Highly sensitive detection of <Emphasis Type="Italic">ESR1</Emphasis> mutations in cell-free DNA from patients with metastatic breast cancer using molecular barcode sequencing

Purpose

We aimed to develop a highly sensitive method to detect ESR1 mutations in cell-free DNA (cfDNA) using next-generation sequencing with molecular barcode (MB–NGS) targeting the hotspot segment (c.1600–1713).

Methods

The sensitivity of MB–NGS was tested using serially diluted ESR1 mutant DNA and then cfDNA samples from 34 patients with metastatic breast cancer were analyzed with MB–NGS. The results of MB–NGS were validated in comparison with conventional NGS and droplet digital PCR (ddPCR).

Results

MB–NGS showed a higher sensitivity (0.1%) than NGS without barcode (1%) by reducing background errors. Of the cfDNA samples from 34 patients with metastatic breast cancer, NGS without barcode revealed seven mutations in six patients (17.6%) and MB–NGS revealed six additional mutations including three mutations not reported in the COSMIC database of breast cancer, resulting in total 13 ESR1 mutations in ten patients (29.4%). Regarding the three hotspot mutations, all the patients with mutations detected by MB–NGS had identical mutations detected by droplet digital PCR (ddPCR), and mutant allele frequency correlated very well between both (r = 0.850, p < 0.01). Moreover, all the patients without these mutations by MB–NGS were found to have no mutations by ddPCR.

Conclusion

In conclusion, MB–NGS could successfully detect ESR1 mutations in cfDNA with a higher sensitivity of 0.1% than conventional NGS and was considered as clinically useful as ddPCR.

     

The incremental value of a geriatric assessment-derived three-item scale on estimating overall survival in older adults with cancer

Objective

A geriatric assessment (GA) assesses functional age of older patients with cancer and is a well-established tool predictive of toxicity and survival. The objective of this study was to investigate the prognostic value of individual GA items.

Automated prediction of dosimetric eligibility of patients with prostate cancer undergoing intensity-modulated radiation therapy using a convolutional neural network

The quality of radiotherapy has greatly improved due to the high precision achieved by intensity-modulated radiation therapy (IMRT). Studies have been conducted to increase the quality of planning and reduce the costs associated with planning through automated planning method; however, few studies have used the deep learning method for optimization of planning. The purpose of this study was to propose an automated method based on a convolutional neural network (CNN) for predicting the dosimetric eligibility of patients with prostate cancer undergoing IMRT. Sixty patients with prostate cancer who underwent IMRT were included in the study. Treatment strategy involved division of the patients into two groups, namely, meeting all dose constraints and not meeting all dose constraints, by experienced medical physicists. We used AlexNet (i.e., one of common CNN architectures) for CNN-based methods to predict the two groups. An AlexNet CNN pre-trained on ImageNet was fine-tuned. Two dataset formats were used as input data: planning computed tomography (CT) images and structure labels. Five-fold cross-validation was used, and performance metrics included sensitivity, specificity, and prediction accuracy. Class activation mapping was used to visualize the internal representation learned by the CNN. Prediction accuracies of the model with the planning CT image dataset and that with the structure label dataset were 56.7?±?9.7% and 70.0?±?11.3%, respectively. Moreover, the model with structure labels focused on areas associated with dose constraints. These results revealed the potential applicability of deep learning to the treatment planning of patients with prostate cancer undergoing IMRT.     

MR findings of the orbit in patients with Vogt–Koyanagi–Harada disease

Purpose

We aimed to evaluate the MR findings of the orbit in patients with Vogt–Koyanagi–Harada disease (VKHD).

Methods

We included 14 patients with clinically diagnosed VKHD, who underwent orbital MR imaging before treatment between May 2011 and August 2017. The mean duration from initial symptom onset to MR imaging was 16 days (range, 2–36 days). Fat-suppressed gadolinium-enhanced T1-weighted images were obtained in six patients. We retrospectively assessed the choroids and Tenon’s capsules for the presence of thickening on unenhanced images and abnormal enhancement on contrast-enhanced images.

Results

Bilateral choroidal thickening was observed in 14 patients (100%) on T1-weighted images and in 12 patients (85.7%) on T2-weighted images. Choroidal thickening showed posterior pole predominance in 11 patients (78.6%) and diffusely distributed in the remaining three patients (21.4%). Bilateral Tenon’s capsule thickening was observed in five patients (35.7%) on T1-weighted images and in 14 patients (100%) on T2-weighted images. On contrast-enhanced images, the choroids and Tenon’s capsules were abnormally enhanced in six patients (100%).

Conclusion

MR imaging sensitively detected abnormalities of the choroids and Tenon’s capsules in patients with VKHD. Bilaterality and predominant posterior pole distribution were characteristic of choroidal VKHD.

     

Associations between early tumor shrinkage and depth of response and clinical outcomes in patients treated with 1st-line chemotherapy for advanced gastric cancer

Background

Although early tumor shrinkage (ETS) predictions of the efficacy and depth of response (DpR) reflects clinical outcomes in chemotherapy with epidermal growth factor receptor inhibitor regimens to treat metastatic colorectal cancer, their value in assessing treatments for advanced gastric cancer (AGC) is unclear. Here we evaluated relationships between ETS and DpR and clinical outcomes in AGC patients treated with first-line chemotherapy.

Methods

We retrospectively enrolled 612 consecutive patients treated with first-line chemotherapy for AGC between January 2010 and June 2016. ETS and DpR were defined as changes from baseline in summed longest diameters in target lesions at 8 (±4) weeks for ETS and at the smallest observed volume for DpR.

Results

Eligible patients were sorted into HER2⁺ (n = 100) and HER2^? (n = 186) groups. Median follow-up was 14.8 months. The overall response rate and disease control rates were 64 and 87% in the HER2⁺ group and 53.2 and 86.0% in the HER2^? group. Respective median PFS and OS were HER2⁺: 7.9 and 20.8 months and HER2^?: 6.6 and 13.8 months. The respective ETS rate and median DpR were HER2⁺: 70 and 44% and HER2^?: 57.5 and 24%. Clinical outcomes and ETS/DpR were correlated, especially in the HER2⁺ group (OS: P < 0.0001; PFS: P < 0.0001). In multivariate analysis, ETS was an independent predictor for OS in the HER2⁺ group and for PFS in both groups.

Conclusion

These results indicate that ETS may be an early-on treatment predictor of the efficacy of HER2⁺ advanced gastric cancer treated with first-line chemotherapy that includes trastuzumab.

     

Is the eCura system useful for selecting patients who require radical surgery after noncurative endoscopic submucosal dissection for early gastric cancer? A comparative study

Background

We have established a risk-scoring system, termed the “eCura system,” for the risk stratification of lymph node metastasis in patients who have received noncurative endoscopic submucosal dissection (ESD) for early gastric cancer (EGC). We aimed to clarify whether this system contributes to the selection of patients requiring radical surgery after ESD.

Methods

Between 2000 and 2011, 1,969 patients with noncurative ESD for EGC were included in this multicenter study. Depending on the treatment strategy after ESD, we had patients with no additional treatment (n = 905) and those with radical surgery after ESD (n = 1,064). After the application of the eCura system to these patients, cancer recurrence and cancer-specific mortality in each risk category of the system were compared between the two patient groups.

Results

Multivariate Cox analysis revealed that in the high-risk category, cancer recurrence was significantly higher (hazard ratio = 3.13, p = 0.024) and cancer-specific mortality tended to be higher (hazard ratio = 2.66, p = 0.063) in patients with no additional treatment than in those with radical surgery after ESD, whereas no significant differences were observed in the intermediate-risk and low-risk categories. In addition, cancer-specific survival in the low-risk category was high in both patient groups (99.6 and 99.7%). A limitation of this study is that it included a small number of cases with undifferentiated-type EGC (292 cases).

Conclusions

The eCura system is a useful aid for selecting the appropriate treatment strategy after noncurative ESD for EGC. However, caution is needed when applying this system to patients with undifferentiated-type EGC.

     

Expression of irnmunoreactivities to 75 kDa nerve growth factor receptor, trk gene product and phosphotyrosine in granular cell tumors

Nineteen granular cell tumors (GCT) of adults, two congenital granular cell epulides and five epulides fibrosae were immunohistochmically examined to detect the expression of 75 kDs nerve growth factor receptor (NGFR), frk gene product, phasphotyrosine (PT), protein gene product 9.5 (PGP9.5) and S-100 protein. The NGFR-immunoreactivity (IR) and trk gene product-IR were expressed on almost all granular cells of GCT. PT-IR was also demonstrated on granular calls of all GCT examined, although the frequency of positive cells was low. Congenital granular celi epulides and epulldes fibrosae were negative for NGFR-IR, trk gene product-IR and PT-IR. S-100 protein was localized in granular cells of adult GCT but not in the granular cells of congenital epulis. On the other hand, PGP9.5 was detected in granular cells of both conditions and in fibroblastic cells of epulis fibrosa. The present results further indicate that GCT is of peripheral nerve Schwann cell origin, while the congenital granular cell epulides are not of neural origin. NGFR and trk gene product expressed on GCT seems to be functional in terms of phosphorylation of the tyrosine residue in the receptor or downstream protein in signal transduction.     

Sister and brother with Vici syndrome: agenesis of the corpus callosum, albinism, and recurrent infections

A sister and brother with Vici syndrome are described. They both had oculocutaneous albinism, agenesis of the corpus callosum, cataracts, and cardiomyopathy. They were born to healthy unrelated parents, and had postnatal growth retardation, profound developmental delay, hypotonia, and cataracts. The sister had recurrent infections, and died of progressive heart failure at age 19 months. The brother is alive at age six months with mild cardiomyopathy, and had a single episode of acute bronchitis at age three months. Review of the clinical manifestations of the sibs we described and six children reported in the literature indicates that Vici syndrome is a distinct clinical entity. Its main clinical manifestations include growth retardation, profound developmental delay, hypotonia, albinism, agenesis of the corpus callosum, cataracts, cardiomyopathy, and recurrent infections. The occurrence of the syndrome in three pairs of sibs of both sexes born to unaffected parents supports autosomal recessive inheritance.