Neoadjuvant anti-PD-1 may improve outcomes for patients with resectable NSCLC and provides a critical window for examining pathologic features associated with response. Resections showing major ...pathologic response to neoadjuvant therapy, defined as ≤10% residual viable tumor (RVT), may predict improved long-term patient outcome. However, %RVT calculations were developed in the context of chemotherapy (%cRVT). An immune-related %RVT (%irRVT) has yet to be developed.
The first trial of neoadjuvant anti-PD-1 (nivolumab, NCT02259621) was just reported. We analyzed hematoxylin and eosin-stained slides from the post-treatment resection specimens of the 20 patients with non-small-cell lung carcinoma who underwent definitive surgery. Pretreatment tumor biopsies and preresection radiographic ‘tumor’ measurements were also assessed.
We found that the regression bed (the area of immune-mediated tumor clearance) accounts for the previously noted discrepancy between CT imaging and pathologic assessment of residual tumor. The regression bed is characterized by (i) immune activation—dense tumor infiltrating lymphocytes with macrophages and tertiary lymphoid structures; (ii) massive tumor cell death—cholesterol clefts; and (iii) tissue repair—neovascularization and proliferative fibrosis (each feature enriched in major pathologic responders versus nonresponders, P<0.05). This distinct constellation of histologic findings was not identified in any pretreatment specimens. Histopathologic features of the regression bed were used to develop ‘Immune-Related Pathologic Response Criteria’ (irPRC), and these criteria were shown to be reproducible amongst pathologists. Specifically, %irRVT had improved interobserver consistency compared with %cRVT median per-case %RVT variability 5% (0%–29%) versus 10% (0%–58%), P=0.007 and a twofold decrease in median standard deviation across pathologists within a sample (4.6 versus 2.2, P=0.002).
irPRC may be used to standardize pathologic assessment of immunotherapeutic efficacy. Long-term follow-up is needed to determine irPRC reliability as a surrogate for recurrence-free and overall survival.
Noninvasive genotyping using plasma cell-free DNA (cfDNA) has the potential to obviate the need for some invasive biopsies in cancer patients while also elucidating disease heterogeneity. We sought ...to develop an ultra-deep plasma next-generation sequencing (NGS) assay for patients with non-small-cell lung cancers (NSCLC) that could detect targetable oncogenic drivers and resistance mutations in patients where tissue biopsy failed to identify an actionable alteration.
Plasma was prospectively collected from patients with advanced, progressive NSCLC. We carried out ultra-deep NGS using cfDNA extracted from plasma and matched white blood cells using a hybrid capture panel covering 37 lung cancer-related genes sequenced to 50000× raw target coverage filtering somatic mutations attributable to clonal hematopoiesis. Clinical sensitivity and specificity for plasma detection of known oncogenic drivers were calculated and compared with tissue genotyping results. Orthogonal ddPCR validation was carried out in a subset of cases.
In 127 assessable patients, plasma NGS detected driver mutations with variant allele fractions ranging from 0.14% to 52%. Plasma ddPCR for EGFR or KRAS mutations revealed findings nearly identical to those of plasma NGS in 21 of 22 patients, with high concordance of variant allele fraction (r=0.98). Blinded to tissue genotype, plasma NGS sensitivity for de novo plasma detection of known oncogenic drivers was 75% (68/91). Specificity of plasma NGS in those who were driver-negative by tissue NGS was 100% (19/19). In 17 patients with tumor tissue deemed insufficient for genotyping, plasma NGS identified four KRAS mutations. In 23 EGFR mutant cases with acquired resistance to targeted therapy, plasma NGS detected potential resistance mechanisms, including EGFR T790M and C797S mutations and ERBB2 amplification.
Ultra-deep plasma NGS with clonal hematopoiesis filtering resulted in de novo detection of targetable oncogenic drivers and resistance mechanisms in patients with NSCLC, including when tissue biopsy was inadequate for genotyping.
The importance of biodiversity for the integrated functioning of ecosystems remains unclear because most evidence comes from analyses of biodiversity's effect on individual functions. Here we show ...that the effects of biodiversity on ecosystem function become more important as more functions are considered. We present the first systematic investigation of biodiversity's effect on ecosystem multifunctionality across multiple taxa, trophic levels and habitats using a comprehensive database of 94 manipulations of species richness. We show that species-rich communities maintained multiple functions at higher levels than depauperate ones. These effects were stronger for herbivore biodiversity than for plant biodiversity, and were remarkably consistent across aquatic and terrestrial habitats. Despite observed tradeoffs, the overall effect of biodiversity on multifunctionality grew stronger as more functions were considered. These results indicate that prior research has underestimated the importance of biodiversity for ecosystem functioning by focusing on individual functions and taxonomic groups.
To minimize the stress of operations, improve the patient experience, reduce variability, and optimize resource utilization, we implemented a thoracic enhanced recovery after surgery (ERAS) protocol ...and evaluated progress after 1 year.
Two protocols were developed: video-assisted thoracic surgery (ERAS-VATS) and thoracotomy (ERAS-T). Each incorporated preoperative patient education, carbohydrate loading, opioid-sparing analgesia, conservative fluid management, and early ambulation. Patient outcomes, length of stay, pain scores, opioid use, fluid administration, and cost for ERAS patients were compared with historic controls from the year before program initiation.
Historic VATS (n = 162) were compared with 81 ERAS-VATS patients. Median postoperative morphine equivalents (86 versus 22 mg, p < 0.0001), total fluid balance (1279 versus 227 mL, p < 0.0001), and mean inflation adjusted hospital costs ($20,169 versus $14,870, p = 0.0003) all decreased significantly. Historic thoracotomy patients (n = 62) were compared with 58 ERAS-T patients. Median postoperative morphine equivalents (130 versus 54 mg, p < 0.0001), total fluid balance (788 versus -489 mL, p = 0.012), length of stay (6.0 versus 4.0 days, p = 0.009), and mean inflation adjusted hospital costs ($41,950 versus $26,089, p < 0.00001) all decreased significantly.
Implementation of thoracic ERAS is a dynamic process with potential to improve outcomes in thoracic surgical procedures. In the first year we shortened length of stay, decreased opioid usage, minimized fluid overload, and decreased hospital costs.
•Growthof spring-planted camelina in western Nebraska were studied under deficit irrigation.•Canopygrowth peaked by 10 weeks after planting and required <25cm of total moisture.•Seedyield increased ...to a maximum of 2540kg/ha with 43cm of applied water.•Linolenicacid (C18:3), the major constituent, increased with irrigation from 32 to 35%.•Oleic and linoleic acids decreased from 20–21% to 18–19%.
The High Plains of the U.S.A. is subject to periodic drought where low-water using crops are desired. Camelina is a potential biofuel crop that may be suitable for this region. The objective was to determine the growth, seed yield, and oil characteristic of camelina exposed to four levels of applied water in western Nebraska. The cultivar Cheyenne was exposed to rain-fed only (RF), and irrigated with 10 (LI), 20 (MI), and 30 (HI) cm water. Irrigation increased plant growth as measured by canopy height, stem length, and canopy weight. Maximum height (70–80cm) was reached by 10 weeks after planting (WAP) with a total of 23cm of applied water or 13cm of irrigation. By 13 WAP, canopy and pod fresh weights were increased by 40–50% by the MI and HI irrigations. Likewise, at harvest (13 WAP), plant dry weight was increased by 50% by the two higher irrigation levels. Seed yields were increased by each incremental increase in irrigation from 890kg/ha for RF to 2540 for HI, a 2.85-fold increase. Oil content was not affected by irrigating at the LI or MI but was increased only by the HI irrigation level. The fatty acid profile was altered by irrigation with an increase in the major constituent, linolenic acid, and a corresponding decrease in two other large constituents, oleic and linoleic acids. There also was a slight increase in the minor constituent of erucic acid. The growth pattern of camelina showed that 23cm of applied water would be required for healthy plant growth but as much as 43cm would be needed for maximum yield. The results indicate that camelina could be grown successfully in western Nebraska, supplying oil for fuel and cooking.
•Growth of spring-planted canola in western Nebraska was studied under deficit irrigation.•Canopy growth peaked by 9 weeks after planting and required less 25cm of total moisture.•Seed yield ...increased irrigation to a maximum of 2900kg/ha with 43cm of applied water.•Maximum seed oil content was 35% with 43cm applied water.•The two major fatty acids, oleic and linoleic acids, were not affected by irrigation level.
Drought is a periodic occurrence in the High Plains of the U.S.A.; thereby low-water using crops are desired. Canola, a biofuel and food oil, has been studied in the region under rain-fed conditions for several years. The study's objective was to measure plant growth, seed yield, and oil characteristic of canola at four levels of applied water in western Nebraska. The cultivar Hyola 357 Magnum was exposed to rain-fed only (RF), and irrigated with 10 (LI), 20 (MI), and 30 (HI) cm water. Adding irrigation increased plant growth, i.e., canopy height, stem length, and canopy weight. Highest canopy height (>100cm for MI and HI) was reached by 10 weeks after planting (WAP) with a total of 23cm of applied water or 13cm of irrigation. By 8 WAP, canopy fresh weight was increased by 37 to 58% by MI and HI irrigations. Pod fresh and dry weights at harvest (13 WAP) were increased >50% and >20%, respectively, by all irrigations. Seed yield were increased by each incremental increase in irrigation from 1220kg/ha for RF to 2905 for HI, a 2.4-fold increase. Seed oil content was increased by MI and HI irrigations (4–8%). The fatty acid profile was not substantially altered by irrigation. There was a slight decrease of palmitic acid and increase in linolenic acid with HI. Canola showed that >20cm of applied water is needed for good vine and pod growth but >40cm was needed to achieve the highest yield. Canola could be grown successfully in western Nebraska, supplying oil for fuel and cooking.
Anatomical resection—often by lobectomy—is the standard of care for patients with early stage NSCLC. With increased diagnosis, survival, and prevalence of persons with early stage NSCLC, the ...incidence of second primary NSCLC, and consequently, the need for contralateral lobectomy for a metachronous cancer, is increasing. Perioperative outcomes after contralateral lobectomy are unknown.
Among patients who underwent contralateral lobectomy for second primary NSCLC during 1995 to 2020, we evaluated 90-day mortality and major morbidity (Clavien-Dindo grades 3–5) rates and their association with clinicopathologic variables, including the year of contralateral lobectomy and duration between lobectomies.
A total of 98 patients underwent contralateral lobectomy for second primary NSCLC; 51 during an early time period (1995–2009) and 47 from a late time period (2010–2020). There were five mortalities and 23 patients with major morbidities after contralateral lobectomy; both rates decreased in 2010 to 2020 compared with 1995 to 2009 (mortality 10%–0%, major morbidity 35%–11%). Major morbidity was associated with an interval of less than 1 year between lobectomies, a diffusing capacity of the lung for carbon monoxide <80%, and right lower lobe resections. Mortality was associated with squamous cell carcinoma. Patients who underwent contralateral lobectomy for stage I NSCLC had 74% (95% confidence interval: 64%–85%) 3-year overall survival and 15% (95% confidence interval: 6.5%–24%) 3-year lung cancer cumulative incidence of death.
Contralateral lobectomy for second primary early stage NSCLC was associated with poor outcomes before 2010. Since 2010, perioperative and long-term outcomes of contralateral lobectomy have been comparable with reported outcomes after unilateral lobectomy.
Context.
The nature of circumstellar envelopes (CSEs) around Cepheids is a matter of ongoing debate. The physical origin of their infrared (IR) excess could be shown to either be made up of a shell ...of ionized gas, a dust envelope, or a combination of both.
Aims.
This study is aimed at constraining the geometry and the IR excess of the environment of the bright long-period Cepheid
ℓ
Car (
P
= 35.5 days) at mid-IR wavelengths in order to understand its physical nature.
Methods.
We first used photometric observations in various bands (from the visible domain to the infrared) and
Spitzer
Space Telescope spectroscopy to constrain the IR excess of
ℓ
Car. Then we analyzed the VLTI/MATISSE measurements at a specific phase of observation in order to determine the flux contribution as well as the size and shape of the environment of the star in the
L
band. Finally, we tested the hypothesis of a shell of ionized gas in order to model the IR excess.
Results.
We report the first detection in the
L
band of a centro-symmetric extended emission around
ℓ
Car, of about 1.7
R
⋆
in full width at half maximum, producing an excess of about 7.0% in this band.This latter value is used to calibrate the IR excess found when comparing the photometric observations in various bands and quasi-static atmosphere models. In the
N
band, there is no clear evidence for dust emission from VLTI/MATISSE correlated flux and
Spitzer
data. On the other side, the modeled shell of ionized gas implies a more compact CSE (1.13 ± 0.02
R
⋆
) that is also fainter (IR excess of 1% in the
L
band).
Conclusions.
We provide new evidence supporting a compact CSE for
ℓ
Car and we demonstrate the capabilities of VLTI/MATISSE for determining common properties of CSEs. While the compact CSE of
ℓ
Car is likely to be of a gaseous nature, the tested model of a shell of ionized gas is not able to simultaneously reproduce the IR excess and the interferometric observations. Further Galactic Cepheid observations with VLTI/MATISSE are necessary for determining the properties of CSEs, which may also depend on both the pulsation period and the evolutionary state of the stars.
Despite the critical need for donor lungs, logistic and geographic barriers hinder lung utilization. We hypothesized that lungs donated after circulatory death subjected to 6 hours of cold ...preservation after ex vivo lung perfusion (EVLP) would have similar outcomes after transplantation as lungs transplanted immediately after EVLP, and that both would perform superiorly compared with lungs transplanted immediately after procurement.
Donor porcine lungs were procured after circulatory death and 15 minutes of warm ischemia. Three groups (n = 5 per group) were randomized: immediate left lung transplantation (Immediate group), EVLP for 4 hours followed by transplantation (EVLP group), or EVLP for 4 hours followed by 6 hours of cold preservation followed by transplantation (EVLP+Cold group). Lungs were reperfused for 2 hours before obtaining pulmonary vein samples for partial pressure of oxygen/fraction of inspired oxygen ratio calculations, airway pressures for compliance measurements, and wet/dry weight ratios.
The partial pressure of oxygen/fraction of inspired oxygen ratios in the EVLP and EVLP+Cold groups were significantly improved compared with those in the Immediate group (429.7 ± 51.8 and 436.7 ± 48.2 versus 117.4 ± 22.9 mm Hg, respectively). In addition, dynamic compliance was significantly improved in the EVLP and EVLP+Cold groups compared with immediate group (26.2 ± 4.2 and 27.9 ± 3.5 versus 11.1 ± 2.4 mL/cmH
O, respectively). There were no differences in oxygenation capacity or dynamic compliance between the EVLP and EVLP+Cold groups. Inflammatory cytokine levels were significantly lower in the EVLP and EVLP+Cold groups.
Lungs donated after circulatory death can be successfully transplanted as much as 6 hours after EVLP. Cold preservation of lungs after ex vivo assessment and rehabilitation may improve organ allocation, even to distant recipients, without compromising allograft function.
PDF
