Prediction of Tumor PD-L1 Expression in Resectable Non-Small Cell Lung Cancer by Machine Learning Models Based on Clinical and Radiological Features: Performance Comparison With Preoperative Biopsy.

OBJECTIVE: We investigated if PD-L1 expression can be predicted by machine learning using clinical and imaging features. METHODS: We included 117 patients with c-stage I/II non-small cell lung cancer who underwent radical resection. A total of 3951 radiomic features were extracted by defining the tumor (within tumor contour), rim (contour ±3 mm) and exterior (contour +10 mm) on preoperative contrast computed tomography. After feature selection by Boruta algorithm, prediction models of tumor PD-L1 expression (22C3: ≥1%, <1%) of resected specimens were constructed using Random Forest: radiomics, clinical, and combined models. Their performance was evaluated by 5-fold cross-validation, and AUCs were compared using Delong test. Next, study groups were categorized as patients without biopsy (training set), and those with biopsy (test set). Predictive ability of biopsy was compared to each prediction model. RESULTS: Of 117 patients (66 ± 10 years old, 48% male), 33 (28.2%) had PD-L1≥1%. Mean AUC of PD-L1≥1% for the validation set in radiomics, clinical, and combined models were 0.80, 0.80, and 0.83 (P = .32 vs. clinical model), respectively. The diagnosis of malignancy was made in 22 of 38 (58%) patients with attempted biopsies, and PD-L1 was measurable in 19 of 38 (50%) patients. Diagnostic accuracies of PD-L1≥1% from 19 determinable biopsies and 38 all attempted biopsies were 0.68 and 0.34, respectively. These were out performed by machine learning: 0.71, 0.71, and 0.74 for radiomics, clinical, and combined models, respectively. CONCLUSIONS: Our machine learning could be an adjunctive tool in estimating PD-L1 expression prior to neoadjuvant treatment, particularly when PD-L1 is indeterminable with biopsy.

Detection of EGFR mutations in early-stage lung adenocarcinoma by machine learning-based radiomics.

Background: We hypothesized that epidermal growth factor receptor (EGFR) mutations could be detected in early-stage lung adenocarcinoma using radiomics. Methods: This retrospective study included consecutive patients with clinical stage I/II lung adenocarcinoma who underwent curative-intent pulmonary resection from March-December 2016. Using preoperative enhanced chest computed tomography, 3,951 radiomic features were extracted in total from the tumor (area within the tumor boundary), tumor rim (area within ±3 mm of the tumor boundary), and tumor exterior (area between +10 mm outside the tumor and tumor boundary). A machine learning-based radiomics model was constructed to detect EGFR mutations. The combined model incorporated both radiomic and clinical features (gender and smoking history). The performance was validated with five-fold cross-validation and evaluated using the mean area under the curve (AUC). Results: Of 99 patients (mean age, 66±11 years; female, 66.6%; clinical stage I/II, 89.9%/10.1%), EGFR mutations in the surgical specimen were detected in 46 (46.5%). A median of 4 (range, 2 to 8) radiomic features was selected for each validation session. The mean AUCs in the radiomics and combined models were 0.75 and 0.83, respectively. The two top-ranked features in the combined model were the radiomic features extracted from the tumor exterior and the tumor, indicating a higher impact of radiomic features over relevant clinical features. Conclusions: Radiomic features, including those in the peri-tumoral area, may help detect EGFR mutations in lung adenocarcinomas in preoperative settings. This non-invasive image-based technology could help guide future precision neoadjuvant therapy.

Morphometric assessment of blastocysts: relationship with the ongoing pregnancy rate.

Objective: To explore a morphometric grading system for blastocysts that is associated with ongoing pregnancy. Design: Cross-sectional study. Setting: None. Patientss: All consecutive vitrified blastocysts at our center from July 2018 to November 2021 that were transferred in single blastocyst transfer cycles until January 2022. Interventions: None. Main Outcome Measures: The ongoing pregnancy rate after a single vitrified-warmed blastocyst transfer. Interobserver agreement on morphometric values among embryologists. Results: Three morphometric variables (blastocyst diameter, area of inner cell mass [ICM], and the estimated trophectoderm cell count) were used to evaluate the expansion, ICM, and trophectoderm morphology. During the study period, 585 blastocysts were involved in this study. Of the 3 morphometric variables, ICM area (per 500 µm2, adjusted odds ratio, 1.19; 95% confidence interval, 1.09-1.30) and estimated trophectoderm cell count (per 10 cells, adjusted odds ratio, 1.25; 95% confidence interval, 1.12-1.39) were significantly associated with the ongoing pregnancy rate after adjustment for confounding factors. The ongoing pregnancy rate was 2.0% (1/49) with an ICM area of <2,500 µm2 and the estimated trophectoderm cell count <70. The ongoing pregnancy rate reached 47.8% (22/46) when the ICM area and the estimated trophectoderm cell count were >3,500 µm2 and >110, respectively. Interobserver agreement on the blastocyst diameter, ICM area, and the estimated trophectoderm cell count was excellent-to-good among 5 embryologists (intraclass correlation coefficients: 0.99, 0.87, and 0.91, respectively). Conclusions: Morphometric values of ICM and trophectoderm are promising predictors of pregnancy success. The high reproducibility suggests that the morphometric variables will contribute to identifying blastocysts with the highest developmental potential as well as those that will not result in a successful pregnancy.

Discovery of two novel ALKBH5 selective inhibitors that exhibit uncompetitive or competitive type and suppress the growth activity of glioblastoma multiforme.

A group of RNA methylation enzymes is currently of interest as a new target for cancer therapy. Alpha-ketoglutarate-dependent dioxygenase B (AlkB) homolog 5 (ALKBH5) is an N6 -methyladenosine (m6 A) demethylation enzyme, and by high-throughput screening from pure small molecule compounds, we identified two novel inhibitors, Ena15 and Ena21, against it. Each compound showed either uncompetitive or competitive inhibition for 2-oxoglutarate (2OG). In addition, Ena21 had little inhibitory activity for fat mass and obesity-associated protein (FTO), which is another N6 -methyladenosine demethylation enzyme, while Ena15 enhanced the demethylase activity of FTO. The predicted binding poses of both compounds with the crystal structure of ALKBH5 (PDB ID: 4NRO) were comparable with these observations pertaining to the interaction of the 2OG catalytic site in this enzyme kinetics. Furthermore, either knockdown of ALKBH5 or inhibition with Ena15 or Ena21 inhibited cell proliferation of glioblastoma multiforme-derived cell lines, decreased cell population in the synthesis phase of the cell cycle, increased m6 A RNA level, and stabilized FOXM1 mRNA. Based on these results, Ena15 and Ena21 were found to be potential candidates that might help in further research into the biological function of ALKBH5.

Double renal cell carcinoma with histological type of clear cell carcinoma and papillary carcinoma in the same kidney concurrently treated with robot-assisted partial nephrectomy.

INTRODUCTION: The presence of two different histologic types of renal cell carcinoma in the same kidney is rare in clinical practice. This report describes a patient with ipsilateral renal cell carcinomas, consisting of a clear cell renal cell carcinoma and a papillary type 1 renal cell carcinoma, who was successfully treated by robot-assisted partial nephrectomy. CASE PRESENTATION: A 70-year man was referred to our hospital for the treatment of two right mid-pole renal tumors, measuring 51 mm and 31 mm in diameter. The two tumors, which differed in contrast enhancement on computed tomography, were removed simultaneously by robot-assisted partial nephrectomy. Histopathological and immunohistochemical findings confirmed that one tumor was a clear cell renal cell carcinoma, pT1a, and the other was a papillary type1 renal cell carcinoma, pT1b. CONCLUSION: This report describes a rare patient presenting with two ipsilateral renal cell carcinomas differing in histology. Robot-assisted partial nephrectomy was the safe and effective nephron-sparing surgery, even in patients with complex double renal tumors.

Primary Intraosseous Squamous Cell Carcinoma Arising from a Dentigerous Cyst of the Maxillary Wisdom Tooth.

The World Health Organization defines primary intraosseous squamous cell carcinoma (PIOSCC) as a squamous cell carcinoma (SCC) arising primarily within the jaws and having no connection with the oral mucosa. Here, we report a case of PIOSCC in which it was difficult to differentiate the condition from pericoronitis of an impacted maxillary wisdom tooth. The patient was a 27-year-old pregnant woman with a pain in the right maxillary wisdom tooth. The pain was diagnosed as pericoronitis of the right maxillary wisdom tooth, and the tooth was extracted under local anesthesia. During extraction, soft tissue was observed in the coronal part of the tooth, and it was diagnosed as SCC arising in a dentigerous cyst. Because the tumor may still be present, surgical resection was performed under general anesthesia. There has been no recurrence or metastasis at the 1-year follow-up. This case was histopathologically considered from being a benign odontogenic tumor to a malignant tumor. However, it revealed an extensive aberrant type and invasion equivalent to SCC. Thus, the histopathological diagnosis was PIOSCC arising from a dentigerous cyst. Although advanced cases of PIOSCC have been published, diagnosis of PIOSCC in the early stages is rare. In this case, we diagnosed pericoronitis of an impacted maxillary wisdom tooth and extracted the tooth. Therefore, we discovered it accidentally. In the early stages, diagnosis can be difficult both clinically and histopathologically.

Road Dust as a Significant Radiocesium Transporter from Land to River.

This study made it clear that road dust plays an important role for Cs-137 dynamics emitted by the Fukushima Daiichi nuclear power plant accident. It was proved from the Cs-137 and heavy metals determination in road dust, drainage gutter sediment beside pavement, and riverbed sediment around the inflow point of the gutter. Road dust and drainage gutter sediment contained significantly higher concentrations of Cs-137 and Cr, Ni, Cu, Zn, Mo, Cd, Sn, Sb, and Pb than riverbed sediment. These heavy metals are typically enriched in road dust in general and originate in anthropogenic sources. Concentrations of Cs-137 and the heavy metals were higher in riverbed sediments at the inflow point of drainage than in non-inflow points. Drainage gutter sediments exhibited Cs-137 and heavy metal accumulation at the downmost of the gutter, which is the inflow point into the river. Accordingly, distribution of Cs-137 and the heavy metals concentrations were consistent with each other. Moreover, the concentrations of Cs-137 and heavy metals were correlated positively and significantly, with different proportions between sampling sites but similar between sample type and survey date. This indicates that the discharge of Cs-137 and heavy metals is characteristic of the features of the locations, such as Cs-137 and heavy metals concentrations, (micro-) topography, structure of the road and gutter, pavement area, traffic density, and so on. We conclude that road dust is a major medium of Cs-137 transport from land into aquatic ecosystems.

CITED2 in breast carcinoma as a potent prognostic predictor associated with proliferation, migration and chemoresistance.

CITED2 (Cbp/p300-interacting transactivator, with Glu/Asp-rich carboxy-terminal domain, 2) is a member of the CITED family and is involved in various cellular functions during development and differentiation. Mounting evidence suggests the importance of CITED in the progression of human malignancies, but the significance of CITED2 protein has not yet been examined in breast carcinoma. Therefore, in the present study, we examined the clinical significance and the biological functions of CITED2 in breast carcinoma by immunohistochemistry and in vitro study. CITED2 immunoreactivity was detected in breast carcinoma tissues, and it was significantly higher compared to those in morphologically normal mammary glands. CITED2 immunoreactivity was significantly associated with stage, pathological T factor, lymph node metastasis, histological grade, HER2 and Ki-67, and inversely correlated with estrogen receptor. Moreover, the immunohistochemical CITED2 status was significantly associated with increased incidence of recurrence and breast cancer-specific death of the breast cancer patients, and multivariate analyses demonstrated CITED2 status as an independent worse prognostic factor for disease-free and breast cancer-specific survival. Subsequent in vitro experiments showed that CITED2 expression significantly increased proliferation activity and migration property in MCF-7and S KBR-3 breast carcinoma cells. Moreover, CITED2 caused chemoresistance to epirubicin and 5-fluorouracil, but not paclitaxel, in these cells, and it inhibited p53 accumulation after 5-fluorouracil treatment in MCF-7 cells. These results suggest that CITED2 plays important roles in the progression and chemoresistance of breast carcinoma and that CITED2 status is a potent prognostic factor in breast cancer patients.

Influence of mechanical unloading on histological changes of the patellar tendon insertion in rabbits.

BACKGROUND: The purpose of this study was to clarify the influence of mechanical unloading on histological changes of the patellar tendon (PT) insertion in rabbits. MATERIALS AND METHODS: The PT was completely released from stress by drawing the patella toward the tibial tubercle with a stainless steel wire installed between the patella and tibial tubercle (mechanical unloading group, n=28). The animals of the sham group underwent the same surgical procedure; however, the wire was not tightened (n=28). The average thickness of the Safranin O-stained glycosaminoglycan (GAG) area, chondrocyte apoptosis rate and chondrocyte proliferation rate of the cartilage layer at the insertion were measured at one, two, four, and six weeks. RESULTS: The chondrocyte apoptosis rate in the mechanical unloading group was significantly higher than that in the sham group at one and four weeks (p<0.05). The chondrocyte proliferation rate in the mechanical unloading group was significantly lower than that in the sham group at four and six weeks (p<0.05). The average thickness of the GAG-stained area in the mechanical unloading group was significantly lower than that in the sham group at six weeks (p<0.05). CONCLUSION: Mechanical unloading significantly affected the increase in the chondrocyte apoptosis rate, decrease in the chondrocyte proliferation rate, and decrease in the GAG layer thickness at the PT insertion for up to six weeks in rabbits. CLINICAL RELEVANCE: We suggest that more than 6 weeks of mechanical unloading should be avoided to prevent degeneration at the PT insertion.