Purpose
A phase I/II trial was performed to evaluate the safety and immunogenicity of a novel vaccination with α-type 1 polarized dendritic cells (αDC1) loaded with synthetic peptides for ...glioma-associated antigen (GAA) epitopes and administration of polyinosinic-polycytidylic acid poly(I:C) stabilized by lysine and carboxymethylcellulose (poly-ICLC) in HLA-A2
+
patients with recurrent malignant gliomas. GAAs for these peptides are EphA2, interleukin (IL)-13 receptor-α2, YKL-40, and gp100.
Patients and Methods
Twenty-two patients (13 with glioblastoma multiforme GBM, five with anaplastic astrocytoma AA, three with anaplastic oligodendroglioma AO, and one with anaplastic oligoastrocytoma AOA) received at least one vaccination, and 19 patients received at least four vaccinations at two αDC1 dose levels (1 × or 3 × 10
7
/dose) at 2-week intervals intranodally. Patients also received twice weekly intramuscular injections of 20 μg/kg poly-ICLC. Patients who demonstrated positive radiologic response or stable disease without major adverse events were allowed to receive booster vaccines. T-lymphocyte responses against GAA epitopes were assessed by enzyme-linked immunosorbent spot and HLA-tetramer assays.
Results
The regimen was well-tolerated. The first four vaccines induced positive immune responses against at least one of the vaccination-targeted GAAs in peripheral blood mononuclear cells in 58% of patients. Peripheral blood samples demonstrated significant upregulation of type 1 cytokines and chemokines, including interferon-α and CXCL10. Nine (four GBM, two AA, two AO, and one AOA) achieved progression-free status lasting at least 12 months. One patient with recurrent GBM demonstrated sustained complete response. IL-12 production levels by αDC1 positively correlated with time to progression.
Conclusion
These data support safety, immunogenicity, and preliminary clinical activity of poly-ICLC-boosted αDC1-based vaccines.
Definitive radiotherapy has been suggested as a treatment alternative to surgical resection in Merkel cell carcinoma (MCC).
Patients with MCC were identified from the National Cancer Database. ...Propensity score matching accounting for age, Charlson-Deyo score, grade, and AJCC stage was used to match patients in 1:1 fashion by primary treatment (surgery vs. radiotherapy).
There were 1227 patients in each group. Median overall survival was improved with surgical resection in stage I/II (76 vs. 25 months, p < 0.001) and stage III disease (30 vs. 15 months, p < 0.001). For stage I/II, 5- and 8-year overall survival were 61% and 42%, in the surgical resection and 32% and 25% in the definitive radiotherapy groups, respectively. For stage III, 5- and 8-year overall survival were 34% and 21% for surgical resection and 19% and 16% in the radiotherapy group, respectively.
Surgical resection for MCC improves median survival compared to definitive radiotherapy while marginally improving long-term survival.
•Surgical resection improves median survival in merkel cell carcinoma.•Resection provides modest benefit compared with definitive radiotherapy.•Long-term survival is achievable in select patient with definitive radiotherapy alone.
Previous studies have demonstrated that the prognosis of disseminated mucinous appendiceal neoplasms is highly dependent upon tumor grade. Reflecting this, the 7th edition of the American Joint ...Committee on Cancer (AJCC) staging system now incorporates a three-tier grading system for prognostic staging of mucinous appendiceal tumors. However, the grading criteria are not well described. In order to address this issue, we evaluated clinicopathologic and molecular features of 219 cases from 151 patients with widely disseminated appendiceal mucinous neoplasia treated at our institution between 2004 and 2012. We identified histologic features that were associated with worse overall survival on univariate analysis: destructive invasion, high cytologic grade, high tumor cellularity, angiolymphatic invasion, perineural invasion, and signet ring cell component (all with P<0.0001). We used these morphologic characteristics to classify neoplasms into three grades: AJCC grade G1 lacked all adverse histologic features; AJCC grade G2 had at least one adverse histologic feature (except a signet ring cell component); and AJCC grade G3 were defined by the presence of a signet ring cell component. Patients with AJCC grade G2 and grade G3 adenocarcinomas had a significantly worse prognosis compared with AJCC grade G1 (P<0.0001 for each). A trend toward worse overall survival was identified for patients with AJCC grade G3 adenocarcinomas compared with AJCC grade G2 adenocarcinomas (P=0.07). Our multivariate analysis found that this three-tier grading system was a significant predictor of outcome (P=0.008), independent of other prognostic variables. After controlling for other prognostic variables, AJCC grade G2 was associated with a 2.7-fold increased risk of death (95% confidence interval (CI), 1.2–6.2) and AJCC grade G3 was associated with a 5.1-fold increased risk of death (95% CI, 1.7–14) relative to grade G1 tumors. Our results indicate that evaluation of a limited set of adverse histologic features allows for the separation of disseminated mucinous neoplasms of appendiceal origin into three morphologically defined and prognostically relevant grades as advocated by the AJCC.
The apolipoprotein E ε4 gene is the most important genetic risk factor for sporadic Alzheimer's disease, but the link between this gene and neurodegeneration remains unclear. Using array tomography, ...we analysed >50000 synapses in brains of 11 patients with Alzheimer's disease and five non-demented control subjects and found that synapse loss around senile plaques in Alzheimer's disease correlates with the burden of oligomeric amyloid-β in the neuropil and that this synaptotoxic oligomerized peptide is present at a subset of synapses. Further analysis reveals apolipoprotein E ε4 patients with Alzheimer's disease have significantly higher oligomeric amyloid-β burden and exacerbated synapse loss around plaques compared with apolipoprotein E ε3 patients. Apolipoprotein E4 protein colocalizes with oligomeric amyloid-β and enhances synaptic localization of oligomeric amyloid-β by >5-fold. Biochemical characterization shows that the amyloid-β enriched at synapses by apolipoprotein E4 includes sodium dodecyl sulphate-stable dimers and trimers. In mouse primary neuronal culture, lipidated apolipoprotein E4 enhances oligomeric amyloid-β association with synapses via a mechanism involving apolipoprotein E receptors. Together, these data suggest that apolipoprotein E4 is a co-factor that enhances the toxicity of oligomeric amyloid-β both by increasing its levels and directing it to synapses, providing a link between apolipoprotein E ε4 genotype and synapse loss, a major correlate of cognitive decline in Alzheimer's disease.
Alzheimer's disease (AD) is the most common progressive neurodegenerative disorder causing dementia. Massive deposition of amyloid β peptide (Aβ) as senile plaques in the brain is the pathological ...hallmark of AD, but oligomeric, soluble forms of Aβ have been implicated as the synaptotoxic component. The apolipoprotein E ε 4 (apoE ε4) allele is known to be a genetic risk factor for developing AD. However, it is still unknown how apoE impacts the process of Aβ oligomerization. Here, we found that the level of Aβ oligomers in APOE ε4/ε4 AD patient brains is 2.7 times higher than those in APOE ε3/ε3 AD patient brains, matched for total plaque burden, suggesting that apoE4 impacts the metabolism of Aβ oligomers. To test this hypothesis, we examined the effect of apoE on Aβ oligomer formation. Using both synthetic Aβ and a split-luciferase method for monitoring Aβ oligomers, we observed that apoE increased the level of Aβ oligomers in an isoform-dependent manner (E2 < E3 < E4). This effect appears to be dependent on the ApoE C-terminal domain. Moreover, these results were confirmed using endogenous apoE isolated from the TBS-soluble fraction of human brain, which increased the formation of Aβ oligomers. Together, these data show that lipidated apoE, especially apoE4, increases Aβ oligomers in the brain. Higher levels of Aβ oligomers in the brains of APOE ε4/ε4 carriers compared with APOE ε3/ε3 carriers may increase the loss of dendritic spines and accelerate memory impairments, leading to earlier cognitive decline in AD.
Background
Colorectal cancer leads to peritoneal metastases (CRPM) in 10% of cases. Cytoreductive surgery with hyperthermic intraperitoneal chemoperfusion (CRS-HIPEC) improves survival. Primary tumor ...location and abnormalities in
RAS
,
BRAF
, and mismatch repair/microsatellite stability (MMR/MSI) may affect post-CRS-HIPEC survival, but studies have not been consistent. We estimated the effects of primary tumor site and genomic alterations on post-CRS-HIPEC survival.
Methods
This retrospective cohort study included CRS-HIPEC cases for CRPM at a high-volume center from 2001 to 2020. Next-generation sequencing and microsatellite testing defined the
RAS
,
BRAF
, and MMR/MSI genotypes. Adjusted effects of tumor sidedness and genomics on survival were evaluated using a multivariable Cox proportional hazards model. We analyzed these variables’ effects on progression-free survival and the effects of immune checkpoint-inhibitors.
Results
A total of 250 patients underwent CRS-HIPEC with testing for
RAS
,
BRAF
, and MMR/MSI; 50.8% of patients were
RAS
-mutated, 12.4% were
BRAF
-mutated, and 6.8% were deficient-MMR/MSI-high (dMMR/MSI-H). Genomic alterations predominated in right-sided cancers. After adjustment for comorbidities and oncological and perioperative variables, rectal origin hazard ratio (HR) 1.9,
p
= 0.01,
RAS
mutation (HR 1.6,
p
= 0.01), and
BRAF
mutation (HR 1.7,
p
= 0.05) were associated with worse survival.
RAS
mutation was also associated with shorter progression-free survival (HR 1.6,
p
= 0.01 at 6 months post-operatively), and dMMR/MSI-H status was associated with superior survival (HR 0.3,
p
= 0.01 at 2 years). dMMR/MSI-H patients receiving immune checkpoint-inhibitors trended toward superior survival.
Conclusions
Rectal origin,
RAS
mutations, and
BRAF
mutations are each associated with poorer survival after CRS-HIPEC for CRPM. Patients with CRPM and dMMR/MSI-H status have superior survival. Further research should evaluate benefits of immune checkpoint-inhibitors in this subgroup.
Background
Cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion (CRS HIPEC) can offer significant survival advantage for select patients with colorectal peritoneal metastases (CRPM). ...Low socioeconomic status (SES) is implicated in disparities in access to care. We analyze the impact of SES on postoperative outcomes and survival at a high-volume tertiary CRS HIPEC center.
Patients and Methods
We conducted a retrospective cohort study examining patients who underwent CRS HIPEC for CRPM from 2000 to 2018. Patients were grouped according to SES. Baseline characteristics, perioperative outcomes, and survival were examined between groups.
Results
A total of 226 patients were analyzed, 107 (47%) low-SES and 119 (53%) high-SES patients. High-SES patients were younger (52 vs. 58 years,
p
= 0.01) and more likely to be White (95.0% vs. 91.6%,
p
= 0.06) and privately insured (83% vs. 57%,
p
< 0.001). They traveled significantly further for treatment and had lower burden of comorbidities and frailty (
p
= 0.01). Low-SES patients more often presented with synchronous peritoneal metastases (48% vs. 35%,
p
= 0.05). Following CRS HIPEC, low-SES patients had longer length of stay and higher burden of postoperative complications, 90-day readmission, and 30-day mortality. Median overall survival following CRS HIPEC was worse for low-SES patients (17.8 vs. 32.4 months,
p
= 0.02). This disparity persisted on multivariate survival analysis (low SES: HR = 1.46,
p
= 0.03).
Conclusions
Despite improving therapies for CRPM, low-SES patients remain at a significant disadvantage. Even patients who overcome barriers to care experience worse short- and long-term outcomes. Improving access and addressing these disparities is crucial to ensure equitable outcomes and improve patient care.
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