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Annals of Oncology : Official Journal... Jun 2024PD-L1 tumor proportion score (TPS) and tumor mutational burden (TMB) are key predictive biomarkers for immune checkpoint inhibitors (ICI) efficacy in non-small cell lung...
Intrapatient variation in PD-L1 expression and tumor mutational burden and the impact on outcomes to immune checkpoint inhibitor therapy in patients with non-small cell lung cancer.
BACKGROUND
PD-L1 tumor proportion score (TPS) and tumor mutational burden (TMB) are key predictive biomarkers for immune checkpoint inhibitors (ICI) efficacy in non-small cell lung cancer (NSCLC). Data on their variation across multiple samples are limited.
METHODS
Patients with NSCLC and multiple PD-L1 TPS and/or TMB assessments were included. Clinicopathologic and genomic data were analyzed according to PD-L1 and TMB variation.
RESULTS
In total, 402 PD-L1 sample pairs and 413 TMB sample pairs were included. Concordance between pairs was moderate for PD-L1 (ρ=0.53, P<0.0001) and high for TMB (ρ=0.80, P<0.0001). Shorter time between biopsies correlated with higher concordance in PD-L1, but not in TMB. Major increases (ΔTPS≥+50%) and decreases (ΔTPS≤-50%) in PD-L1 were observed in 9.7% and 8.0% of cases, respectively. PD-L1, but not TMB, decreased with intervening ICI (P=0.02). Acquired copy number loss of CD274, PDCD1LG2, and JAK2 were associated with major decrease in PD-L1 (q<0.05). Among patients with multiple PD-L1 assessments before ICI, cases where all samples had a PD-L1 ≥1%, compared to cases with at least one sample with PD-L1 <1% and another with PD-L1 ≥1%, achieved improved objective response rate and progression-free survival (PFS). Among patients with at least one PD-L1 <1% and one ≥1% before ICI, cases where the most proximal sample was PD-L1 ≥1% had longer median PFS compared to cases where the most proximal PD-L1 was <1%. Among patients with multiple TMB assessments before ICI, patients with a TMB ≥10 mut/Mb based on the most recent assessment, as compared to those with a TMB <10 mut/Mb, achieved improved PFS and OS to ICI; instead, no differences were observed when patients were categorized using the oldest TMB assessment.
CONCLUSION
Despite intrapatient concordance in PD-L1 and TMB, variation in these biomarkers can influence ICI outcomes, warranting consideration for reassessment prior to ICI initiation when feasible.
PubMed: 38950679
DOI: 10.1016/j.annonc.2024.06.014 -
Acta Medica Portuguesa Jul 2024Minimally invasive surgery has been increasingly accepted and used in colorectal surgery. Several studies report that robotic surgery may provide advantages over...
INTRODUCTION
Minimally invasive surgery has been increasingly accepted and used in colorectal surgery. Several studies report that robotic surgery may provide advantages over 'conventional' laparoscopy, namely in rectal surgery. This paper provides an account of the first three years of experience with robotic surgery in the Unidade de Patologia Colorretal of the Unidade Local de Saúde S. José.
METHODS
Variables were defined to develop a prospective database containing the data of consecutive patients operated by three internationally certified colorectal surgeons using the Da Vinci Xi® system between November 2019 and October 2022. The database was converted into an anonymized version that was used for this study. The analysis was performed on the data of all the patients operated during this period.
RESULTS
Eighty patients were included, 47 male, median age 70 years, and median BMI 26 kg/m2 . ASA score was II in 53.7% and III in 41.3% of pa- tients. Of the total, 97.6% had malignant or potentially malignant disease. Operative procedures consisted of 34 colectomies proximal to the splenic flexure, 20 distal colectomies and 26 anterior resections. There were two synchronous resections of liver metastases. Early perioperative outcomes and histopathological results were analyzed: median operative time: 300 minutes; median estimated blood loss: 50 mL; conversion rate: 2.5%; median days until first bowel movement: three days; median length of hospital stay: six days; complication rate: 20%, of which 5% were Clavien III and 0% Clavien IV/V; anastomotic leak rate: 2.5%; 30-day readmission rate: 1.3%; median lymph nodes resected: 20; R0 resection rate: 100%; mesorectal integrity rate: 95,8% complete/near complete.
CONCLUSION
Our results show that the adoption of robotic colorectal surgery in our center was safe and resulted in similar or improved short-term clinical outcomes and histopathological results when compared to those described in the literature.
Topics: Humans; Male; Robotic Surgical Procedures; Aged; Female; Portugal; Middle Aged; Aged, 80 and over; Colectomy; Time Factors; Operative Time; Prospective Studies; Adult; Length of Stay; Laparoscopy
PubMed: 38950618
DOI: 10.20344/amp.20204 -
Critical Reviews in Food Science and... Jul 2024The human diet requires a more plant-based approach due to the exhaustive effects animal-based foods have on the environment. However, plant-based proteins generally... (Review)
Review
The human diet requires a more plant-based approach due to the exhaustive effects animal-based foods have on the environment. However, plant-based proteins generally miss a few or have a lower variety in essential amino acids and are more difficult to digest. Subsequently they might be prone to fermentation by the microbiome in the proximal colon. Proteolytic fermentation can induce microbial-metabolites with beneficial and negative health effects. We review current insight into how balances in saccharolytic and proteolytic fermentation can be maintained when the diet consists predominantly of plant-based proteins. Some proteolytic fermentation metabolites may negatively impact balances in gut microbiota composition in the large intestine and influence immunity. However, proteolytic fermentation can potentially be prevented in the proximal colon toward more saccharolytic fermentation through the addition of non-digestible carbohydrates in the diet. Knowledge on this combination of plant-based proteins and non-digestible carbohydrates on colonic- and general health is limited. Current data suggest that transitioning toward a more plant-based protein diet should be accompanied with a consumption of increased quantities and more complex structures of carbohydrates or by application of technological strategies to enhances digestibility. This can reduce or prevent proteolytic fermentation which might consequently improve human health.
PubMed: 38950600
DOI: 10.1080/10408398.2024.2352523 -
Journal of Biomechanics Jun 2024The interosseous membrane (IOM) of the forearm plays a crucial role in facilitating forearm function and mechanical load transmission between the radius and ulna....
The interosseous membrane (IOM) of the forearm plays a crucial role in facilitating forearm function and mechanical load transmission between the radius and ulna. Accurate characterization of its biomechanical properties is essential for developing realistic finite element models of the forearm. This study aimed to investigate the mechanical behavior and material properties of the central fibrous regions of the IOM using fresh frozen cadavers. Ten forearms from five cadavers were dissected, preserving the IOM and identifying the distal accessory band (DAB), central band (CB), and proximal accessory band (PAB). Bone-ligament-bone specimens were prepared and subjected to uniaxial tensile testing, with the loading direction aligned with the fiber orientation. Force-displacement curves were obtained and converted to force-strain and stress-strain curves using premeasured fiber lengths and cross-sectional areas. The results demonstrated distinct mechanical responses among the IOM regions, with the PAB exhibiting significantly lower force-strain behavior compared to the DAB and CB. The derived force-strain and stress-strain relationships provide valuable insights into the regional variations in stiffness and strength of the IOM, highlighting the importance of considering these differences when modeling the IOM in finite element analysis. In conclusion, this study establishes a foundation for the development of advanced finite element models of the forearm that accurately capture the biomechanical behavior of the IOM.
PubMed: 38950484
DOI: 10.1016/j.jbiomech.2024.112204 -
The Journal of Clinical Investigation Jun 2024Cytoplasmic and nuclear iron-sulfur (Fe-S) enzymes that are essential for genome maintenance and replication depend on the cytoplasmic Fe-S assembly (CIA) machinery for...
Cytoplasmic and nuclear iron-sulfur (Fe-S) enzymes that are essential for genome maintenance and replication depend on the cytoplasmic Fe-S assembly (CIA) machinery for cluster acquisition. The core of the CIA machinery consists of a complex of CIAO1, MMS19 and FAM96B. The physiological consequences of loss of function in the components of the CIA pathway have thus far remained uncharacterized. Our study revealed that patients with biallelic loss of function in CIAO1 developed proximal and axial muscle weakness, fluctuating creatine kinase elevation, and respiratory insufficiency. In addition, they presented with CNS symptoms including learning difficulties and neurobehavioral comorbidities, along with iron deposition in deep brain nuclei, mild normocytic to macrocytic anemia, and gastrointestinal symptoms. Mutational analysis revealed reduced stability of the variants compared with WT CIAO1. Functional assays demonstrated failure of the variants identified in patients to recruit Fe-S recipient proteins, resulting in compromised activities of DNA helicases, polymerases, and repair enzymes that rely on the CIA complex to acquire their Fe-S cofactors. Lentivirus-mediated restoration of CIAO1 expression reversed all patient-derived cellular abnormalities. Our study identifies CIAO1 as a human disease gene and provides insights into the broader implications of the cytosolic Fe-S assembly pathway in human health and disease.
Topics: Humans; Iron-Sulfur Proteins; Male; Female; Neuromuscular Diseases; Child; Cell Nucleus; Cytoplasm; Metallochaperones
PubMed: 38950322
DOI: 10.1172/JCI179559 -
Optics Letters Jul 2024Solving the distorted wavefront in wavefront sensorless adaptive optics (WFSL-AO) relies on excellent optimizers. Many local or global optimization algorithms have been...
Solving the distorted wavefront in wavefront sensorless adaptive optics (WFSL-AO) relies on excellent optimizers. Many local or global optimization algorithms have been applied to WFSL-AO; however, there is still a challenge to balance the effect and speed of correcting aberrations. To overcome this, a novel global optimization algorithm named asymptotic proximal point (APP) method is introduced into WFSL-AO in this Letter. We compare this algorithm with the various existing optimization algorithms in convergence speed and correction capability by performing numerical simulations. The results show that the APP method beats all competitors with a better correction effect and faster speed.
PubMed: 38950205
DOI: 10.1364/OL.524854 -
PLoS Genetics Jul 2024Lactococcus lactis is a lactic acid bacterium of major importance for food fermentation and biotechnological applications. The ability to manipulate its genome quickly...
Lactococcus lactis is a lactic acid bacterium of major importance for food fermentation and biotechnological applications. The ability to manipulate its genome quickly and easily through competence for DNA transformation would accelerate its general use as a platform for a variety of applications. Natural transformation in this species requires the activation of the master regulator ComX. However, the growth conditions that lead to spontaneous transformation, as well as the regulators that control ComX production, are unknown. Here, we identified the carbon source, nitrogen supply, and pH as key factors controlling competence development in this species. Notably, we showed that these conditions are sensed by three global regulators (i.e., CcpA, CodY, and CovR), which repress comX transcription directly. Furthermore, our systematic inactivation of known signaling systems suggests that classical pheromone-sensing regulators are not involved. Finally, we revealed that the ComX-degrading MecA-ClpCP machinery plays a predominant role based on the identification of a single amino-acid substitution in the adaptor protein MecA of a highly transformable strain. Contrasting with closely-related streptococci, the master competence regulator in L. lactis is regulated both proximally by general sensors and distantly by the Clp degradation machinery. This study not only highlights the diversity of regulatory networks for competence control in Gram-positive bacteria, but it also paves the way for the use of natural transformation as a tool to manipulate this biotechnologically important bacterium.
PubMed: 38950059
DOI: 10.1371/journal.pgen.1011340 -
Clinical Cancer Research : An Official... Jul 2024Classic Hodgkin lymphoma (cHL) is a B cell lymphoma that occurs primarily in young adults and, less frequently, in elderly individuals. A hallmark of cHL is the...
PURPOSE
Classic Hodgkin lymphoma (cHL) is a B cell lymphoma that occurs primarily in young adults and, less frequently, in elderly individuals. A hallmark of cHL is the exceptional scarcity (1-5%) of the malignant Hodgkin Reed-Sternberg (HRS) cells within a network of non-malignant immune cells. Molecular determinants governing the relationship between HRS cells and their proximal microenvironment remain largely unknown.
EXPERIMENTAL DESIGN
We performed spatially resolved multiplexed protein imaging and transcriptomic sequencing to characterize HRS cell states, cellular neighborhoods, and gene expression signatures of 23.6 million cells from 36 newly diagnosed Epstein-Barr virus (EBV) positive and EBV-negative cHL tumors.
RESULTS
We show that MHC-I expression on HRS cells is associated with immune inflamed neighborhoods containing CD8+ T cells, MHC-II+ macrophages, and immune checkpoint expression (i.e., PD-1 and VISTA). We identified spatial clustering of HRS cells, consistent with the syncytial variant of cHL, and its association with T cell excluded neighborhoods in a subset of EBV-negative tumors. Finally, a subset of both EBV-positive and EBV-negative tumors contained regulatory T cells high neighborhoods harboring HRS cells with augmented proliferative capacity.
CONCLUSIONS
Our study links HRS cell properties with distinct immunophenotypes and potential immune escape mechanisms in cHL.
PubMed: 38949890
DOI: 10.1158/1078-0432.CCR-24-0942 -
Molecular Imaging and Radionuclide... Jun 2024A 71-year-old female patient with a known history of signet-ring cell carcinoma presented with diffuse bone pain and anemic symptoms. An F-fluorodeoxyglucose (FDG)...
A 71-year-old female patient with a known history of signet-ring cell carcinoma presented with diffuse bone pain and anemic symptoms. An F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography study revealed diffuse heterogeneous hypermetabolic sclerotic lesions in the axial and proximal appendicular skeleton. No other F-FDG-avid lesions were detected. Subsequent bone marrow biopsy confirmed the diagnosis of metastatic carcinoma originating from the gastric primary site. Palliative treatment was initiated; however, the patient's condition deteriorated, and she succumbed to the disease two months later.
PubMed: 38949558
DOI: 10.4274/mirt.galenos.2023.17037 -
Acta Paediatrica (Oslo, Norway : 1992) Jul 2024Extended total colonic aganglionosis (ETCA) represents uncommon forms of Hirschsprung disease (HD), with aganglionosis extending into the proximal small bowel. ETCA...
AIM
Extended total colonic aganglionosis (ETCA) represents uncommon forms of Hirschsprung disease (HD), with aganglionosis extending into the proximal small bowel. ETCA management is challenging and associated with poor outcomes and high mortality. This study compares management and outcomes of ETCA to more common HD forms.
METHODS
A retrospective cohort of HD patients (2012-2023) from two institutions. Three HD forms were compared: short-segment HD (SSHD, n = 19), long-segment HD or total colonic aganglionosis (LS/TCA, n = 9) and ETCA (n = 7).
RESULTS
Normally innervated segments in ETCA patients ranged 0-70 cm. Median times to first surgery were; ETCA = 3 days versus TCA = 21 days (p = 0.017) and SSHD = 95 days (p < 0.001), respectively. Median number of surgeries were; ETCA = 4, versus TCA = 2 (p = 0.17) and SSHD = 1 (p = 0.002), respectively. All the patients underwent a definitive pull-through procedure, except four ETCA patients with a permanent jejunostomy and residual aganglionic segment of 57-130 cm. ETCA patients had 92% lower odds of enterocolitis (14%) compared to TCA patients (67%, p = 0.054), and comparable odds to SSHD patients (16%, p = 0.92). ETCA mortality was 14%.
CONCLUSION
Extended total colonic aganglionosis patients require earlier and multiple interventions. Leaving an aganglionic segment may be advantageous, without increasing risk for enterocolitis. Tailored surgical treatment and rehabilitation programmes may prevent mortality and need for transplantation.
PubMed: 38949557
DOI: 10.1111/apa.17341