Background
CT scans are used in routine clinical practice for the diagnosis and treatment surveillance of non‐small cell lung cancer (NSCLC). However, more sensitive methods are desirable. Liquid ...biopsy analyses of RNA and DNA can offer more sensitive diagnostic approaches. Cell‐free RNA (cfRNA) has been described in several malignancies, but its clinical utility has not previously been explored.
Methods
We evaluated the clinical utility of cfRNA for early detection and surveillance of tumor disease in a proof‐of‐concept study. Using real‐time‐droplet digital polymerase chain reaction we characterized a candidate transcript (MORF4L2) in plasma samples from 41 advanced stage, 38 early stage NSCLC and 39 healthy samples. We compared its diagnostic performance with tumor markers and evaluated its utility for disease monitoring.
Results
MORF4L2 cfRNA was more abundant in patients than in healthy donors (p < 0.0001). Using the Youden index approach (cutoff value of 537 copies/ml was established) with a sensitivity of 0.73 (95% CI: 0.61–0.82) and a specificity of 0.87 (95% CI: 0.73–0.96). Positive and negative predictive values of 0.92 (95% CI: 0.83–0.95) and 0.59 (95% CI: 0.47–0.83) were achieved. Combination of cfRNA and Cyfra21‐1 improved its predictive value from 89.5% to 94.7%. Low baseline MORF4L2 levels were associated with better overall survival (HR:0.25, 95% CI: 0.09–0.7, p = 0.009) and progression‐free survival for patients treated with tyrosine kinase inhibitors (p = 0.011) and chemotherapy (p = 0.019). MORF4L2 profile between baseline and follow‐up mirrored radiological response and tumor dynamics better than tumor markers. cfRNA transcripts allowed monitoring tumor dynamics in patients without tumor‐reported genetic alterations.
Conclusion
Our data support clinical utility of cfRNA for detection and surveillance of NSCLC. Further studies with larger cohorts are required.
A substantial amount of cell‐free RNA(cfRNA) encountered in blood is free, circulating and not carried in extracellular vesicles. Combining cfRNA with the tumor marker CYFRA21‐1 improves its diagnostic strength and could allow for early detection of NSCLC and monitoring of treatment response. High plasma levels of the cfRNA transcript MORF4L2 were associated with poor overall survival.
KRAS is one of the most commonly mutated oncogene and a negative predictive factor for a number of targeted therapies. Therefore, the development of targeting strategies against mutant KRAS is ...urgently needed. One potential strategy involves disruption of K-Ras membrane localization, which is necessary for its proper function. In this review, we summarize the current data about the importance of membrane-anchorage of K-Ras and provide a critical evaluation of this targeting paradigm focusing mainly on prenylation inhibition. Additionally, we performed a RAS mutation-specific analysis of prenylation-related drug sensitivity data from a publicly available database (
https://depmap.org/repurposing/
) of three classes of prenylation inhibitors: statins, N-bisphosphonates, and farnesyl-transferase inhibitors. We observed significant differences in sensitivity to N-bisphosphonates and farnesyl-transferase inhibitors depending on KRAS mutational status and tissue of origin. These observations emphasize the importance of factors affecting efficacy of prenylation inhibition, like distinct features of different KRAS mutations, tissue-specific mutational patterns, K-Ras turnover, and changes in regulation of prenylation process. Finally, we enlist the factors that might be responsible for the large discrepancy between the outcomes in preclinical and clinical studies including methodological pitfalls, the incomplete understanding of K-Ras protein turnover, and the variation of KRAS dependency in KRAS mutant tumors.
Prolonged air leak (PAL) after pulmonary resection is one if the most common complications in thoracic surgery. The dataset was obtained from a prospective randomized study investigating autologous ...blood patch pleurodesis in PAL. Patients were randomized to either receiving 100 ml autologous blood injected at postoperative days five and six (group A) or to watchful waiting (group B). The primary and secondary endpoints focused on differences in the duration of PAL in each group and possible complications. The results were reported in The Journal of Surgical Research. In this Data in Brief article, we provide additional data concerning pain medication and pain score during the first ten postoperative days. This should provide additional insights into the trial.
Gasoline-like hydrocarbon products obtained from the distillation of different pyrolysis oils produced from solid wastes of polypropylene (PP), polystyrene (PS), polyethylene (PE), and their blends ...were investigated as these materials together form a good candidate for providing gasoline with properties approaching or fulfilling standard requirements in various countries. A laboratory-scale batch reactor equipped with reflux was used in this research, while the gasoline fractions of pyrolysis oils processed by distillation were further analyzed by GC-MS. Fuel density, volatility, distillation curves, olefin content, aromatics (including benzene) content, and oxygenates were analyzed, and various scenarios were proposed for reaching standard quality. The results were compared to a commercial gasoline sample from Hungary. It was found that the gasoline-like product of low-density PE (LDPE) and high-density PE (HDPE) showed the most similarities to standard requirements regarding molecular distribution. The PS produced mainly aromatics, while the gasoline yield of PP contained 53.5 vol% 2,4-dimethyl-1-heptene, which severely affects the distillation requirements presented by gasoline fuel standards. The results show that the mass ratio of plastic materials used in the pyrolysis process can heavily influence the oil products’ applicability as a transportation fuel. The optimal plastic waste mixture combined with the saturation of the olefin content by catalytic hydrogenation can provide standard-quality gasoline.
Prolonged air leaks (PALs) after lung resection are one of the most common complications in thoracic surgery. Several options are available to treat PALs. The autologous blood patch pleurodesis is ...commonly used but has not been thoroughly investigated.
We conducted a prospective randomized study including all consecutive patients with PALs after pulmonary resections. Patients were randomized to either having received pleurodesis by injecting 100 mL autologous blood at d 5 and 6 (Group A) or being placed under observation (Group B). Patients from either group undergoing revisions were further investigated by a post hoc analysis and formed Group C.
A total of 24 patients were included: 10 patients were randomized to group A and 14 to group B. Six patients (3 from each group) underwent surgical revision and were included in Group C. Groups A and B did not differ in baseline characteristics. The median time to drainage removal was 9 d (range: 5-23 d) in Group A; 9 d (range: 2-20 d) in Group B; and 6 d in Group C (range: 3-10 d), (A/B versus C, P < 0.04; A versus B was not significant).
There is no evidence indicating a benefit for blood patch pleurodeses in patients undergoing lung resections and presenting with postoperative PALs for more than 5 d. An early operative closure of postoperative air leakage seems to be more effective.
PMCA4 is a critical regulator of Ca
homeostasis in mammalian cells. While its biological and prognostic relevance in several cancer types has already been demonstrated, only preclinical ...investigations suggested a metastasis suppressor function in melanoma. Therefore, we studied the expression pattern of PMCA4 in human skin, nevus, as well as in primary and metastatic melanoma using immunohistochemistry. Furthermore, we analyzed the prognostic power of PMCA4 mRNA levels in cutaneous melanoma both at the non-metastatic stage as well as after PD-1 blockade in advanced disease. PMCA4 localizes to the plasma membrane in a differentiation dependent manner in human skin and mucosa, while nevus cells showed no plasma membrane staining. In contrast, primary cutaneous, choroidal and conjunctival melanoma cells showed specific plasma membrane localization of PMCA4 with a wide range of intensities. Analyzing the TCGA cohort, PMCA4 mRNA levels showed a gender specific prognostic impact in stage I-III melanoma. Female patients with high transcript levels had a significantly longer progression-free survival. Melanoma cell specific PMCA4 protein expression is associated with anaplasticity in melanoma lung metastasis but had no impact on survival after lung metastasectomy. Importantly, high PMCA4 transcript levels derived from RNA-seq of cutaneous melanoma are associated with significantly longer overall survival after PD-1 blockade. In summary, we demonstrated that human melanoma cells express PMCA4 and PMCA4 transcript levels carry prognostic information in a gender specific manner.
Resection of the bulk of a tumour often cannot eliminate all cancer cells, due to their infiltration into the surrounding healthy tissue. This may lead to recurrence of the tumour at a later time. We ...use a reaction-diffusion equation based model of tumour growth to investigate how the invasion front is delayed by resection, and how this depends on the density and behaviour of the remaining cancer cells. We show that the delay time is highly sensitive to qualitative details of the proliferation dynamics of the cancer cell population. The typically assumed logistic type proliferation leads to unrealistic results, predicting immediate recurrence. We find that in glioblastoma cell cultures the cell proliferation rate is an increasing function of the density at small cell densities. Our analysis suggests that cooperative behaviour of cancer cells, analogous to the Allee effect in ecology, can play a critical role in determining the time until tumour recurrence.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•Preoperative CT is the most important tool for planning surgical resection extent•CT interpretation by surgeons was adequate in 70 % for the best interpreter•Adequacy of CT interpretation strongly ...depends on interpreters’ experience•Residents did less accurately interpret preoperative CTs than attending surgeons
Preoperative planning of lung resection extent is decisive for preoperative functional work-up and selection for multimodal treatment. It is mainly based on preoperative chest CT. We aimed at evaluating chest CT adequacy to predict the extent of lung resection and hypothesized a relation with CT interpreters’ level of experience.
A pseudonymized CT library was built from patients who had curative intent lung resection for centrally located NSCLC. CT library was interpreted by 20 thoracic surgery residents or attendings. Interpreters were blinded to intraoperative findings and scored one point when lung resection was adequately planned. Points were summed up in a score from 0 to 20. Interpreters’ experience was evaluated through nine variables: age, position (resident vs. attending), years of experience in evaluating chest CTs, number of anatomic resections and sleeve resections attended as first assistant or performed as surgeon in presence of a teaching assistant or as main surgeon/teaching assistant.
Variables characterizing interpreters’ experience were divided into equal sized groups. Independent sample T-test and one-way ANOVA/Tukey post hoc tests were used to compare scores between groups.
CT library included 20 patients. Lung resections were lobectomy (n = 7, 35 %), sleeve lobectomy (n = 10, 50 %), sleeve bilobectomy (n = 2, 10 %), pneumonectomy (n = 1, 5%). Twenty interpreters scored a median of 10 (4–14). Attending surgeons had significantly higher mean scores (11.2 ± 1.3) compared to residents (7.7 ± 2.3, p = 0.001). All scores were significantly different between groups related to interpreters’ levels of experience, except for interpreters’age.
Preoperative CT evaluation for predicting intraoperative lung resection for centrally located NSCLC strongly depends on interpreters’ experience.
No tyrosine kinase inhibitors are approved for malignant pleural mesothelioma (MPM). Preclinical studies identified focal adhesion kinase (FAK) as a target in MPM. Accordingly, we assessed the novel, ...highly selective FAK inhibitor (BI 853520) in 2D and 3D cultures and in vivo. IC
50
values were measured by adherent cell viability assay. Cell migration and 3D growth were quantified by video microscopy and spheroid formation, respectively. Phosphorylation of FAK, Akt, S6, and Erk was measured by immunoblot. The mRNA expression of the putative tumor stem cell markers SOX2, Nanog, CD44, ALDH1, c-myc, and Oct4 was analyzed by qPCR. Cell proliferation, apoptosis, and tumor tissue microvessel density (MVD) were investigated in orthotopic MPM xenografts. In all 12 MPM cell lines, IC
50
exceeded 5 μM and loss of NF2 did not correlate with sensitivity. No synergism was found with cisplatin in adherent cells. BI 853520 decreased migration in 3 out of 4 cell lines. FAK phosphorylation was reduced upon treatment but activation of Erk, Akt, or S6 remained unaffected. Nevertheless, BI 853520 inhibited spheroid growth and significantly reduced tumor weight, cell proliferation, and MVD in vivo. BI 853520 has limited effect in adherent cultures but demonstrates potent activity in spheroids and in orthotopic tumors in vivo. Based on our findings, further studies are warranted to explore the clinical utility of BI 853520 in human MPM.
Key messages
Response to FAK inhibition in MPM is independent of NF2 expression or histotype.
FAK inhibition strongly interfered with MPM spheroid formation.
BI 853520 has been shown to exert anti-tumor effect in MPM.
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