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Nipple fluid for breast cancer diagnosis using the nanopore of Phi29 DNA-packaging motor.

Detection of cancer in its early stage is a challenging task for oncologists. Inflammatory breast cancer has symptoms that are similar to mastitis and can be mistaken for microbial infection. Currently, the differential diagnosis between mastitis and Inflammatory breast cancer via nipple aspirate fluid (NAF) is difficult. Here, we report a label-free and amplification-free detection platform using an engineered nanopore of the phi29 DNA-packaging motor with biomarker Galectin3 (GAL3), Thomsen-Friedenreich (TF) binding peptide as the probe fused at its C-terminus. The binding of the biomarker in NAF samples from breast cancer patients to the probe results in the connectors conformational change with a current blockage of 32 %. Utilization of dwell time, blockage ratio, and peak signature enable us to detect basal levels of biomarkers from patient NAF samples at the single-molecule level. This platform will allow for breast cancers to be resolved at an early stage with accuracy and thoroughness.

Brachial Plexopathy After Single-Fraction Stereotactic Body Radiation Therapy in Apical Lung Tumors.

The objective of this study was to evaluate the incidence of brachial plexus injury (BPI) after single-fraction stereotactic body radiation therapy (SBRT) to apical lung tumors. A retrospective cohort analysis was performed of all patients treated with single-fraction lung SBRT at our institution from 2007 to 2022. Apical tumors were identified as those with an epicenter located above the arch of the aorta. Dosimetric analysis of dose to the brachial plexus (BP) was done using both the subclavian vessel (SCV) surrogate structure and anatomic BP. BPI was assessed per Common Terminology Criteria for Adverse Events, version 4.0, as regional paresthesia, marked discomfort and muscle weakness, and limited movement of the arm or hand. A total of 45 patients met inclusion criteria with median follow-up of 21 months. There were 9 patients who exceeded the BP dose constraint using the SCV or anatomic BP volume. Only 1 patient (2.2%) developed grade 2 BPI, occurring 7 months after SBRT. Dose to the anatomic BP for the affected patient was 26.39 Gy. For the entire cohort, the median SCV and anatomic maximum BP doses were 8.44 and 7.14 Gy, respectively. There is considerable variability in dose delivered to the BP after SBRT to apical lung tumors. BPI after single-fraction SBRT to apical tumors is rare and rates are comparable with those reported with multifraction regimens.

TRANSTHORACIC FINE NEEDLE ASPIRATION CYTOLOGY OF PULMONARY SPINDLE AND MESENCHYMAL NEOPLASMS A PANDORAS BOX.

Pulmonary spindle cell and mesenchymal lesions are paradox for pathologists due to their rarity, overlapping morphology and differentials ranging from benign to malignant lesions, correct diagnosis is essential due to major treatment implications. This study highlights the role of fine-needle aspiration cytology (FNAC), clot core biopsycell block and immunohistochemistry in diagnosis of spindle-cell lesions in lung, thus playing a key role in patient management. It is a retrospective study of lung FNA with predominantly spindle and mesenchymal cells from 2015-2020 which were classified cytomorphologically into spindle, epithelioid, small round cell and biphasic and IHC panels are applied accordingly. Granulomatous lesions, FNA from mediastinum and chest wall were excluded. 60 cases of lung FNA with spindle and mesenchymal cells were identified and included 6 benign and 54 malignancies which included 24 primary pulmonary and 30 metastases. Most common primary malignancies sarcomatoid carcinoma and most common metastasis was malignant peripheral nerve sheath tumour. FNA was paucicellular in 7 cases, was reported as benign in 7 cases and malignant in 46 cases. There were two false negative cases. One case of pulmonary blastoma was reported as inflammatory pseudotumour on cytology, other case of chondrosarcoma was reported as chondroid tumour. Sensitivity and specificity of FNA in distinguishing benign lesions and malignancies was 93.8% and 100% respectively. FNA along with clot core and IHC plays a pivotal role in the subsequent pathway taken for diagnostic or therapeutic management of these patients without the need for second sampling or trucut biopsies in a low resource setting.

Cutaneous adverse events in lung cancer patients on the therapy based on PD-1PD-L1 inhibitors A prospective observational cohort study.

This is a prospective study of cutaneous adverse events (CAEs) in lung cancer patients treated by programmed cell death-1(PD-1) inhibitors and programmed cell death-ligand 1(PD-L1) inhibitors-based single or combination therapy. It were included that lung cancer patients who developed CAEs from January 2019 to July 2021 after applying PD-1PD-L1 inhibitors in our institution. A total of 107 patients with 112 CAEs were enrolled, of which 71 patients received PD-1PD-L1 inhibitors plus chemotherapy, 31 patients received PD-1PD-L1 inhibitors plus anti-angiogenictargeted therapy, and 5 patients received PD-1PD-L1 inhibitors monotherapy. The median time to CAEs onset was 8.7w (0.3w-70.7w) for PD-1PD-L1 inhibitors plus chemotherapy, 10.1w (0.4w-103.0w) for PD-1PD-L1 inhibitors plus anti-angiogenictargeted therapy, and 13.6w (0.7w-50.6w) for PD-1PD-L1 inhibitors monotherapy. The most common CAEs were reactive cutaneous capillary endothelial proliferation (RCCEP) (30.8%, 33107), followed by eczematous (21.5%, 23107) and pruritus only (15.9%, 17107). 7 patients (6.5%, 7107) had grade 3-4 CAE. Most CAEs are mild to moderate and easily controlled. Early diagnosis and intervention for CAEs are important.

Evaluation of sulfone-labeled amino acid derivatives as potential PET agents for cancer imaging.

As one of the most important and frequently used molecular imaging techniques in the clinic, positron emission tomography (PET) features high sensitivity and specificity, which generally involves the use of PET contrast agents. Despite the exceptional promise, the availability of novel PET agents could limit its application and there is a clear need to develop new PET agents to improve our understanding of targets of interest and increase the diagnostic specificity. Based on the fact that amino acid transport and protein anabolism are increased in tumor tissues, a series of Our data shows that Clearly,

Clinical impact of histologic type on survival and recurrence in patients with surgically resected stage II and III non-small cell lung cancer.

This study aimed to investigate the clinical impact of histologic type on the survival and recurrence outcomes of patients with stage II and III non-small cell lung cancer (NSCLC). A total of 2155 consecutive adult patients who underwent complete resection of stage II and III NSCLC between 2008 and 2018 were enrolled. The primary endpoints were freedom from recurrence (FFR) and overall survival (OS). The secondary endpoint was the time to lung cancer or non-lung cancer death. Of the 2155 patients, 1436 (66.6 %) had adenocarcinoma (ADC) and 719 (33.4 %) had squamous cell carcinoma (SqCC). Patients with SqCC had better FFR than those with ADC (stage II, p < 0.001 stage III, p < 0.001). Although patients with ADC showed a slightly better OS until 5 years than those with SqCC, the difference was insignificant (stage II, p 0.292 stage III, p 0.196). Patients with SqCC had higher rates of non-lung cancer death than patients with ADC (stage II, p < 0.001 stage III, p 0.039). The time from lung cancer recurrence to death was shorter in patients with SqCC than in those with ADC (stage II, median 13 vs 37 months, p < 0.001 stage III, median 11 vs 26 months, p < 0.001). In stage II and III NSCLC, ADC had a higher risk of recurrence than SqCC, with no difference in OS. These results were related to significant differences in non-lung cancer mortality and recurrence-to-death time between the two histologic types.

2D mapping of radiation dose and clonogenic survival for accurate assessment of

Spatially fractionated radiation therapy (SFRT or GRID) is an approach to deliver high local radiation doses in an on-off pattern. To better appraise the radiobiological effects from GRID, a framework to link local radiation dose to clonogenic survival needs to be developed. A549 lung cancer cells were irradiated in T25 cm

Buprenorphine-Naloxone in the Setting of Kratom Withdrawal, Opioid Use Disorder, and Stage IV Lung Adenocarcinoma.

Management of cancer-associated pain warrants consideration of many factors, including characterization and etiology of the pain, socioeconomic factors, medication tolerance, and substance use history. Kratom (

Testing for EGFR Variants in Pleural and Pericardial Effusion Cell-Free DNA in Patients With Non-Small Cell Lung Cancer.

Molecular testing in non-small cell lung cancer (NSCLC) is commonly limited by inadequate tumor sample. Plasma cell-free DNA (cfDNA) genotyping as a complementary test is specific but only moderately sensitive. Genotyping of cfDNA in pleural and pericardial effusion (PE-cfDNA) can further optimize molecular diagnostic yield and reduce the need for repeated biopsies. To prospectively validate droplet digital polymerase chain reaction (ddPCR) for detection of sensitizing EGFR variants and acquired Thr790Met variant (T790M) from PE-cfDNA in patients with NSCLC. This prospective diagnostic validation study was conducted between September 6, 2016, and January 21, 2021 at 2 major Hong Kong cancer centers. Patients with advanced NSCLC with both wild-type and variant EGFR status and exudative PE who underwent thoracocentesis or pericardiocentesis were randomly enrolled. Patients were either EGFR-tyrosine kinase inhibitor (TKI) naive (cohort 1) or EGFR-TKI treated but osimertinib naive (cohort 2). Enrolled patients underwent pleural- or pericardial-fluid and blood sampling for ddPCR EGFR testing. EGFR status results with ddPCR testing of PE-cfDNA and blood were compared with EGFR status in matched tumor biopsy or PE cell block samples. Specificity, sensitivity, and concordance of PE-cfDNA for detection of sensitizing EGFR variants and acquired T790M variation. Among 171 patients (54% female) enrolled, there were 104 in cohort 1 and 67 in cohort 2. In cohort 1, 37% (38102) were EGFR-variant positive PE-cfDNA showed 97% sensitivity (95% CI, 92%-100%), 97% specificity (95% CI, 93%-100%), and 97% concordance (ĸ 0.94, P < .001) for the detection of sensitizing EGFR variants. It was more sensitive than plasma in detecting sensitizing EGFR variants (97% vs 74%, P < .001). In cohort 2, 38% (15 of 40) were positive for the EGFR T790M variant PE-cfDNA showed 87% sensitivity (95% CI, 69%-100%), 60% specificity (95% CI, 41%-79%), and 70% concordance (ĸ 0.42, P .004) for acquired T790M. The EGFR T790M variant was detected in 51% of PE-cfDNA vs 25% of PE cell block samples. In this diagnostic study, EGFR variants could be accurately detected from PE-cfDNA in patients with NSCLC. More EGFR T790M was detected in PE-cfDNA than in guideline-recommended PE cell block preparations. These results suggest that PE-cfDNA can complement plasma and tumor genotyping for detecting EGFR variants in patients with advanced NSCLC.

Nonalcoholic fatty liver disease Hepatic manifestations of metabolic syndrome.

Nonalcoholic fatty liver disease (NAFLD) is nowadays the leading cause of chronic liver disease worldwide and shows a strong association with the metabolic syndrome. The NAFLD is a systemic disease associated with a plethora of extrahepatic manifestations and comorbidities, such as type 2 diabetes, obesity and dyslipidemia. These extrahepatic disorders are related either to secondary effects of the associated obesity or to pathophysiological effects of insulin resistance in NAFLD. The three most common causes of the observed increased morbidity and mortality associated with NAFLD are cardiovascular diseases, liver diseases, such as cirrhosis, and cancer. In this overview, cardiovascular diseases, type 2 diabetes mellitus and chronic kidney diseases in connection with NAFLD are discussed as examples, as well as tumor entities, in particular colon cancer, lung diseases (obstructive sleep apnea), endocrine diseases (hypothyroidism) and systemic phenomena associated with NAFLD (e.g. iron overload and thrombophilia). In addition to focusing on the pathogenesis of these extrahepatic manifestations, the clinical implications are highlighted. So far there are no drugs approved for the indication NAFLD in Germany. The new NAFLD S2k guidelines offer a way out of the current therapeutic nihilism. Diagnostic and therapeutic algorithms based on the metabolic comorbidities and the stage of fibrosis are designed with practical relevance and can be used in everyday medical practice. Therefore, clear basic measures and drug recommendations can be given for NAFLD depending on the comorbidities and stage of fibrosis. Die nichtalkoholische Fettlebererkrankung („nonalcoholic fatty liver disease“, NAFLD) ist heute weltweit die Hauptursache für chronische Lebererkrankungen und zeigt eine starke Assoziation zum metabolischen Syndrom. Die NAFLD ist eine systemische Erkrankung und mit einer Fülle von extrahepatischen Manifestationen und Komorbiditäten verbunden, wie Typ-2-Diabetes, Adipositas und Fettstoffwechselstörungen. Diese extrahepatischen Erkrankungen stehen entweder im Zusammenhang mit sekundären Effekten der assoziierten Adipositas oder mit pathophysiologischen Effekten der Insulinresistenz bei NAFLD. Die 3 häufigsten Ursachen für die beobachtete erhöhte Morbidität und Mortalität im Zusammenhang mit NAFLD sind Herz-Kreislauf-Erkrankungen, Lebererkrankungen wie z. B. die Leberzirrhose und Krebserkrankungen. In der vorliegenden Übersicht werden Herz-Kreislauf-Erkrankungen, Typ-2-Diabetes mellitus und chronische Nierenerkrankungen im Zusammenhang mit der NAFLD beispielhaft diskutiert, ebenso Tumorentitäten, insbesondere Darmkrebs, Lungenerkrankungen (obstruktive Schlafapnoe), endokrine Erkrankungen (Hypothyreose) und systemische mit NALFD assoziierte Phänomene (z. B. Eisenüberladung und Thromboseneigung). Neben der Fokussierung auf die Pathogenese dieser extrahepatischen Manifestationen werden klinische Implikationen hervorgehoben. Bislang gibt es in Deutschland keine für die Indikation NAFLD zugelassenen Medikamente. Die neue NAFLD-Leitlinie bietet einen Ausweg aus diesem „therapeutischen Nihilismus“. Diagnostische und therapeutische Algorithmen, basierend auf metabolischen Komorbiditäten und dem Fibrosestadium, sind praxisrelevant gestaltet und im ärztlichen Alltag anwendbar. Daher können klare Basismaßnahmen sowie medikamentöse Empfehlungen bei NAFLD in Abhängigkeit von Komorbiditäten und Fibrosestadien gegeben werden.

CT radiomic predictors of local relapse after SBRT for lung oligometastases from colorectal cancer a single institute pilot study.

To assess the potential of radiomic features (RFs) extracted from simulation computed tomography (CT) images in discriminating local progression (LP) after stereotactic body radiotherapy (SBRT) in the management of lung oligometastases (LOM) from colorectal cancer (CRC). Thirty-eight patients with 70 LOM treated with SBRT were analyzed. The largest LOM was considered as most representative for each patient and was manually delineated by two blinded radiation oncologists. In all, 141 RFs were extracted from both contours according to IBSI (International Biomarker Standardization Initiative) recommendations. Based on the agreement between the two observers, 134141 RFs were found to be robust against delineation (intraclass correlation coefficient ICC > 0.80) independent RFs were then assessed by Spearman correlation coefficients. The association between RFs and LP was assessed with Mann-Whitney test and univariate logistic regression (ULR) the discriminative power of the most informative RF was quantified by receiver-operating characteristics (ROC) analysis through area under curve (AUC). In all, 1538 patients presented LP. Median time to progression was 14.6 months (range 2.4-66 months) 5141 RFs were significantly associated to LP at ULR analysis (p < 0.05) among them, 4 RFs were selected as robust and independent StatisticalVariance (AUC 0.75, p 0.002), StatisticalRange (AUC 0.72, p 0.013), Grey Level Size Zone Matrix (GLSZM) zoneSizeNonUniformity (AUC 0.70, p 0.022), Grey Level Dependence Zone Matrix (GLDZM) zoneDistanceEntropy (AUC 0.70, p 0.026). Importantly, the RF with the best performance (StatisicalVariance) is simply representative of density heterogeneity within LOM. Four RFs extracted from planning CT were significantly associated with LP of LOM from CRC treated with SBRT. Results encourage further research on a larger population aiming to define a usable radiomic score combining the most predictive RFs and, possibly, additional clinical features.

Anti-mitochondrial antibodies predict erosive disease development in rheumatoid arthritis.

Mitochondria are found in the extracellular space in rheumatoid arthritis (RA). However, whether mitochondria are a source of autoantigens in RA has not been carefully addressed. Thus, we investigated the presence and significance of anti-mitochondrial antibodies (AMA) in patients with RA. AMAs were measured in sera from three cross-sectional RA cohorts (n95, n192, and n117) and healthy individuals (n38, n72, n50) using a flow cytometry-based assay. Further, AMAs were detected using anti-mitofusin-1 (MFN1) IgG ELISA and Western blot. A longitudinal inception cohort, followed for a median of 8 years, was used to study disease progression. AMA levels were elevated in all three RA cohorts as compared to healthy individuals (p<0.001, p<0.05, and p<0.01), with a range of 14-26% positivity. Levels of anti-MFN1 antibodies correlated with AMA levels (r0.31, p0.006) and were elevated in RA as compared to healthy individuals (p<0.001). Presence of AMA was associated with erosive disease (p<0.05) and interstitial lung disease (p<0.01). Further, AMA levels could predict erosive disease (OR4.59, p0.006) and joint space narrowing (OR3.08, p0.02) independent of anti-citrullinated protein antibodies. Finally, anti-MFN1 antibodies identified seronegative patients developing erosive disease (OR9.33, p0.02). Our findings demonstrate the presence of novel autoantibodies targeting mitochondria in RA. AMAs stratified patients based on disease phenotype and predicted development of erosive disease, including in patients with seronegative disease. Our results highlight the essential role of mitochondria in RA pathogenesis and suggest a possible benefit of therapies targeting mitochondrial-mediated inflammation and clearance in these patients. This article is protected by copyright. All rights reserved.

A Dosimetric and Radiobiological Comparison of Intensity Modulated Radiotherapy, Volumetric Modulated Arc Therapy and Helical Tomotherapy Planning Techniques in Synchronous Bilateral Breast Cancer.

The present investigation intends to identify the optimal radiotherapy treatment plan for synchronous bilateral breast cancer (SBBC) using dosimetric and radiobiological indexes for three techniques, namely, helical tomotherapy (HT), volumetric modulated arc therapy (VMAT), and intensity-modulated radiotherapy (IMRT). Twenty SBBC treated female patients treatment planning data (average age of 52.5 years) were used as the sample for the present study. Three different plans were created using 50 Gy in a 25 fraction dose regime. Poisson, Niemierko, and LKB models were applied for calculating normal tissue complication probability (NTCP) and tumour control probability (TCP). The target average dose comparison between IMRT with HT and VMAT with HT was highly substantial (P0.001). The percentage of TCP for IMRT, VMAT, and HT in the Poisson model were 93.70±0.28, 94.68±0.30, and 94.34±0.57, respectively (p<0.05). The dose maximum was lower for the whole lung in the HT plan, with an average dose of 49.31Gy±3.9 (p<0.009). The NTCP values of both Niemierko and LKB models were lower for the heart, lungs, and liver for the IMRT plan. The sparing of organs at risk was higher in the HT plan dosimetrically, and the TCP was higher in the three techniques. The comparison between the three techniques shows that the IMRT and HT techniques could be considered for treating SBBC.

Evaluation of Inhomogeneity Correction Performed by Radiotherapy Treatment Planning System.

Aim of this study is to evaluate the efficacy of inhomogeneity corrections calculated by radiotherapy treatment planning system (TPS) using various densities of materials. Gammex Computed tomography electron density inserts (EDIs 14 nos) were used to generate the CT to ED curve with high speed GE CT scanner by noting down the respective HU values of each rod. Treatment plans were generated in XiO TPS with three inhomogeneous phantoms (comprising combination of water, lung and bone equivalent slabs) with different field sizes and for EDI (8 nos) inserted in slots of acrylic tray and validation was carried out using 2D array detector with 20cm×20cm field size for 200 MU. Point dose and fluence measurements were carried with inhomogeneous phantoms combinations and EDIs (placed on the locally fabricated box filled with water medium). The mean percentage deviations with standard deviation of calculated point doses against measured ones obtained with 2D array detector at iso-center plane for all three inhomogeneous phantom combinations were found to be -1.13%±0.13%, -3.51%±0.14% and -0.63%±0.27% respectively. On point doses measured under each individual EDI, over all percentage deviation with standard deviation observed is -2.04% ± 1.1%. The described method can be implemented in any newly established radiotherapy department as a routine quality measure of TPS to verify its efficacy in performing of inhomogeneity calculation.

Downregulation of LRPLR with siRNA inhibits several cancer hallmarks in lung cancer cells.

The incidence and mortality rates of cancer are growing rapidly worldwide, with lung cancer being the most commonly occurring cancer in males. Human carcinomas circumvent the inhibitory pathways induced by DNA damage and senescence through the upregulation of telomerase activity. The 37 kDa67 kDa laminin receptor (LRPLR) is a cell surface receptor which plays a role in several cancer hallmarks, including metastasis, angiogenesis, cell viability maintenance, apoptotic evasion, and mediating telomerase activity. We have previously shown that the knockdown of LRPLR with an LRP-specific siRNA significantly impedes adhesion and invasion, induces apoptosis, and inhibits telomerase activity in various cancer cell lines in vitro. Here, we investigated the effect of downregulating LRPLR with LRP-specific siRNA in A549 lung cancer cells. Downregulation of LRPLR resulted in a significant decrease in cell viability, migration potential, and telomerase activity, as well as a significant increase in apoptosis. Proteomic analysis further suggested the re-establishment of immune control over the lung cancer cells, a previously unidentified facet of LRP downregulation in cancer. Altogether, we suggest that targeting LRPLR for downregulation may have therapeutic potential for inhibiting several cancer hallmarks.

Inducible lncRNA transgenic mice reveal continual role of

Construction and Preclinical Evaluation of a

Programmed cell death-ligand 2 (PD-L2) is an important emerging molecule of the immune checkpoint, which is closely related to the prognosis of patients with immune checkpoint inhibitor (ICI) therapy. The quantification of PD-L2 can provide a potential reference for patients who benefit from ICI treatment. In this study, we used iodine isotope (

A Phase 1 Drug-Drug Interaction Study Between Brigatinib and the CYP3A Substrate Midazolam in Patients With ALK-Positive or ROS1-Positive Solid Tumors.

Brigatinib is a next-generation anaplastic lymphoma kinase (ALK) inhibitor approved for the treatment of patients with ALK-positive (ALK) non-small cell lung cancer (NSCLC). A phase 1 drug-drug interaction study was conducted to evaluate the effect of multiple-dose administration of brigatinib on the single-dose pharmacokinetics of midazolam, a sensitive cytochrome P450 3A substrate. In cycle 1, patients with ALK or ROS1 solid tumors, including NSCLC, received a single 3-mg dose of midazolam as an oral solution alone on day 1 and then coadministered with brigatinib on day 21 (brigatinib 90 mg once daily on days 2-8 180 mg once daily on days 9-28). After cycle 1, patients could continue to receive brigatinib in 28-day treatment cycles. The primary study objective was to characterize the effect of brigatinib 180 mg once daily on midazolam pharmacokinetics. The secondary objective was to assess safety. Exploratory efficacy endpoints included objective response rate and progression-free survival. Brigatinib was generally well tolerated, and safety data were consistent with the known safety profile. Among the 10 patients with ALK NSCLC, the confirmed objective response rate was 30% and median progression-free survival was 7.2 months. Coadministration of brigatinib reduced midazolam maximum observed plasma concentration by ≈16% (geometric least-squares mean ratio, 0.836 90%CI, 0.662-1.056) and area under the plasma concentration-time curve from time 0 to infinity by ≈26% (geometric least-squares mean ratio, 0.741 90%CI, 0.600-0.915). Thus, brigatinib is a weak inducer of cytochrome P450 3A in vivo.

A Radiomics Approach on Chest CT Distinguishes Primary Lung Cancer from Solitary Lung Metastasis in Colorectal Cancer Patients.

This study utilized a radiomics approach combined with a machine learning algorithm to distinguish primary lung cancer (LC) from solitary lung metastasis (LM) in colorectal cancer (CRC) patients with a solitary pulmonary nodule (SPN). In a retrospective study, 239 patients who underwent chest computerized tomography (CT) at three different institutions between 2011 and 2019 and were diagnosed as primary LC or solitary LM were included. The data from the first institution were divided into training and internal testing datasets. The data from the second and third institutions were used as an external testing dataset. Radiomic features were extracted from the intra and perinodular regions of interest (ROI). After a feature selection process, Support vector machine (SVM) was used to train models for classifying between LC and LM. The performances of the SVM classifiers were evaluated with both the internal and external testing datasets. The performances of the model were compared to those of two radiologists who reviewed the CT images of the testing datasets for the binary prediction of LC versus LM. The SVM classifier trained with the radiomic features from the intranodular ROI and achieved the sensitivityspecificity of 0.5450.828 in the internal test dataset, and 0.8330.964 in the external test dataset, respectively. The SVM classifier trained with the combined radiomic features from the intra- and perinodular ROIs achieved the sensitivityspecificity of 0.5450.966 in the internal test dataset, and 0.8331.000 in the external test data set, respectively. Two radiologists demonstrated the sensitivityspecificity of 0.5450.966 and 0.6360.828 in the internal test dataset, and 0.9170.929 and 0.8330.929 in the external test dataset, which were comparable to the performance of the model trained with the combined radiomics features. Our results suggested that the machine learning classifiers trained using radiomics features of SPN in CRC patients can be used to distinguish the primary LC and the solitary LM with a similar level of performance to radiologists.

Dynamical Synergy of Drug Combinations during Cancer Chemotherapy.

Synergistic drug combinations often provide effective strategies to increase treatment efficacy and, during therapy, it is a time-dependent process. Data for colorectal and lung cancer in vivo were used for the phenomenological study of dynamical synergy during treatments. The proposed approach takes into consideration tumor regrowth by macroscopic laws. The time dependencies of synergistic drug combinations are analyzed by different parametric indicators. The cumulative effects of the single therapy and drug combinations are quantitatively well described and related to the cumulative doses. In conclusion, the analysis of dynamical synergy during chemotherapy has to take into account the effects of the drug doses and the tumor regrowth, which can provide a reliable description of the synergistic time dependence.

Liquid Biopsy in the Oncological Management of a Histologically Undiagnosed Lung Carcinoma A Case Report.

Lung cancer is one of the most common and lethal cancers worldwide. Numerous medications targeting specific molecular alterations in non-small cell lung cancer have been introduced in the last decade and have revolutionized the clinical management of the disease. Their use has brought to a parallel evolution of molecular testing techniques to identify alterations in druggable molecular targets within the genetic material of the tumors. To perform molecular testing, biopsy or surgery tissue specimens are needed, which in addition allow the histological characterization of the tumors. Unfortunately, in real-life practice not all the patients are suitable for biopsy or surgery procedures. The use of liquid biopsy for blood extracted tumoral DNA analysis is a promising approach in unbiopsied cases, but it is also weighted by several methodological and technical limitations. We report here a case of histologically undiagnosed lung cancer managed with a liquid biopsy and subsequently with anti-EGFR treatment. Our report highlights that the use of liquid biopsy molecular testing in specific clinical situations can offer treatment opportunities for fragile patients affected by lung cancer.

A novel NGS-based diagnostic algorithm for classifying multifocal lung adenocarcinomas in pN0M0 patients.

The classification of multifocal lung adenocarcinomas (MLAs), including multiple primary lung adenocarcinomas (MPLAs) and intrapulmonary metastases (IPMs), has great clinical significance in staging and treatment determination. However, the application of molecular approaches in pN0M0 MLA diagnosis has not been well investigated. Here, we performed next-generation sequencing (NGS) analysis in 45 pN0M0 MLA patients (101 lesion pairs) who were initially diagnosed as having MPLA by comprehensive histologic assessment (CHA). Five additional patients with intrathoracic metastases were used as positive controls, while 197 patients with unifocal lung adenocarcinomas (425 random lesion pairs) were used as negative controls. By utilizing a predefined NGS criterion, all IPMs in the positive control group could be accurately classified, whereas 13 lesion pairs (3.1%) in the negative control cohort were misdiagnosed as IPMs. Additionally, 14 IPM lesion pairs were diagnosed in the study group, with at least 7 misdiagnoses. We thus developed a refined algorithm, incorporating both NGS and histologic results, that could correctly diagnose all the known MPLAs and IPMs. In particular, all IPMs identified by the refined algorithm were diagnosed to be IPMs or suspected IPMs by CHA reassessment. The refined algorithm-diagnosed MPLAs patients also had significantly better progression-free survival than the refined algorithm-diagnosed IPMs (p < 0.0001), which is superior to conventional NGS or CHA diagnoses. Overall, we developed an NGS-based algorithm that could accurately distinguish IPMs from MPLAs in MLA patients. Our results demonstrate a promising clinical utility of NGS to complement traditional CHA-based MLA diagnosis and help determine patient staging and treatment.

NTRK Gene Fusions in Solid Tumors and TRK Inhibitors A Systematic Review of Case Reports and Case Series.

The approval of larotrectinib and entrectinib for cancer patients harboring an NTRK gene fusion has represented a milestone in the era of histology-agnostic drugs. Among the clinical trials that led to the approval of these two drugs, most of the enrolled patients were affected by soft tissue sarcomas, lung, and salivary gland cancer. However, as next-generation sequencing assays are increasingly available in the clinical setting, health care professionals may be able to detect NTRK gene fusions in patients affected by tumor types under or not represented in the clinical trials. To this aim, we systematically reviewed MEDLINE from its inception to 31 August 2022 for case reports and case series on patients with NTRK gene fusion-positive tumors treated with TRK inhibitors. A virtual cohort of 43 patients was created, excluding those enrolled in the above-mentioned clinical trials. Although our results align with those existing in the literature, various cases of central nervous system tumors were registered in our cohort, confirming the benefit of these agents in this subgroup of patients. Large, multi-institutional registries are needed to provide more information about the efficacy of TRK inhibitors in cancer patients affected by tumor types under or not represented in the clinical trials.

Novel Small-Molecule PD-L1 Inhibitor Induces PD-L1 Internalization and Optimizes the Immune Microenvironment.

Blocking the PD-1PD-L1 interaction has become an important strategy for tumor therapy, which has shown outstanding therapeutic effects in clinical settings. However, unsatisfactory response rates and immune-related adverse effects limit the use of anti-PD1PD-L1 antibodies. Here, we report the discovery and identification of

Three-Arm Robotic Lung Resection via the Open-Thoracotomy-View Approach Using Vertical Port Placement and Confronting Monitor Setting Focusing on Segmentectomy.

To perform robotic lung resections with views similar to those in thoracotomy, we devised a vertical port placement and confronting upside-down monitor setting the three-arm, robotic open-thoracotomy-view approach (OTVA). We described the robotic OTVA experiences focusing on segmentectomy and its technical aspects. We retrospectively reviewed 114 consecutive patients who underwent robotic lung resections (76 lobectomies and 38 segmentectomies) with OTVA using the da Vinci Xi Surgical System between February 2019 and June 2022. To identify segmental boundaries, we administered indocyanine green intravenously and used the robotic fluorescence imaging system (Firefly). In all procedures, cranial-side intrathoracic structures, which are often hidden in the conventional look-up-view method, were well visualized. The mean durations of surgery and console operation were 195 and 140 min, respectively, and 225 and 173 min, for segmentectomy and lobectomy, respectively. In segmentectomy, console operation was significantly shorter (approximately 30 min,

Design, synthesis, characterizing and DFT calculations of a binary CT complex co-crystal of bioactive moieties in different polar solvents to investigate its pharmacological activity.

Imidazole (IM) and salicylic acid (SA) have a significant class among the medical compound. These are widely used as topical drugs like antifungal, antibacterial, anticancer, immunosuppressive agent, etc. These two bioactive organic moieties are combined by a weak hydrogen bond formed by hydrogen transfer. The charge transfer (CT) complex of acceptor (SA) and donor (IM), has been synthesized at room temperature in methanol and confirmed by signal-crystal XRD, conductance and UV-visible spectroscopy. The X-ray crystallography provides the original structural information of CT complex and displays the existence of N

HIF-1αMalat1miR-141 Axis Activates Autophagy to Increase Proliferation, Migration, and Invasion in Triple-negative Breast Cancer.

The mechanism of metastasis-associated lung adenocarcinoma transcript 1 (Malat1) in triple-negative breast cancer (TNBC) is still unclear. This study aimed to investigate the role of miR-141-3p and Malat1 in autophagy in TNBC under hypoxia. The expression levels of Malat1 and miR-141-3p were detected via quantitative real-time polymerase chain reaction (qRT-PCR). The protein expression levels of hypoxia-inducible factor 1α (HIF-1α), HIF-2α, MMP9, p62 and LC3 were determined via western blotting. A Cell Counting Kit-8 assay was used to detect cell viability, while a Transwell assay to detect cell proliferation and invasion. A luciferase assay was used to confirm the relationship between Malat1 and miR-141-3p. A significant increase was observed in the expression level of Malat1 and the autophagic activity in TNBC tissues and cells. The expression level of Malat1 was higher in a hypoxic environment, which can significantly promote the proliferation, migration, and invasion of TNBC cells by activating autophagy. HIF-1α, but not HIF-2α, was identified to induce the upregulation of Malat1 in TNBC cells. The dual-luciferase assay results identified a miR-141-binding site in Malat1. Malat1 knockdown and miR-141-3p overexpression were demonstrated to significantly inhibit autophagy, thereby inhibiting cell proliferation, invasion, and migration. Moreover, hypoxia can inhibit the effect of miR-141-3p on TNBC cells. miR-141-3p could suppress autophagy and inhibit proliferation, migration, and invasion by targeting Malat1 in TNBC cells under hypoxia. The existence of the HIF-1αMalat1miR-141 axis plays a vital role in the development of TNBC and may be a target for the diagnosis and treatment of TNBC.

Major pathological response exhibited distinct prognostic significance for lung adenocarcinoma post different modalities of neoadjuvant therapy.

For non-small-cell lung cancer (NSCLC) patients receiving neoadjuvant therapy, the major pathological response (MPR) is defined as the percentage of residual viable tumour cells (%RVT) in the tumour bed of no more than 10%. It has been proposed as a predictor of survival in neoadjuvant therapy-treated cohorts. Nonetheless, the significance of %RVT in the pathological assessment of lung adenocarcinoma cohorts remains undetermined. Overall, 152 lung adenocarcinoma patients were included in this retrospective study, among whom 67 received neoadjuvant targeted therapy and 85 received neoadjuvant chemotherapy. Clinicopathological characteristics, neoadjuvant treatment response and survival status were investigated. The routinely adopted standard for MPR (%RVT ≤ 10%) failed to differentiate prognosis in the lung adenocarcinoma population. For the neoadjuvant chemotherapy cohort, the optimal %RVT cut-off value of RFS was 60%. However, this cut-off value was clinically insignificant in the neoadjuvant targeted-therapy cohort. Hence, for these patients, we built a nomogram model including high-grade patterns and ypN stage to predict disease recurrence, demonstrating high efficacy (a bootstrap-corrected C-index of 0.731). %RVT served as a strong indicator of the prognosis of lung adenocarcinoma in patients receiving neoadjuvant chemotherapy but not neoadjuvant targeted therapy. Residual high-grade pathological patterns might substitute MPR in prognostic evaluation of lung adenocarcinoma post-targeted therapy.

Presentation of Lung Carcinoid Tumor as Post-obstructive Pneumonia.

Carcinoid tumors consist of neuroendocrine cells that produce amines, polypeptides, and prostaglandins. The majority of carcinoid tumors are found in the gastrointestinal system while a minority originate as pulmonary neoplasms. Among lung cancers, carcinoid tumors are rare, compromising 1-2% of lung malignancies in the United States. Lung carcinoid tumors are characterized into typical and atypical classifications. Typical lung carcinoid tumors are often lower grade, slower growing, and more well-defined than atypical tumors. Atypical tumors are also more likely to metastasize than their typical counterparts. The patient presented in this article is a 35-year-old male with a history of recent hospital admission for pneumonia who presented with right chest pain. The patient was admitted eight days prior due to cough and acute hypoxemic respiratory failure secondary to post-obstructive pneumonia. During that admission, which totaled five days, he underwent a bronchoscopy and biopsy for a nodular right infrahilar opaque mass that appeared on computed tomography angiography of the chest. After the workup was negative, the patient was discharged. Three days later, he was re-admitted with continued chest pain. Biopsy results from the initial admission characterized the obstructing infrahilar mass as a carcinoid tumor with positive synaptophysin chromogranin stain and low proliferation (Mib1 < 2%). Following his discharge three days later, he was seen in follow-up by cardiothoracic surgery and underwent further imaging studies. Two months later, the patient underwent robotic right middle and lower bilobectomy. Pathologic analysis showed negative excised nodes and tumor margins. Often, patients presenting with post-obstructive pneumonia are thought to have an underlying etiology that is purely infectious. This can lead to a delay in the discovery of the primary cause of the obstruction, and the underlying malignancy. Fortunately for this case, a biopsy was performed during the initial hospitalization, which led to a modification of his treatment plan early on in his second hospital stay after the tumor was characterized.

Hypertensive pneumothorax with cystic lesions Pleuropulmonary blastoma in an infant.

Pleuropulmonary blastoma (PPB) is a rare primitive malignant lung cancer that occurs in pediatric age. Its main differential diagnosis is congenital cystic pulmonary malformation (CPAM). A 30-day-old infant with respiratory failure obtained a chest x-ray and a computed tomography scan (CT) which revealed hypertensive pneumothorax with multifocal bilateral cysts. After thoracic drainage, the patient underwent multiple thoracoscopic pulmonary resections. The first histological diagnosis was of type 2 CPAM. During the radiological follow-up, an increase in the number and dimension of the lesions was detected. Thus, a histological revision was performed, leading to the diagnosis of type I PPB, at nine months. The patient subsequently underwent chemotherapy. At the five-year follow-up appointment, chest magnetic resonance (MR) and CT scans showed a dimensional increase in size of the lesions, with the risk of recurrent pneumothorax. An upper right lobectomy and wedge resection of the residual cysts were performed. Control MR scans showed normalization of the lung parenchyma and the patient showed substantial clinical improvement.

Adrenocortical Carcinoma With Cushings Syndrome and Extensive Tumor Thrombosis of the Inferior Vena Cava in a 30-Year-Old Filipino Female.

Adrenocortical carcinoma (ACC) is a rare and aggressive neoplasm with poor prognosis. We report a case of a 30-year-old female who presented with profound classic features of an adrenocorticotrophic hormone (ACTH)-independent Cushings syndrome (CS) and a large adrenal mass with massive venous tumor thrombosis of the entire inferior vena cava (IVC), left renal and adrenal veins confirmed by imaging. Adrenal biopsy histopathology and immunohistochemistry confirmed ACC. Systemic palliative chemotherapy was administered. This rare case presents a unique and atypical presentation of an extensive tumor thrombosis of IVC. With the advanced stage at diagnosis, aggressive nature and poor prognosis of the disease, there is still a need to determine viable therapeutic options for metastatic ACC associated with venous invasion.

Collision of Two Tumors A Case Report of a Lung Adenocarcinoma With Metastasis to a Pituitary Adenoma.

A collision tumor involving metastasis to a pituitary adenoma is rare. We describe a case of a 68-year-old Bidayuh woman with underlying treatment-responsive lung adenocarcinoma, who presented with mass effect, panhypopituitarism and polyuria. Her initial imaging study reported pituitary macroadenoma, and she was treated with hormone replacement therapy. She then underwent transsphenoidal tumor debulking surgery with subsequent histopathological findings of a collision tumor of an adenocarcinoma with metastasis to a non-functioning pituitary adenoma.

The Association of Increased Oxidative Stress and Tumor Biomarkers Related to Polyaromatic Hydrocarbons Exposure for Different Occupational Workers in Makkah, Saudi Arabia.

Exposure to occupational polyaromatic hydrocarbons (PAHs) is correlated with several adverse effects on human health, including bladder, lung, and skin cancer. The correlation between PAH exposure and oxidative stress and tumor markers needs to be further explored. Therefore, we conducted this study to examine the effect of acute exposure to PAHs on oxidative stress and tumor marker levels in occupational workers during the Hajj season in Makkah. We conducted a cross-sectional study of 105 workers during Hajj 60 workers were employed in the open air for ≥eight hoursday, exposed them to high levels of considerable traffic and huge crowds, and 45 workers served as our control group who were unexposed and working in a rural area. Using high-performance liquid chromatography, we analyzed participants urinary 1-hydroxypyrene to determine PAH levels. Oxidative stress markers malondialdehyde (MDA), glutathione S-transferase (GST), and lactate dehydrogenase (LDH) were analyzed in serum using a spectrophotometer. The serum p53 and p21 proteins were analyzed using an enzyme-linked immunosorbent assay. We used IBM SPSS Statistics for Windows, Version 21.0 (IBM Corp., Armonk, NY, USA) to calculate multivariate logistic regression analysis for oxidative stress and tumor markers such as age, working period, and smoking status risk factors. Additionally, we evaluated associations between oxidative stress and tumor markers. The mean levels of MDA, GST, and LDH were significantly elevated in exposed workers compared to the control group (p<.001). Also, p53 and p21 protein levels were significantly higher in the occupationally exposed group than in the unexposed control group (p<0.05). No significant correlation between age and increased levels of p53 and p21 was found. In our study, PAH exposure is significantly correlated with higher levels of oxidative stress and tumor marker levels in occupational workers. The evaluation of oxidative stress and tumor marker indicators can efficiently identify workers at high risk of PAH exposure and may assist in preventing future health concerns. More biomarkers should be included in other longitudinal studies to address exposure related to different health risks among workers, especially cancer risk. More prospective studies are required to validate diagnostic utilities and efficiencies of different biomarker combinations.

A Rare Case of Aggressive Atypical Cervical Cancer With Multi-Organ Involvement.

Squamous cell carcinoma (SCC) of cervical origin with metastasis to the brain is rare. Our patient was a 30-year-old Caucasian female with squamous cell carcinoma, initially with unknown primary, with metastases to the brain, kidney, cervix, lung, adrenal glands, vulva, pelvic wall, and scalp. She initially presented to her outpatient gynecologist for a vulvar mass. A biopsy of the vulvar mass was consistent with SCC. The patient continued to have fatigue along with thoracic rib pain. An initial work-up was performed, including imaging which showed diffuse metastatic disease involving the lungs, kidneys and adrenal glands, as well as a pathological compression fracture of the seventh thoracic vertebra with cord compression. Brain magnetic resonance imaging (MRI) showed multiple metastatic lesions and she underwent craniotomy for brain lesion resection. Given the aggressive nature of the patients disease and her symptomatic burden, she was started on chemotherapy in the hospital with Carboplatin, Paclitaxel, and Pembrolizumab.

Incidence and Risk of Lung Cancer in Tuberculosis Patients, and Vice Versa A Literature Review of the Last Decade.

The incidence and risk of both lung cancer (LC) and tuberculosis (TB) are increasing rapidly. These two diseases frequently exist together and can influence the incidence and risk of each other. The aim of the current review was to summarize the incidence and risk of LC in TB patients, and vice versa, short out research gap, and contemplate future research perspectives. We found higher incidence rate and risks (1.64 to 6 times higher) of LC in TB patients in comparison to non-TB participants. However, the incidence rate and risks of TB in LC patients were comparatively low. Male patients were exhibited higher risks than female. The medical comorbidities, smoking habits, and age can also influence the associations and risks of LC in TB patients or vice versa. Our summarized studies might suggest that existing active TB may increase the incidence and risk of LC. However, large prospective cohort study is warranted to explore the real scenario worldwide.

Survival analysis of small cell carcinomas of the genitourinary system.

Due to low incidence, there are no large prospective studies or clinical trials for small cell carcinoma (SCC) of the genitourinary system (GU), and most data are extrapolated from SCC of the lung. Using the SEER database, we analyzed incidence trends, overall survival, and cancer-specific survival using the log-rank test. Analysis of variables was performed using the Cox proportional hazards regression model. The analysis showed that SCC of the bladder and prostate were the most common types of GU SCC, with 1836 and 606 cases, respectively. In 2018, the incidence of SCC of the bladder and prostate was twice that of 2010 (

Non-small cell lung cancer presenting as back cyst.

Cutaneous metastasis as the presenting sign of lung cancer is rare, with a poor prognosis and a life expectancy of 3 to 5 months. We present the complicated course of a 60-year-old woman with extensive metastatic non-small cell lung cancer that presented as a back cyst. Due to the benign appearance of the cyst and the difficulty discovering the location of the primary malignancy, diagnosis and treatment were delayed. Unfortunately, once aggressive treatment was initiated at the request of the patient, she died 2 weeks later. This case highlights the importance of recognizing cutaneous lesions as a sign of internal malignancy and emphasizes multidisciplinary discussion that focuses on the patients quality of life.

Cancer and Neurodegenerative diseases are one of the most dreadful diseases to cure and chemotherapy has found a prime place in cancerous treatments while as different strategies have been tested in neurodegenerative diseases as well. However, due to adverse shortcomings like the resistance of cancerous cells and inefficiency in neurodegenerative disease, plant sources have always found a prime importance in medicinal use for decades,

Association between radiotherapy protocol variations and outcome in the CONVERT trial.

Radiotherapy quality assurance (QA) is integral to radiotherapy delivery. Here we report comprehensive contouring, dosimetry, and treatment delivery QA, describe protocol compliance, and detail the impact of protocol variations on acute grade ≥3 toxicity, progression free survival (PFS), and overall survival (OS) in the phase III CONVERT trial. Radiotherapy planning data from one hundred randomly selected patients were requested. Members of the CONVERT Trial Management Group (TMG) recontoured the heart, lung, and spinal cord organs at risk (OAR) according to the trial guideline. The existing radiotherapy plan were re-applied to the new structures and the new dosimetric data were recollected. Compliance with radiotherapy QA components were recorded and radiotherapy QA components were pooled into protocol variations acceptable, acceptable variation, and unacceptable variation. Univariable analysis with a Cox proportional hazards model established the relationship between protocol variations and patient outcome. Ninety-three cases were submitted for retrospective radiotherapy QA review. Demographics of the radiotherapy QA cohort (n93) matched the non-QA (n450) cohort. 97.8% of gross tumour volume (GTV) contours were protocol compliant. OAR contours were non-compliant in 79.6% instances of the heart, 37.6% lung, and 75.3% spinal cord. Of the non-compliant heart contours, 86.5% and 2.7% had contours caudal and cranial to the protocol-defined heart borders. 10.8% did not include the pericardial sac and 2.7% did not include the anterior aspect of the pericardium. Eleven (11.8%) submissions exceeded protocol-defined dosimetric heart constraints six of which were only noted on the application of protocol-compliant contours. Unacceptable variations were not associated with an increase in grade 3 toxicity (p0.808), PFS (p0.232), or OS (p0.743). Non-protocol compliant heart contours were associated with increased dose delivered to the heart OAR, with 11.8 % of submitted heart structures exceeding protocol-defined constraints. In this QA cohort of patients with small cell lung cancer, unacceptable variations were not associated with acute grade ≥3 toxicity, PFS, or OS. Radiotherapy QA remains the cornerstone of high-quality radiotherapy delivery and should be embedded into clinical trial and non-clinical trial practice clinical trials should report standardised radiotherapy QA parameters alongside trial outcomes.

An autophagy-inducing stapled peptide promotes c-MET degradation and overrides adaptive resistance to sorafenib in c-MET

Hepatocellular carcinoma (HCC) accounts for approximately 90% of primary liver cancer cases and ranks as the second leading cause of cancer related death. Multiple receptor tyrosine kinases such as EGFR, FGFR and c-MET have been shown to drive tumorigenesis and progression of HCC. However, tyrosine kinase inhibitors (TKIs) that target these kinases, including the FDA-approved sorafenib, only offer limited clinical success. Resistance to sorafenib and other TKIs also readily emerge in HCC patients, further limiting the usage of these drugs. Novel therapeutic strategies are needed to address the urgent unmet medical need for HCC patients. Autophagy is an evolutionally conserved lysosome-dependent degradation process that is also functionally implicated in HCC. We previously developed an autophagy-inducing stapled peptide (Tat-SP4) that induced autophagy and endolysosomal degradation of EGFR in lung cancer and breast cancer cells. Here we present data to show that Tat-SP4 also induced significant autophagic response in multiple HCC cell lines and promoted the endolysosomal degradation of c-MET to attenuate its downstream signaling activities although it didnt affect the intrinsically fast turnover of EGFR. Tat-SP4 also overrode adaptive resistance to sorafenib in c-MET With its distinct mechanism of promoting autophagy and endolysosomal degradation of c-MET, Tat-SP4 may serve as a novel therapeutic agent that complement and synergize with sorafenib to enhance its clinical efficacy in HCC patients.

Erratum Real-world landscape transition of death causes in the immunotherapy era for metastatic non-small cell lung cancer.

This corrects the article DOI 10.3389fimmu.2022.1058819..

Innate immune function during antineoplastic treatment is associated with 12-months survival in non-small cell lung cancer.

The immune system has proven to be a key player in the progression as well as containment of cancer with new treatment strategies based on immunotherapy targeting this interaction. Assessing immune function could reveal critical information about the immune response to therapeutic interventions, revealing predictive biomarkers for tailored care and precision medicine. We investigated immune function in 37 patients with inoperable non-small cell lung cancer (NSCLC) undergoing treatment with PD-L1 immune checkpoint inhibitor (ICI), chemotherapy (CT) or chemo-radiotherapy (CTRT). Blood samples before (day 0) and during therapy (day 7, 21 and 80) were investigated by a standardized immunoassay, TruCulture®. Outcomes revealed a developing innate immune response induced by both immunotherapy and chemotherapy. NSCLC-patients displayed evidence of chronic innate immune activation and exhaustion prior to treatment. This pattern was particularly pronounced during treatment in patients dying within 12-months follow-up. Compared to treatment with CT, ICI demonstrated a higher ex vivo-stimulated release of proinflammatory cytokines. These preliminary findings may pave the way for tailored treatment and immune-monitoring.

Radiotherapy prognosis-associated gene GCNT3 promotes the proliferation, migration and invasion of lung adenocarcinoma cells.

Lung cancer is a life-threatening malignant tumour that is prevalent worldwide. Here, the GCNT3 gene in lung adenocarcinoma was studied via public databases, and cytology and molecular biology experiments were performed to further explore the role of this gene in lung adenocarcinoma. In this study, abnormally high GCNT3 expression levels were observed in tumour tissues compared with normal tissues at both the mRNA and protein levels. In the pancancer analysis, abnormal GCNT3 expression was observed in many tumour types. Moreover, the survival analysis revealed that among patients receiving radiotherapy, those with high GCNT3 expression levels had a worse prognosis. Cell and molecular biology experiments showed that the proliferation, migration and invasion capabilities of the A549 cell line were decreased after knockdown of GCNT3, and epithelial-mesenchymal transformation was significantly inhibited. In subsequent studies, we found that the sensitivity of cells to radiotherapy was enhanced after GCNT3 knockdown. Overall, our findings reveal that GCNT3 is an important factor affecting the radiotherapy sensitivity of lung adenocarcinoma, and GCNT3 inhibition deserves further study as a radiotherapy sensitising strategy.

Family-oriented dignity therapy for patients with lung cancer undergoing chemotherapy How does it work better

This study aimed to examine the fidelity of intervention delivery and identify precursory factors contributing to the successful delivery and beneficial effects of family-oriented dignity therapy. This was a process evaluation with quantitative and qualitative methods alongside a randomized controlled trial from March to May 2019. Nonparametric statistics were used to analyze how participants demographics ( The fidelity was achieved with minor deviations from the protocol. Higher educational level and higher income were significantly correlated with lower levels of existential distress (H ​ ​12.20, Fidelity and precursory factors that enhance the beneficial effects of family-oriented dignity therapy were identified. Reinforcement strategies, such as using supplementary video, audio, and reading materials developing a flexible approach to expressing feelings and exploring lessons and achievements from various perspectives, are recommended for future research to enhance intervention effects. The study was registered in the Chinese Clinical Trial Registry (registration number ChiCTR1900020806).

High-Risk Non-Small Cell Lung Cancer Treated With Active Scanning Proton Beam Radiation Therapy and Immunotherapy.

Non-small cell lung cancer (NSCLC) is a deadly malignancy that is frequently diagnosed in patients with significant medical comorbidities. When delivering local and regional therapy, an exceedingly narrow therapeutic window is encountered, which often precludes patients from receiving aggressive curative therapy. Radiation therapy advances including particle therapy have been employed in an effort to expand this therapeutic window. Here we report outcomes with the use of proton therapy with curative intent and immunotherapy to treat patients diagnosed with high-risk NSCLC. Patients were determined to be high risk if they had severe underlying cardiopulmonary dysfunction, history of prior thoracic radiation therapy, andor large volume or unfavorable location of disease (eg, bilateral hilar involvement, supraclavicular involvement). As such, patients were determined to be ineligible for conventional x-ray-based radiation therapy and were treated with pencil beam scanning proton beam therapy (PBS-PBT). Patients who demonstrated excess respiratory motion (ie, greater than 1 cm in any dimension noted on the 4-dimensional computed tomography simulation scan) were deemed to be ineligible for PBT. Toxicity was reported using the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Overall survival and progression-free survival were calculated using the Kaplan-Meier method. A total of 29 patients with high-risk NSCLC diagnoses were treated with PBS-PBT. The majority (55%) of patients were defined as high risk due to severe cardiopulmonary dysfunction. Most commonly, patients were treated definitively to a total dose of 6000 cGy (relative biological effectiveness) in 30 fractions with concurrent chemotherapy. Overall, there were a total of 6 acute grade 3 toxicities observed in our cohort. Acute high-grade toxicities included esophagitis (n 4, 14%), dyspnea (n 1, 3.5%), and cough (n 1, 3.5%). No patients developed grade 4 or higher toxicity. The majority of patients went on to receive immunotherapy, and high-grade pneumonitis was rare. Two-year progression-free and overall survival was estimated to be 51% and 67%, respectively. COVID-19 was confirmed or suspected to be responsible for 2 patient deaths during the follow-up period. Radical PBS-PBT treatment delivered in a cohort of patients with high-risk lung cancer with immunotherapy is feasible with careful multidisciplinary evaluation and rigorous follow-up.

Clinical Outcomes of Patients With Metastatic NSCLC After Discontinuation of Immunotherapy Because of Immune-Related Adverse Effects.

Immune checkpoint inhibition (ICI) is an important treatment modality in metastatic NSCLC and management of immunotherapy-related adverse effects (irAEs) can be challenging. Retreatment after discontinuation of ICI because of irAEs is a frequent clinical dilemma with limited available data. This single-center retrospective observational study reviewed the clinical course of 30 patients with metastatic NSCLC in whom ICI had to be discontinued owing to a serious irAE after an initial objective response to therapy. After ICI discontinuation, 14 patients (47%) developed a durable response of more than 6 months, seven patients (23%) developed oligoprogression treated with local radiotherapy leading to disease control, six patients (20%) had progression of disease within 6 months, and three patients (10%) died owing to a severe irAE. A watchful waiting approach is justified after discontinuation of ICI owing to irAEs in patients with metastatic NSCLC with an initial response to therapy.

D-allose molecular pathways and therapeutic capacity in cancer.

Despite the implementation of various cancer therapies, adequate therapeutic efficacy has not been achieved. A growing number of studies have been dedicated to the discovery of new molecules to combat refractory cancer cells efficiently. Recently, the use of a rare type of sugar, D-allose, has attracted the attention of research communities. In combination with the first-line treatment of cancers, including different types of radiotherapies and chemotherapies, D-allose has been detected with favorable complementary effects. Understanding the mechanism of therapeutic target molecules will enable us to develop new strategies for cancer patients that do not currently respond to the present therapies. We aimed to provide a review of the effects of D-allose in cancer treatment, its mechanisms of action, and gaps in this field that require more investigations. With rare exceptions, in many cancer types, including head and neck, lung, liver, bladder, blood, and breast, D-allose consistently has exhibited anticancer activity in vitro andor in vivo. Most of the D-allose functions are mediated through thioredoxin-interacting protein molecules. D-allose exerts its effects via reactive oxygen species regulation, cell cycle arrest, metabolic reprogramming, autophagy, apoptosis induction, and sensitizing tumors to radiotherapy and chemotherapy. D-allose has shown great promise for combating tumor cells with no side effects, especially in combination with first-line drugs however, its potential for cancer therapy has not been comprehensively investigated in vitro or in vivo.

Tumor size, but not consolidation-to-tumor ratio, is an independent prognostic factor for part-solid clinical T1 non-small cell lung cancer.

Tumor size and consolidation-to-tumor ratio (CTR) are crucial for non-small cell lung cancer (NSCLC) prognosis. However, the optimal CTR cutoff remains unclear. Whether tumor size and CTR are independent prognostic factors for part-solid NSCLC is under debate. Here, we aimed to evaluate the prognostic impacts of CTR and tumor size on NSCLC, especially on part-solid NSCLC. We reviewed 1366 clinical T1 NSCLC patients who underwent surgical treatment. Log-rank test and Cox regression analyses were adopted for prognostic evaluation. The survcutpoint function was used to identify the optimal CTR and tumor size cutoff values. There were 416, 510, and 440 subjects with pure ground-glass opacity (pGGO), part-solid, and pure solid nodules. The 5-year overall survival (disease-free survival) for patients with pGGO, part-solid, and pure solid nodules were 99.5% (99.5%), 97.3% (95.8%), and 90.4% (78.9%), respectively. Multivariate Cox regression analysis indicated that CTR was an independent prognostic factor for the whole patients, and the optimal CTR cutoff was 0.99. However, for part-solid NSCLC, CTR was not independently associated with survival, even if categorized by the optimal cutoffs. The predicted optimal cutoffs of total tumor size and solid component size were 2.4 and 1.4 cm for part-solid NSCLC. Total tumor size (HR 6.21, 95% CI 1.58-24.34, p 0.009) and solid component size (HR 2.27, 95% CI 1.04-5.92, p 0.045) grouped by the cutoffs were significantly associated with part-solid NSCLC prognosis. CTR was an independent prognostic factor for the whole NSCLC, but not for the part-solid NSCLC. Tumor size was still meaningful for part-solid NSCLC.

Bronchiolar adenomaciliated muconodular papillary tumor mixed with adenocarcinoma in situ in the same tumor.

Bronchiolar adenoma (BA)ciliated muconodular papillary tumor (CMPT) is defined as a benign tumor composed of epithelial and basal cells. Recently, some cases with driver mutations or malignant transformation have been observed. Thus, whether BACMPT is benign or malignant remains controversial. We herein report an extremely rare case of a 68-year-old woman with a CMPT accompanied by adenocarcinoma in situ (AIS). BACMPT existed inside the AIS. The BACMPT component did not show any driver mutations however, the AIS component had an EGFR driver mutation in exon 19. The accumulation of cases and further studies are needed to discuss the malignant potential of BACMPT.

TAPO in first-line osimertinib therapy and continuation of osimertinib.

Osimertinib is associated with a relatively high frequency of drug-induced interstitial lung disease (D-ILD), and transient asymptomatic pulmonary opacities (TAPO) have been reported to occur during osimertinib administration. The frequency of TAPO during first-line treatment and the pros and cons of osimertinib continuation is unknown. This was a multicenter, retrospective study. The purpose of this study was to research the frequency of TAPO and to evaluate osimertinib continuation in first-line therapy. We also evaluated progression-free survival (PFS) including subgroup analysis. From August 2018 to December 2020, 133 patients were enrolled into the study. The median observation period was 23.2 months (0.3-48.3 months). Thirty patients (22.6%) experienced D-ILD events, including 16 patients (12.1%) with CTCAE grade 1, five patients (3.8%) with grade 2, and nine patients (6.7%) with grade 3 and above D-ILD. Among the patients with grade 1 D-ILD, 11 cases (8.3%) of TAPO were observed, and all patients succeeded in osimertinib continuation. The TAPO images were characterized by localized patchy opacities (73%). The median PFS was 22.6 months (95% confidence interval CI 17.8-28.7 months). Patients with TAPO had a significantly longer PFS than patients with non-TAPO D-ILD in the multivariate analysis. This study showed that grade 1 D-ILD might include TAPO and that patients with TAPO might have good PFS. We need to consider the possibility of osimertinib continuation when lung opacities appear.

SAMHD1 silencing cooperates with radiotherapy to enhance anti-tumor immunity through IFI16-STING pathway in lung adenocarcinoma.

Sterile alpha motif domain and histidine-aspartate domain-containing protein 1 (SAMHD1) is a DNA end resection factor, which is involved in DNA damage repair and innate immunity. However, the role of SAMHD1 in anti-tumor immunity is still unknown. This study investigated the effects of SAMHD1 on stimulator of interferon genes (STING)-type I interferon (IFN) pathway and radiation-induced immune responses. The roles of SAMHD1 in the activation of cytosolic DNA sensing STING pathway in lung adenocarcinoma (LUAD) cells were investigated with flow cytometry, immunofluorescence, immunoblotting and qPCR. The combined effects of SAMHD1 silencing and radiation on tumor cell growth and STING pathway activation were also evaluated with colony formation and CCK8 assay. The Lewis lung cancer mouse model was used to evaluate the combined efficiency of SAMHD1 silencing and radiotherapy in vivo. Macrophage M1 polarization and cytotoxic T cell infiltration were evaluated with flow cytometry. The single-stranded DNA (ssDNA) accumulated in the cytosol of SAMHD1-deficient lung adenocarcinoma (LUAD) cells, accompanied by upregulated DNA sensor IFN-γ-inducible protein 16 (IFI16) and activated STING pathway. The translocation of IFI16 from nucleus to cytosol was detected in SAMHD1-deficient cells. IFI16 and STING were acquired in the activation of STING-IFN-I pathway in SAMHD1-deficient cells. SAMHD1 silencing in LUAD cells promoted macrophage M1 polarization in vitro. SAMHD1 silencing synergized with radiation to activate ssDNA-STING-IFN-I pathway, inhibit proliferation, promote apoptosis and regulate cell cycle. SAMHD1 silencing cooperated with radiotherapy to inhibit tumor growth and increase CD86 SAMHD1 deficiency induced IFN-I production through cytosolic IFI16-STING pathway in LUAD cells. Moreover, SAMHD1 downregulation and radiation cooperated to inhibit tumor growth and enhance anti-tumor immune responses through macrophage M1 polarization and CD8

Ginger supplement significantly reduced length of hospital stay in individuals with COVID-19.

Evidence from previous studies has suggested that ginger extract exhibits the potential as an alternative treatment for Coronavirus disease 2019 (COVID-19). Here, we want to investigate whether ginger supplement improves the clinical manifestation of hospitalized COVID-19 individuals. A total of 227 hospitalized individuals with COVID-19 were randomized to either the control (n 132) or intervention group (n 95). The intervention group took ginger supplement orally at the dosage of 1.5 g twice daily, until they were discharged from the hospital. Both groups received the same standard of general medical care during hospitalization, and the length of stay was recorded and compared between groups. Among all participants, a significant reduction in hospitalization time (the difference between the treatment and control groups was 2.4 d, 95% CI 1.6-3.2) was detected in response to the ginger supplement. This effect was more pronounced in men, participants aged 60 years or older, and participants with pre-existing medical conditions, relative to their counterparts (P-interactions < 0.05 for all). Ginger supplement significantly shortened the length of stay of hospitalized individuals with COVID-19. The trial was registered on the Chinese Clinical Trial Registry (ChiCTR2200059824).

Mebendazole prevents distant organ metastases in part by decreasing ITGβ4 expression and cancer stemness.

Breast cancer is the most diagnosed cancer among women. Approximately 15-20% of all breast cancers are highly invasive triple-negative breast cancer (TNBC) and lack estrogen, progesterone, and ERBB2 receptors. TNBC is challenging to treat due to its aggressive nature with far fewer targeted therapies than other breast cancer subtypes. Current treatments for patients with TNBC consist of cytotoxic chemotherapies, surgery, radiation, and in some instances PARP inhibitors and immunotherapy. To advance current therapeutics, we repurposed mebendazole (MBZ), an orally available FDA-approved anthelmintic that has shown preclinical efficacy for cancers. MBZ has low toxicity in humans and efficacy in multiple cancer models including breast cancer, glioblastoma multiforme, medulloblastoma, colon cancer, pancreatic and thyroid cancer. MBZ was well-tolerated in a phase I clinical trial of adults recently diagnosed with glioma. We determined that the half-maximal inhibitory concentration (IC

Deletion of PD-1 destabilizes the lineage identity and metabolic fitness of tumor-infiltrating regulatory T cells.

Regulatory T (T

Emerging Biomarkers in Immune Oncology to Guide Lung Cancer Management.

Over the last decade, the use of targeted therapies and immune therapies led to drastic changes in the management lung cancer and translated to improved survival outcomes. This growing arsenal of therapies available for the management of non-small cell lung cancer added more complexity to treatment decisions. The genomic profiling of tumors and the molecular characterization of the tumor microenvironment gradually became essential steps in exploring and identifying markers that can enhance patient selection to facilitate treatment personalization and narrow down therapy options. The advent of innovative diagnostic platforms, such as next-generation sequencing and plasma genotyping (also known as liquid biopsies), has aided in this quest. Currently, programmed cell death ligand 1 expression remains the most recognized and fully validated predictive biomarker of response to immune checkpoint inhibitors. Other markers such as tumor mutational burden, tumor infiltrating lymphocytes, driver mutations, and other molecular elements of the tumor microenvironment bear the potential to be predictive tools however, the majority are still investigational. In this review, we describe the advances noted thus far on currently validated as well as novel emerging biomarkers that have the potential to guide the use of immunotherapy agents in the management of non-small cell lung cancer.

Lung cancer mortality attributable to residential radon a systematic scoping review.

After smoking, residential radon is the second risk factor of lung cancer in general population and the first in never-smokers. Previous studies have analyzed radon attributable lung cancer mortality for some countries. We aim to identify, summarize, and critically analyze the available data regarding the mortality burden of lung cancer due to radon, performing a quality assessment of the papers included, and comparing the results from different countries. We performed a systematic scoping review using the main biomedical databases. We included original studies with attributable mortality data related to radon exposure. We selected studies according to specific inclusion and exclusion criteria. PRISMA 2020 methodology and PRISMA Extension for Scoping Reviews requirements were followed. Data were abstracted using a standardized data sheet and a tailored scale was used to assess quality. We selected 24 studies describing radon attributable mortality derived from 14 different countries. Overall, 13 studies used risk models based on cohorts of miners, 8 used risks from residential radon case-control studies and 3 used both risk model options. Radon geometric mean concentration ranged from 11 to 83 Becquerels per cubic meter (Bqm

Phosphorylation chemistry of the Bordetella PlrSR TCS and its contribution to bacterial persistence in the lower respiratory tract.

Bordetella species cause lower respiratory tract infections in mammals. B. pertussis and B. bronchiseptica are the causative agents of whooping cough and kennel cough, respectively. The current acellular vaccine for B. pertussis protects against disease but does not prevent transmission or colonization. Cases of pertussis are on the rise even in areas of high vaccination. The PlrSR two-component system, is required for persistence in the mouse lung. A partial plrS deletion strain and a plrS H521Q strain cannot survive past 3 days in the lung, suggesting PlrSR works in a phosphorylation-dependent mechanism. We characterized the biochemistry of B. bronchiseptica PlrSR and found that both proteins function as a canonical two-component system. His521 was essential and Glu522 was critical for PlrS autophosphorylation. Asn525 was essential for phosphatase activity. The PAS domain was critical for both PlrS autophosphorylation and phosphatase activities. PlrS could both phosphotransfer to and exert phosphatase activity toward PlrR. Unexpectedly, PlrR formed a tetramer when unphosphorylated and a dimer upon phosphorylation. Finally, we demonstrated the importance of PlrS phosphatase activity for persistence within the murine lung. By characterizing PlrSR we hope to guide future in vivo investigation for development of new vaccines and therapeutics.

Bronchoscopic management of malignant central airway obstructions.

Up to 30% of lung cancer patients suffer from central airway obstruction, resulting in major deterioration in prognosis and quality of life. Interventional bronchoscopy combines a number of invasive techniques used during rigid bronchoscopy. It is designed to rapidly improve symptoms, primarily dyspnea. Applied according to very precise indications, this technique requires careful patient selection and needs to be incorporated into the multimodal oncological management in combination with systemic treatments, radiation therapy and surgery.

MRI features and whole-lesion apparent diffusion coefficient histogram analysis of brain metastasis from non-small cell lung cancer for differentiating epidermal growth factor receptor mutation status.

To explore the utility of magnetic resonance imaging (MRI) characteristics and whole-lesion apparent diffusion coefficient histogram analysis of brain metastasis from non-small cell lung cancer (NSCLC) in the differentiation of epidermal growth factor receptor (EGFR) mutation status. Forty-eight patients with brain metastases from NSCLC were enrolled in this retrospective study. Patients were subtyped into EGFR mutation (23 cases) and wild-type (25 cases) groups. Whole-lesion histogram metrics were derived from the apparent diffusion coefficient (ADC) maps, and imaging features were evaluated according to conventional MRI. Students t-test or Mann-Whitney U-test, chi-squared test, and receiver operating characteristic (ROC) curve analysis were performed to discriminate the two groups and to determine the diagnostic efficacy of ADC histogram parameters. EGFR mutation group had more multiple brain metastases, less peritumoural brain oedema (PTBO), and lower peritumoural brain oedema index (PTBO-I) than EGFR wild-type group (all p<0.05). In addition, 90th and 75th percentiles of ADC and maximum ADC in the EGFR mutation group were significantly higher than in the EGFR wild-type group (all p<0.05). Ninetieth percentile of ADC had the highest area under the curve (AUC 0.711), and it was found to outperform 75th percentile of ADC (AUC, 0.662 p0.039) and maximum ADC (AUC, 0.681). Whole-lesion ADC histogram analysis and MRI features of brain metastasis from NSCLC are expected to be potential biomarkers to non-invasively differentiate the EGFR mutation status.

Localised Synovial Sarcoma in Adolescents and Young Adults Versus Adults - Is There a Difference in Outcome

Synovial sarcomas are a rare subgroup of soft-tissue sarcoma arising in adolescents and young adults (AYA) and in adult patients. The objective of our analysis was to investigate the outcomes and potential differences of AYA versus adult patients with initially localised disease. In total, 51 patients (25 AYA and 26 adult) were identified and evaluated in this retrospective single centre analysis. Baseline characteristics, treatment and outcome were assessed. The predominant subtype in both groups was monophasic synovial sarcoma (17 AYA and 21 adult) and the most common site was the extremities (14 and 19 patients) with deep tumour location in both groups (33 and 24 patients). More AYA patients had tumours >5 cm (1325 patients) when compared with adults (1026 patients, P n.s.). Primary wide resection was carried out in 15 AYAs and in 18 adults. Postoperative radiation therapy was the only statistical difference between AYA (n 19) and adult patients (n 12 P 0.029). Nineteen and 17 patients, respectively, received adjuvant chemotherapy with no evidence of disease after six cycles. Nine and 11 patients relapsed after initial therapy and the most common metastatic site was the lung (eight versus nine patients). Five-year overall survival rates were 85% and 75%. Female gender, tumour size ≤5 cm and absence of progressive disease showed a significant association with overall survival in AYA patients (P 0.013, P 0.04 and P < 0.001), whereas non-extremity tumours and progression after initial therapy were significant for worse overall survival in adult patients (P 0.012 and P < 0.001). No difference in overall survival between AYA and adult patients was observed (P 0.899). AYA and adult patients showed no significant difference in terms of overall survival. Male gender, tumour size >5 cm and progressive disease were prognostic markers for worse outcome, whereas tumour location (non-extremity) and progression after initial therapy were markers for worse outcome in adult patients.

Case report olaparib use in metastatic lung adenocarcinoma with

Poly (ADP-ribose) polymerase (PARP) inhibitors have been approved in malignancies associated with germline

Effect of total intravenous anesthesia versus inhalation anesthesia on long-term oncologic outcomes in patients undergoing curative resection for early-stage non-small cell lung cancer A retrospective cohort study.

Compared with inhalation anesthesia, propofol-based total intravenous anesthesia (TIVA) improves long-term outcomes after cancer surgery. However, its effect on patients undergoing non-small cell lung cancer (NSCLC) surgery remains unclear. We aimed to compare the oncological outcomes of TIVA and inhalation anesthesia after curative resection of early-stage NSCLC. We analyzed the medical records of patients diagnosed with stage I or II NSCLC who underwent curative resection at a tertiary university hospital between January 2010 and December 2017. The primary outcomes were recurrence-free survival (RFS) and overall survival (OS) according to anesthesia type. We included 1,508 patients with stage III NSCLC. The patients were divided into the TIVA (n 980) and inhalation (n 528) groups. The two groups were well balanced in terms of baseline clinical characteristics. The TIVA group showed a better RFS (7.7 years 95% confidence interval CI, 7.37-8.02) than the inhalation group (6.8 years 95% CI, 6.30-7.22, P 0.003). Similarly, TIVA was superior to inhalation agents with respect to OS (median OS, 8.4 years 95% CI, 8.08-8.69 vs. 7.3 years 95% CI, 6.81-7.71 P < 0.0001). Multivariable Cox regression analysis revealed that TIVA was an independent prognostic factor related to recurrence (hazard ratio HR 1.24, 95% CI 1.04-1.47, P 0.014) and OS (HR 1.39, 95% CI 1.12-1.72, P 0.002). Propofol-based TIVA was associated with better RFS and OS than inhalation anesthesia in patients with stage III NSCLC who underwent curative resection.

Initial therapeutic approach with pembrolizumab in synchronous multiple cancers, including non-small cell lung cancer highly positive for programmed death-ligand 1 expression.

Treatment of synchronous multiple primary cancers is clinically difficult. We report four cases of synchronous primary cancers, including advanced and metastatic non-small cell lung cancer (NSCLCs) highly positive for programmed death-ligand 1 (PD-L1) expression and initially treated with pembrolizumab. Pembrolizumab was efficacious in two patients with NSCLC lesions, followed by chemoradiotherapy for esophageal cancer (case 1) and chemotherapy for gastric cancer (case 2). Both cancers in case 1 showed a complete response for 3 years, while progression of the accompanying gastric cancer resulted in mortality at 20 months in case 2. Both NSCLC and gastric cancer in case 3 failed to respond to pembrolizumab, but the accompanying laryngeal cancer in case 4 showed a complete response, and cytotoxic chemotherapy for NSCLC was continued for 18.0 months. Our clinical experience suggests that pembrolizumab is a useful therapeutic approach for patients with synchronous cancers, including NSCLC that highly expresses PD-L1.

Patient effective dose and radiation biological risk in the chest and abdominopelvic computed tomography.

The incidence and mortality (per 100,000) rates in chest CT are highest for the lungs and breasts (incidence lung 116, breast 98.64 mortality lung 113.43, breast 49.72). Abdominopelvic CT scans showed the highest incidence for stomach (79.57), colon (62.86), bladder (48.69), and liver (28.63), respectively. Mortality is highest for the bladder (80.44), stomach (72.43), colon (69.02), and liver (63.78), respectively. This study helps to better understand the concept of radiation dose and the numbers reported as organ dose and effective dose and identify the probability of the stochastic effect.

Sotorasib in KRAS

The KRAS oncogene is present in up to 25% of solid tumors and for decades had been undruggable. Sotorasib was the first-in-class KRAS inhibitor to reach the US and European market, and its pharmacological inhibition is restricted to the KRAS p.G12C mutation. Sotorasib showed activity (tumor shrinkage) in patients with non-small cell lung cancer harboring this specific mutation, and efficacy was tested in the CodeBreaK 200, open-label, phase 3 trial (NCT04303780). The results were presented in the ESMO 2022 meeting. CodeBreaK 200 found an improvement in the primary endpoint of progression-free survival (PFS), but overall survival, a key secondary endpoint, was not improved. However, critical questions about the trials design may limit inferences regarding the reported results. The control arm treatment was inferior to the best standard of care. A late protocol modification (which lowered the sample size and allowed a problematic crossover) prohibited the trial from making a determination regarding overall survival. Imbalance in censoring rates, with potential informative censoring, makes PFS estimates unreliable. Quality-of-life data were also limited. Ultimately, CodeBreaK 200 does not clarify how this therapy should be used in practice, and while we maintain cautious enthusiasm for this and other Ras inhibitors, we await more informative trials.

Photothermic therapy with cuttlefish ink-based nanoparticles in combination with anti-OX40 mAb achieve remission of triple-negative breast cancer.

Immunostimulatory monoclonal antibodies (IS-mAb) have been proven to enhance the therapeutic effectiveness of various anticancer therapy. In the present investigation, we launched a separate combinational therapy for the treatment of triple-negative breast cancer (TNBC) using cuttlefish ink-based nanoparticles (CINPs) for photothermal therapy (PTT) and anti-OX40 antibody. Our goal was to increase the therapeutic response to the disease. CINPs were characterized by their physicochemical properties, which revealed that they had a hydrodynamic diameter ranging from 128 to 148 nm, a negative surface charge, and a high photothermal conversion efficiency under both in vitro and in vivo settings. In TNBC model, we evaluated the therapeutic effectiveness of the following groups CINP-PTT anti-OX40 Ab (G1), CINPs-PTT (G2), CINPs anti-OX40 Ab (G3), anti-OX40 (G4) or PBS (G5). In each case, we assessed the efficacy of these groups against one another. The intratumor administration of all of the substances and therapies was performed. CINP-PTT anti-OX40 Ab and CINP anti-OX40 Ab (particularly CINP-PTT anti-OX40 Ab) induced significant tumor regression in treated (breast) and non-treated (flank) tumor, and completely inhibited lung metastasis, thereby inducing a higher survival rate in mice in comparison to CINP-PTT, anti-OX40 Ab, or PBS. This was the case because in CINPs-treated tumors, particularly those treated with CINPs-PTT, intratumoral injection of CINPs increased the frequency of OX40, CD8 double-positive T cells. CINPs improved the conversion of the macrophage phenotype from M2 to M1 in vitro, which is significant from an immunological point of view. In addition, anti-OX40 Ab combined with CINPs or, more specifically, CINPs-PPT produced a larger frequency of preexisting and newly formed tumor-specific CD8 T cells, as well as an enhanced frequency of CD8 T cells infiltrating non-treated tumors, in comparison to respective monotherapies. When the data were taken into consideration as a whole, it seemed that CINPs-based PTT may effectively enhance the antitumor response effectiveness of anti-OX40 Ab.

Weakly supervised semantic segmentation of histological tissue via attention accumulation and pixel-level contrast learning.

Effects of p450 Polymorphisms on the Clinical Outcomes of Gefitinib Treatment in Patients with Epidermal Growth Factor Receptor Mutation-Positive Non-Small Cell Lung Cancer.

Machine Learning and Real-World Data to Predict Lung Cancer Risk in Routine Care.

This study used machine learning to develop a 3-year lung cancer risk prediction model with large real-world data in a mostly younger population. Over 4.7 million individuals, aged 45-65 years with no history of any cancer or lung cancer screening, diagnostic, or treatment procedures, with an outpatient visit in 2013 were identified in the Optum® De-identified Electronic Health Record (EHR) Dataset. A Least Absolute Shrinkage and Selection Operator model was fit using all available data in the 365 days prior. Temporal validation was assessed with recent data. External validation was assessed with data from Mercy Health Systems EHR and Optum® De-Identified Clinformatics Data Mart. Racial inequities in model discrimination were assessed with xAUCs. The model AUC was 0.76. Top predictors included age, smoking, race, ethnicity, and diagnosis of chronic obstructive pulmonary disease. The model identified a high-risk group with lung cancer incidence 9 times the average cohort incidence, representing 10% of lung cancer patients. Model performed well temporally and externally, while performance was reduced for Asians and Hispanics. A high-dimensional model trained using big data identified a subset of patients with high lung cancer risk. The model demonstrated transportability to EHR and claims data, while underscoring the need to assess racial disparities when using machine learning methods. This internally and externally validated real-world data-based lung cancer prediction model is available on an open-source platform for broad sharing and application. Model integration into an EHR system could minimize physician burden by automating identification of high-risk patients.

Feasibility study of deep learning-based markerless real-time lung tumor tracking with orthogonal X-ray projection images.

The feasibility of a deep learning-based markerless real-time tumor tracking (RTTT) method was retrospectively studied with orthogonal kV X-ray images and clinical tracking records acquired during lung cancer treatment. Ten patients with lung cancer treated with marker-implanted RTTT were included. The prescription dose was 50 Gy in four fractions, using seven- to nine-port non-coplanar static beams. This corresponds to 14-18 X-ray tube angles for an orthogonal X-ray imaging system rotating with the gantry. All patients underwent 10 respiratory phases four-dimensional computed tomography. After a data augmentation approach, for each X-ray tube angle of a patient, 2250 digitally reconstructed radiograph (DRR) images with gross tumor volume (GTV) contour labeled were obtained. These images were adopted to train the patient and X-ray tube angle-specific GTV contour prediction model. During the testing, the model trained with DRR images predicted GTV contour on X-ray projection images acquired during treatment. The predicted three-dimensional (3D) positions of the GTV were calculated based on the centroids of the contours in the orthogonal images. The 3D positions of GTV determined by the marker-implanted RTTT during the treatment were considered as the ground truth. The 3D deviations between the prediction and the ground truth were calculated to evaluate the performance of the model. The median GTV volume and motion range were 7.42 (range, 1.18-25.74) cm The evaluation results and calculation efficiency show the proposed deep learning-based markerless RTTT method may be feasible for patients with lung cancer.

Circ-PGAM1 Enhances Matrine Resistance of Non-Small Cell Lung Cancer via the miR-326CXCR5 Axis.

Validation of a Deep Learning-Based Model to Predict Lung Cancer Risk Using Chest Radiographs and Electronic Medical Record Data.

Lung cancer screening with chest computed tomography (CT) prevents lung cancer death however, fewer than 5% of eligible Americans are screened. CXR-LC, an open-source deep learning tool that estimates lung cancer risk from existing chest radiograph images and commonly available electronic medical record (EMR) data, may enable automated identification of high-risk patients as a step toward improving lung cancer screening participation. To validate CXR-LC using EMR data to identify individuals at high-risk for lung cancer to complement 2022 US Centers for Medicare Medicaid Services (CMS) lung cancer screening eligibility guidelines. This prognostic study compared CXR-LC estimates with CMS screening guidelines using patient data from a large US hospital system. Included participants were persons who currently or formerly smoked cigarettes with an outpatient posterior-anterior chest radiograph between January 1, 2013, and December 31, 2014, with no history of lung cancer or screening CT. Data analysis was performed between May 2021 and June 2022. CXR-LC lung cancer screening eligibility (previously defined as having a 3.297% or greater 12-year risk) based on inputs (chest radiograph image, age, sex, and whether currently smoking) extracted from the EMR. 6-year incident lung cancer. A total of 14 737 persons were included in the study population (mean SD age, 62.6 6.8 years 7154 48.5% male 204 1.4% Asian, 1051 7.3% Black, 432 2.9% Hispanic, 12 330 85.2% White) with a 2.4% rate of incident lung cancer over 6 years (361 patients with cancer). CMS eligibility could be determined in 6277 patients (42.6%) using smoking pack-year and quit-date from the EMR. Patients eligible by both CXR-LC and 2022 CMS criteria had a high rate of lung cancer (83 of 974 patients 8.5%), higher than those eligible by 2022 CMS criteria alone (5 of 177 patients 2.8% P < .001). Patients eligible by CXR-LC but not 2022 CMS criteria also had a high 6-year incidence of lung cancer (121 of 3703 3.3%). In the 8460 cases (57.4%) where CMS eligibility was unknown, CXR-LC eligible patients had a 5-fold higher rate of lung cancer than ineligible (127 of 5177 2.5% vs 18 of 2283 0.5% P < .001). Similar results were found in subgroups, including female patients and Black persons. Using routine chest radiographs and other data automatically extracted from the EMR, CXR-LC identified high-risk individuals who may benefit from lung cancer screening CT.

The aim of this study was to assess the diagnostic value of gallium-68-prostate specific membrane antigen ( A comprehensive literature search of studies published before August 2021 in PubMed, Embase and Cochrane Library databases was conducted.The methodological quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 tool. Studies investigating the diagnostic value of Twenty-five articles using Gallium-68-PSMA PETCT demonstrated outstanding diagnostic performance for bone metastases in PCa patients. The majority of lymph node metastases, lung metastases, and liver metastases overexpressed PSMA, which could be directly detected. However, a considerable number of lesions were false negatives.

A comparative analysis of segmentectomy-aswere medicated withinsociated factors influencing bronchial tortuosity in early-stage left upper lung cancer.

Several studies of early-stage non-small cell lung cancer (NSCLC) have reported a notable therapeutic effect of segmentectomy. However, the secondary benefits of lung volume preservation remain unclear. This study aimed to investigate the potential benefits of segmentectomy, in terms of its impact on postoperative bronchial change. Patients who underwent left-sided upper lobectomy and upper division segmentectomy for pStage 0-IA2 NSCLC, were retrospectively analyzed. Degree of the left main bronchial deviation was measured by the curvature index (CI), determined using computed tomography. Variables, including CI value and postoperative rate of change in CI were compared for postoperative cough management the lobectomy and segmentectomy groups. Sixty-seven patients were reviewed. Thirty-seven and 30 patients underwent lobectomy and segmentectomy, respectively, without any significant differences in baseline and surgical variables. The 5-year overall survival rates in the lobectomy and segmentectomy groups were 86.7 and 95.2%, respectively (p 0.437). While there was no significant difference in postoperative complications, the rate of change in CI was significantly higher in the lobectomy group than in the segmentectomy group (113 vs. 106%, p 0.005). In addition, the analysis based on postoperative cough reveals the rate of change in CI to be significantly higher in patients requiring medical treatment (p 0.005). Conclusions Left upper division segmentectomy provides satisfactory treatment and relief of postoperative bronchial tortuosity. Our study suggests that there is a possibility the mitigation of environmental changes in the thoracic cavity may reduce symptoms, thus contributing to an improved quality of life.

FAT4 activation inhibits epithelial-mesenchymal transition (EMT) by promoting autophagy in H2228Cer cells.

As a tumor suppressor in lung cancer, FAT atypical cadherin 4 (FAT4) has a critical role in epithelial-mesenchymal transition (EMT). However, the role of FAT4 in ceritinib-resistant anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer (NSCLC) EMT has not been reported. It is necessary to discuss the role of FAT4 in this process and its potential mechanism of interaction. We found that the expression level of FAT4 was downregulated markedly in ceritinib-resistant NCI-H2228 (H2228Cer) cells. Jujuboside A, a FAT4 activator, diminished EMT and metastasis of H2228Cer cells. Importantly, autophagy inhibition inverted the inhibitory effect of FAT4 activation on EMT. Furthermore, we found the regulatory action of FAT4 on autophagy was related to proteasome 26S subunit ubiquitin receptor and non-ATPase 4 (PSMD4) and proteasome 20S subunit beta 4 (PSMB4), and the inhibitory effect of autophagy on EMT might be related to ROSNF-κBIκB-α and Wntβ-catenin pathways. In conclusion, FAT4 activation can inhibit the process of EMT in H2228Cer cells by promoting autophagy, which provides a potential target for ceritinib-resistant ALK positive NSCLC therapy.

Long-term safety profile of tirabrutinib final results of a Japanese Phase I study in patients with relapsed or refractory B-cell malignancies.

Tirabrutinib is a Brutons tyrosine kinase inhibitor for treating B-cell malignancies. We report the final results of a Phase I study of tirabrutinib in 17 Japanese patients with B-cell malignancies. Patients were administered tirabrutinib at a dose of 160 mg, 320 mg, or 480 mg once daily, or 300 mg twice daily (N 3, 3, 4, and 7, respectively). Three patients continued tirabrutinib until study completion (November 30, 2020). Adverse events (AEs) occurred in all 17 patients, with Grade 3-4 AEs in 8 (47.1%), serious AEs in 7 (41.2%), drug-related AEs in 16 (94.1%), and Grade 3-4 drug-related AEs in 6 (35.3%). Drug-related AEs reported in 3 or more patients were rash, vomiting, neutropenia, arthralgia, and malaise. One additional serious AE (benign neoplasm of the lung, unrelated to tirabrutinib) occurred after the previous data cutoff (January 4, 2018). Tirabrutinib administration and response assessment were continued for over 4 years in 4 patients. The overall response rate was 76.5% (1317 patients). The median (range) time to response and duration of response were 0.9 (0.9-5.9) months and 2.59 (0.08-5.45) years, respectively. These findings demonstrate the long-term safety and efficacy of tirabrutinib in Japanese patients with B-cell malignancies.Clinical trial registration JapicCTI-142682 ( httpwww.clinicaltrials.jp ).

Insights into pralsetinib resistance to the non-gatekeeper RET kinase G810C mutation through molecular dynamics simulations.

RET (rearranged during transfection) kinase, as a transmembrane receptor tyrosine kinase, is a therapeutic target for several human cancer such as non-small cell lung cancer (NSCLC) and thyroid cancer. Pralsetinib is a recently approved drug for the treatment of RET-driven NSCLC and thyroid cancers. A single point mutation G810C at the C-lobe of the RET kinase causes pralsetinib resistance to this non-gatekeeper variant. However, the detailed mechanism remains poorly understood. Here, multiple microsecond molecular dynamics (MD) simulations, molecular mechanicsgeneralized born surface area (MMGBSA) binding free energy calculations, and community network analysis were performed to reveal the mechanism of pralsetinib resistance to the RET G810C mutant. The simulations showed that the G810C mutation had a minor effect on the overall conformational dynamics of the RET kinase domain. Energetic analysis suggested that the G810C mutation reduced the binding affinity of pralsetinib to the mutant. Per-residue energy contribution and structural analyses revealed that the hydrogen bonding interactions between pralsetinib and the hinge residues Glu805 and Ala807 were disrupted in the G810C mutant, which were responsible for the decreased binding affinity of pralsetinib to the mutant. The obtained results may provide understanding of the mechanism of pralsetinib resistance to the non-gatekeeper RET G810C mutant.

Combined time-restricted feeding and cisplatin enhance the anti-tumor effects in cisplatin-resistant and -sensitive lung cancer cells.

Combination therapy as an important treatment option for lung cancer has been attracting attention due to the primary and acquired resistance of chemotherapeutic drugs in the clinical application. In the present study, as a new therapy strategy, concomitant treatment with time-restricted feeding (TRF) plus cisplatin (DDP) on lung cancer growth was investigated in DDP-resistant and DDP-sensitive lung cancer cells. We first found that TRF significantly enhanced the drug susceptibility of DDP in DDP-resistant A549 (A549DDP) cell line, illustrated by reversing the inhibitory concentration 50 (IC

High-Throughput Prediction of the Impact of Genetic Variability on Drug Sensitivity and Resistance Patterns for Clinically Relevant Epidermal Growth Factor Receptor Mutations from Atomistic Simulations.

Mutations in the kinase domain of the epidermal growth factor receptor (EGFR) can be drivers of cancer and also trigger drug resistance in patients receiving chemotherapy treatment based on kinase inhibitors.

Acid-Ionizable Iron Nanoadjuvant Augments STING Activation for Personalized Vaccination Immunotherapy of Cancer.

The critical challenge for cancer vaccine-induced T-cell immunity is the sustained activation of antigen cross-presentation in antigen-presenting cells (APCs) with innate immune stimulation. In this study, it is first discovered that the clinically used magnetic contrast agents, iron oxide nanoparticles (IONPs), markedly augment the type-I interferon (IFN-I) production profile of the stimulator of interferon genes (STING) agonist MSA-2 and achieve a 16-fold dosage-sparing effect in the human STING haplotype. Acid-ionizable copolymers are coassembled with IONPs and MSA-2 into iron nanoadjuvants to concentrate STING activation in the draining lymph nodes. The top candidate iron nanoadjuvant (PEIM) efficiently delivers the model antigen ovalbumin (OVA) to CD169 APCs and facilitates antigen cross-presentation to elicit a 55-fold greater frequency of antigen-specific CD8

Intake of local vegetables and decreased risk of mortality and cancer incidence in Amami island regions, Japan.

There is emerging scientific evidence of the health benefits of traditional food plants at both molecular and folk remedy levels however, epidemiological observations are limited. The Amami island region of Japan has a variety of unique traditions conserved till today, where a cohort study was conducted in 2005. The objective of this study was to investigate the associations between the intake of common and local vegetables and the risk of mortality and cancer incidence in Amami. Participants were enrolled from the general population of Amami as part of the Japan Multi-institutional Collaborative Cohort (J-MICC) Study. In total, 5,015 participants (2,053 men and 2,962 women) aged 35-69 years were enrolled in this study. They were followed up to obtain information on movement, death, and cancer incidence. The hazard ratios (HRs) and 95% CIs were estimated using the Cox proportional hazard model after adjusting for potential confounding factors. A significant inverse association was observed between cabbage intake and the HRs for overall mortality (p for trend0.046) and lung cancer incidence (p0.016). Intake of handama and togan as local vegetables was associated with decreased HRs for overall mortality (p0.019 and 0.036, respectively). While the molecular and biochemical reasoning and residual confounding factors behind this association remain unclear, the findings of this study suggest that the dietary lifestyle in Amami has a positive impact on the residents, which can significantly decrease mortality risk.

9th Immunotherapy of Cancer conference (ITOC) A meeting report.

The Immunotherapy of Cancer conference (ITOC) is an European meeting providing a global platform for discussions where all those dedicated to the immunotherapy of cancer can exchange their knowledge and the latest findings about immuno-oncology. The 9th ITOC was held in Munich in September 2022. Major highlights of the 2022 edition included the key note address and life time achievement to Laurence Zitvogel on her contributions on the understanding of the role of microbiota in cancer development and therapy resistance. Her research has paved the way for therapeutic exploitation of the microbiome.

PUNDIT Pulmonary nodule detection with image category transformation.

Convolutional neural networks (CNNs) have achieved great success in pulmonary nodules detection, which plays an important role in lung cancer screening. In this paper, we proposed a novel strategy for pulmonary nodule detection by learning it from a harder task, which was to transform nodule images into normal images. We named this strategy as pulmonary nodule detection with image category transformation (PUNDIT). There were two steps for nodules detection, nodule candidate detection and false positive (FP) reduction. In nodule candidate detection step, a segmentation-based framework was built for detection. We designed an image category transformation (ICT) task to translate nodule images into pixel-to-pixel normal images and share the information of detection and transformation tasks by multitask learning. As for references of transformation tasks, we proposed background consistency losses into standard cycle-consistent adversarial networks, which can solve the problem of background uncontrolled changing. A three-dimensional network was used in FP reduction step. PUNDIT was evaluated in two datasets, cancer screening dataset (CSD) with 1186 nodules for cross-validation and (CTD) with 3668 nodules for external test. Results were mainly evaluated by competition performance metric (CPM), the average sensitivity at seven predefined FP rates. The CPM was improved from 0.906 to 0.931 in CSD, and from 0.835 to 0.848 in CTD. Experimental results showed that PUNDIT can improve the performance of pulmonary nodules detection effectively.

Expression of autocrine motility factor receptor (AMFR) in human breast and lung invasive micropapillary carcinomas.

The aim of this study was to evaluate the clinicopathological significance of autocrine motility factor receptor (AMFR) expression in a variety of human invasive micropapillary carcinomas (IMPC). AMFR expression was compared in 111 samples of a variety of human IMPCs which had intrinsic non-micropapillary components and with 26 cases of control pulmonary adenocarcinoma (CPA, carcinoma without an IMPC component) by immunohistochemistry (IHC). In the 137 cases analysed, AMFR expression was significantly elevated in the IMPC components compared to the non-IMPC components (p .005) and normal tissues (p < .001). AMFR expression was also higher in the IMPC samples compared to their intrinsic non-IMPC components (p .0234). Between the 69 cases of lung IMPC and 26 cases of CPA, AMFR expression was notably higher in the IMPC components than in the CPA components (p .0455). However, there was no significant difference between the non-IMPC components in the lung and the CPA components (p .4584). Moreover, in breast cancer, elevated AMFR expression was not significantly correlated with mixed type or pure type IMPC (p .5969) or with age, gender, T stage, or lymph node metastasis (LNM). Between IMPC and CPA of the lung, there was no statistical significance in age, T stage, and LNM, where AMFR expression was higher in IMPC (p .0071). Thus this study demonstrated that AMFR was overexpressed in a variety of human IMPC components compared with non-micropapillary components. This suggests that AMFR expression is a potential new prognostic indicator for different types of human IMPC, which might thus be a new therapeutic target.

Deducing the Interplay Between Gut Flora and Respiratory Diseases A New Therapeutic Strategy

The gastrointestinal system, also referred to as the gut, is a universe that colonizes trillions of microbes. In addition to its digestive functions, the gut represents a biosystem that determines all the health vectors. It is now recognized as one of the bodys defense systems, and good gut health regulates the bodys immune responses. Disturbance of this barrier can trigger many diseases, including respiratory tract infections, as there is a close correlation between the gut microbiome and the chances of triggering illness. This review investigates the various factors affecting the gut microbiome, the diseases that can result from the dysregulation of the same, and their molecular mechanisms. The most basic solution to tackle this problem is to maintain the gut microbiome at the desired level. Timely diagnosis and interventions are needed for the proper management of the ensuing conditions. It is important to address the effects of factors on the gut microbiome and thereby regulate this level. The study also found that dysregulation in the system can lead to various diseases such as asthma, COPD, lung cancer following their respective pathways. In short, this paper reinforces the importance of the gut microbiome, the need to maintain its average level, and the need for proper interventions to treat the consequences. The manuscript posit that medications, diet as well and good physiological conditions of the human body can alter the microbiome and can ward off respiratory infections.

Capecitabine and Temozolomide (CAPTEM) in Advanced Neuroendocrine Neoplasms (NENs) A Systematic Review and Pooled Analysis.

Retrospective studies and single center experiences suggest a role of capecitabine combined with temozolomide (CAPTEM) in neuroendocrine tumors (NENs). We performed a systematic review to assess the efficacy and safety of CAPTEM in patients affected with NENs, with the aim to better clarify the role of this regimen in the therapeutic algorithm of NENs. A total of 42 articles and 1818 patients were included in our review. The overall disease control rate was 77% (range 43.5%-100%). The median progression free survival ranged from 4 to 38.5 months, while the median overall survival ranged from 8 to 103 months. Safety analysis showed an occurrence of G3-G4 toxicities in 16.4% of the entire population. The most common toxicities were hematological (27.2%), gastrointestinal (8.3%,) and cutaneous (3.2%). This systematic review demonstrated that CAPTEM was an effective and relatively safe treatment for patients with advanced well-moderate differentiated NENs of gastroenteropancreatic, lung and unknown origin.

Effect of the respiratory motion of pulmonary nodules on CT-guided percutaneous transthoracic needle biopsy.

Computed tomography (CT)-guided percutaneous transthoracic needle biopsy (PTNB) is highly affected by respiratory motion however, respiratory motion of target nodule during the PTNB and its effect on CT-guided lung biopsy have not been studied. To investigate the effect of the respiratory motion of pulmonary nodules on CT-guided PTNB. We retrospectively reviewed the procedural CT scans of 426 pulmonary nodules that underwent PTNB during quiet breathing. Maximal and average respiratory motions were measured using the difference of table position of the targeted nodule between multiple procedural scans. Diagnostic performance, complications, and technical factors of PTNB in nodules with large motion (maximal motion >1 cm) were compared with those in nodules with small motion (≤1 cm). The mean maximal and average respiratory motions between tidal volume breathing were 5.4 ± 4.4 and 2.7 ± 2.6 mm, respectively. Sensitivity and accuracy were 93.1% and 96.1% in nodules with large motion, compared with 94.7% and 95.9% in nodules with small motion, respectively. Respiratory targeting ( The respiratory motion of pulmonary nodules during CT-guided PTNB may cause technical difficulties but does not affect diagnostic performance nor complications associated with PTNB.

Thoracic surgery in the non-intubated spontaneously breathing patient.

The interest in non-intubated video-assisted thoracic surgery (NIVATS) has risen over the last decade and numerous terms have been used to describe this technique. They all have in common, that the surgical procedure is performed in a spontaneously breathing patient under locoregional anaesthesia in combination with intravenous sedation but have also been performed on awake patients without sedation. Evidence has been generated favouring NIVATS compared to one-lung-ventilation under general anaesthesia. We want to give an overview of how NIVATS is performed, and which different techniques are possible. We discuss advantages such as shorter length of hospital stay or (relative) contraindications like airway difficulties. Technical aspects, for instance intraoperative handling of the vagus nerve, are considered from a thoracic surgeons point of view. Furthermore, special attention is paid to the cohort of patients with interstitial lung diseases, who seem to benefit from NIVATS due to the avoidance of positive pressure ventilation. Whenever a new technique is introduced, it must prove noninferiority to the state of the art. Under this aspect current literature on NIVATS for lung cancer surgery has been reviewed. NIVATS technique may safely be applied to minor, moderate, and major thoracic procedures and is appropriate for a selected group of patients, especially in interstitial lung disease. However, prospective studies are urgently needed.

Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.

Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.

A novel glycosylation-related gene signature predicts survival in patients with lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is the most common malignant tumor that seriously affects human health. Previous studies have indicated that abnormal levels of glycosylation promote progression and poor prognosis of lung cancer. Thus, the present study aimed to explore the prognostic signature related to glycosyltransferases (GTs) for LUAD. The gene expression profiles were obtained from The Cancer Genome Atlas (TCGA) database, and GTs were obtained from the GlycomeDB database. Differentially expressed GTs-related genes (DGTs) were identified using edge package and Venn diagram. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and ingenuity pathway analysis (IPA) methods were used to investigate the biological processes of DGTs. Subsequently, Cox and Least Absolute Shrinkage and Selection Operator (LASSO) regression analyses were performed to construct a prognostic model for LUAD. Kaplan-Meier (K-M) analysis was adopted to explore the overall survival (OS) of LUAD patients. The accuracy and specificity of the prognostic model were evaluated by receiver operating characteristic analysis (ROC). In addition, single-sample gene set enrichment analysis (ssGSEA) algorithm was used to analyze the infiltrating immune cells in the tumor environment. A total of 48 DGTs were mainly enriched in the processes of glycosylation, glycoprotein biosynthetic process, glycosphingolipid biosynthesis-lacto and neolacto series, and cell-mediated immune response. Furthermore, B3GNT3, MFNG, GYLTL1B, ALG3, and GALNT13 were screened as prognostic genes to construct a risk model for LUAD, and the LUAD patients were divided into high- and low-risk groups. K-M curve suggested that patients with a high-risk score had shorter OS than those with a low-risk score. The ROC analysis demonstrated that the risk model efficiently diagnoses LUAD. Additionally, the proportion of infiltrating aDCs (p < 0.05) and Tgds (p < 0.01) was higher in the high-risk group than in the low-risk group. Spearmans correlation analysis manifested that the prognostic genes (MFNG and ALG3) were significantly correlated with infiltrating immune cells. In summary, this study established a novel GTs-related risk model for the prognosis of LUAD patients, providing new therapeutic targets for LUAD. However, the biological role of glycosylation-related genes in LUAD needs to be explored further.

Novel immunogenic cell death-related risk signature to predict prognosis and immune microenvironment in lung adenocarcinoma.

Immunogenic cell death (ICD) is a type of regulated cell death (RCD) which was discovered to activate adaptive immunity. To date, the effect of ICD on lung adenocarcinoma (LUAD) remains unclear. In this research, we will study the role of ICD-related genes (ICDG) in LUAD. RNA sequencing and clinical data were gathered from TCGA-LUAD cohorts and GEO database. Using unsupervised cluster analysis, three clusters were identified with distinctive immune characteristics and significant overall survival based on 18 ICDG. Using LASSO Cox regression, three genes were identified and used to construct the prognosis signature. The association between the 3-ICDG risk signature and immune microenvironment analysis, somatic mutation, and enriched molecular pathways was investigated. Consensus clustering separated the LUAD samples into three clusters (ICDcluster A, B and C), and ICDcluster B had the best prognosis. Different TME cell infiltration characteristics and biological behavior were found in three ICD clusters. Prognostic risk model was contrasted based on the 3 best prognostic ICD-related genes. Subsequently, vitro experiments verified the above analysis results. The high-risk group showed a poor prognosis and enrichment of cancer promoting signal pathway. Multivariate analysis indicated that this 3-ICDG prognostic model might be an accurate prediction parameter for LUAD. Moreover, conducting immune related analysis, we found that the 3-ICDG risk signature was characterized by an immune-active subtype on account of the high infiltration of immune-active cells. This study expands our cognition of ICD in LUAD microenvironment, excavated prognostic biomarkers, and provided potential value for guiding immunotherapy and chemotherapy.

Data-Driven Identification of Targets for Fluorescence-Guided Surgery in Non-Small Cell Lung Cancer.

Intraoperative identification of lung tumors can be challenging. Tumor-targeted fluorescence-guided surgery can provide surgeons with a tool for real-time intraoperative tumor detection. This study evaluated cell surface biomarkers, partially selected via data-driven selection software, as potential targets for fluorescence-guided surgery in non-small cell lung cancers adenocarcinomas (ADC), adenocarcinomas in situ (AIS), and squamous cell carcinomas (SCC). Formalin-fixed paraffin-embedded tissue slides of resection specimens from 15 patients with ADC and 15 patients with SCC were used and compared to healthy tissue. Molecular targets were selected based on two strategies (1) a data-driven selection using > 275 multi-omics databases, literature, and experimental evidence and (2) the availability of a fluorescent targeting ligand in advanced stages of clinical development. The selected targets were carbonic anhydrase 9 (CAIX), collagen type XVII alpha 1 chain (collagen XVII), glucose transporter 1 (GLUT1), G protein-coupled receptor 87 (GPR87), transmembrane protease serine 4 (TMPRSS4), carcinoembryonic antigen (CEA), epithelial cell adhesion molecule (EpCAM), folate receptor alpha (FRα), integrin αvβ6 (αvβ6), and urokinase-type plasminogen activator receptor (uPAR). Tumor expression of these targets was assessed by immunohistochemical staining. A total immunostaining score (TIS, range 0-12), combining the percentage and intensity of stained cells, was calculated. The most promising targets in ADC were explored in six AIS tissue slides to explore its potential in non-palpable lesions. Statistically significant differences in TIS between healthy lung and tumor tissue for ADC samples were found for CEA, EpCAM, FRα, αvβ6, CAIX, collagen XVII, GLUT-1, and TMPRSS4, and of these, CEA, CAIX, and collagen XVII were also found in AIS. For SCC, EpCAM, uPAR, CAIX, collagen XVII, and GLUT-1 were found to be overexpressed. EpCAM, CAIX, and Collagen XVII were identified using concomitant use of data-driven selection software and clinical evidence as promising targets for intraoperative fluorescence imaging for both major subtypes of non-small cell lung carcinomas.

Volumetric parameters of the primary tumor and whole-body tumor burden derived from baseline

Metabolic tumor volume (MTV) and total lesion glycolysis (TLG) are volumetric parameters derived from Thirty biopsy-proven NSCLC patients who had not begun anti-tumor therapy were included in this prospective study. A baseline At a median follow-up of 22.73 months, the mean OS was shorter among patients with higher tu MTV and tu TLG and high WBTB. High WB TLG was independently associated with the risk of death (p < 0.025). Other parameters, e.g., SUV In patients with NSCLC, tu MTV, tu TLG, and WBTB determined on initial staging

TLR3 stimulation improves the migratory potency of adipose-derived mesenchymal stem cells through the stress response pathway in the melanoma mouse model.

Mesenchymal stem cells (MSCs) are utilized as a carrier of anti-tumor agents in targeted anti-cancer therapy. Despite the improvements in this area, there are still some unsolved issues in determining the appropriate dose, method of administration and biodistribution of MSCs. The current study aimed to determine the influence of toll-like receptor 3 (TLR3) stimulation on the potential of MSCs migration to the neoplasm environment in the mouse melanoma model. Adipose-derived MSCs (ADMSCs) were isolated from the GFP This research identified that TLR3 activation might improve the migration via the stimulation of stress response in the cells and depending on the agonist concentration and time exposure, this activated pathway drives the migratory behavior of MSCs.

HPV status represents dominant trait driving delineation of survival-associated gene co-expression networks in head and neck cancer.

Integration of high-dimensional tumor gene expression data with clinicopathological data can increase our understanding of disease diversity, enable retrospective patient stratification, and identify new potential biomarkers and therapeutic targets. Using a systems biology approach, we provide a holistic overview of gene co-expression networks in head and neck squamous cell carcinomas (HNSCC). Weighted gene co-expression network analysis of HNSCC RNA sequencing data from 519 patients from The Cancer Genome Atlas (TCGA) was used to determine correlates of 5-year survival, using regression tree-based optimal threshold calculations. Survival-associated gene sets were transformed to gene set scores that were assessed for correlation with clinicopathological data. We identified 8 gene co-expression modules for HNSCC tumors, each of which contained co-expressed genes associated significantly with 5-year survival. Survival-associated co-expression gene signatures correlated dominantly with tumor HPV and p16 status. Network analysis identified that survival was associated with signaling networks of infection, immunity, epithelial-mesenchymal transition (EMT), hypoxia, glycolysis, focal adhesion, extracellular matrix, MYC signaling, autophagy and transcriptional regulation. EMT-associated gene signatures were expressed dominantly in fibroblasts, and cancer-associated fibroblasts were inversely correlated with immune activity. Interestingly, a high Immune Suppression Score based on expression of 21 genes associated with immune inhibition and including immune checkpoints, cytokines and regulatory T cell factors, was also associated with increased survival probability, and was significantly higher in HPV HNSCC. Networks associated with HNSCC survival were further associated with survival in cervical cancer, melanoma and lung cancer. This study defines 5129 genes associated with HNSCC survival, organized into co-expressed networks, their correlation with clinicopathological data, and with gene expression data from other malignant diseases, and provides a source for the discovery of biomarkers and novel therapies for HNSCC.

Similar programmed death ligand 1 (PD-L1) expression profile in patients with mild COPD and lung cancer.

Programmed Death Ligand 1 (PD-L1) is crucial in regulating the immunological tolerance in non-small cell lung cancer (NSCLC). Alveolar macrophage (AM)-derived PD-L1 binds to its receptor, PD-1, on surveilling lymphocytes, leading to lymphocyte exhaustion. Increased PD-L1 expression is associated with cigarette smoke (CS)-exposure. However, the PD-L1 role in CS-associated lung diseases associated with NSCLC, such as chronic obstructive pulmonary disease (COPD), is still unclear. In two different cohorts of ever smokers with COPD or NSCLC, and ever and never smoker controls, we evaluated PD-L1 expression (1) via cutting-edge digital spatial proteomic and transcriptomic profiling (Geomx) of formalin-fixed paraffin-embedded (FFPE) lung tissue sections (n 19) and (2) via triple immunofluorescence staining of bronchoalveolar lavage (BAL) AMs (n 83). PD-L1 mRNA expression was also quantified in BAL AMs exposed to CS extract. PD-L1 expression was increased in the bronchiolar wall, parenchyma, and vascular wall from mild-moderate (GOLD 1-2) COPD patients compared to severe-very severe (GOLD 3-4) COPD patients and controls. Within all the COPD patients, PD-L1 protein expression was associated with upregulation of genes involved in tumor progression and downregulation of oncosuppressive genes, and strongly directly correlated with the FEV

Hemodiafiltration combined with polymyxin B-immobilized fiber column direct hemoperfusion is effective for acute postoperative exacerbation of interstitial pneumonia a case report.

Postoperative acute exacerbation of interstitial pneumonia has a high mortality rate however, its treatment methods have not been standardized. A 72-year-old man with rheumatoid arthritis developed acute respiratory failure about 3 weeks after lung cancer surgery. There were increased diffuse frosted shadows in both lung fields. His condition was diagnosed as an acute exacerbation of interstitial pneumonia associated with rheumatoid arthritis, and he was started on steroid pulse therapy however, his respiratory condition deteriorated. He was urgently intubated and started on veno-venous extracorporeal membrane oxygenation. Further, intensive care, including blood purification therapy, was initiated. The blood purification therapy comprised a combination of hemodiafiltration and 6-h polymyxin B-immobilized fiber column direct hemoperfusion. The patient was weaned off veno-venous extracorporeal membrane oxygenation, extubated, and discharged from the intensive care unit on the ninth day. Blood purification therapy was effective for acute exacerbation of interstitial pneumonia.

The landscape of therapeutic vulnerabilities in EGFR inhibitor osimertinib drug tolerant persister cells.

Third-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs), including osimertinib, an irreversible EGFR-TKI, are important treatments for non-small cell lung cancer with EGFR-TKI sensitizing or EGFR T790M resistance mutations. While patients treated with osimertinib show clinical benefit, disease progression and drug resistance are common. Emergence of de novo acquired resistance from a drug tolerant persister (DTP) cell population is one mechanism proposed to explain progression on osimertinib and other targeted cancer therapies. Here we profiled osimertinib DTPs using RNA-seq and ATAC-seq to characterize the features of these cells and performed drug screens to identify therapeutic vulnerabilities. We identified several vulnerabilities in osimertinib DTPs that were common across models, including sensitivity to MEK, AURKB, BRD4, and TEAD inhibition. We linked several of these vulnerabilities to gene regulatory changes, for example, TEAD vulnerability was consistent with evidence of Hippo pathway turning off in osimertinib DTPs. Last, we used genetic approaches using siRNA knockdown or CRISPR knockout to validate AURKB, BRD4, and TEAD as the direct targets responsible for the vulnerabilities observed in the drug screen.

4EBP1 senses extracellular glucose deprivation and initiates cell death signaling in lung cancer.

Nutrient-limiting conditions are common during cancer development. The coordination of cellular glucose levels and cell survival is a fundamental question in cell biology and has not been completely understood. 4EBP1 is known as a translational repressor to regulate cell proliferation and survival by controlling translation initiation, however, whether 4EBP1 could participate in tumor survival by other mechanism except for translational repression function, especially under glucose starvation conditions remains unknown. Here, we found that protein levels of 4EBP1 was up-regulated in the central region of the tumor which always suffered nutrient deprivation compared with the peripheral region. We further discovered that 4EBP1 was dephosphorylated by PTPMT1 under glucose starvation conditions, which prevented 4EBP1 from being targeted for ubiquitin-mediated proteasomal degradation by HERC5. After that, 4EBP1 translocated to cytoplasm and interacted with STAT3 by competing with JAK and ERK, leading to the inactivation of STAT3 in the cytoplasm, resulting in apoptosis under glucose withdrawal conditions. Moreover, 4EBP1 knockdown increased the tumor volume and weight in xenograft models by inhibiting apoptosis in the central region of tumor. These findings highlight a novel mechanism for 4EBP1 as a new cellular glucose sensor in regulating cancer cell death under glucose deprivation conditions, which was different from its classical function as a translational repressor.

PRSS2 remodels the tumor microenvironment via repression of Tsp1 to stimulate tumor growth and progression.

The progression of cancer from localized to metastatic disease is the primary cause of morbidity and mortality. The interplay between the tumor and its microenvironment is the key driver in this process of tumor progression. In order for tumors to progress and metastasize they must reprogram the cells that make up the microenvironment to promote tumor growth and suppress endogenous defense systems, such as the immune and inflammatory response. We have previously demonstrated that stimulation of Tsp-1 in the tumor microenvironment (TME) potently inhibits tumor growth and progression. Here, we identify a novel tumor-mediated mechanism that represses the expression of Tsp-1 in the TME via secretion of the serine protease PRSS2. We demonstrate that PRSS2 represses Tsp-1, not via its enzymatic activity, but by binding to low-density lipoprotein receptor-related protein 1 (LRP1). These findings describe a hitherto undescribed activity for PRSS2 through binding to LRP1 and represent a potential therapeutic strategy to treat cancer by blocking the PRSS2-mediated repression of Tsp-1. Based on the ability of PRSS2 to reprogram the tumor microenvironment, this discovery could lead to the development of therapeutic agents that are indication agnostic.