher’s internet ...portal (currently SpringerLink) on 13 July 2019 without open access.
Earlier work has shown that a fracture mechanics approach can predict fatigue failure in rubber or elastomer components using a finite element analysis technique that calculates the strain energy ...release rate for cracks introduced into bonded rubber components. This paper extends this previous work to examine real fatigue measurements made at both room temperature and 70±1°C in both tension and shear using a cylindrical rubber to metal bonded component. This component generated fatigue failures not only in the bulk of the component but also at the rubber to metal bond interface. The fatigue crack growth characteristics were measured independently using a pure shear crack test piece. Using this independent crack growth data and an accurate estimate for the initial flaw size allowed the fatigue life to be calculated. This fracture mechanics approach predicted the crack growth rates well at both room temperature and 70±1°C.
In recent years there has been growing interest in the use of nonintrusive systems such as radar and infrared systems for vehicle recognition. State-of-the-art nonintrusive systems can report up to ...eight classes of vehicle types. Video-based systems, which arguably are the most popular nonintrusive detection systems, can report only very coarse classification levels (up to four classes), even with the best-performing vision systems. The present study developed a vision system that can report finer vehicle classifications according to FHWA’s scheme and is also comparable to other nonintrusive recognition systems. The proposed system decoupled object recognition into two main tasks: localization and classification. It began with localization by generating class-independent region proposals for each video frame, then it used deep convolutional neural networks to extract feature descriptors for each proposed region, and, finally, the system scored and classified the proposed regions by using a linear support vector machines template on the feature descriptors. The precision of the system varied by vehicle class. Passenger cars and SUVs were detected at a precision rate of 95%. The precision rates for single-unit, single-trailer, and double-trailer trucks ranged between 92% and 94%. According to receiver operating characteristic curves, the best system performance can be achieved under free flow, daytime or nighttime, and with good video resolution.
A number of accounting tasks require an evaluation of competing hypotheses. For instance, a management accountant considers alternative reasons for a significant standard cost variance while an ...auditor must determine whether an unexpected fluctuation in a client's account balance was caused by an error, irregularity or a change in economic conditions. In spite of the prevalence of hypothesis evaluation in practice, little is known about the process. In this paper we provide evidence on two issues that could compromise effective and efficient hypothesis evaluation: (1) the revision of beliefs over competing hypotheses given diagnostic evidence; and (2) whether an eliminated hypothesis is subsequently resuscitated (i.e. reconsidered as plausible). To address these issues, 55 auditors were provided audit test results and were asked to evaluate five potential hypotheses that may have caused a material fluctuation in the gross margin ratio of a client. The findings indicate that, when presented with diagnostic evidence about a target hypothesis, auditors were prone to adjusting the likelihood of the target hypothesis but not revising the likelihoods of the competing hypotheses. This non-Bayesian revision strategy, which we label the “one-hypothesis syndrome”, appears to represent a trade-off reflecting competing forces of cognitive strain, efficiency and accountability. While our preliminary results indicate high performance (in identifying the actual cause), additional research in less controlled settings is needed to fully evaluate the effect of this trade-off on efficiency and effectiveness. Finally, contrary to anecdotal evidence from an SEC release, auditors were reluctant to eliminate hypotheses and those who did, did not regard their eliminations as permanent.
The discharging ear is a common presentation in medical practice affecting all age groups but primarily children. This study shows the current aetiological causes of ear discharge and their ...antibiograms, data which would guide empirical treatment of ear infections, and also form a basis for further research.
This was a retrospective review of laboratory records of all ear swabs submitted for culture over a two year period in the Korle Bu Teaching Hospital Accra, Ghana. Data was obtained on demographic characteristics of patients, clinical diagnosis, isolated organisms and antibiotic susceptibility patterns of the isolated organisms. Data was analyzed by simple descriptive statistics.
A total of 351 ear swabs were received by the laboratory for processing over the two year period. Of these 277(78.9%) had microorganisms isolated. A significant number127 (47%) was obtained from children under five years. Pseudomonas spp was the commonly isolated organism 121(46%) followed by Staphylococcus aureus 33(12.5%) and Proteus spp 32(12.2%). Candida was the commonest isolated fungi 9 (69.2%). Susceptibility of Pseudomonas spp to commonly used ototopics (ciprofloxacin & gentamicin) was 93% and 74% respectively.
Most cases of the discharging ear were found in children under the age of five years. The most common bacteriologic cause of the discharging ear was Pseudomonas spp followed by Staphylococcus aureus. Candida species was the commonest fungal cause of ear discharge. Ciprofloxacin and gentamicin are effective ototopic antimicrobial agents for empirical treatment of the discharging ear.
Freshwater turtles as a group are more resistant to anoxia than other vertebrates, but some species, such as painted turtles, for reasons not fully understood, can remain anoxic at winter ...temperatures far longer than others. Because buffering of lactic acid by the shell of the painted turtle is crucial to its long-term anoxic survival, we have tested the hypothesis that previously described differences in anoxia tolerance of five species of North American freshwater turtles may be explained at least in part by differences in their shell composition and buffering capacity. All species tested have large mineralized shells. Shell comparisons included 1) total shell CO2 concentration, 2) volume of titrated acid required to hold incubating shell powder at pH 7.0 for 3 h (an indication of buffer release from shell), and 3) lactate concentration of shell samples incubated to equilibrium in a standard lactate solution. For each measurement, the more anoxia-tolerant species (painted turtle, Chrysemys picta; snapping turtle, Chelydra serpentina) had higher values than the less anoxia-tolerant species (musk turtle, Sternotherus odoratus; map turtle, Graptemys geographica; red-eared slider, Trachemys scripta). We suggest that greater concentrations of accessible CO2 (as carbonate or bicarbonate) in the more tolerant species enable these species, when acidotic, to release more buffer into the extracellular fluid and to take up more lactic acid into their shells. We conclude that the interspecific differences in shell composition and buffering can contribute to, but cannot explain fully, the variations observed in anoxia tolerance among freshwater turtles.
PDF
