The Seneca Valley virus (NTX-010) is an oncolytic picornavirus with tropism for SCLC. This phase II double-blind, placebo-controlled trial evaluated NTX-010 in patients with extensive-stage (ES) SCLC ...after completion of first-line chemotherapy.
Patients with ES SCLC who did not progress after four or more cycles of platinum-based chemotherapy were randomized 1:1 to a single dose of NTX-010 or placebo within 12 weeks of chemotherapy. The primary end point was progression-free survival (PFS). A prespecified interim analysis for futility was performed after 40 events. Viral clearance and the development of neutralizing antibodies were followed.
From January 15, 2010, to January 10, 2013, a total of 50 patients were randomized and received therapy on study (26 received NTX-010 and 24 received placebo). At the specified interim analysis, the median PFS was 1.7 months (95% confidence interval CI: 1.4–3.1 months) for the NTX-010 group versus 1.7 months (95% CI: 1.4–4.3 months) for the placebo group (hazard ratio = 1.03, p = 0.92), and the trial was terminated owing to futility. In the NTX-010 group, PFS was shorter in patients with detectable virus at days 7 and 14 versus in those in whom it was not detected after treatment (1.0 month 95% CI: 0.4–1.5 months versus 1.8 months 95% CI: 1.3–5.5 months, p = 0.008 and 0.9 months 95% CI: 0.4–2.6 months versus 1.3 months 95% CI: 1.0–5.3 months, respectively p = 0.04).
Patients with ES SCLC did not benefit from NTX-010 treatment after chemotherapy with a platinum doublet. Persistence of NTX-010 in the blood 1 or 2 weeks after treatment was associated with a shorter PFS.
Numerous cell states are known to comprise the pancreatic ductal adenocarcinoma (PDAC) tumor microenvironment (TME). However, the developmental stemness and co-occurrence of these cell states remain ...poorly defined. Here, we performed single-cell RNA sequencing (scRNA-seq) on a cohort of treatment-naive PDAC time-of-diagnosis endoscopic ultrasound-guided fine needle biopsy (EUS-FNB) samples (n = 25). We then combined these samples with surgical resection (n = 6) and publicly available samples to increase statistical power (n = 80). Following annotation into 25 distinct cell states, cells were scored for developmental stemness, and a customized version of the Ecotyper tool was used to identify communities of co-occurring cell states in bulk RNA-seq samples (n = 268). We discovered a tumor microenvironmental community comprised of aggressive basal-like malignant cells, tumor-promoting SPP1+ macrophages, and myofibroblastic cancer-associated fibroblasts associated with especially poor prognosis. We also found a developmental stemness continuum with implications for survival that is present in both malignant cells and cancer-associated fibroblasts (CAFs). We further demonstrated that high-dimensional analyses predictive of survival are feasible using standard-of-care, time-of-diagnosis EUS-FNB specimens. In summary, we identified tumor microenvironmental and developmental stemness characteristics from a high-dimensional gene expression analysis of PDAC using human tissue specimens, including time-of-diagnosis EUS-FNB samples. These reveal new connections between tumor microenvironmental composition, CAF and malignant cell stemness, and patient survival that could lead to better upfront risk stratification and more personalized upfront clinical decision-making.
Abstract only
7509
Background: NTX-010 is a naturally occurring replication-competent picornavirus with potent and selective tropism for SCLC tumor cells expressing neuroendocrine markers. A phase I ...study of NTX-010 showed evidence of antitumor activity in patients with SCLC. Methods: ES-SCLC patients (pts) with SD, PR or CR after at least 4 cycles of platinum-based chemotherapy were pre-registered to confirm diagnosis of SCLC with > 1 neuroendocrine marker by a central pathology review. Eligible pts were.randomized 1:1 to placebo (B) or NTX-010 (A). NTX-010 or placebo was administered intravenously as a 1-hour infusion in 100 mL normal saline as a single dose of 1 x10
11
vp/kg. Viral studies to determine distribution, clearance of the virus and the presence of neutralizing antibodies were done. The primary goal of this trial was to compare the progression-free survival (PFS) of arm A to B based on a sample size of 45 patients per arm to detect an improvement in median PFS from 3 to 5 months (m). A pre-planned interim futility analysis was done after 40 PFS events, and reported here. Results: The trial is permanently closed to accrual. One-hundred and twenty pts were pre-registered, of whom 58 were randomized. Baseline age, gender, ECOG performance status, and histology were balanced between arms. Median age was 63 (range: 44 - 82). 31% of pts had a PS of 0 and 69% of 1. Grade 4 adverse events were seen in 3 (12.5%) patients in arm A and none in arm B. Based on the interim futility analysis, PFS was 1.7 m (95% CI: 1.3-3.1) for arm A and 1.7 m (95% CI: 1.4-4.3) for arm B. Pts with viral RNA at 7 (7 pts) and 14 (6 pts) days had worse PFS compared to those with no detectable levels within arm A (1.0 vs 1.6 m, p=0.02; 0.9 vs. 1.2 m, p=0.06). Median follow-up in pts is 6.1 m. The 3-month OS estimates are 83% (95% CI: 69%-100%) and 85% (70%-100%) for arms A and B respectively. Conclusions: This phase II study showed no benefit in PFS for ES-SCLC patients receiving NTX-010. Pts with detectable virus at 7 and 14 days had worse PFS. Clinical trial information: NCT01017601.
Ocean acidification refers to the lowering of the ocean's pH due to the uptake of anthropogenic CO
from the atmosphere. Coral reef calcification is expected to decrease as the oceans become more ...acidic. Dissolving calcium carbonate (CaCO
) sands could greatly exacerbate reef loss associated with reduced calcification but is presently poorly constrained. Here we show that CaCO
dissolution in reef sediments across five globally distributed sites is negatively correlated with the aragonite saturation state (Ω
) of overlying seawater and that CaCO
sediment dissolution is 10-fold more sensitive to ocean acidification than coral calcification. Consequently, reef sediments globally will transition from net precipitation to net dissolution when seawater Ω
reaches 2.92 ± 0.16 (expected circa 2050 CE). Notably, some reefs are already experiencing net sediment dissolution.
The Sonoran Desert region, encompassing most of southern Arizona, has an extreme climate that is famous for dust storms known as haboobs. These storms lead to decreased visibility and potentially ...hazardous driving conditions. In this study we evaluate the relationship between haboob events and emergency department (ED) visits due to motor vehicle collisions (MVCs) in Phoenix, Arizona.
This study is a retrospective analysis of MVC-related trauma presentations to Phoenix, AZ, hospitals before and following haboob dust storms. These events were identified from 2009-2017 primarily using Phoenix International Airport weather data. De-identified trauma data were obtained from the Arizona Department of Health Services (ADHS) Arizona State Trauma Registry (ASTR) from seven trauma centers within a 10-mile radius of the airport. We compared MVC-related trauma using six- and 24-hour windows before and following the onset of haboob events.
There were 31,133 MVC-related trauma encounters included from 2009-2017 and 111 haboob events meeting meteorological criteria during that period. There was a 17% decrease in MVC-related ED encounters in the six hours following haboob onset compared to before onset (235 vs 283, P = 0.04), with proportionally more injuries among males (P < 0.001) and higher mortality (P = 0.02). There was no difference in frequency of presentations (P = 0.82), demographics, or outcomes among the 24-hour pre-and post-haboob groups.
Haboob dust storms in Phoenix, Arizona, are associated with a decrease in MVC-related injuries during the six-hour period following storm onset, likely indicating the success of public safety messaging efforts. Males made up a higher proportion of those injured during the storms, suggesting a target for future interventions. Future public-targeted weather-safety initiatives should be accompanied more closely by monitoring and evaluation efforts to assess for effectiveness.
To meet the ambitious objectives of biodiversity and climate conventions, the international community requires clarity on how these objectives can be operationalized spatially and how multiple ...targets can be pursued concurrently. To support goal setting and the implementation of international strategies and action plans, spatial guidance is needed to identify which land areas have the potential to generate the greatest synergies between conserving biodiversity and nature's contributions to people. Here we present results from a joint optimization that minimizes the number of threatened species, maximizes carbon retention and water quality regulation, and ranks terrestrial conservation priorities globally. We found that selecting the top-ranked 30% and 50% of terrestrial land area would conserve respectively 60.7% and 85.3% of the estimated total carbon stock and 66% and 89.8% of all clean water, in addition to meeting conservation targets for 57.9% and 79% of all species considered. Our data and prioritization further suggest that adequately conserving all species considered (vertebrates and plants) would require giving conservation attention to ~70% of the terrestrial land surface. If priority was given to biodiversity only, managing 30% of optimally located land area for conservation may be sufficient to meet conservation targets for 81.3% of the terrestrial plant and vertebrate species considered. Our results provide a global assessment of where land could be optimally managed for conservation. We discuss how such a spatial prioritization framework can support the implementation of the biodiversity and climate conventions.
Immune checkpoint blockade (ICB) agents and adoptive cell transfer (ACT) of tumor-infiltrating lymphocytes (TIL) are prominent immunotherapies used for the treatment of advanced melanoma. Both ...therapies rely on activation of lymphocytes that target shared tumor antigens or neoantigens. Recent analysis of patients with metastatic melanoma who underwent treatment with TIL ACT at the NCI demonstrated decreased responses in patients previously treated with anti-PD-1 agents. We aimed to find a basis for the difference in response rates between anti-PD-1 naïve and experienced patients.
We examined the tumor mutational burden (TMB) of resected tumors and the repertoire of neoantigens targeted by autologous TIL in a cohort of 112 anti-PD-1 naïve and 69 anti-PD-1 experienced patients.
Anti-PD-1 naïve patients were found to possess tumors with higher TMBs (352.0 vs. 213.5, P = 0.005) and received TIL reactive with more neoantigens (2 vs. 1, P = 0.003) compared with anti-PD-1 experienced patients. Among patients treated with TIL ACT, TMB and number of neoantigens identified were higher in ACT responders than ACT nonresponders in both anti-PD-1 naïve and experienced patients. Among patients with comparable TMBs and predicted neoantigen loads, treatment products administered to anti-PD-1 naïve patients were more likely to contain T cells reactive against neoantigens than treatment products for anti-PD-1 experienced patients (2.5 vs. 1, P = 0.02).
These results indicate that decreases in TMB and targeted neoantigens partially account for the difference in response to ACT and that additional factors likely influence responses in these patients. See related commentary by Blass and Ott, p. 2980.
Hepatotoxicity of chemotherapy Floyd, Justin; Mirza, Irfan; Sachs, Bradley ...
Seminars in oncology,
02/2006, Letnik:
33, Številka:
1
Journal Article
Recenzirano
The selection of an antineoplastic regimen for an oncology patient is based first on the availability of effective drugs and then on a balancing of potential treatment-related toxicities with the ...patient's clinical condition and associated comorbidities. Liver function abnormalities are commonly observed in this patient population and identifying their etiology is often difficult. Immunosuppression, paraneoplastic phenomena, infectious diseases, metastases, and poly-pharmacy may cloud the picture. While criteria for standardizing liver injury have been established, dose modifications often rely on empiric clinical judgment. Therefore, a comprehensive understanding of hepatotoxic manifestations for the most common chemotherapeutic agents is essential. We herein review the hepatotoxicity of commonly used antineoplastic agents and regimens.
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