Predictability is known to modulate semantic processing in language, but it is unclear to what extent this applies for other modalities. Here we ask whether similar cognitive processes are at play in predicting upcoming events in a non-verbal visual narrative. Typically developing adults viewed comics sequences in which a target panel was highly predictable (“high cloze”), less predictable (“low cloze”), or incongruent with the preceding narrative context  during EEG recording. High and low predictable sequences were determined by a pretest where participants assessed “what happened next?”, resulting in cloze probability scores for sequence outcomes comparable to those used to measure predictability in sentence processing. Through both factorial and correlational analyses, we show a significant modulation of neural responses by cloze such that N400 effects are diminished as a target panel in a comic sequence becomes more predictable. Predictability thus appears to play a similar role in non-verbal comprehension of sequential images as in language comprehension, providing further evidence for the domain generality of semantic processing in the brain. In studies of the brain using event-related potentials (ERPs), semantic processing is indexed by a negativity peaking around 400 ms after the presentation of a stimulus, the N4007. While there is still debate and discussion around the specific functions of semantic processing that this component reflects, such as semantic integration or retrieval of lexical information10 (see Kutas & Federmeier7 for a broader discussion), this component has long been shown to be sensitive to predictability11, making it central to research questions about prediction in language processing. Studies of predictability with the N400 have typically manipulated cloze probability12: the expectancy of a specific target word given the contextual constraints of a preceding sentence. Cloze probability is generally quantified by obtaining cloze ratings: measures of agreement about an upcoming target word in a sentence. In “high-cloze” sentences, a target word is highly predictable given the preceding sentence context (e.g. “He mailed the letter without a STAMP”), while in “low-cloze” sentences, it is less predictable (e.g. “The bill was due at the end of the HOUR”)11. Cloze ratings range from 0 (meaning that 0% of people would predict the same upcoming word) to 1 (meaning that 100% of people would agree upon a predicted word). High-cloze words generate a reduced N400 compared to low-cloze words, suggesting that the greater the predictability of a word given the constraints of the preceding sentence context, the smaller the N400 amplitude. This effect is continuous, such that cloze rating is inversely correlated with N400 negative amplitude (with larger negative amplitudes occurring for lower-cloze words)12.Prediction in language processing remains a widely debated topicacross modalities, as N400s have also been observed across modalities of pictures, sounds, and other sensory stimuli7. N400 effects to visual stimuli tend to be more anteriorly distributed than those found to linguistic stimuli16 and are also often preceded by a slightly earlier component called the N300, an anterior negativity peaking approximately 200–300 ms after stimulus presentation which is also modulated by semantic incongruencies19. The N300 has been associated with object categorization or identification15. While some studies have concluded that the N300 and N400 components reflect similar neurocognitive mechanisms21, others have concluded that the two are separable22.Linguistic debates about the nature of predictive processing related to the N400 remain focused on the verbal modality. However, N400s have long been acknowledged as a default neural mechanism for semantic processing 24. Given these similarities between visual and linguistic semantic processing, and the wealth of research examining predictability in the linguistic domain, it is curious that only a few studies to date have discussed the role of prediction in comprehending visual sequences28.Discourse and narrative research has accumulated a wealth of evidence suggesting that visual and linguistic narratives rely on domain-general cognitive mechanisms. For instance, as in sentences, incongruous or unexpected panels in a visual narrative sequence have been shown to evoke larger N400s than congruous panelset al.27 present a theoretical argument called Event Segmentation Theory (EST) which proposes that event perception involves segmenting narratives into boundaries based on prediction error. As comprehenders view visual sequences, they form predictions about what will happen next. When those predictions are disconfirmed (a prediction error), the viewer perceives this as a boundary in the narrative event. In a series of follow-up experiments, Zacks et al.26 presented participants with movies of everyday events. The movies were paused approximately once per minute and participants were asked to predict what would happen five seconds later in the film. They found that participants provided less accurate predictions, slower response times, and lower confidence in their predictions when the movies were stopped at an event boundary compared to in the middle of an event. In other words, it is harder to predict near-future events when one film scene has just ended and the other has not yet begun, compared to in the middle of an ongoing scene. Although this work clearly highlights the importance of prediction in visual event comprehension, none of these studies by Zacks and colleagues actually manipulate predictability by, for example, including predictable or unpredictable events or classifying stimuli based on cloze ratings.Zacks 25 explored the “Agent advantage” in visual narratives: the phenomenon that, when describing an event, people tend to mention the actor (or ‘Agent’) who has initiated the action before the undergoer (or ‘Patient’) who has received the action. In their Experiment 2, participants were presented with single comic panels depicting either an Agent or a Patient in a preparatory state and asked to describe “what happens next”? For instance, a panel of a character wearing a boxing glove with their fist pulled back might be expected to generate predictions that they were about to punch someone or something. They found that Agents in preparatory states generated more accurate predictions  than Patients in preparatory states, suggesting that these characters can facilitate predictions about upcoming actions. Although this work provides valuable insight into how comprehenders make predictions about upcoming events, like the work by Zacks and colleagues, it did not specifically manipulate predictability by comparing predictable and unpredictable events.In a series of experiments, Cohn & Paczynski23, who presented participants with videos of an actress performing three different goal-directed actions: inserting a spoon into her mouth; putting on shoes; and answering a telephone. In addition to the predictable goal-directed actions, the video sequences also included “unpredictable” actions such as putting an empty spoon into the mouth, putting on only one shoe, or answering the phone by placing it on top of the head. The authors reported no significant differences between predictable and unpredictable actions for the shoe and telephone actions, but a larger N400 to unpredictable actions compared to predictable actions for the eating sequences. The authors attributed the lack of significant effects in two of the three conditions to factors such as spatial ERP smearing between participants, anticipatory processes due to the repeated presentations of the stimuli, or fundamental differences between putting on shoes/answering the phone compared to eating, with the latter having more concrete intentions. Nevertheless, all of the “unpredictable” actions in this study could be viewed as semantic anomalies (e.g. putting an empty spoon in the mouth) which were semantically implausible in addition to being unpredictable. This is an important distinction to make, since in the psycholinguistic literature it is clear that predictability (expected/unexpected) and semantic congruity (plausible/implausible) are separable effects: words can be unexpected but still semantically congruent29, and just the manipulation of expectedness  is enough to elicit N400 differences30. We would therefore argue that because the Reid & Striano study included only semantically congruent and incongruent actions, they did not manipulate predictability , and they included no quantifiable measurement of such “predictability.” Therefore, it remains unclear whether plausible events that are more or less predictable (e.g. high versus low cloze) would modulate the N400 for visual sequences in the same way as in language. Furthermore, Reid & Striano only included three different video sequences that were presented multiple times, meaning that an investigation of how predictability modulates N400 amplitude at the item level could not be performed. It thus remains unknown whether predictability would modulate the N400 for visual sequences in a continuous and graded way (i.e. would inversely correlate with N400 amplitude), as observed in language31.Predictability was specifically manipulated in an ERP study by Reid & Striano15, we do not expect this component to be modulated by cloze.The current study aims to quantify predictability using cloze ratings and systematically investigate how visual narrative sequences that are more or less predictable, yet still semantically plausible, modulate the N400 effect. Predictability in visual narratives can be tested using the same type of paradigm as in language studies, in which a target panel is more or less expected based on the prior narrative context. Here we examined the N400s to short visual narratives of comic strips, which, like sentences, unfold across a sequence with predictable or unpredictable outcomes. Notably, and in contrast to previous studies examining predictability in visual narrative sequences, we obtain quantifiable cloze ratings based on a previous norming study, as is the typical procedure in psycholinguistic studies of cloze. By quantifying and manipulating cloze in this way, we aim to demonstrate that predictability in visual narrative sequences modulates the N400 response in similar ways as in language, thereby providing further evidence that visual and linguistic narrative processing rely on similar cognitive mechanisms. We expect that low-cloze stimuli overall will show larger N400 amplitudes compared to high cloze stimuli. Furthermore, we expect this effect to be continuous: that is, cloze rating will be positively correlated with amplitude . As the N300 component has been more associated with object categorization or identificationM = 26, SD = 9.3; 17 female, 5 male) without any histories of neurological disorders or learning disabilities. The data from two additional participants were not usable and were not included in analyses. Using a repeated-measures ANOVA with 3 conditions, this sample size allows us to detect a medium-to-large effect size at a power of 0.80 and an alpha of 0.05 (see Supplementary Methods), similar to a previous ERP paradigm using visual narratives24. Participants were recruited from the University of Vermont and the broader Burlington, Vermont community through newspaper advertisements, fliers, and public announcements. All procedures were approved by the Institutional Review Board at the University of Vermont and were performed according to the guidelines and regulations of this committee. We obtained written informed consent from each participant before experimental testing. Participants were monetarily compensated for their time.Participants were 22 typically developing adults ages 18–50 . The total score on this questionnaire correlates with metrics of visual narrative comprehension33. A VLFI score of 12 is considered “average” comic reading expertise, with <8 being considered “low” and >22 considered “high” fluency34. On the VLFI participants also confirmed and rated their familiarity with Peanuts comics. All participants rated themselves as being familiar with the Peanuts comics. Although this familiarity could have influenced predictability mechanisms, as described in the next section, the strips used here were created by recombining panels of original Peanuts comics and, in some cases, unique panels were created to form fully novel strips. This renders it virtually impossible for participants to predict upcoming events in these sequences based on prior familiarity with these specific Peanuts comics, though common themes may have prevailed. We also note that “familiarity” may be vaguely interpreted, since the Peanuts franchise comprises different media .All participants self-reported normal or corrected-to-normal vision. Two participants were left-handed.  Participants completed the Visual Language Fluency Index (VLFI) which assesses expertise with visual narratives  to create novel experimental sequences as used in several prior studies34. We obtained cloze ratings for 265 sequences during a pre-test with 200 healthy adults who were not included in the main experiment. Stimuli were presented via Survey Monkey. Each 6-panel sequence was cropped just before the climactic “Peak” panel35, which occurred between positions 3 and 6, depending on the sequence. These cropped sequence stems, which varied from 2 to 5 panels long, were presented to participants who were asked “what comes next?” They typed descriptions of their predicted events at the next panel into a text box. Answers were coded based on their reference to topical statements capturing the main idea of what would happen next, regardless of the specific linguistic utterances. See Supplementary Table We selected stimuli from a corpus of over 500 visual narrative sequences recombined from panels of Charles Schulz’s M = 0.6; see Fig. M = 0.2; Fig. M = 0.4) with semantically incongruous panels from different sequences. The constraint ratings for anomalous strips (i.e. the degree to which the preceding narrative context biases the prediction of a certain event7) also ranged from 0 to 0.83 (M = 0.40).The predicted responses for each sequence across all participants were then collated to determine cloze ratings. Cloze ratings for each sequence corresponded to the proportion of participants who agreed on the ending (ranging from 0–1). Thus, if 100 of the 200 respondents (50%) had agreed upon the outcome depicted in the subsequent Peak panel, that sequence would have a cloze rating of 0.5. Using these cloze ratings, we selected 60 sequences with high cloze Peak  panels  which comprised of consenting and paperwork, behavioral tests, application of the EEG net, and experimental testing. Stimuli were presented using E-Prime version 2.0.10.356. The 180 total stimuli were presented as 6 blocks of 30 stimuli. Each block contained an equal number of sequences from each condition, presented in pseudorandom order. Before each trial a “Ready?” screen was presented until participants pressed a button, followed by a fixation cross for 500 ms. Panels were presented one at a time in the center of the screen for 1350 ms each with an ISI of 350 msA subset of trials (20%) included a comprehension question. After each sequence, an additional panel appeared in the center of the screen, marked as a comprehension question by a red question mark above the panel and a red border around the slide. Participants indicated whether the panel was related to the sequence they had just seen. Comprehension questions were evenly distributed across conditions and blocks, and contained an equal number of ‘related’ and ‘unrelated’ correct answers. The comprehension questions emphasized accuracy rather than speed.Stimuli were presented on a Dell 21.5” LCD monitor with 1920 × 1080 resolution. Participants sat in a comfortable chair in a quiet room separate from the experimenter and computers. Participants sat approximately 24” away from the screen and each comic panel was 5.25” wide and 4.125” high, yielding a visual angle of 12.56° horizontally and 9.8° vertically.36 and Matlab 2017a. The data were filtered using a 0.1–50 Hz bandpass filter. Epochs were time-locked to the onset of the critical (Peak) panel in each sequence and extended from 100 ms before to 1500 ms after the critical panel. Independent component analysis (ICA)38 was used for artifact correction. Before ICA decomposition the mean of each trial was removed39 and data were reduced to 32 dimensions. After ICA decomposition the ERP waveforms and topographic plots of each component were reviewed and a trained examiner marked any components contributing to movement, eye blinks or saccades, or other sources of noise for removal. Segments were then baseline corrected using the first 100 ms of the segment and re-referenced to the average of the left and right mastoids. Additional bad trials were identified and rejected using a joint probability computation38 with a threshold of 3 standard deviations. Finally, each trial was visually reviewed and any further bad trials not caught by the joint probability algorithm were marked for removal by a trained experimenter.  400, a 128-channel EGI Geodesics Sensor net, and NetStation version 5.4. A 4 kHz antialiasing lowpass filter was applied during acquisition and data were referenced online to the Cz electrode. Impedances were kept under 50 kΩ wherever possible. EEG data preprocessing was performed with EEGlab version 14.1.1b40; Fig. 40 to provide a broad scalp representation and ensure we did not miss potential effects outside of a predefined analysis region, since visual narratives are known to elicit N400 effects at slightly different scalp topographies than linguistic stimuli32. Time windows for analyses were based on visual inspection and included windows from 200–300, 400–500, 500–600, 600–800, and 800–1000 ms (out of the full epoch of 0–1500 ms with a 100 ms prestimulus baseline period). To evaluate effects of condition on ERP amplitude, repeated-measure ANOVAs were run with within-subject factors of condition , site , and laterality (left/midline/right). Full results are shown in Table t-tests were used to examine significant effects of condition. Generalized eta-squared (η²G) and Cohen’s d are reported as measures of effect sizes for ANOVAs and t-tests, respectively. Finally, to examine whether the effects of predictability elicited continuous modulations of ERP amplitude, cloze ratings for each visual narrative sequence in the high and low cloze conditions were correlated with amplitude at every timepoint (downsampled to 250 Hz) from 200–1000 ms at each cluster and in the time window showing significant differences in the overall ANOVA. Cluster mass permutation tests were used to account for multiple comparisons in the full timecourse analysis.Statistical analyses were performed in R version 3.4.1 . ERP amplitude was evaluated at nine electrode clusters centered based on the 10–20 distribution  = 8.37, p < 0.001) such that accuracy was significantly lower for anomalous conditions (M = 81%) compared to the other two conditions , whereas the high and low cloze conditions did not differ (p = 0.28). All three conditions had significantly higher accuracy rates compared to chance (50%), as determined by one-sample t-tests . This suggests that participants were able to successfully understand the narratives.We first confirmed that participants were all attending to and understanding the narratives by evaluating behavioral performance on the comprehension questions. A 3-way ANOVA showed a main effect of condition  = 4.71, p < 0.001, η²G = 0.0006; Table F = 2.76, p < 0.05, η²G = 0.003). However, follow-up testing with one-way ANOVAs at each site with condition as a factor revealed no main effects of condition at any site, suggesting no effects of condition on the N300 component.A significant interaction occurred between condition, site, and laterality  = 8.73, p < 0.001, η²G = 0.007; Table F = 3.96, p < 0.05, η²G = 0.02) only. Follow-up paired-samples t-tests comparing conditions at frontal sites indicated that anomalous conditions were significantly more negative than high cloze (t(65) = 3.39, p < 0.01, d = 0.42) and low cloze (t(65) = 3.67, p < 0.001, d = 0.45) conditions, but high and low cloze did not differ (p = 0.19).A significant interaction occurred between condition and site  = 6.78, p < 0.01, η²G = 0.006; Table F = 5.56, p < 0.01, η²G = 0.03) and central sites  = 3.39, p < 0.05, η²G = 0.03). At frontal sites, paired-sample t-tests indicated that the anomalous condition was significantly more negative than high cloze (t(65) = 4.51, p < 0.0001, d = 0.56) and low cloze (t(65) = 3.63, p < 0.001, d = 0.45) conditions, but high and low cloze did not differ (p = 0.44). At central sites, the anomalous condition was significantly more negative than high cloze (t(65) = 3.50, p < 0.001, d = 0.43) and low cloze (t(65) = 2.10, p < 0.05, d = 0.26), and while low cloze was more negative than high cloze (t(65) = 3.03, p < 0.01, d = 0.37).A significant interaction occurred between condition and site  = 2.97, p < 0.05, η²G = 0.002; Table F = 3.75, p < 0.05, η²G = 0.03) only. Paired-sample t-tests between conditions at frontal sites indicated that the anomalous condition was significantly more negative than high cloze (t(65) = 3.61, p < 0.001, d = 0.44) and low cloze (t(65) = 3.43, p < 0.01, d = 0.42), but high and low cloze did not differ (p = 0.98).A significant interaction occurred between condition and site  = 3.02, p < 0.05, η²G = 0.003; Table F = 3.00, p = 0.06, η²G = 0.03). Paired-sample t-tests between conditions at right-hemisphere sites indicated that the high cloze condition was significantly more positive than the anomalous (t(65) = 4.51, p < 0.001, d = 0.55) and low cloze conditions (t(65) = 2.59, p < 0.05, d = 0.31), but there were no differences between anomalous and low cloze conditions (p = 0.26).A significant interaction occurred between condition and laterality  at each cluster. Corrections for multiple comparisons were performed using cluster mass permutation testsr correlation coefficients across the scalp, there was a cluster of significant (p < 0.05) correlations over right centro-parietal scalp.Second, we correlated cloze with amplitude from 500–600 ms (the window in which the N400 ERP amplitude showed differences between high and low cloze conditions) at every electrode across the scalp. As can be seen in Fig. 43. This relationship is depicted in Fig. r = 0.57, p < 0.05), the correlation at the P4 cluster did not reach significance . , but not at the C4 cluster ; see Supplementary Material Third, we correlated cloze with amplitude over the 500–600 ms window at two selected electrodes, C4 and P4 . Items were binned over cloze ratings, as has been done in previous studiesAcross all three of these analyses the correlations were positive, indicating that as cloze rating decreases (i.e. as sequences become less predictable), amplitude decreases (i.e. becomes more negative).31, we would expect visual narratives to elicit larger N400 amplitudes for low cloze stimuli compared to high cloze stimuli, as is found in the language literature, with N400 amplitudes for anomalous stimuli being the largest of the three conditions.This study tested the hypothesis that understanding narrative sequences of images, like understanding sequences of words in sentences, is modulated by the predictability of upcoming information. To do so we employed a cloze probability ERP paradigm in which a critical panel in a visual narrative sequence was either more or less predictable given the preceding context of the story. We examined N400 ERP responses to three types of sequences: high cloze, low cloze, and anomalous. If visual narrative processing relies on similar cognitive mechanisms as language32. However, our main finding of this study is that the low cloze conditions were also more negative than the high cloze conditions from 500–600 ms over central scalp. These results demonstrate that N400 amplitude is sensitive to cloze probability in visual narrative sequences, just as in linguistic stimuli. We acknowledge that this effect was small, being observed in a relatively short time window (500–600 ms) and with a small-to-moderate effect size (Cohen’s d = 0.37). Nevertheless, this finding offers support for the common sensitivity to predictability underlying comprehension across domains.We did indeed observe this expected pattern. The anomalous images evoked more negative amplitudes than the high and low cloze conditions from 400–800 ms over fronto-central scalp. This replicates previous findings that semantic violations in narrative comprehension elicit large N400 responses as a result of trying to process unpredictable semantic informationr-value of 0.57 at the C4 cluster, corresponding to a small correlation44), and in the full timecourse analysis appeared in a narrow time window (approximately 590–600 ms), likely as a result of the stricter correction for multiple comparisons. Nevertheless, taken together, these results do suggest that cloze modulates ERP amplitude in a continuous way, as in language7. Interestingly, the correlations of amplitude with cloze ratings showed slightly different scalp distributions than effects observed in the overall ANOVA. Over all methods of correlational analyses, correlations were strongest over the right hemisphere at central and parietal sites (C4 and P4 clusters), whereas significant modulations of N400 amplitude by condition occurred only at central sites and were not lateralized to one hemisphere. These correlations may be picking up more subtle modulations of amplitude by cloze rating which are not captured when items are grouped together into high or low cloze categories or over larger analysis windows. In any case, the small but significant associations of cloze ratings and negative amplitudes replicate previous findings in the linguistic domain12.Our second main finding of this study is that we observed small but significant correlations of cloze rating with amplitude across high and low cloze items. More specifically, ERP amplitude was positively correlated with cloze ratings in a graded, non-discrete way, such that larger N400 amplitudes  were associated with less predictable stimuli (i.e. lower cloze ratings). This association indicates that for less predictable sequences, comprehenders must work harder to integrate incoming information with the unfolding narrative representation, resulting in larger negativities. These correlations were modest . This could have introduced variability in the N400 response that mitigated the overall difference between high and low cloze. However, over all high and low cloze items, our cloze ratings ranged from 0 to 0.96, meaning that our correlational analyses  should have been able to identify the full range of cloze effects. We did indeed observe significant correlations of cloze with amplitude, although again these effects were small and require further replication. Despite the small effect sizes in the current study, this work is notable given the limited literature systematically manipulating predictability in visual narratives. As discussed earlier, although predictability has been discussed in terms of how comprehenders segment narratives into event boundaries27, there has been only one study that directly compared predictable and unpredictable events within a visual event sequence23. However, as we argue above, this prior study actually compared anomalous events to predictable events, which in essence only replicates the known anomaly effect on the N4007. Here we manipulate predictability using quantifiable metrics of expectedness based on cloze ratings, thereby including graded variations in predictability. By modeling our cloze probability paradigm for visual narratives on the well-established paradigm in linguistic research, we demonstrate that predictability in visual narratives modulates the N400 effect in a graded, continuous way. The similarities of predictability effects between our results and those documented in the linguistics literature29 serve to further demonstrate the similar cognitive mechanisms underlying narrative comprehension processes across domains.In turn, our high cloze condition included items with cloze ratings of <0.4, with a mean of 0.6. This is a lower cutoff compared to many linguistic studies (e.g. the high-cloze stimuli used in DeLong p’s < 0.22). This suggests that modulation of the N400 effect by predictability does not depend on participants’ experience with comic reading, consistent with prior observations that comics reading expertise does not modulate the N400, despite modulation of other ERP components45.Of note, the participants tested here were not recruited on the basis of comic-reading fluency and, indeed, showed low-to-average levels of comic-reading expertise . In a post-hoc analysis we also correlated VLFI scores with the N400 effect between high cloze and low cloze conditions from 500–600 ms, but no significant correlations emerged (all 29. Here, we observed larger N400 amplitudes for anomalous conditions compared to low and high cloze from 400–800 ms, and between low and high cloze from 500–600 ms. These later time windows may be reflective of the more complex visual information inherent in these stimuli. The timing of these effects are, however, consistent with previous studies using visual sequences which have shown slightly later and more sustained negativities resulting from semantic processing and integration46. In a previous study of predictable and unpredictable visual action sequences, Reid & Striano23 also found modulation of the N400 effect in a slightly later window from 500–700 ms. The fronto-central distribution of the N400 effects observed here is also consistent with prior studies using visual narratives, which have shown more anterior negativities, in contrast to the more parietal N400 distributions for linguistic stimuli7. Therefore, although we observed slight differences in scalp distribution and timing of the predictability effect on ERP amplitude, the underlying cognitive mechanism of how predictability influences narrative comprehension appears to be similar between visual and linguistic narratives.It is also worth noting that the timing of N400 effects observed here is slightly later than typical N400 effects documented in the language literature. N400 effects for high or low cloze words in sentences generally elicit N400 effects from approximately 200–500 ms31, and provide further support for the domain generality of semantic processing in the brain.In sum, these results demonstrate that the N400 ERP component is sensitive to cloze probability in visual narratives, just as in linguistic narratives. These data offer further evidence that sequential images are processed using similar cognitive and neural mechanisms as languageSupplementary information.


ATM) were associated with a non‐significantly higher ORR to PD‐1/PD‐L1 blockade . Patients with DDR alterations (excluding ATM) had non‐significantly longer OS, likely due to a small sample size . ATM alterations were associated with a non‐significantly higher ORR , but also with significantly shorter OS . Patients with ≥ 3 DDR alterations (including ATM) had substantially higher TMB (p = 0.01) and higher ORR (80%) with PD‐1/PD‐L1 blockade versus 24% ORR in patients with <3 DDR alterations. In summary, DDR alterations were associated with non‐significantly higher ORR and longer OS for patients with advanced UC receiving anti‐PD‐1/PD‐L1 agents. ATM alterations were associated with shorter OS.DNA damage response (DDR) gene alterations in cancer are associated with a higher tumor mutational burden (TMB) and may impact clinical outcomes of urothelial cancer (UC). Here, we explore the prognostic role of DDR alterations in advanced UC treated with anti‐PD‐1/PD‐L1 agents. The study included 53 patients who had FoundationOne genomic sequencing and received anti‐PD‐1/PD‐L1 therapy. Fisher exact test and trend test were used to assess differences in objective response rate (ORR). Overall survival (OS) was measured from the time of initial UC diagnosis and Cox proportional hazard regression analysis was performed to calculate hazard ratio (HR) and 95% confidence interval (CI). The cohort had a median age of 66 with 64% receiving platinum‐based chemotherapy. DDR alterations (including  ATM alterations correlated with shorter OS, irrespective of a nonsignificant trend towards higher ORR to anti‐PD‐1/PD‐L1 agents.DDR alterations are associated with higher ORR and nonsignificantly prolonged OS in patients with advanced UC receiving PD‐1/PD‐L1 inhibitors. However, presence of  There is a growing body of literature suggesting that DDR alterations may have prognostic value in UC. Mutations in DDR genes, such as ERCC2, ATM, RB1, FANCC, have been correlated with an improved response to cisplatin‐based neoadjuvant chemotherapyDDR alterations are associated with improved response to PD‐1/PD‐L1 blockade in advanced UC;ATM) defects correlated with shorter OS in advanced UC.ATM mutations in advanced UC treated with anti‐PD‐1/PD‐L1 agents. We hypothesized that ATM mutations would be associated with shorter OS, while other DDR alterations would be associated with longer OS in patients with advanced UC treated with anti‐PD‐1/PD‐L1 agents.Defects in 22.1de novo metastatic disease (N2‐3 or M1) based on the American Joint Committee on Cancer 7th edition or relapsed disease after treatment for localized disease, comprehensive somatic genomic analyses of tumor tissue by FoundationOne, and received anti‐PD‐1/PD‐L1 therapy with palliative intent. We extracted data for disease status, baseline and clinicopathological features, treatment response and outcomes, as well as genomic analyses. Additionally, we collected 38 patients with metastatic UC who did not receive anti‐PD‐1/PD‐L1 treatment as a nonrandomized control population.We collected data from 53 patients from three institutions: (a) Penn State Cancer Institute (b) The Ohio State University Comprehensive Cancer Center (c) Cleveland Clinic Taussig Cancer Institute. The study was approved independently by the institutional review board at all three institutions. Key eligibility criteria include: presence of advanced UC defined as either 2.2The methodology for FoundationOne sequencing has been described.2.3DDR alterations. Nonparametric test  was used to compare mutation counts between groups because of presence of outliers . Pearson correlation test was performed to assess the correlation between number of DDR alterations and TMB. OS was measured from time of initial UC diagnosis to death of any cause or last follow‐up. Both univariable and multivariable Cox proportional hazard regression analysis were performed to calculate the hazard ratio (HR) and 95% confidence interval (CI), with adjustment of age, gender, race, extirpative surgery of primary tumor, smoking history, relapsed or de novo metastasis, and platinum‐based chemotherapy. Kaplan‐Meier curve was used for cumulative probabilities. A number of 28 DDR genes selected from FoundationOne gene panel were used for analyses , which was defined as complete or partial response. Cochran‐Armitage trend test was used to determine whether ORR increases along with the number of es Table . Since A33.1de novo) UC (66%), and ever smokers (70%). DDR alterations were present in 49% (26/53) patients in our cohort. There was no difference in the proportion of patients receiving prior platinum‐based chemotherapy based on the presence or absence of DDR alterations . We noted that patients who received PD‐1/PD‐L1 treatment had longer OS when compared with 38 patients with metastatic UC .Our cohort of 53 patients had a median age of 66 range 21–81 years) and a median follow‐up time of 21 months (range: 4.4–138.5 months); 64% of patients had received platinum‐based chemotherapy. As shown in Table –81 yearsUC Table  who did 3.2DDR alterations with or without ATM   showed substantially higher tumor mutation burden [TMB] . Most importantly, these patients experienced a higher ORR to PD‐1/PD‐L1 blockade compared with patients with <3 DDR alterations . Overall, there was a trend for higher ORR with the presence of higher number of DDR alterations (including ATM) to PD‐1/PD‐L1 inhibitors (ptrend = 0.02).Among the 50 patients with available ORR information (assessed by the investigator), we observed a nonsignificantly higher ORR to PD‐1/PD‐L1 blockade in patients who had 3.3DDR gene alterations into five different pathways, including: homologous recombination (HR) , Fanconi anemia (FA) (9), mismatch repair (MMR) (4), checkpoint (4) and “all others” (10). Alterations in all five DDR pathways seemed to correlate with higher ORR, which was most pronounced in MMR, checkpoint and “all others” pathways  showed similar OS with those without DDR alterations . After multivariable analysis with adjustment of age, gender, race, surgery, smoking history, relapsed or de novo metastasis and platinum treatment, the conclusion was not changed . However, patients with DDR alterations (excluding ATM) seemed to have longer OS, although significance was not reached  , but statistical significance was not reached (p = 0.33).Patients with s Figure ; median 3.5ATM alterations in the tumor. We were unable to demonstrate the difference between deleterious mutations and variants of unknown significance given the small number of patients. Patients with ATM alterations seemed to favor higher ORR to PD‐1/PD‐L1 blockade , but the difference was not significant . Additionally, similar to our previous findings we noted that the presence of ATM alterations was associated with significantly shorter OS  in the overall cohort .In our present cohort we observed 11% (6/53) of patients harboring 3.6ATM alterations were associated with higher TMB, although the large variability in TMB precluded detecting a statistically significant impact . We observed a trend of higher TMB with increasing number of DDR gene alterations (mean TMB: 8.6 for 0 DDR vs. 16.4 for 1–2 DDR vs. 32.5 for ≥3 DDR) .TMB data were available for 34 patients. We found that ) Figure ; this di3.7p = 0.04). There was a moderate but significant correlation between the number of DDR alterations and tiers of TMB . The Kaplan‐Meier curve showed that the 3rd‐tier patients (with high TMB) seemed to have the longest OS .To determine whether TMB may play a role in mediating treatment response and outcomes, we split patients into 3‐tiers  based on TMB and found that ORR was 0% versus 33.3% versus 54.6% in the three groups, respectively .DDR alterations was associated with a trend towards longer OS. Moreover, there was a trend for higher ORR with increased number of DDR alterations (p = 0.02), while patients with ≥3 DDR alterations (including ATM) benefited the most from PD‐1/PD‐L1 blockade. Furthermore, we were able to show a favorable ORR for alterations in each of the five DDR pathways, particularly in MMR, checkpoint and “all others” pathways. We observed that patients’ tumors with ≥3 DDR alterations tended to have substantially higher TMB, while those patients appeared to benefit the most from PD‐1/PD‐L1 blockade compared with patients with tumors having <3 DDR alterations.There is an imperative need to identify prognostic and predictive biomarkers in the era of personalized medicine. Alterations in ATM is a well‐recognized tumor suppressing gene located on chromosome 11q 22‐23, in the family of PIKK genes and is activated with double DNA strand breaks. Activation of ATM results in phosphorylation of p53 and cell cycle checkpoint arrest (CHK2), resulting in G1/S cell cycle arrest via CDC25A and Cyclin‐CDK (Cyclin‐dependent kinase) complexes.ATM are common across multiple cancer types, and the presence of ATM alterations in metastatic/advanced UC is a poor prognostic biomarker, irrespective of platinum‐based treatment.ATM alterations was associated with a nonsignificant trend for higher ORR to PD‐1/PD‐L1 blockade. Thus, with OS seemingly poor in multiple cancer types with ATM alterations regardless of immunotherapy or platinum‐based treatment,ATM alterations would need a novel therapeutic approach for improving outcomes. Perhaps treating this subset of patients with ATM, ATR or PARP pathway‐directed targeted therapy, with or without immunotherapy, could be a potential therapeutic approach to be explored in clinical trials.DDR genes can contribute directly to higher TMB .DDR alterations, which correlated with ORR. These results were consistent with findings from Teo et al.ATM alterations seemed to be associated with higher TMB, which may explain the numerically (but not significantly) higher ORR to PD‐1/PD‐L1 therapy in patients with ATM altered tumors. ATM alterations may have harmful effects facilitating tumor progression due to functional loss beyond its role in DNA repair. Indeed, ATM plays multiple roles in cancer biology.TMB has been considered a potential biomarker predictive of response to immune checkpoint inhibitors across tumor types, including UC.DDR alterations in our analyses without differentiating alteration type, mono‐ versus bi‐allelic status, germline versus somatic, and potential functional impact . However, Teo et al. showed that both DDR alterations of “unknown significance” and of deleterious nature may have prognostic value in patients with advanced UC treated with anti‐PD1/PD‐L1 agents.DDR genes, such as NER pathway, genome‐wide loss of heterozygosity, homologous recombination deficiency, molecular subtypes, microsatellite instability, and other putative biomarkers were not evaluated in this study.There are a number of limitations of our study. First, we were only able to use OS, instead of cancer‐specific survival (CSS) or progression‐free survival (PFS), for endpoint comparison because CSS/PFS information was not available in our dataset; however, OS is still a meaningful and clinical relevant endpoint. Secondly, due to the retrospective nature of the study, patients may not have received uniform treatment and may not have had the same type and interval of tumor assessments. Although we tried to control confounding factors with multivariable analyses, a number of factors, such as Bajorin or Bellmunt risk scores, were not collected and adjusted for. Moreover, there may have been variability in the timing and site of tumor sample collection. The captured genomic alterations may possibly reflect posttreatment changes, and therefore cannot be used as predictive biomarkers, based only on this study. Furthermore, we included any 5DDR alterations are associated with higher ORR and nonsignificantly prolonged OS in patients with advanced UC receiving PD‐1/PD‐L1 inhibitors. We observed higher TMB in tumors with ≥3 DDR alterations and the higher ORR in these patients to PD‐1/PD‐L1 inhibitors could possibly be also due to higher TMB. However, in line with our previous findings, presence of ATM alterations correlated with shorter OS, irrespective of a nonsignificant trend towards higher ORR to anti‐PD1/PD‐L1 agents, suggesting the possibility that these patients may require additional novel therapeutic approaches. Further studies are needed to assess the clinical utility of DDR alterations in directing therapies in UC.Monika Joshi has research grant through Big Ten Cancer Research Consortium from AstraZeneca and Pfizer/EMD Soreno. Petros Grivas has done consulting for AstraZeneca, Bayer, Bristol‐Myers Squibb, Clovis Oncology, Driver, EMD Serono, Exelixis, Foundation Medicine, GlaxoSmithKline, Genentech, Genzyme, Heron Therapeutics, Janssen, Merck, Mirati Therapeutics, Pfizer, Roche, Seattle Genetics, QED Therapeutics; previously participated in an educational program for Bristol‐Myers Squibb; his institutions have received research funding from AstraZeneca, Bavarian Nordic, Bayer, Bristol‐Myers Squibb, Clovis Oncology, Debiopharm, Genentech, GlaxoSmithKline, Immunomedics, Kure It Cancer Research, Merck, Mirati Therapeutics, Oncogenex, Pfizer, QED Therapeutics . Amir Mortazavi serves in advisory board of Seattle Genetics, Janssen, Debiopharm Group. Ming Yin is a stockholder of Novavax, Inc. All others have no conflicts of interest relevant to the subject matter or materials discussed in the manuscript.Conceptualization: Ming Yin, Monika Joshi and Petros Grivas, Collection of the data: Ming Yin, Monika Joshi and Petros Grivas, Statistical analysis: Ming Yin and Monika Joshi, Writing–original draft: Ming Yin, Writing–review and editing: Ming Yin, Monika Joshi, Petros Grivas, Amir Mortazavi, Paul Monk, Steven K Clinton, Michele Sue‐Ann Woo, Sheldon L. Holder and Joseph J. Drabick.Table S1‐S2Click here for additional data file.


A 61‐year‐old woman with hypereosinophilia and elevated interleukin (IL)‐5 level was admitted to our hospital after detection of multiple liver tumors. Liver biopsy demonstrated that the tumor consisted of scar tissue with remnants of eosinophilic infiltration, suggesting that it had formed by massive eosinophilic infiltration. The hypereosinophilia was treated mainly by prednisolone, and thereafter, the liver tumors disappeared. However, 10 months postadmission, CD4+ T‐cell lymphoma, which can produce IL‐5, was detected in the nasopharynx and oropharynx. Therefore, we believe that this is a rare case of hypereosinophilia‐related liver pseudotumor induced by presumed by IL‐5 elevation. Multiple liver tumors due to hypereosinophilia caused by interleukin (IL)‐5 disappeared mainly on steroid therapy. IL‐5 elevation that induced hypereosinophilia was due to the potent hidden T‐cell malignant lymphoma. Hypereosinophilia can lead to pseudotumors in the liver, most of which are treated by prednisolone.4/μL), alanine aminotransferase was 43 IU/L , alkaline phosphatase was 2200 U/L , and γ‐glutamyl transpeptidase was 190 IU/L . Carcinoembryonic antigen, carbohydrate antigen 19–9, α‐fetoprotein, and des‐gamma‐carboxy prothrombin were within the normal range; however, IL‐5 , IgG4 , and IL‐2 receptor  levels were markedly elevated. After admission, ultrasonography (US) was performed to guide the liver biopsy; however, no tumors could be detected by conventional US.A 61‐year‐old woman was admitted to our hospital after multiple liver tumors were detected using computed tomography (CT) . Liver biopsy using a 21‐gauge needle showed that the tumor consisted of scar tissue with remnants of eosinophil infiltration. Eosinophil infiltration was also observed in the parenchyma surrounding the lesion , allergic inflammation to a specific antigen, and neoplastic hematopoietic disorders. In this case, the malignant lymphoma was not detected in the biopsy samples, CT, and PET‐CT performed during the first admission. However, it was readily apparent 10 months later. Looking back to the first admission, we could see that IL‐5, which is produced by CD4+ T cells and induces eosinophil proliferation, differentiation, and migration, was increased.


However, HIIT resulted in impressive improvement in CRF. Peak oxygen uptake , AT , peak power , minute ventilation , and peak heart rate  all increased. Ventilatory equivalents for carbon dioxide at AT (V˙E/V˙CO2‐AT) improved . The improvement in CRF resulted in surgical reclassification from high to low risk. In conclusion, preoperative HIIT training can confer a marked improvement in CRF in an elderly surgical patient and is associated with a corresponding reduction in perioperative risk.Exercise prehabilitation prior to major surgery can improve cardiorespiratory fitness (CRF) and clinical outcome. However, in patients deemed “high‐‐risk” for surgery, the feasibility, optimum training modality and its intensity, duration, and frequency are yet to be defined. We assessed the cardiorespiratory fitness of a 70‐year‐old female patient requiring major thoraco‐abdominal surgery for reconstruction of her esophagus. Cardiopulmonary exercise testing (CPET) on a cycle ergometer was used to determine CRF. A baseline CPET confirmed poor CRF and placed her in a high surgical risk group. This was followed by 16 weeks of unsupervised, home‐based, moderate‐intensity steady‐state (MISS) training followed by 10 weeks of high‐intensity interval training (HIIT) under the combined supervision of an exercise physiologist and clinician in hospital. Following MISS training, CPET metrics failed to improve: peak oxygen uptake decreased  and placed her in a high surgical risk group. Ten weeks of supervised preoperative high-intensity interval training (HIIT) enabled impressive improvement in CRF (36% increase in peak oxygen uptake). The improvement in CRF resulted in surgical reclassification from high to low risk. Despite being well motivated, the patient's own efforts failed to improve her CPET metrics. This led to further detailed discussion of perioperative risk and adequate preoperative preparation, and she agreed to undertake a 10‐week HIIT exercise program jointly supervised by an exercise physiologist and clinician.HIIT consisted of three exercise sessions per week on a cycle ergometer, each of 40 min duration. Sessions comprised six, 2‐min bouts of heavy exercise (50% difference between power output at peak exercise and anaerobic threshold [AT]) interspersed with 3 min of moderate exercise (80% power at AT) based on previous research by West et al. . Heart r2.42.4.1V˙O2 peak) was then undertaken to symptom limited termination and followed by 1‐ to 5‐min recovery period.Objective assessment of functional capacity was performed using CPET. All CPETs were conducted to volitional fatigue using a MedGraphics Ultima metabolic cart (MedGraphics™) and an electromagnetically braked cycle ergometer  in accordance with UK national guidelines for CPET  and oxygen uptake efficiency slope (OUES). The AT was manually interpreted by a clinician using the modified V‐slope method  and carbon dioxide (V˙E/V˙CO2) and end‐tidal partial pressures of oxygen and carbon dioxide in accordance with UK national guidelines for perioperative CPET  and biological variation (represented by CVB), in order to determine if any change is to be considered “clinically meaningful.” We have previously calculated the CD for VO2‐AT, VO2peak, and VE/VCO2‐AT to be 19%, 13%, and 10%, respectively , but small improvements in V˙O2 peak , and minute ventilation  . Her hemoglobin levels were normal throughout the training programs and her body mass remained constant.V˙O2 peak , AT , peak power , minute ventilation , and oxygen uptake efficiency slope (OUES) . V˙E/V˙CO2‐AT decreased . Peak heart rate increased 33% (100–133 b.min−1). . This allowed targeted training using a planned program of exercise. Second, the HIIT program was supervised throughout by both a medical professional and exercise physiologist. This joint supervision allowed for psychological, behavioral, and environmental factors to be addressed through regular encouragement, reassurance, and motivation in a safe and secure environment. While the patient ultimately must do the training, the health professionals must supervise the HIIT program to harness and maintain patient motivation while ensuring safety. While we have demonstrated beneficial increases in CRF, the present HIIT program is admittedly resource intensive in terms of equipment and professional input. Further research is required to evaluate the potential for its widespread implementation in the preoperative setting, given the inevitable financial and logistical constraints.We acknowledge the idiosyncrasies present when comparing the type of exercise intervention (supervised vs. unsupervised), intensity of exercise (HIIT vs. MISS), and mode of exercise , and that a controlled experiment with an age‐matched healthy participant was outside the scope of this work. We simply aimed to demonstrate the impact of a theoretically effective exercise intervention on a single patient to improve clinical outcome. The efficacy of our HIIT intervention may be attributed to some key factors. First, the HIIT program was individualized using the cycle ergometer to adjust work rate based on the patient's power output at two measured physiological parameters (AT and V˙O2 max) following HIIT compared to MISS  are declared by the authors.R.D., I.A., and G.R. performed the experiment and supervised the exercise interventions. M.A., R.D., I.A., G.R., and D.M.B. analyzed the data and interpreted the findings. M.A., G.R., R.D., and I.A. drafted the manuscript. All authors edited and revised the manuscript and approved the final version.


Depression is more prevalent in breast cancer (BC) survivors than in the general population. However, little is known about depression in long‐term survivors. Study objectives were: (1) to compare the age‐specific prevalence of depressive symptoms (a) in BC survivors vs female population controls, (b) in disease‐free BC survivors vs BC survivors with self‐reported recurrence vs controls, and (2) to explore determinants of depression in BC survivors.About 3010 BC survivors , and 1005 population controls were recruited in German multi‐regional population‐based studies. Depression was assessed by the Geriatric Depression Scale‐15. Prevalence of mild/severe and severe depression only were estimated via logistic regression, controlling for age and education. Multinomial logistic regression was used to explore determinants of mild and severe depression.p = .0003), adjusted for age and education. At all age groups <80 years, prevalence of both mild/severe and severe depression only was significantly higher in BC survivors, while BC survivors ≥80 years reported severe depression less frequently than controls. BC survivors with recurrence reported significantly higher prevalence of mild/severe depression than disease‐free survivors and controls, but prevalence in disease‐free survivors and controls was comparable. Age, income, living independently, recurrence, and BMI were significant determinants of mild depression in BC survivors. Age, education, employment, income, recurrence, and BMI were significant determinants of severe depression.Compared with population controls, BC survivors were more likely to report mild/severe depression  with recurrence reported significantly higher prevalence of mild/severe depression than disease‐free survivors and controls, but prevalence in disease‐free survivors and controls was comparable. Cancer recurrence, age, education, employment, income, living independently, and BMI were significant determinants of depression in breast cancer survivors. Being overweight or obese are reciprocally associated with depression.Pertinent studies also did not account for different disease trajectories such as remission and recurrence states.The objectives of this population‐based study are to compare the prevalence of depression in (1) BC long‐term survivors (stage I to III at primary diagnosis) vs female general population controls, (2) BC long‐term survivors who remained disease‐free after treatment vs those with self‐report of recurrence, and (3) to assess potential factors associated with depression in BC survivors and controls.22.1Participants were recruited in two multi‐regional population‐based studies in Germany, CAESAR+  and LINDE . All procedures were performed after approval by the responsible institutional ethics committees. Written informed consent was obtained from each participant.2.1.1The CAESAR+ study included long‐term breast, colorectal, and prostate cancer survivors diagnosed between 1994 and 2004, and reported to one of six participating German cancer registries .2.1.2The LINDE study aimed to provide reference values on a range of patient‐reported outcomes from a representative sample of the German population. A total of 10,580 men and women, aged 18 and above, stratified by age and sex, were randomly selected from the general German population via regional municipal offices. Data were collected between 2013 and 2014 by postal questionnaire. Non‐respondents received two follow‐up reminder letters and a telephone contact . In total, 2849 individuals participated (response rate: 29%). As a comparison group for BC survivors, only females who completed the full‐length questionnaire (n = 1306) were included. Women with self‐reported history of cancer (n = 165) and who were younger  or older than the BC sample  were excluded for this analysis. The final sample comprised 1005 female LINDE participants.2.22.2.1Geriatric Depression Scale (GDS‐15)Depression was assessed by the German short form 2.2.2In both studies, the questionnaires included sociodemographic, personal, and clinical information such as marital status, education, income, comorbidities, weight, and body size. In BC survivors, information on treatment and on recurrence, metastasis or new cancer (“disease recurrence”) since initial diagnosis were also assessed via self‐report. The particular cancer registries provided additional clinical information on cancer survivors such as year of diagnosis and cancer stage.2.3Differences between the characteristics of BC survivors and controls were evaluated with Cochran‐Mantel‐Haenszel tests (CMH). Dummy variables were created for each characteristic to allow for a comparison by variable level and to allow for age standardization. The age distribution of population controls reflected a stratified sampling scheme but was still significantly different from that of BC survivors (mean age 58.7 vs 65.3 years). Consequently, for the comparison of further characteristics, we used direct standardization by age  to adjust the age distribution of population controls to that of BC survivors. The comparison of BC survivors with and without recurrence was also done using dummy variables and CMH tests, but without age standardization.Prevalence of mild/severe and severe depression only (according to GDS cut‐off‐scores) was estimated via logistic regression, controlling for age and education by including these factors in all models . Contrasts were estimated to compare subgroups. Mild depression was not analyzed as intermediate distinct category in subgroup comparison, as otherwise a higher prevalence of severe depression in one group could have led to a lower prevalence of mild depression in this group. Employment status and comorbidity also differed between BC survivors and controls, but were not included for adjustment, as they reflect the situation at the time of the survey and differences could also be cancer‐related.For age‐stratified comparison of depression prevalence, age at the survey was categorized as follows: 30‐49, 50‐59, 60‐69, 70‐79, and 80‐89 years. Further stratification was done by self‐reported recurrence status of BC survivors at survey (disease recurrence vs disease‐free).Multinomial logistic regression was applied to explore determinants of mild and severe depression in BC survivors and controls. Both outcomes were modeled simultaneously. The regression model for controls comprised the same factors as the model for BC survivors, except for the cancer‐related variables.p‐value <.05 (two‐sided) was considered statistically significant.We employed multiple imputation, based on the Markov Chain Monte Carlo method with 25 repetitions, to reduce possible bias due to missing values . All analyses were conducted with SAS . A 33.1As reported previously, respondents and non‐respondents of the CAESAR+ study were comparable on most variables, except that respondents were slightly younger at diagnosis, had a shorter time since diagnosis, and were less likely to have distant metastasis/ stage IV disease.3.2Even after age standardization, BC survivors reported lower education , were less likely to work full‐time (7.5% vs 13.6%), and were more often retired at the time of the survey (49.9% vs 43.8%) in comparison to controls. BC survivors reported higher proportions of heart failure (9.3% vs 6.4%) and ever having had depression (22.9% vs 18.9%). There were no differences in having a partner or children (Table BC survivors with recurrence in contrast to disease‐free survivors were more often of a younger age (30‐49 years) at survey (11.8% vs 6.5%). They had less often stage I at diagnosis (34.2% vs 46.7%) and more often stage II (53.1% vs 45.7%) or stage III (12.7% vs 7.7%). Also, they reported less breast‐conserving therapy (55.6% vs 78.1%) and were more likely to be treated with chemotherapy (69.5% vs 58.6%). No significant differences were found with respect to axilla dissection, radio‐, or hormone therapy (Table 3.3p = .0003), and severe depression only in 4.7% of BC survivors and 3.8% of controls (p = .22) .Overall, mild/severe depression was found in 30.4% of BC survivors and in 23.8% of population controls , and having a monthly household income of <€1500 were associated with both mild and severe depression  of ≥30 kg/mWhen looking at factors associated with depression in controls, a similar pattern was found concerning age, employment, income, and BMI Figure . However4With increasing numbers of long‐term BC survivors, it is essential to learn about persisting symptoms, and thus, potential supportive care needs of these individuals. This study demonstrated that even 5‐15 years after diagnosis, almost a third of BC survivors showed signs of a mild or a severe depression. Symptoms of a mild depression were more prevalent in BC survivors than in the general population of the same age. A recent population‐based Korean study found no difference between cancer survivors and controls.When stratified by age at survey, BC survivors reported slightly but significantly higher proportions of mild/severe and severe depression than controls in every age group <80 years. At 80‐89 years, BC survivors reported the same prevalence of mild/severe depression, and even lower prevalence of severe depression when compared to controls. Another German study on persons with various cancer entities also did not find any differences in the oldest studied age group (71‐85 years) compared to controls.Many other previous studies on depression did not include long‐term survivors aged ≥80 years at survey. Given our results and the given high incidence rates of BC in women aged ≥70 years of ~183/100.000 globally,In our study, risk of depression was higher in BC survivors who had a recurrence, metastasis or a secondary cancer after primary diagnosis. Recurrence in BC survivors is associated with distressOnly personal and sociodemographic factors but not cancer‐ or treatment‐related variables other than recurrence were associated with depression in BC survivors. Previous results on the role of treatment factors for depression are mixed. A literature review showed that studies using bivariate analyses identified 10 cancer‐related risk factors for depression in BC survivors, while in multivariate analyses, only 3 factors remained significant.Having a partner was shown as a significant protecting factor for controls, but not for BC survivors. This is in contrast to previous multivariate studies, showing that partner support is associated with lower depression in BC survivors.Education was a significant factor for explaining severe depression in BC survivors. The protective role of education against the development of depression has been shown before.Obesity was associated with depression, both in BC survivors and controls. The relation between obesity and depression is supposed to be reciprocal, although the exact mechanism is not fully understood and both phenomena might also be based on common lifestyle factors like, for example, physical activity.Some limitations have to be considered when interpreting the results of this study. The GDS was constructed for a geriatric context and is not validated for younger participants. Therefore, the prevalence of depression in younger age groups should be interpreted in relation to the age‐stratified population norms and not on an absolute level. Also, the GDS assesses the affective and cognitive but not the somatic domains of depression.Healthy survivor and/or participation bias could have led to an underrepresentation of BC survivors with poorer health in our study. As such, the prevalence of reported depression might be underestimated. Likewise, non‐participation among controls might also have introduced bias.Strengths of the study include the population‐based recruitment of both samples with a comparable data collection mode. Both cohorts showed a variance in ages and sociodemographic variables, and the large sample size allowed for stratification according to age at survey and recurrence. There were no major differences between respondents and non‐respondents in the BC survivors’ cohort. We also conducted sensitivity analyses without excluding the small number of stage IV BC survivors and came to similar results.A considerable number of long‐term BC survivors met the cut‐off for mild depression, although unlikely due to the primary cancer itself. Rather, recurrence explained most of the differences in depression prevalence between BC survivors and controls. Thus, when treating BC survivors for a recurrence, clinicians should be aware of the psychological effects and the existential meaning of being confronted with the illness again, refer to psychological care when needed, and normalize referral.In conclusion, BC survivors, especially those who are younger and show additional risk factors for depression, should be monitored during follow‐up. Besides psychological support, information on financial aid and motivation to start/maintain some physical activity might be needed for this group.No conflict of interest.Daniela Doege: Formal analysis, methodology, visualization, writing ‐ original draft, review & editing. Melissa SY Thong: Methodology, writing – review & editing. Lena Koch‐Gallenkamp: Conceptualization, project administration, data curation, writing ‐ review & editing. Lina Jansen: Conceptualization, data curation, writing ‐ review & editing. Heike Bertram: Investigation, writing – review & editing. Andrea Eberle: Investigation, writing – review & editing. Bernd Holleczek: Investigation, writing – review & editing. Ron Pritzkuleit: Investigation, writing – review & editing. Annika Waldmann: Conceptualization, writing – review & editing. Sylke R. Zeissig: Investigation, writing – review & editing. Hermann Brenner: Conceptualization, funding acquisition, writing – review & editing. Volker Arndt: Conceptualization, funding acquisition, project administration, data curation, methodology, writing – review & editing, supervision.Supplementary MaterialClick here for additional data file.


To investigate whether closed suction drainage (CSD) is related to accelerated rehabilitation of patients after open reduction and internal fixation (ORIF) for closed distal femur fractures.This study was a prospective, randomized controlled clinical trial. Between October 2018 and June 2020, 160 closed distal femur fracture patients who were prepared for ORIF were prospectively randomized into two groups: a CSD group with the mean age of 57.91 ± 14.38 years (32 [40%] men and 48 [60%] women) and a non‐CSD group with the mean age of 59.73 ± 17.55 years (27 [34%] men and 54 [66%] women). Wound visual analogue scale (VAS) pain scores, peri‐wound skin temperature, hematocrit (Hct), hemoglobin (Hb) concentrations, hidden blood loss (HBL), dressing change, period of wound oozing, postoperative blood transfusion, and length of postoperative hospital stay were recorded. Postoperative wound complications, namely wound infections, wound haematoma, wound dehiscence, erythema of wound, and lower limb deep vein thrombosis (DVT) were collected. All the patients were administrated by a single surgical team and followed up for 1 month after the ORIF.vs 36.86 ± 0.38 °C, P = 0.002; 1.88 ± 0.82 vs 3.15 ± 1.15, P = 0.000). However, both the peri‐wound skin temperature and wound VAS pain scores did not differ significantly between the two groups on the fifth postoperative day. In addition, patients with CSD had a longer length of postoperative hospitalization time . There was no statistically significant difference between CSD and non‐CSD groups within 1 month after the ORIF regarding blood loss, period of wound oozing, and postoperative complications, such as incidence of wound infection, haematoma, erythema, dehiscence, and lower limb DVT.The patients without CSD were identified with lower peri‐wound skin temperature and wound VAS pain scores during the first three postoperative days (36.69 ± 0.33 Prophylactic CSD after primary ORIF for closed distal femur fractures not only had no significant advantage to minimize blood loss and wound complications, but increased local inflammation and postoperative hospital stay, and thus we suggest that prophylactic CSD after primary ORIF for closed distal femur fractures is not recommended for optimized clinical pathways and accelerated recovery. Non‐use of prophylactic drains after primary surgery for closed distal femur fractures was related to less local inflammation and shorter postoperative hospital stay. Prophylactic drains had no significant advantage to minimize blood loss and wound complications, and we suggest that prophylactic drains after surgery are not recommended for this type fractures. Closed suction drainage (CSD) has been routinely applied in orthopaedic and trauma surgery. The CSD was used for the purpose of a relatively lower infection risk and less potential dead space of orthopaedic wounds, which was first proposed by Waugh in 1961However, an adverse effect of prophylactic CSD is that they may become a potential infection source and act as an infection path into the depths of the woundDistal femur fractures are relatively rare but severe in orthopaedic trauma, comprising approximately 8.65% of all femoral fractures and 0.8% of total body fractures in Chinese adultsTherefore, we performed a prospective clinical randomized controlled trial to more specifically and quantitatively assess the systemic and local efficacy of prophylactic CSD in early recovery of surgical site after one‐stage ORIF for closed distal femur fractures. We hypothesized that: (i) the prophylactic CSD would be correlated to more postoperative wound pain and higher peri‐wound skin temperature; (ii) the prophylactic CSD would have no significant advantage to minimize blood loss and wound complications within 1 month after the ORIF; and (iii) non‐use of prophylactic CSD would contribute to shorter hospitalization time.From October 2018 to June 2020, a prospective clinical randomized controlled trial including consecutive patients undergoing one‐stage ORIF for acute closed distal femur fractures was conducted at the Third Hospital of Hebei Medical University. The study protocol was conducted according to the Declaration of Helsinki and was approved by the Institutional Review Board (NO 2018–026‐1), and all the participants provided written informed consent. The exclusion criteria were listed as follows: (i) age less than 18 years; (ii) old fractures ; (iii) open or pathological fractures; (iv) simultaneous bilateral ORIFs or revision surgery; (v) history of femur surgery and deep vein thrombosis (DVT).As presented in Fig. All the ORIFs were carried out under general anesthesia in a supine position by a single surgical team in the same operating room. A tourniquet was inflated to 260 mm Hg before skin incision until skin closure. An anterolateral or anteromedial distal femoral approach for surgical exposures were uniformly chosen in all cases. The major component used in the ORIFs was the same kind of locking compression plates. As is shown in Fig. The CSD maintained patency and was removed 48 h after operations. Antibiotic prophylaxis (2.0 g cefazolin) was injected intravenously 30 min prior to surgery. All cases were managed and early rehabilitation exercises of quadriceps muscle were performed. Blood transfusions were performed according to the criteria of hemoglobin (Hb) values <70 g/L or 70–100 g/L with symptoms of severe anemia. To prevent DVT, low‐molecular‐weight heparin (LMWH) was administered within 24 h of presentation. The LMWH administered was enoxaparin (40 mg daily). If wound dressing was soaked with exudate, the dressing was directly changed.During the study period, detailed variables of interest were collected and divided into four aspects.2). The BMI is equal to the weight divided by the square of height. Fracture‐related variables included affected side and relevant fracture type according to Arbeitsgemeinschaft für Osteosynthesefragen/Orthopaedic Trauma Association (AO/OTA) classification system. Differences between the two groups were not statistically significant with respect to demographic characteristics, involving age, gender, BMI, side, and relevant fracture type according to AO/OTA classification system, which are shown in Table Demographic variables included age (years), gender, height (m), weight (kg), and body mass index , operation duration (minutes), and the American Society of Anesthesiologists  classification systemThe values of hemoglobin (Hb) and hematocrit (Hct) were recorded from the day before operation to the fifth postoperative day (POD 5). With demographic factors such as gender, height, weight, and transfusion amount taken into calculation, the gross equation quantifies actual postoperative blood lossPostoperative wound complications including wound infections, wound haematoma, wound dehiscence, erythema of wound, and DVT were recorded. The Doppler ultrasonography was performed before and after surgery for DVT confirmation.U test or t test was used to compare continuous variables between CSD and non‐CSD groups depending on the equal variance and normality distribution status. Pearson's chi‐square or Fisher's exact test was utilized to analyze categorical variables. Normally, a P < 0.05 was considered statistically significant. Sample size was estimated from the length of postoperative hospital stay. A minimum difference of 1 day according to postoperative hospital stay was considered to be of clinical significance. A sample size was 64 in each group with a power of 80%, which was analyzed by G*Power 3.1.9.2.Statistical analysis was performed by SPSS version 25.0 . The continuous variables are shown as mean ± standard deviation (SD). The distributions of all data were evaluated for normality by the Shapiro–Wilk test. A Whitney 2. No statistical differences of the two groups were identified with respect to preoperative Hb, Hct, VAS pain score, peri‐wound skin temperature, ASA, intraoperative blood loss, and surgical duration (Table For the 160 patients (80 in each group), the average age was 58.82 ± 16.01 years (59 [37%] men and 101 [63%] women), and the average BMI was 26.18 ± 4.29 kg/mP = 0.087). The average length of postoperative hospital stay was 9.78 ± 4.64 and 11.45 ± 5.95 days in the non‐CSD and CSD groups; the difference was statistically significant (P = 0.049).Postoperative variables were shown in Table P = 0.000). The average scores of VAS pain at POD 3 was 1.88 ± 0.82 and 3.15 ± 1.15 in the non‐CSD and CSD patients; the difference was statistically significant (P = 0.000). Nevertheless, the pain scores of the two groups were found to be nearly identical on POD 5.Both the VAS pain scores and peri‐wound skin temperature were two quantitative outcomes related to local inflammation. As is shown in Table P = 0.001). The average peri‐wound skin temperature of the patients at POD 2 was 37.00 ± 0.50 and 37.26 ± 0.44 °C in the non‐CSD and CSD groups; the difference was statistically significant (P = 0.020). The average peri‐wound skin temperature of the patients at POD 3 was 36.69 ± 0.33 and 36.86 ± 0.38 °C in the non‐CSD and CSD groups; the difference was statistically significant (P = 0.002). There was no statistical significance found between the two groups in respect to peri‐wound skin temperature from POD 4 to POD 7.The average peri‐wound skin temperature of the patients at POD 1 was 37.00 ± 0.50 and 37.26 ± 0.44 °C in the non‐CSD and CSD groups; the difference was statistically significant  on POD 15. Furthermore, no significant difference between the CSD and non‐CSD groups with respect to wound dehiscence, wound erythema, and DVT was observed.Postoperative complications were summarized in Table Despite the inadequate criteria to recommend its use, CSDs are applied widely in orthopaedics for the intention of preventing the postoperative seroma, and when to remove CSD often influences the discharge time. Nevertheless, patients often report discomfort associated with drains, and drain sites may represent potential sources of infectionIncision healing is associated with period of wound oozing and dressing change. Previous studies involving a meta‐analysis have revealed that CSD facilitates the reduction of wound oozing time and dressing changeRedness, swelling, heat, and pain are four common clinical signs, which reflect local inflammationPain and discomfort during removal of surgical drains is an obvious problemProvided that drainage placement may increase transfusion requirements, routine drainage use after hip fracture surgery is not recommendedIt has been reported that drainage decreases the occurrence of subcutaneous ecchymosis and frequency of dressing reinforcementStaphylococcus aureus infection, which may have been attributable to the unstable glycaemic control. The reason for less wound infection in our study may involve the following factors. Firstly, our follow‐up period (postoperative 1 month) was inadequate to manifest accurate infection outcomes. Secondly, appropriate selection of prophylactic antibiotics and strictly aseptic techniques may decrease the rate of wound infections. Finally, no significant difference of postoperative DVTs were identified between the two groups, which may be interpreted partly by the daily administration of LMWH started from the day of admission.In our present study, only one patient with diabetes from the non‐CSD group developed the Our present study has two strengths. First, it was designed as a prospective clinical randomized controlled trial and 160 participants were matched according to related preoperative data. Second, few studies have focused on the efficacy of CSD in patients with one‐stage ORIF for acute closed distal femur fractures. However, it is a primary report and all data are measured during hospitalization. Further follow‐up is still needed for evaluating the long‐term prognosis of deep infection and renovation. In addition, some variables that potentially reflect the early recovery were not included, such as the degree of swelling and fracture healing time.In this randomized study, non‐use of prophylactic CSD after primary ORIF for closed distal femur fractures was related to less local inflammation and shorter postoperative hospital stay. Prophylactic CSD not only had no significant advantage to minimize blood loss and wound complications, but increased hospitalization costs. Therefore, we suggest that prophylactic CSD after primary ORIF for closed distal femur fractures is not recommended for optimized clinical pathways and accelerated recovery.All data are available from the corresponding author upon reasonable request.The study protocol was approved by the ethics committee of the Third Hospital of Hebei Medical University (NO 2018–026‐1) and is in line with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.This study was supported by the Innovation Project for Postgraduates of Hebei Province Education Department (grant number: CXZZBS2020123).Yingze Zhang designed the study; Junzhe Zhang and Kuo Zhao searched relevant studies; Junyong Li and Hongyu Meng analyzed and interpreted the data; Yanbin Zhu and Junzhe Zhang wrote the manuscript; and Yingze Zhang approved the final version of the manuscript.


Patients with malignancy are particularly vulnerable to infection with Severe Acute Respiratory Disease‐Coronavirus‐2 (SARS‐CoV‐2) given their immunodeficiency secondary to their underlying disease and cancer‐directed therapy. We report a case series of patients with cancer who received convalescent plasma, an investigational therapy for severe Coronavirus Disease 2019 (COVID‐19).Patients with cancer were identified who received convalescent plasma. Enrolled patients had confirmed COVID‐19 with severe or life‐threatening disease and were transfused with convalescent plasma from donors with a SARS‐CoV‐2 anti‐spike antibody titer of ≥ 1:320 dilution. Oxygen requirements and clinical outcomes of interests were captured as well as laboratory parameters at baseline and 3 days after treatment.We identified 24 patients with cancer, 14 of whom had a hematological malignancy, who were treated with convalescent plasma. Fifteen patients (62.5%) were on cancer‐directed treatment at the time of COVID‐19 infection. After a median of hospital duration of 9 days, 13 patients (54.2%) had been discharged home, 1 patient (4.2%) was still hospitalized, and 10 patients had died (41.7%). Non‐intubated patients, particularly those on nasal cannula alone, had favorable outcomes. Three mild febrile non‐hemolytic transfusion reactions were observed. C‐reactive protein significantly decreased after 3 days of treatment, while other laboratory parameters including ferritin and D‐dimer remained unchanged.Convalescent plasma may be a promising therapy in cancer patients with COVID‐19. Patients with cancer are particularly vulnerable to infection with COVID‐19 given immunodeficiency secondary to their underlying disease and cancer‐directed therapy. Here, we report a case series of 24 cancer patients with COVID‐19 treated with convalescent plasma. Non‐intubated patients, particularly those on nasal cannula alone, had favorable outcomes, suggesting convalescent plasma may be a viable treatment options for cancer patients with COVID‐19, particularly if utilized early in the disease course. Many patients are immunocompromised as a consequence of their underlying disease and/or cancer‐directed treatment, which often includes myelosuppressive chemotherapy, immunosuppressive targeted agents, and radiation therapy. In addition, patients with cancer frequent healthcare centers, which have been implicated in COVID‐19 transmission.At present, few treatment options exist for patients with COVID‐19. Convalescent plasma has been employed in prior pandemics, with some evidence of efficacy in patients with H1N1 influenza and SARS.22.1https://www.uscovidplasma.org/). Expanded access permits the use of an investigational therapy when the primary purpose is to diagnose, monitor, or treat a patient's disease or condition, rather than to obtain the kind of information that is generally derived from clinical trials. Under current FDA regulations, patients with serious or immediately life‐threatening diseases who lack other therapeutic alternatives may be treated with investigational agents under several categories of expanded access, one of which includes protocols, such as the current convalescent plasma EAP, that are designed for widespread use in large patient populations (21 CFR 312.320).The Convalescent Plasma Program at Icahn School of Medicine at Mount Sinai initiated convalescent plasma transfusions on March 28, 2020, via the United States Food and Drug Administration (FDA) single‐patient emergency investigational new drug (eIND) pathway, announced on March 24, 2020. All patients in this case series, however, were treated between April 11 and May 10, 2020 under the FDA’s national Expanded Access Protocol (EAP), an FDA‐initiated, national, multicenter, open‐label program whose lead institution is the Mayo Clinic  SARS‐CoV‐2 assay of a nasopharyngeal swab specimen; were hospitalized; and had severe or life‐threatening disease or were judged to be at risk for severe or life‐threatening disease. Severe disease was defined by one or more of the following: dyspnea; respiratory frequency greater than or equal to 30 breaths per minute; blood oxygen saturation of less than or equal to 93%; partial pressure of arterial oxygen to fraction of inspired oxygen ratio of less than 300; or lung infiltrates occupying greater than 50% of lung fields. Life‐threatening disease was defined by one or more of the following: respiratory failure; septic shock; multi‐organ dysfunction or failure. Each patient, or a legally authorized representative, provided informed consent prior to transfusion. The study protocol was approved and overseen by the Mayo Clinic Institutional Review Board (IRB) (#20‐003312) and endorsed by Icahn School of Medicine at Mount Sinai IRB (#20‐03393).Patients reported in this case series had a documented cancer diagnosis prior to COVID‐19. Active cancer patients were defined as those currently receiving cancer‐directed therapy or those with radiographic or pathologic evidence of active disease. Patients were considered to be receiving cancer‐directed therapy if they had received treatment within the preceding 2 months prior to diagnosis of SARS‐CoV‐2 infection.2.2Convalescent plasma donors were screened for SARS‐CoV‐2 antibody titers by a two‐step Spike protein‐directed ELISA.2.3Clinical information on all patients was obtained via the electronic medical record and included baseline demographic data, information related to their cancer diagnosis and treatment, and COVID‐19 treatment. Data were analyzed through June 22, 2020. Disease severity was quantified by a 7‐point ordinal scale used in previous COVID‐19 therapeutic trials and was developed by the World Health Organization (WHO) R&D Blueprint expert groupIn addition to death, hospitalization status, and oxygenation requirements, we also assessed key safety information including transfusion reactions, which were defined and graded according to the Centers for Disease Control Hemovigilance Protocol.2.4Data presented in this case series are primarily descriptive. Laboratory values before and after convalescent plasma treatment were compared by Wilcoxon signed‐rank test. All data were assessed for normality using the Shapiro‐Wilk test with alpha = 0.05. Summary statistics for all data that were not normally distributed were reported as median ± interquartile range (IQR). Graphs were plotted using ggplot2_3.1.1 and ggpubr_0.2 R libraries. Statistical analysis was conducted in R using the dplyr_0.8.5 library.33.1We identified 24 cancer patients who were treated with convalescent plasma for COVID‐19. As shown in Table Ten patients (41.7%) had a solid tumor, with breast, colorectal, and endometrial cancers being the most common. Four of these patients (40%) had active disease, and these same patients were receiving active therapy at time of COVID‐19 infection. The median time from last therapy to convalescent plasma was 35 days (range 12‐91 days) None of the patients in this series had metastatic disease, although this was not an exclusion criterion for convalescent plasma treatment. One patient had staging imaging performed at an outside institution, and therefore staging was unknown.9 cells/L), however, 14 patients (58.3%) were lymphocytopenic (absolute lymphocyte count less than 1.0 × 109cells/L).Other comorbidities present in the cohort include hypertension in 15 patients (62.5%), diabetes in eight patients (33.3%), chronic kidney disease in seven patients (29.2%), coronary artery disease in five patients (20.8%), chronic obstructive pulmonary disease in five patients (20.8%), and congestive heart failure in two patients (8.3%). In terms of smoking status, four patients (16.7%) were current smokers and 10 patients (41.7%) were former smokers. Five patients (20.8%) were obese and 11 patients (45.8%) were overweight. At time of convalescent plasma transfusion, no patients were neutropenic . The median time from hospital admission to convalescent plasma treatment was 3 days (IQR 2‐7 days). Thirteen patients (54.2%) were discharged home. As of June 22, 2020, one patient was still hospitalized. Ten patients died (41.7%). Nine patients died of progressive respiratory failure and one (patient 16) expired after a subarachnoid hemorrhage while on ECMO. Figure 5.5 days.Three patients experienced a transfusion reaction, all of which were febrile non‐hemolytic transfusion reactions (FNHTR). These were all determined to be non‐severe and imputability was determined to be probable. No other transfusion reactions were noted.3.3We compared C‐reactive protein (CRP), ferritin, D‐dimer, and lymphocyte percentage before and 3 days after convalescent plasma infusion. As shown in Figure 4Patients with cancer are a particularly vulnerable population during the COVID‐19 pandemic and there remains a paucity of effective treatments.In our series, patients who received convalescent plasma while on mechanical ventilation, NIPPV, or HFNC had dismal survival. While this cohort is too small to draw definitive conclusions, this finding accords with prior studiesTransfusion reactions were uncommon and mild, with only three patients experiencing a FNHTR. We did not observe other transfusion reactions, in particular transfusion‐related acute lung injury (TRALI) or transfusion associated circulatory overload (TACO), which could be particularly disastrous in patients with respiratory decompensation from COVID‐19. Another concern, albeit theoretical, is that convalescent plasma may promote thrombosis formation as it contains coagulation factors. This concern is compounded by emerging data on the procoagulant state of COVID‐19 and known thrombotic risk of malignancy.Patients with hematologic malignancies may be particularly vulnerable to COVID‐19, and preliminary evidence suggests that they have increased mortality as compared with the general population.Two patients received investigational remdesivir prior to convalescent plasma infusion. The United States FDA has provided emergency use authorization with some reports suggesting a decreased time to recovery with this agent.This case series has a number of limitations to consider. Aside from a limited sample size, there is an absence of a control cohort to reach any conclusive benefits with convalescent plasma treatment. It is worth noting that while donor anti‐SARS‐CoV‐2 spike antibodies titers were elevated (≥1:320), we have not yet assessed if these antibodies are neutralizing. In our study, there was also inconsistent availability and follow up on laboratory values, making it difficult to estimate the impact of convalescent plasma on relevant laboratory parameters. Additionally, there are a number of important confounders that can contribute to changes in laboratory values, in particularly concomitant therapies and interventions.Despite these limitations, this series provides the clinical experience of convalescent plasma unique to patients with COVID‐19 who have an underlying malignancy. Although descriptive, this series supports further consideration of convalescent plasma as a therapeutic modality in patients with cancer, particularly when utilized early in the disease course prior to respiratory collapse.Judith A. Aberg receives grants and personal fees from Gilead, grants and personal fees from Merck, grants and personal fees from Janssen, personal fees from Theratech, personal fees from Medicure, grants from Regeneron, grants and personal fees from Viiv, outside of the submitted work. Sean T. H. Liu and Farah Rahman are sub‐investigators for Gilead, Regeneron, and Kinevan. These relationships are outside of the submitted work. The remaining authors have no conflicts of interest to disclose.Conceptualization and design: Douglas Tremblay, Carina Seah, Sean T. H. Liu, Judith A. Aberg, Nicole Bouvier. Data collection and curation: Douglas Tremblay, Carina Seah, Thomas Schneider. Patient recruitment: Douglas Tremblay, Sheena Bhalla, Jonathan Feld, Leonard Naymagon, Bo Wang, Vaibhav Patel, Tomi Jun, Thomas Jandl, Farah Rahman, Sean T. H. Liu, Nicole Bouvier. Drafting of article: Douglas Tremblay, Carina Seah, Sean T. H. Liu, Judith Aberg, Nicole Bouvier. All authors reviewed the manuscript. Douglas Tremblay and Carina Seah had full access to the data and take responsibility for the integrity of the data and the accuracy of the data analysis.