Patients with advanced pancreatic adenocarcinoma have a poor prognosis and limited second-line treatment options. Evidence suggests a role for the Janus kinase (JAK)/signal transducer and activator ...of transcription pathway in the pathogenesis and clinical course of pancreatic cancer.
In this double-blind, phase II study, patients with metastatic pancreatic cancer who had experienced treatment failure with gemcitabine were randomly assigned 1:1 to the JAK1/JAK2 inhibitor ruxolitinib (15 mg twice daily) plus capecitabine (1,000 mg/m(2) twice daily) or placebo plus capecitabine. The primary end point was overall survival (OS); secondary end points included progression-free survival, clinical benefit response, objective response rate, and safety. Prespecified subgroup analyses evaluated treatment heterogeneity and efficacy in patients with evidence of inflammation.
In the intent-to-treat population (ruxolitinib, n = 64; placebo, n = 63), the hazard ratio was 0.79 (95% CI, 0.53 to 1.18; P = .25) for OS and was 0.75 (95% CI, 0.52 to 1.10; P = .14) for progression-free survival. In a prespecified subgroup analysis of patients with inflammation, defined by serum C-reactive protein levels greater than the study population median (ie, 13 mg/L), OS was significantly greater with ruxolitinib than with placebo (hazard ratio, 0.47; 95% CI, 0.26 to 0.85; P = .011). Prolonged survival in this subgroup was supported by post hoc analyses of OS that categorized patients by the modified Glasgow Prognostic Score, a systemic inflammation-based prognostic system. Grade 3 or greater adverse events were observed with similar frequency in the ruxolitinib (74.6%) and placebo (81.7%) groups. Grade 3 or greater anemia was more frequent with ruxolitinib (15.3%; placebo, 1.7%).
Ruxolitinib plus capecitabine was generally well tolerated and may improve survival in patients with metastatic pancreatic cancer and evidence of systemic inflammation.
Glioblastoma is the most lethal primary brain cancer. Clinical outcomes for glioblastoma remain poor, and new treatments are needed.
To investigate whether adding autologous tumor lysate-loaded ...dendritic cell vaccine (DCVax-L) to standard of care (SOC) extends survival among patients with glioblastoma.
This phase 3, prospective, externally controlled nonrandomized trial compared overall survival (OS) in patients with newly diagnosed glioblastoma (nGBM) and recurrent glioblastoma (rGBM) treated with DCVax-L plus SOC vs contemporaneous matched external control patients treated with SOC. This international, multicenter trial was conducted at 94 sites in 4 countries from August 2007 to November 2015. Data analysis was conducted from October 2020 to September 2021.
The active treatment was DCVax-L plus SOC temozolomide. The nGBM external control patients received SOC temozolomide and placebo; the rGBM external controls received approved rGBM therapies.
The primary and secondary end points compared overall survival (OS) in nGBM and rGBM, respectively, with contemporaneous matched external control populations from the control groups of other formal randomized clinical trials.
A total of 331 patients were enrolled in the trial, with 232 randomized to the DCVax-L group and 99 to the placebo group. Median OS (mOS) for the 232 patients with nGBM receiving DCVax-L was 19.3 (95% CI, 17.5-21.3) months from randomization (22.4 months from surgery) vs 16.5 (95% CI, 16.0-17.5) months from randomization in control patients (HR = 0.80; 98% CI, 0.00-0.94; P = .002). Survival at 48 months from randomization was 15.7% vs 9.9%, and at 60 months, it was 13.0% vs 5.7%. For 64 patients with rGBM receiving DCVax-L, mOS was 13.2 (95% CI, 9.7-16.8) months from relapse vs 7.8 (95% CI, 7.2-8.2) months among control patients (HR, 0.58; 98% CI, 0.00-0.76; P < .001). Survival at 24 and 30 months after recurrence was 20.7% vs 9.6% and 11.1% vs 5.1%, respectively. Survival was improved in patients with nGBM with methylated MGMT receiving DCVax-L compared with external control patients (HR, 0.74; 98% CI, 0.55-1.00; P = .03).
In this study, adding DCVax-L to SOC resulted in clinically meaningful and statistically significant extension of survival for patients with both nGBM and rGBM compared with contemporaneous, matched external controls who received SOC alone.
ClinicalTrials.gov Identifier: NCT00045968.
Abstract
This study determined the prevalence of chronic traumatic encephalopathy (CTE) and cortical aging-related tau astrogliopathy (ARTAG) in a European community-based population (n = 310). The ...frontal, parietal, and temporal cortices, representing initial stages of CTE were assessed. No case fulfilling CTE consensus criteria was found. However, isolated astroglial or neuronal tau pathologies were recognized in the depths of cortical sulci (<2%). A single case (female, 85 years) without a history of traumatic brain injury (TBI) showed combined tau-immunoreactive features confined to frontal sulci without perivascular accumulation. Another 24 cases had single tau pathologies in cortical sulci. ARTAG was identified in 117 cases (38%), with a similar regional prevalence. Gray matter ARTAG was the most common followed by subpial, white matter, and perivascular. The presence of any type of ARTAG was strongly associated with having another type of ARTAG in the same region (p < 0.05). In summary, although isolated tau pathologies in the depths of cortical sulci were identified, no case fulfilled diagnostic criteria of CTE. Cortical ARTAG in this population is common and contrasts the high prevalence of CTE in individuals with repeated mild TBI. ARTAG in isolation might not be indicative of CTE although commonalities in pathogenesis should be considered.
Despite many studies showing that landscape corridors increase dispersal and species richness for disparate taxa, concerns persist that corridors can have unintended negative effects. In particular, ...some of the same mechanisms that underlie positive effects of corridors on species of conservation interest may also increase the spread and impact of antagonistic species (e.g., predators and pathogens), foster negative effects of edges, increase invasion by exotic species, increase the spread of unwanted disturbances such as fire, or increase population synchrony and thus reduce persistence. We conducted a literature review and meta‐analysis to evaluate the prevalence of each of these negative effects. We found no evidence that corridors increase unwanted disturbance or non‐native species invasion; however, these have not been well‐studied concerns (1 and 6 studies, respectively). Other effects of corridors were more often studied and yielded inconsistent results; mean effect sizes were indistinguishable from zero. The effect of edges on abundances of target species was as likely to be positive as negative. Corridors were as likely to have no effect on antagonists or population synchrony as they were to increase those negative effects. We found 3 deficiencies in the literature. First, despite studies on how corridors affect predators, there are few studies of related consequences for prey population size and persistence. Second, properly designed studies of negative corridor effects are needed in natural corridors at scales larger than those achievable in experimental systems. Third, studies are needed to test more targeted hypotheses about when corridor‐mediated effects on invasive species or disturbance may be negative for species of management concern. Overall, we found no overarching support for concerns that construction and maintenance of habitat corridors may result in unintended negative consequences. Negative edge effects may be mitigated by widening corridors or softening edges between corridors and the matrix. Other negative effects are relatively small and manageable compared with the large positive effects of facilitating dispersal and increasing diversity of native species.
The term "aging-related tau astrogliopathy" (ARTAG) describes pathological accumulation of abnormally phosphorylated tau protein in astrocytes. We evaluated the correlates of ARTAG types (i.e., ...subpial, subependymal, white and gray matter, and perivascular) in different neuroanatomical regions. Clinical, neuropathological, and genetic (eg, APOE ε4 allele, MAPT H1/H2 haplotype) data from 628 postmortem brains from subjects were investigated; most of the patients had been longitudinally followed at the University of Pennsylvania. We found that (i) the amygdala is a hotspot for all ARTAG types; (ii) age at death, male sex, and presence of primary frontotemporal lobar degeneration (FTLD) tauopathy are significantly associated with ARTAG; (iii) age at death, greater degree of brain atrophy, ventricular enlargement, and Alzheimer disease (AD)-related variables are associated with subpial, white matter, and perivascular ARTAG types; (iv) AD-related variables are associated particularly with lobar white matter ARTAG; and (v) gray matter ARTAG in primary FTLD-tauopathies appears in areas without neuronal tau pathology. We provide a reference map of ARTAG types and propose at least 5 constellations of ARTAG. Furthermore, we propose a conceptual link between primary FTLD-tauopathy and ARTAG-related astrocytic tau pathologies. Our observations serve as a basis for etiological stratification and definition of progression patterns of ARTAG.
There is no patient-reported functional scale specific for osteochondral lesion of the ankle (OCLA). Therefore, the objectives of this study were to develop a questionnaire that measures symptom ...severity, function, and sports capacity in patients with osteochondral lesions of the ankle and to determine the psychometric properties of the tool in German language (OCLA-G).
The OCLA-G questionnaire was developed according to the COSMIN guidelines. Scalable items were generated from a literature search, based on an evaluation of 71 own OCLA patients, and from expert opinions. Following a twofold item reduction the questionnaire underwent explorative data analysis and principal component analysis. Validity and reliability were analysed in four groups of participants (40 patients with OCLA, 40 patients with other foot and ankle injuries, 40 asymptomatic athletes serving as a population at risk, and 40 asymptomatic persons playing sports not at risk). The minimum age for participation in the study was set at 18 years. The mean age was 39.3 ± 15.1 years.
The final OCLA-G questionnaire consists of eight and five questions to mirror activities of daily life (ADL) and sports, respectively. Excellent internal consistency (Cronbach's α = 0.950 for the ADL subscore and 0.965 for the sport subscale, respectively) was found. Spearman's rank correlation coefficients for test-retest reliability were 0.992 for the ADL subscore and 0.999 for the sport subscale (p < 0.001). The results of the exploratory and confirmatory factor analyses indicated that item difficulty was between 23.4 and 62.8. The Pearson correlation for the OCLA subscales ADL and sport was 0.853 (p < 0.001). Construct validity as tested against the SF-12 questionnaire subscales (Physical and Mental component scale) were r = -0.164 to -0.663 (p < 0.05). Statistically, there was no ADL and sport OCLA mean score difference between OCLA patients and patients with other foot and ankle injuries (p = 0.993 and 0.179, respectively), but both groups differed from the uninjured control groups (p < 0.001). There were no ceiling or floor effects.
The OCLA-G was successfully developed as the first patient reported and injury specific outcome scale to measure the impact of OCLA induced symptoms on activities of daily living and sport. This study provides evidence for the reliability and validity of the OCLA-G assessing patients with OCLA.
The registration trial number is DRKS00009401 on DRKS. 'Retrospectively registered'. Date of registration: 10/12/2015.
Background
MET signaling is a well described mechanism of resistance to anti‐EGFR therapy, and MET overexpression is common in head and neck squamous cell carcinomas (HNSCCs). In the current trial, ...the authors compared the oral MET inhibitor tivantinib (ARQ197) in combination with cetuximab (the TC arm) versus a control arm that received cetuximab monotherapy (C) in patients with recurrent/metastatic HNSCC.
Methods
In total, 78 evaluable patients with cetuximab‐naive, platinum‐refractory HNSCC were enrolled, including 40 on the TC arm and 38 on the C arm (stratified by human papillomavirus HPV status). Patients received oral tivantinib 360 mg twice daily and intravenous cetuximab 500 mg/m2 once every 2 weeks. The primary outcome was the response rate (according to Response Evaluation Criteria in Solid Tumors, version 1.1), and secondary outcomes included progression‐free and overall survival. After patients progressed on the C arm, tivantinib monotherapy was optional.
Results
The response rate was 7.5% in the TC arm (N = 3; 1 complete response) and 7.9% in the C arm (N = 3; not significantly different NS). The median progression‐free survival in both arms was 4 months (NS), and the median overall survival was 8 months (NS). Both treatments were well tolerated, with a trend toward increased hematologic toxicities in the TC arm (12.5% had grade 3 leukopenia). The response rate in 31 HPV‐positive/p16‐positive patients was 0% in both arms, whereas the response rate in HPV‐negative patients was 12.7% (12.5% in the TC arm and 13% in the C arm). Fifteen patients received tivantinib monotherapy, and no responses were observed.
Conclusions
Combined tivantinib plus cetuximab does not significantly improve the response rate or survival compared with cetuximab alone but does increase toxicity in an unselected HNSCC population. Cetuximab responses appear to be limited to patients who have HPV‐negative HNSCC. MET‐aberration–focused trials for HNSCC and the use of higher potency, selective MET inhibitors remain of interest.
In recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), combined tivantinib and cetuximab did not significantly improve the tumor response rate or overall survival compared with cetuximab alone but increased toxicity. Patients with human papillomavirus‐positive/p16‐positive disease had a 0% response rate within the study, consistent with other reports that EGFR inhibitors appear to be less active in patients who have HPV‐positive/p16‐positive HNSCC.
Persistence phenotype and small colony variants (SCVs) can be part of a bacterial bet-hedging strategy for survival under environmental stresses, such as antimicrobial exposure. These phenotypes are ...of particular concern in persistent and relapsing infections, since cells resume to normal growth after cessation of the stressful condition. In this context, we found persisters and unstable SCVs as phenotypic variants of Salmonella enterica that were able to survive ciprofloxacin exposure. A high heterogeneity in persister levels was observed among S. enterica isolates grown under planktonic and biofilm conditions and exposed to ciprofloxacin or ceftazidime, which may indicate persistence as a non-multidrug-tolerant phenotype. Nevertheless, a comparable variability was not found in the formation of SCVs among the isolates. Indeed, similar proportions of SCV in relation to normal colony phenotype (NCP) were maintained even after three successive cycles of ciprofloxacin exposure testing colonies from both origins (SCV or NCP). Additionally, we found filamentous and dividing cells in the same scanning electron microscopy images from both SCV and NCP. These findings lead us to hypothesize that besides variability among isolates, a single isolate may generate distinct populations of persisters, where cells growing under distinct conditions may adopt different and perhaps complementary survival strategies.
: High doses of ionizing radiation in radiotherapy can elicit undesirable side effects to the skin. Proton minibeam radiotherapy (pMBRT) may circumvent such limitations due to tissue-sparing effects ...observed at the macro scale. Here, we mapped DNA damage dynamics in a 3D tissue context at the sub-cellular level.
Epidermis models were irradiated with planar proton minibeams of 66 µm, 408 µm and 920 µm widths and inter-beam-distances of 2.5 mm at an average dose of 2 Gy using the scanning-ion-microscope SNAKE in Garching, GER. γ-H2AX + 53BP1 and cleaved-caspase-3 immunostaining revealed dsDNA damage and cell death, respectively, in time courses from 0.5 to 72 h after irradiation.
Focused 66 µm pMBRT induced sharply localized severe DNA damage (pan-γ-H2AX) in cells at the dose peaks, while damage in the dose valleys was similar to sham control. pMBRT with 408 µm and 920 µm minibeams induced DSB foci in all cells. At 72 h after irradiation, DNA damage had reached sham levels, indicating successful DNA repair. Increased frequencies of active-caspase-3 and pan-γ-H2AX-positive cells revealed incipient cell death at late time points.
: The spatially confined distribution of DNA damage appears to underlie the tissue-sparing effect after focused pMBRT. Thus, pMBRT may be the method of choice in radiotherapy to reduce side effects to the skin.
PDF
