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Background: More than 95% of recent cancer randomized controlled trials used the log-rank test to detect a treatment difference making it the predominant tool for comparing two survival functions. As with other tests, the log-rank test has both advantages and disadvantages. One advantage is that it offers the highest power against proportional hazards differences, which may be a major reason why alternative methods have rarely been employed in practice. The performance of statistical tests has traditionally been investigated both theoretically and numerically for several patterns of difference between two survival functions. However, to the best of our knowledge, there has been no attempt to compare the performance of various statistical tests using empirical data from past oncology randomized controlled trials. So, it is unknown whether the log-rank test offers a meaningful power advantage over alternative testing methods in contemporary cancer randomized controlled trials. Focusing on recently reported phase III cancer randomized controlled trials, we assessed whether the log-rank test gave meaningfully greater power when compared with five alternative testing methods: generalized Wilcoxon, test based on maximum of test statistics from multiple weighted log-rank tests, difference in t -year event rate, and difference in restricted mean survival time with fixed and adaptive τ ., Methods: Using manuscripts from cancer randomized controlled trials recently published in high-tier clinical journals, we reconstructed patient-level data for overall survival (69 trials) and progression-free survival (54 trials). For each trial endpoint, we estimated the empirical power of each test. Empirical power was measured as the proportion of trials for which a test would have identified a significant result ( p value < .05)., Results: For overall survival, t -year event rate offered the lowest (30.4%) empirical power and restricted mean survival time with fixed τ offered the highest (43.5%). The empirical power of the other types of tests was almost identical (36.2%-37.7%). For progression-free survival, the tests we investigated offered numerically equivalent empirical power (55.6%-61.1%). No single test consistently outperformed any other test., Conclusion: The empirical power assessment with the past cancer randomized controlled trials provided new insights on the performance of statistical tests. Although the log-rank test has been used in almost all trials, our study suggests that the log-rank test is not the only option from an empirical power perspective. Near universal use of the log-rank test is not supported by a meaningful difference in empirical power. Clinical trial investigators could consider alternative methods, beyond the log-rank test, for their primary analysis when designing a cancer randomized controlled trial. Factors other than power (e.g. interpretability of the estimated treatment effect) should garner greater consideration when selecting statistical tests for cancer randomized controlled trials.

Purpose: Tumor testing for microsatellite instability and/or mismatch repair-deficiency (MSI/IHC) and clinical prediction models effectively screen for Lynch syndrome (LS)-associated colorectal cancer (CRC) and endometrial cancer (EC), but they have not been assessed for their ability to identify non-LS forms of inherited risk. The aim of this study was to compare MSI/IHC and the PREMM 5 prediction model to identify carriers of LS and non-LS pathogenic variants (PVs) among patients with CRC and EC., Patients and Methods: Data were retrospectively analyzed from two single-institution cohorts: 706 patients with CRC and/or EC referred for genetic evaluation/testing (high-risk cohort) and 1,058 consecutively ascertained patients with CRC (oncology clinic cohort), unselected for familial risk. All participants underwent germline multigene panel testing. PREMM 5 scores were calculated from personal/family cancer history. The primary outcome was the proportion of individuals with germline PVs (LS PVs, high-penetrance PVs, and any PVs) who had abnormal MSI/IHC testing and/or PREMM 5 score ≥ 2.5%., Results: MSI/IHC and PREMM 5 had comparable sensitivity for identifying LS carriers in high-risk (89.3% v 85.7%; P = .712) and oncology clinic patients (96.6% v 96.6%; P = 1.000), although MSI/IHC had significantly superior specificity for LS (81.3% v 20.1%; P < .001; 92.3% v 24.3%; P < .001). In both cohorts, PREMM 5 had superior sensitivity to MSI/IHC at identifying patients with any high-penetrance PVs and any low-, moderate-, and high-penetrance PVs. Among patients with normal MSI/IHC, PREMM 5 identified 84.2% and 83.3% of high-risk patients with CRC/EC and oncology clinic CRC patients with high-penetrance PVs, respectively., Conclusion: MSI/IHC and PREMM 5 effectively identify patients with CRC and/or EC with LS, although MSI/IHC has better specificity for LS. Because PREMM 5 identifies non-LS, high-penetrance germline PVs, patients with CRC and/or EC with PREMM 5 score ≥ 2.5%, including those with normal MSI/IHC, should be offered multigene panel testing.

The t-year mean survival or restricted mean survival time (RMST) has been used as an appealing summary of the survival distribution within a time window [0, t]. RMST is the patient's life expectancy until time t and can be estimated nonparametrically by the area under the Kaplan-Meier curve up to t. In a comparative study, the difference or ratio of two RMSTs has been utilized to quantify the between-group-difference as a clinically interpretable alternative summary to the hazard ratio. The choice of the time window [0, t] may be prespecified at the design stage of the study based on clinical considerations. On the other hand, after the survival data have been collected, the choice of time point t could be data-dependent. The standard inferential procedures for the corresponding RMST, which is also data-dependent, ignore this subtle yet important issue. In this paper, we clarify how to make inference about a random "parameter." Moreover, we demonstrate that under a rather mild condition on the censoring distribution, one can make inference about the RMST up to t, where t is less than or even equal to the largest follow-up time (either observed or censored) in the study. This finding reduces the subjectivity of the choice of t empirically. The proposal is illustrated with the survival data from a primary biliary cirrhosis study, and its finite sample properties are investigated via an extensive simulation study., (© 2020 The International Biometric Society.)

Performing bottom-up synthesis by using molecules adsorbed on a surface is an effective method to yield functional polycyclic aromatic hydrocarbons (PAHs) and nanocarbon materials. The intramolecular cyclodehydrogenation of hydrocarbons is a critical process in this synthesis; however, thus far, its elementary steps have not been elucidated thoroughly. In this study, we utilize the metal tip of a low-temperature noncontact atomic force microscope as a manipulable metal surface to locally activate dehydrogenation for PAH-forming cyclodehydrogenation. This method leads to the dissociation of a H atom of an intermediate to yield the cyclodehydrogenated product in a target-selective and reproducible manner. We demonstrate the metal-tip-catalyzed dehydrogenation for both benzenoid and nonbenzonoid PAHs, suggesting its universal applicability as a catalyst for nanographene synthesis.

The first example of a chiral halogen-bond donor with a sp 3 -hybridized carbon-iodine moiety in a fluorobissulfonyl scaffold is described. The binaphthyl backbone was designed as a chiral source and the chiral halogen-bond donor (R)-1 was synthesized from (R)-1,1'-binaphthol in 11 steps. An NMR titration experiment demonstrated that (R)-1 worked as a halogen-bond donor. The Mukaiyama aldol reaction and quinoline reduction were examined using (R)-1 as a catalyst to evaluate the asymmetric induction., Competing Interests: The authors declare no conflicts of interest.

Context: Racial and ethnic disparities in end-of-life care are well documented among adults with advanced cancer., Objectives: To examine the extent to which communication and care differ by race and ethnicity among children with advanced cancer., Methods: We conducted a prospective cohort study at nine pediatric cancer centers enrolling 95 parents (42% racial/ethnic minorities) of children with poor prognosis cancer (relapsed/refractory high-risk neuroblastoma). Parents were surveyed about whether prognosis was discussed; likelihood of cure; intent of current treatment; and primary goal of care. Medical records were used to identify high-intensity medical care since the most recent recurrence. Logistic regression evaluated differences between white non-Hispanic and minority (black, Hispanic, and Asian/other race) parents., Results: About 26% of parents recognized the child's low likelihood of cure. Minority parents were less likely to recognize the poor prognosis (odds ratio [OR] = 0.19; 95% CI = 0.06-0.63; P = 0.006) and the fact that current treatment was unlikely to offer cure (OR = 0.07; 95% CI = 0.02-0.27; P < 0.0001). Children of minority parents were more likely to experience high-intensity medical care (OR = 3.01; 95% CI = 1.29-7.02; P = 0.01). After adjustment for understanding of prognosis, race/ethnicity was no longer associated with high-intensity medical care (adjusted odds ratio = 2.14; 95% CI = 0.84-5.46; P = 0.11), although power to detect an association was limited., Conclusion: Parental understanding of prognosis is limited across racial and ethnic groups; racial and ethnic minorities are disproportionately affected. Perhaps as a result, minority children experience higher rates of high-intensity medical care. Work to improve prognostic understanding should include focused work to meet needs of minority populations., (Copyright © 2020 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Objectives: Receiver operating characteristic (ROC) curves show how well a risk prediction model discriminates between patients with and without a condition. We aim to investigate how ROC curves are presented in the literature and discuss and illustrate their potential limitations., Study Design and Setting: We conducted a pragmatic literature review of contemporary publications that externally validated clinical prediction models. We illustrated limitations of ROC curves using a testicular cancer case study and simulated data., Results: Of 86 identified prediction modeling studies, 52 (60%) presented ROC curves without thresholds and one (1%) presented an ROC curve with only a few thresholds. We illustrate that ROC curves in their standard form withhold threshold information have an unstable shape even for the same area under the curve (AUC) and are problematic for comparing model performance conditional on threshold. We compare ROC curves with classification plots, which show sensitivity and specificity conditional on risk thresholds., Conclusion: ROC curves do not offer more information than the AUC to indicate discriminative ability. To assess the model's performance for decision-making, results should be provided conditional on risk thresholds. Therefore, if discriminatory ability must be visualized, classification plots are attractive., (Copyright © 2020. Published by Elsevier Inc.)

Background: Catheter ablation for atrial fibrillation (AF) is an established therapy. However, postoperative recurrence is a serious issue caused by the reconduction of the isolated pulmonary veins (PV) and the onset of non-PV foci. The objectives of this study were to elucidate dormant conduction, confirm PV arrhythmia substrate, induce non-PV foci after PV isolation, and assess the acute efficacy of high dose isoproterenol (ISP) when administered in addition to adenosine., Methods: The study consisted of 100 patients with drug-refractory AF (paroxysmal and persistent) who underwent ablation therapy (either radio-frequency or cryoballoon ablation) as the first-line of therapy at our hospital. All patients first underwent PV isolation (PVI) and were administered adenosine followed by ISP (6 μg × 5 min). The effects were observed, and the therapeutic strategy was evaluated., Results: Persistent dormant conduction due to ISP administration was observed in 13 patients. In over half of the patients, arrhythmia substrates were identified in the PV. Ten patients presented with persistent PV firing. The ablation of non-PV foci was additionally performed in 23 patients., Conclusions: We found that dormant conduction, as a result of ISP administration, is persistent and ISP is useful when performing an ablation. In addition, ISP administration is useful for the identification of PV arrhythmia substrates and induction of non-PV foci. However, the effectiveness of ISP may be partially due to the complementary effect of adenosine, and, therefore, a combination of the two drugs seems preferable.

Importance: Despite requirements of informed consent, patients with advanced cancer often receive palliative chemotherapy (PC) without understanding that the likelihood of cure is remote., Objective: To determine whether a PC educational video and booklet at treatment initiation could improve patients' understanding of its benefits and risks., Interventions: Regimen-specific PC videos and booklets presenting information about logistics, potential benefits, life expectancy (optional), adverse effects, and alternatives. Videos featured authentic patients sharing diverse experiences. After receiving treatment recommendations, research assistants distributed materials to patients for independent review., Design, Setting, and Participants: Multicenter randomized clinical trial of patients with advanced colorectal or pancreatic cancer starting first-line or second-line PC in 5 US cancer centers with enrollment from June 2015 to September 2017 and follow-up to December 2019., Main Outcomes and Measures: The primary outcome was accurate expectations of chemotherapy benefits at 3 months, defined as responding "not at all likely" to "What is your understanding of how likely the chemotherapy is to cure your cancer?" (from the Cancer Care Outcomes Research and Surveillance study). Secondary outcomes included understanding of adverse effects, decisional conflict (SURE test), regret (Decisional Regret Scale), and distress (Functional Assessment of Cancer Therapy-General emotional well-being subscale)., Results: Among 186 patients with advanced colorectal or pancreatic cancer who were starting first-line or second-line PC (94 randomized to usual care, 92 to intervention; mean [SD] age, 59.3 [12.6] [range, 28-86] years; 107 [58%] male; 118 [63.4%] colorectal and 68 [36.6%] pancreatic cancer), most patients wanted "a lot" of information or "as much information as possible" about adverse effects (149, 80.1%), likelihood of cure (148, 79.6%), and prognosis (148, 79.6%). Among the intervention arm, 59 (78%) reviewed the booklet and 30 (40%) reviewed the video within 2 weeks. The primary outcome did not differ between intervention and control arms (52.6%; 95% CI, 40.3%-65.0%; vs 55.5%; 95% CI, 45.1%-66.0%). Accurate adverse effect understanding was more common among intervention than control patients (56.0%; 95% CI, 44.3%-67.7%; vs 40.2%; 95% CI, 29.5%-50.9%; P = .05), although this did not meet the threshold for statistical significance. The intervention did not increase distress, despite frank prognostic information. Other secondary outcomes were similar., Conclusions and Relevance: Provision of an educational video and booklet did not alter patients' expectation of cure from PC. Alternative delivery strategies, such as integration with nurse teaching, could be explored in future studies., Trial Registration: ClinicalTrials.gov Identifier: NCT02282722.

Background: Fatigue is a common and distressing symptom for patients with gynecologic cancers. Few studies have empirically examined whether it spontaneously resolves. This study was aimed at identifying longitudinal patterns of fatigue and predictors of clinically significant fatigue 1 year after treatment completion., Methods: This was a prospective cohort study of women with newly diagnosed ovarian (n = 81) or endometrial cancer (n = 181) that did not progress or recur within 1 year of treatment completion. Symptoms of fatigue, depression, and anxiety were assessed after surgery and 6 and 12 months after treatment completion with the Fatigue Assessment Scale and the Hospital Anxiety and Depression Scale. Patients' fatigue scores over time were classified (scores of 22-50, clinically significant; scores of 10-21, not clinically significant). Logistic regression models were fit to examine associations between fatigue and patient characteristics., Results: Among 262 participants, 48% reported clinically significant fatigue after surgery. One year later, 39% reported fatigue. There were 6 patterns over time: always low (37%), always high (25%), high then resolves (18%), new onset (10%), fluctuating (6%), and incidental (5%). Patients with fatigue after surgery were more likely to report fatigue at 12 months in comparison with others (odds ratio [OR], 6.08; 95% confidence interval [CI], 2.82-13.11; P < .001). Patients with depressive symptoms also had higher odds of fatigue (OR, 3.36; 95% CI, 1.08-10.65; P = .039), although only one-third of fatigued patients reported depressive symptoms., Conclusion: Nearly half of women with gynecologic cancers had clinically significant fatigue after surgery, whereas 44% and 39% had fatigue 6 months and 1 year later; this suggests that spontaneous regression of symptoms is relatively rare. Women who reported fatigue, depressive symptoms, or 2 or more medical comorbidities had higher odds of reporting fatigue 1 year later. Future studies should test scalable interventions to improve fatigue in women with gynecologic cancers., (© 2020 American Cancer Society.)

Spontaneous theory of mind (ToM) is an unconscious and automatic understanding of others' mental states. Recently, individuals with attention-deficit hyperactivity disorder (ADHD) have been shown to have social and communication difficulties, and ToM in ADHD has come under scrutiny. Although some studies have employed explicit ToM tasks to this end with contradictory results, none, to our knowledge, has investigated spontaneous ToM in individuals with ADHD. Therefore, we performed this study to examine implicit mentalizing in adults with ADHD using the anticipatory-looking paradigm designed by Senju et al. (2009) with a sample of 24 adults with ADHD and 18 neurotypical adults. The total fixation times to three areas of interest, i.e., the actor and the false-belief congruent and incongruent sides of the scene were measured. We found that neither group showed looking bias toward either the false-belief congruent or incongruent side. We interpret that this similar gaze pattern and the absence of looking bias to the false-belief incongruent side in both groups is indicative of intact implicit ToM in adults with ADHD. Adults with ADHD looked significantly less at the actor than did neurotypical individuals, possibly due to inattention and further experimental modifications should be considered., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Hexapyrrolohexaazacoronene (HPHAC) is one of the N-containing polycyclic aromatic hydrocarbons in which six pyrroles are fused circularly around a benzene. Despite the recent development of HPHAC analogues, there is no report on direct introduction of functional groups into the HPHAC skeleton. This work reports the first example of nitration reaction of decaethylHPHAC. The structures of nitrodecaethylHPHAC including neutral and two oxidized species (radical cation and dication), intramolecular charge transfer (ICT) character, and global aromaticity of the dication are discussed., Competing Interests: The authors declare no conflict of interest.

The two enantiomers of trifluoromethyl-benzo[c][1,5]oxazonines, (R)-4 and (S)-4, can be selectively accessed with high enantiopurity by the Pd-catalyzed ring-expansion reaction of trifluoromethyl-benzo[d][1,3]oxazinones (1) with vinyl ethylene carbonates (3) using one antipode of a chiral ligand. Initially, the reaction proceeds by a double decarboxylative ring-expansion with kinetic resolution of 1 in the presence of a Pd-catalyst/chiral ligand to provide (R)-4 with high enantiopurity. At the same time, the nonreactive antipode of 1, (S)-1, which was recovered with an impeccable s factor of up to 713 and an ideal chemical yield, was transferred into the antipode of the products, (S)-4, with high enantiopurity by a second run of the Pd-catalyzed double decarboxylation reaction, but this time without any chiral auxiliary. Thus, both antipodes of the chiral trifluoromethyl heterocycles 4 can be obtained in excellent enantiopurity using only a single antipode of the chiral catalyst., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A bicyclo[2.2.2]octadiene(BCOD)-fused bis(dipyrromethane) derivative was reacted with methylal in the presence of trifluoroacetic acid followed by oxidation with chloranil to give a doubly N-confused phlorin derivative, which did not undergo the retro-Diels-Alder reaction extruding an ethylene molecule on heating. In contrast, a 7-tert-butoxybicyclo[2.2.1]heptadiene(7-BuOBCHD)-fused bis(dipyrromethane) yielded benzene-ring-fused doubly N-confused porphyrins by following similar reaction sequences., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Most simian immunodeficiency viruses use Nef to counteract the tetherin proteins of their nonhuman primate hosts. Nef also downmodulates cell-surface CD4 and MHC class I (MHC I) molecules and enhances viral infectivity by counteracting SERINC5. We previously demonstrated that tetherin antagonism by SIV Nef is genetically separable from CD4- and MHC I-downmodulation. Here we show that disruption of tetherin antagonism by Nef impairs virus replication during acute SIV infection of rhesus macaques. A combination of mutations was introduced into the SIVmac239 genome resulting in three amino acid substitutions in Nef that impair tetherin antagonism, but not CD3-, CD4- or MHC I-downmodulation. Further characterization of this mutant (SIVmac239AAA) revealed that these changes also result in partial sensitivity to SERINC5. Separate groups of four rhesus macaques were infected with either wild-type SIVmac239 or SIVmac239AAA, and viral RNA loads in plasma and sequence changes in the viral genome were monitored. Viral loads were significantly lower during acute infection in animals infected with SIVmac239AAA than in animals infected with wild-type SIVmac239. Sequence analysis of the virus population in plasma confirmed that the substitutions in Nef were retained during acute infection; however, changes were observed by week 24 post-infection that fully restored anti-tetherin activity and partially restored anti-SERINC5 activity. These observations reveal overlap in the residues of SIV Nef required for counteracting tetherin and SERINC5 and selective pressure to overcome these restriction factors in vivo., Competing Interests: Dr. Lifson is employed by Leidos Biomedical Research, Inc., which exists solely to operate the Frederick National Laboratory for Cancer Research on behalf of the National Institutes of Health and the National Cancer Institute. There are no competing interests to declare.

Background: Patients with blood cancers experience high-intensity medical care near the end of life (EOL) and low rates of hospice use; attributes of goals of care (GOC) discussions may partly explain these outcomes., Methods: By using a retrospective cohort of patients with blood cancer who received care at Dana-Farber Cancer Institute and died in 2014, the authors assessed the potential relationship between timing, location, and the involvement of hematologic oncologists in the first GOC discussion with intensity of care near the EOL and timely hospice use., Results: Among 383 patients, 39.2% had leukemia/myelodysplastic syndromes, 37.1% had lymphoma, and 23.7% had myeloma. Overall, 65.3% of patients had a documented GOC discussion. Of the first discussions, 33.2% occurred >30 days before death, 34.8% occurred in the outpatient setting, and 46.4% included a hematologic oncologist. In multivariable analyses, having the first discussion >30 days before death (odds ratio [OR], 0.37; 95% CI, 0.17-0.81), in the outpatient setting (OR, 0.21; 95% CI, 0.09-0.50), and having a hematologic oncologist present (OR, 0.40; 95% CI, 0.21-0.77) were associated with lower odds of intensive care unit admission ≤30 days before death. The presence of a hematologic oncologist at the first discussion (OR, 3.07; 95% CI, 1.58-5.96) also was associated with earlier hospice use (>3 days before death)., Conclusions: In this large cohort of blood cancer decedents, most initial GOC discussions occurred close to death and in the inpatient setting. When discussions were timely, outpatient, or involved hematologic oncologists, patients were less likely to experience intensive health care use near death and were more likely to enroll in hospice., (© 2019 American Cancer Society.)

Background: Many parents of children with advanced cancer pursue curative goals when cure is no longer possible. To the authors' knowledge, no pediatric studies to date have prospectively evaluated prognosis communication or influences on decision making in poor-prognosis childhood cancer., Methods: The authors conducted a prospective cohort study at 9 pediatric cancer centers that enrolled 95 parents of children with recurrent or refractory, high-risk neuroblastoma (63% of those who were approached), a condition for which cure rarely is achieved. Parents were surveyed regarding the child's likelihood of cure; their primary goal of care; the child's symptoms, suffering, and quality of life; and regret concerning the last treatment decision. Medical records identified care and treatment decisions., Results: Only 26% of parents recognized that the chance of cure was <25%. When asked to choose a single most important goal of care, approximately 72% chose cure, 10% chose longer life, and 18% chose quality of life. Parents were more likely to prioritize quality of life when they recognized the child's poor prognosis (P = .002). Approximately 41% of parents expressed regret about the most recent treatment decision. Parents were more likely to experience regret if the child had received higher intensity medical care (odds ratio [OR], 3.14; 95% CI, 1.31-7.51), experienced suffering with limited benefit from the most recent treatment (OR, 4.78; 95% CI, 1.16-19.72), or experienced suffering from symptoms (OR, 2.91; 95% CI, 1.18-7.16)., Conclusions: Parents of children with poor-prognosis cancer frequently make decisions based on unrealistic expectations. New strategies for effective prognosis communication are needed., (© 2019 American Cancer Society.)

Background: Lynch syndrome confers markedly increased risks of various malignancies, including urinary tract cancers (UTC; renal pelvis, ureter, bladder, and possibly kidney cancers). It is unknown how to determine which Lynch syndrome carriers are at highest UTC risk. Our aim was to identify clinical factors associated with UTC among Lynch syndrome carriers., Methods: The study population was a cohort of 52,758 consecutively ascertained individuals undergoing Lynch syndrome testing at a commercial laboratory. Clinical data were obtained from test request forms completed by the ordering provider. Univariate analysis and multivariate logistic regression were performed to identify factors associated with UTC among Lynch syndrome carriers., Results: Compared with noncarriers, Lynch syndrome carriers were significantly more likely to have had UTC (4.1% vs. 1.2%; P < 0.0001). Lynch syndrome-associated UTC was independently associated with male sex [OR 1.95; 95% confidence interval (CI), 1.38-2.76], increased age (OR 2.44 per 10 years; 95% CI, 2.11-2.82), familial burden of UTC (OR 2.69 per first-/second-degree relative with UTC; 95% CI, 1.99-3.63), and pathogenic EPCAM / MSH2 variants (OR 4.01; 95% CI, 2.39-6.72) but not MLH1 variants (OR 1.17; 95% CI, 0.63-2.17), race, or history of other Lynch syndrome-associated malignancy. A total of 143 of 158 (90.5%) Lynch syndrome carriers with UTC had ≥1 of the following characteristics: male sex, EPCAM / MSH2 variants, or family history of UTC; 1,236 of 1,251 (98.8%) Lynch syndrome carriers lacking all of these characteristics had no history of UTC., Conclusions: Specific clinical factors can reliably identify Lynch syndrome carriers most likely to be at risk for UTC., Impact: A predictable subset of Lynch syndrome carriers may be most likely to benefit from UTC surveillance/prevention., (©2019 American Association for Cancer Research.)

A 52-year-old man underwent upper gastrointestinal endoscopy screening that identified a submucosal tumor in the gastric fornix, and a solid tumor with a maximum diameter of 35mm was suspected based on abdominal computed tomography. An endoscopic ultrasound-guided fine needle aspiration biopsy showed spindle-shaped cells with KIT, CD34, desmin, and S-100 all testing negative. Based on the diagnosis of a gastrointestinal stromal tumor, subtotal gastrectomy was performed laparoscopically. Postsurgical histopathological testing led to a diagnosis of a primary gastric inflammatory myofibroblastic tumor. The present case has been defined as one involving a tumor part way along the spectrum between benign and malignant, with local recurrence and distal metastasis. Reports indicate that recurrence occurs frequently in cases wherein sufficient margins are not obtained or wherein there is enucleation, and complete surgical resection is recommended. With laparoscopic surgery, because an enlarged field of view can be obtained, and depending on the lesion site, good exposure of the operative field is possible, the authors believe that this approach would be beneficial in terms of local control. Moreover, it has been reported that anaplastic lymphoma kinase(ALK), which is a tyrosine kinase receptor protein, tests positive in approximately 60% of cases. Reports have also indicated that distal metastasis occurs frequently in cases in which ALK tests negative, and watchful waiting of these cases at regular intervals should be carried out to the same extent as of cases involving malignant tumors.

An antiaromatic cation of the expanded hexapyrrolohexaazacoronene (HPHAC) 1 + was synthesized by a Vilsmeier-type reaction of the partially unfused HPHAC 2 . X-ray diffraction analysis revealed the formation of a seven-membered ring with a methyne linkage between the pyrrole moieties. Although 1 H NMR spectra, indicating 24π antiaromaticity. Global antiaromaticity was also supported by nucleus-independent chemical shift and anisotropy of the induced current density calculations. Cation + is a monocation, upfield shifts of the peripheral ethyl protons were clearly observed in the 1 H NMR spectra, indicating 24π antiaromaticity. Global antiaromaticity was also supported by nucleus-independent chemical shift and anisotropy of the induced current density calculations. Cation 1 + displayed two reversible oxidations and one irreversible reduction in the cyclic voltammetry measurements. Treatment of 1 + with NOSbF 6 gave aromatic trication 1 3+ with 22π-electron conjugation.

Analysis of the restricted mean survival time (RMST) has become increasingly common in biomedical studies during the last decade as a means of estimating treatment or covariate effects on survival. Advantages of RMST over the hazard ratio (HR) include increased interpretability and lack of reliance on the often tenuous proportional hazards assumption. Some authors have argued that RMST regression should generally be the frontline analysis as opposed to methods based on counting process increments. However, in order for the use of the RMST to be more mainstream, it is necessary to broaden the range of data structures to which pertinent methods can be applied. In this report, we address this issue from two angles. First, most of existing methodological development for directly modeling RMST has focused on multiplicative models. An additive model may be preferred due to goodness of fit and/or parameter interpretation. Second, many settings encountered nowadays feature high-dimensional categorical (nuisance) covariates, for which parameter estimation is best avoided. Motivated by these considerations, we propose stratified additive models for direct RMST analysis. The proposed methods feature additive covariate effects. Moreover, nuisance factors can be factored out of the estimation, akin to stratification in Cox regression, such that focus can be appropriately awarded to the parameters of chief interest. Large-sample properties of the proposed estimators are derived, and a simulation study is performed to assess finite-sample performance. In addition, we provide techniques for evaluating a fitted model with respect to risk discrimination and predictive accuracy. The proposed methods are then applied to liver transplant data to estimate the effects of donor characteristics on posttransplant survival time., (© 2024 Wiley‐VCH GmbH.)

Many clinical trials assess time-to-event endpoints. To describe the difference between groups in terms of time to event, we often employ hazard ratios. However, the hazard ratio is only informative in the case of proportional hazards (PHs) over time. There exist many other effect measures that do not require PHs. One of them is the average hazard ratio (AHR). Its core idea is to utilize a time-dependent weighting function that accounts for time variation. Though propagated in methodological research papers, the AHR is rarely used in practice. To facilitate its application, we unfold approaches for sample size calculation of an AHR test. We assess the reliability of the sample size calculation by extensive simulation studies covering various survival and censoring distributions with proportional as well as nonproportional hazards (N-PHs). The findings suggest that a simulation-based sample size calculation approach can be useful for designing clinical trials with N-PHs. Using the AHR can result in increased statistical power to detect differences between groups with more efficient sample sizes., (© 2024 The Author(s). Biometrical Journal published by Wiley‐VCH GmbH.)

Background: Serving as a reservoir, the gastric fundus can expand significantly, with an initial receptive and a following adaptive relaxation, controlled by extrinsic and intrinsic reflex circuits, respectively. We hypothesize that mechanosensitive enteric neurons (MEN) are involved in the adaptive relaxation, which is initiated when a particular gastric volume and a certain stretch of the stomach wall is reached. To investigate whether the responsiveness of MEN in the gastric fundus is dependent on tissue stretch, we performed mechanical stimulations in stretched versus ganglia "at rest"., Methods: Responses of myenteric neurons in the guinea pig gastric fundus were recorded with membrane potential imaging using Di-8-ANEPPS. MEN were identified by small-volume intraganglionic injection in ganglia stretched to different degrees using a self-constructed stretching tool. Immunohistochemical staining identified the neurochemical phenotype of MEN. Hexamethonium and capsaicin were added to test their effect on recruited MEN., Key Results: In stretched compared to "at rest" ganglia, significantly more MEN were activated. The change in the ganglionic area correlated significantly with the number of additional recruited MEN. The additional recruitment of MEN was independent from nicotinic transmission and the ratio of active MEN in stretched ganglia shifted towards a nitrergic phenotype., Conclusion and Inferences: The higher number of active MEN with increasing stretch of the ganglia and their greater share of nitrergic phenotype might indicate their contribution to the adaptive relaxation. Further experiments are necessary to address the receptors involved in mechanotransduction., (© 2024 The Author(s). Neurogastroenterology & Motility published by John Wiley & Sons Ltd.)

Purpose: The authors sought to understand bereaved family preferences for end-of-life (EOL) care, particularly among Black families and those in the South., Methods: Semi-structured interviews were conducted with parents of children who died of cancer ≥6 months before at Children's of Alabama. Themes were identified via content analysis. Quotes related to medical intensity, chemotherapy, and location of death (LOD) were scored on 5-point Likert scales, ranging from 1 (comfort care, chemotherapy, or home death) to 5 (medically intense care, avoidance of chemotherapy, or hospital death)., Results: Twenty-seven bereaved parents (12 Black) were interviewed. Children died at a mean of 13.1 years (SD = 6.1 years) and a median of 3 years before the interview (range = 1-12 years). Ten children (42%) had central nervous system tumors and the majority (63%) died in the hospital. Family decision-making involved maintaining hope, not causing harm, doing what was best for their child and themselves, and religious beliefs. There was no clear preference for home versus hospital death (3.0 [1.8-4.0]). Instead, parents considered their child's desires and/or medical needs, siblings, and prior experiences with death. To have a comfortable death, parents highlighted the need for comprehensive education about their child's EOL, a caring and comfortable environment, and 24/7 access to their care team. Families expressed a dual preference for comfort care (1.8 [1.3-2.8]) and chemotherapy (3.5 [2.7-4.1]) at EOL., Conclusions: Families did not see chemotherapy and comfort care as conflicting goals. They sought quality care emphasizing flexibility, quality time with their child, and open access to their care team, regardless of LOD., (© 2024 American Cancer Society.)

Objective: Differentiating hepatic epithelioid hemangioendothelioma (EHE) and angiosarcoma (AS), the two most common vascular tumors in the liver, is important due to disparities in their prognosis and treatment. We aimed to compare clinical and MRI features of the two tumors., Methods: This retrospective study included patients with pathologically-confirmed AS or EHE who underwent MRI using gadoxetate disodium between 2008 and 2023. Two radiologists independently reviewed MR images. Wilcoxon rank sum and Fisher's exact tests were used to compare clinical and imaging features. Overall survival was compared using restricted mean survival time at 3 years., Results: 32 patients with AS (18 women [56.3%]; median age, 68 years) and 38 with EHE (24 women [63.2%]; 51 years) were included. Patients with AS were generally older (81.3% ≥ 60 years; P < 0.001), had more frequent laboratory abnormalities (P ≤ 0.018), and poorer overall survival (11.2 vs. 31.8 months; P < 0.001) than those with EHE. On MRI, a large dominant mass accompanied by smaller nodules (14/32, 43.8%), often with ill-defined margins (15/32, 46.9%) was prevalent in AS; compared with nodules of similar sizes (24/38, 63.2%; P = 0.015) with well-defined margin (30/38, 78.9%; P = 0.002) in EHE. Cirrhotic appearance of the liver was more frequent in AS (62.5%, P < 0.001), along with decreased parenchymal enhancement on hepatobiliary phase (31.3%, P < 0.001) and ascites (37.5%, P = 0.010). AS frequently presented with avid enhancement of bizarrely-shaped foci, with a centrifugal enhancement pattern. In comparison, targetoid appearance was characteristic of EHE (78.9% on T2-weighted, 54.1% on diffusion-weighted, 65.8% on multiphase images) (P ≤ 0.002), with enhancement degree typically lower than that of the aorta. On hepatobiliary phase, all the AS exhibited hypointensity, while 39.5% of EHE showed targetoid appearance (P < 0.001)., Conclusion: Patients aged ≥ 60 years presenting with laboratory abnormalities, typically with a large dominant mass accompanied by smaller nodules, exhibiting avid, bizarre, and centrifugal enhancement-particularly in the cirrhotic-appearing liver-suggests the likelihood of AS over EHE., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

A person's phenotypic sex (i.e., endogenous expression of primary, secondary, and endocrinological sex characteristics) can impact crucial aspects of genetic assessment and resulting clinical care recommendations. In studies with genetics components, it is critical to collect phenotypic sex, information about current organ/tissue inventory and hormonal milieu, and gender identity. If researchers do not carefully construct data models, transgender, gender diverse, and sex diverse (TGSD) individuals may be given inappropriate care recommendations and/or be subjected to misgendering, inflicting medical and psychosocial harms. The recognized need for an inclusive care experience should not be limited to clinical practice but should extend to the research setting, where researchers must build an inclusive experience for TGSD participants. Here, we review three TGSD participants in the Family History and Cancer Risk Study (FOREST) to critically evaluate sex- and gender-related survey measures and associated data models in a study seeking to identify patients at risk for hereditary cancer syndromes. Furthermore, we leverage these participants' responses to sex- and gender identity-related questions in FOREST to inform needed changes to the FOREST data model and to make recommendations for TGSD-inclusive genetics research design, data models, and processes., (© 2023 The Authors. Journal of Genetic Counseling published by Wiley Periodicals LLC on behalf of National Society of Genetic Counselors.)

There is emerging evidence that the live herpes zoster (shingles) vaccine might protect against dementia. However, the existing data are limited and refer only to the live vaccine, which is now discontinued in the United States and many other countries in favor of a recombinant vaccine. Whether the recombinant shingles vaccine protects against dementia remains unknown. Here we used a natural experiment opportunity created by the rapid transition from the use of live to the use of recombinant vaccines to compare the risk of dementia between vaccine types. We show that the recombinant vaccine is associated with a significantly lower risk of dementia in the 6 years post-vaccination. Specifically, receiving the recombinant vaccine is associated with a 17% increase in diagnosis-free time, translating into 164 additional days lived without a diagnosis of dementia in those subsequently affected. The recombinant shingles vaccine was also associated with lower risks of dementia than were two other vaccines commonly used in older people: influenza and tetanus-diphtheria-pertussis vaccines. The effect was robust across multiple secondary analyses, and was present in both men and women but was greater in women. These findings should stimulate studies investigating the mechanisms underpinning the protection and could facilitate the design of a large-scale randomized control trial to confirm the possible additional benefit of the recombinant shingles vaccine., (© 2024. The Author(s).)

Background: The treatment and prognosis of de novo metastatic hormone-sensitive prostate cancer (mHSPC) vary. We established and validated a novel prognostic model for predicting cancer-specific survival (CSS) in patients with mHSPC using retrospective data from a contemporary cohort., Methods: 1092 Japanese patients diagnosed with de novo mHSPC between 2014 and 2020 were registered. The patients treated with androgen deprivation therapy and first-generation anti-androgens (ADT/CAB) were assigned to the Discovery (N = 467) or Validation (N = 328) cohorts. Those treated with ADT and androgen-receptor signaling inhibitors (ARSIs) were assigned to the ARSI cohort (N = 81)., Results: Using the Discovery cohort, independent prognostic factors of CSS, the extent of disease score ≥ 2 or the presence of liver metastasis; lactate dehydrogenase levels > 250U/L; a primary Gleason pattern of 5, and serum albumin levels ≤ 3.7 g/dl, were identified. The prognostic model incorporating these factors showed high predictability and reproducibility in the Validation cohort. The 5-year CSS of the low-risk group was 86% and that of the high-risk group was 22%. Approximately 26.4%, 62.7%, and 10.9% of the patients in the Validation cohort defined as high-risk by the LATITUDE criteria were further grouped into high-, intermediate-, and low-risk groups by the new model with significant differences in CSS. In the ARSIs cohort, high-risk group had a significantly shorter time to castration resistance than the intermediate-risk group., Conclusions: The novel model based on prognostic factors can predict patient outcomes with high accuracy and reproducibility. The model may be used to optimize the treatment intensity of de novo mHSPC., (© 2024. The Author(s).)

Background: The therapeutic role of pelvic lymph node dissection (PLND) during radical prostatectomy (RP) for prostate cancer is not established. In clinical practice, PLND is primarily performed in cases of high-risk prostate cancer. The detection of lymph node metastasis plays a crucial role in determining the need for subsequent treatments. This study aims to evaluate the prognosis of prostate cancer patients with lymph node involvement (LNI) by stratifying them based on postoperative prostate-specific antigen (PSA) levels to identify biomarkers that can guide postoperative treatment strategies., Methods: Analysis was conducted on 383 patients, selected from 572 initially eligible, who underwent RP with LNI across 33 Japanese Urological Oncology Group institutions from 2006 to 2019. Patients were grouped according to postoperative PSA levels and salvage treatments received. Follow-up focused on castration resistance-free survival (CRFS), metastasis-free survival (MFS), and overall survival (OS)., Results: In the persistent PSA group (PSA ≥ 0.1 ng/mL), CRFS and MFS were significantly shorter compared to the non-persistent PSA group (PSA < 0.1 ng/mL), and there was a tendency for shorter OS. In the persistent PSA group, patients with postoperative PSA values above the median (PSA ≥ 0.52 ng/mL) showed shorter CRFS and MFS. Furthermore, in the PSA ≥ 0.52 group, androgen deprivation therapy (ADT) plus radiotherapy (RT) combination had prolonged CRFS and MFS compared with ADT alone., Conclusions: This study provides valuable insights into stratifying patients based on postoperative PSA levels to tailor postoperative treatment strategies, potentially improving the prognosis of prostate cancer patients with LNI., (© 2024. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

A typical biosimilar study in oncology uses the overall response evaluated at a specific time point as the primary endpoint, which is generally acceptable regulatorily, to assess clinical equivalence between a biosimilar and its reference product. The standard primary endpoint for evaluating an anticancer therapy, progression-free or overall survival would be a secondary endpoint in a biosimilar trial. With a conventional analytic procedure via, for example, hazard ratio to quantify the group difference, it is difficult and challenging to assess clinical equivalence with respect to progression-free or overall survival because the study generally has a limited number of clinical events observed in the study. In this article, we show that an alternative procedure based on the restricted mean survival time, which has been discussed extensively for design and analysis of a general equivalence study, is readily applicable to a biosimilar trial. Unlike the hazard ratio, this procedure provides a clinically interpretable estimate for assessing equivalence. Using the restricted mean survival time as a summary measure of the survival curve will enhance better treatment decision making in adopting a biosimilar product over the reference product., (© The Author(s) 2019. Published by Oxford University Press.)

Purpose: Spending for patients with advanced cancer is substantial. Past efforts to characterize this spending usually have not included patients with recurrence (who may differ from those with de novo stage IV disease) or described which services drive spending., Methods: Using SEER-Medicare data from 2008 to 2013, we identified patients with breast, colorectal, and lung cancer with either de novo stage IV or recurrent advanced cancer. Mean spending/patient/month (2012 US dollars) was estimated from 12 months before to 11 months after diagnosis for all services and by the type of service. We describe the absolute difference in mean monthly spending for de novo versus recurrent patients, and we estimate differences after controlling for type of advanced cancer, year of diagnosis, age, sex, comorbidity, and other factors., Results: We identified 54,982 patients with advanced cancer. Before diagnosis, mean monthly spending was higher for recurrent patients (absolute difference: breast, $1,412; colorectal, $3,002; lung, $2,805; all P < .001), whereas after the diagnosis, it was higher for de novo patients (absolute difference: breast, $2,443; colorectal, $4,844; lung, $2,356; all P < .001). Spending differences were driven by inpatient, physician, and hospice services. Across the 2-year period around the advanced cancer diagnosis, adjusted mean monthly spending was higher for de novo versus recurrent patients (spending ratio: breast, 2.39 [95% CI, 2.05 to 2.77]; colorectal, 2.64 [95% CI, 2.31 to 3.01]; lung, 1.46 [95% CI, 1.30 to 1.65])., Conclusion: Spending for de novo cancer was greater than spending for recurrent advanced cancer. Understanding the patterns and drivers of spending is necessary to design alternative payment models and to improve value.

In randomized clinical trials, the magnitude of the treatment effect is often reported using the hazard ratio (HR) even when the proportional hazards (PH) assumption is not met. Conducting numerical studies, this commentary illustrates how/why the HR estimate via the standard Cox's procedure is difficult to interpret even as an “average” treatment effect for non‐PH cases., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article.

Bis(bicyclic) molecules dimethanochrysene and diethanochrysene were prepared by Diels-Alder reaction of the naphthodiyne equivalent with cyclopentadiene and 1,3-cyclohexadiene, respectively. Reaction of dimethanochrysene and 7,9-diphenyl-8H-cyclopent[a]acenaphthylen-8-one resulted in the generation of a fluorescent hydrocarbon in unexpected multistep pericyclic reactions. Syn-oriented diethanochrysene-connected bisporphyrin tweezers was prepared from the reaction of chrysene-bridged syn-dipyrrole with tripyrranedicarbaldehyde. The structure of the receptor and its 1 : 1 complex with C 60 or C 70 was determined by X-ray diffraction analysis. The dihedral angles of the bicyclo[2.2.2]octadiene moieties were narrowed by complexation of the receptor with the fullerenes. The binding affinities of the tweezers with C 60 and C 70 were calculated to be 2.7(4)×10 4 and 8.01(7)×10 4  M -1 , respectively by UV-vis and fluorescence spectroscopy., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Purpose: Hospitalizations are a common occurrence during chemotherapy for advanced cancer. Validated risk stratification tools could facilitate proactive approaches for reducing hospitalizations by identifying at-risk patients., Patients and Methods: We assembled two retrospective cohorts of patients receiving chemotherapy for advanced nonhematologic cancer; cohorts were drawn from three integrated health plans of the Cancer Research Network. We used these cohorts to develop and validate logistic regression models estimating 30-day hospitalization risk after chemotherapy initiation. The development cohort included patients in two health plans from 2005 to 2013. The validation cohort included patients in a third health plan from 2007 to 2016. Candidate predictor variables were derived from clinical data in institutional data warehouses. Models were validated based on the C-statistic, positive predictive value, and negative predictive value. Positive predictive value and negative predictive value were calculated in reference to a prespecified risk threshold (hospitalization risk ≥ 18.0%)., Results: There were 3,606 patients in the development cohort (median age, 63 years) and 634 evaluable patients in the validation cohort (median age, 64 years). Lung cancer was the most common diagnosis in both cohorts (26% and 31%, respectively). The selected risk stratification model included two variables: albumin and sodium. The model C-statistic in the validation cohort was 0.69 (95% CI, 0.62 to 0.75); 39% of patients were classified as high risk according to the prespecified threshold; 30-day hospitalization risk was 24.2% (95% CI, 19.9% to 32.0%) in the high-risk group and 8.7% (95% CI, 6.1% to 12.0%) in the low-risk group., Conclusion: A model based on data elements routinely collected during cancer treatment can reliably identify patients at high risk for hospitalization after chemotherapy initiation. Additional research is necessary to determine whether this model can be deployed to prevent chemotherapy-related hospitalizations.