Background:
More than 30% of estrogen receptor-positive breast cancers are resistant to primary hormone therapy, and about 40% that initially respond to hormone therapy eventually acquire resistance. ...Although the mechanisms of hormone therapy resistance remain unclear, aberrant DNA methylation has been implicated in oncogenesis and drug resistance.
Purpose:
We investigated the relationship between methylome variations in circulating tumor DNA and exemestane resistance, to track hormone therapy efficacy.
Methods:
We prospectively recruited 16 patients who were receiving first-line therapy in our center. All patients received exemestane-based hormone therapy after enrollment. We collected blood samples at baseline, first follow-up (after 2 therapeutic cycles) and at detection of disease progression. Disease that progressed within 6 months under exemestane treatment was considered exemestane resistance but was considered relatively exemestane-sensitive otherwise. We obtained circulating tumor DNA-derived methylomes using the whole-genome bisulfide sequencing method. Methylation calling was done by BISMARK software; differentially methylated regions for exemestane resistance were calculated afterward.
Results:
Median follow-up for the 16 patients was 19.0 months. We found 7 exemestane resistance-related differentially methylated regions, located in different chromosomes, with both significantly different methylation density and methylation ratio. Baseline methylation density and methylation ratio of chromosome 6 32400000-32599999 were both high in exemestane resistance. High baseline methylation ratios of chromosome 3 67800000-67999999 (P = .013), chromosome 3 140200000-140399999 (P = .037), and chromosome 12 101200000-101399999 (P = .026) could also predict exemestane resistance. During exemestane treatment, synchronized changes in methylation density and methylation ratio in chromosome 6 32400000-32599999 could accurately stratify patients in terms of progression-free survival (P = .000033). Cutoff values of methylation density and methylation ratio for chromosome 6 149600000-149799999 were 0.066 and 0.076, respectively.
Conclusion:
Methylation change in chromosome 6 149600000-149799999 is an ideal predictor of exemestane resistance with great clinical potential.
Objectives: To investigate the dosimetric advantages of the voluntary deep inspiration breath-hold technique assisted by optical surface monitoring system for whole breast irradiation in left breast ...cancer after breast-conserving surgery and verify the reproducibility and acceptability of this technique. Methods: Twenty patients with left breast cancer receiving whole breast irradiation after breast-conserving surgery were enrolled in this prospective phase II study. Computed tomography simulation was performed during both free breathing and voluntary deep inspiration breath-hold for all patients. Whole breast irradiation plans were designed, and the volumes and doses of the heart, left anterior descending coronary artery, and lung were compared between free breathing and voluntary deep inspiration breath-hold. Cone beam computed tomography was performed for the first 3 treatments, then weekly during voluntary deep inspiration breath-hold treatment to evaluate the accuracy of the optical surface monitoring system technique. The acceptance of this technique was evaluated with in-house questionnaires completed by patients and radiotherapists. Results: The median age was 45 (27-63) years. All patients received hypofractionated whole breast irradiation using intensity-modulated radiation therapy up to a total dose of 43.5 Gy/2.9 Gy/15f. Seventeen of the 20 patients received concomitant tumor bed boost to a total dose of 49.5 Gy/3.3 Gy/15f. Voluntary deep inspiration breath-hold showed a significant decrease in the heart mean dose (262 ± 163 cGy vs 515 ± 216 cGy, P < .001) and left anterior descending coronary artery (1191 ± 827 cGy vs 1794 ± 833 cGy, P < .001). The median delivery time of radiotherapy was 4 (1.5-11) min. The median deep breathing cycles were 4 (2-9) times. The average score for acceptance of voluntary deep inspiration breath-hold by patients and radiotherapists was 8.7 ± 0.9 (out of 12) and 10.6 ± 3.2 (out of 15), respectively, indicating good acceptance by both. Conclusions: The voluntary deep inspiration breath-hold technique for whole breast irradiation after breast-conserving surgery in patients with left breast cancer significantly reduces the cardiopulmonary dose. Optical surface monitoring system–assisted voluntary deep inspiration breath-hold is reproducible and feasible and showed good acceptance by both patients and radiotherapists.
Ultrasound is a critical non-invasive test for preoperative diagnosis of ovarian cancer. Deep learning is making advances in image-recognition tasks; therefore, we aimed to develop a deep ...convolutional neural network (DCNN) model that automates evaluation of ultrasound images and to facilitate a more accurate diagnosis of ovarian cancer than existing methods.
In this retrospective, multicentre, diagnostic study, we collected pelvic ultrasound images from ten hospitals across China between September 2003, and May 2019. We included consecutive adult patients (aged ≥18 years) with adnexal lesions in ultrasonography and healthy controls and excluded duplicated cases and patients without adnexa or pathological diagnosis. For DCNN model development, patients were assigned to the training dataset (34 488 images of 3755 patients with ovarian cancer, 541 442 images of 101 777 controls). For model validation, patients were assigned to the internal validation dataset (3031 images of 266 patients with ovarian cancer, 5385 images of 602 with benign adnexal lesions), external validation datasets 1 (486 images of 67 with ovarian cancer, 933 images of 268 with benign adnexal lesions), and 2 (1253 images of 166 with ovarian cancer, 5257 images of 723 benign adnexal lesions). Using these datasets, we assessed the diagnostic value of DCNN, compared DCNN with 35 radiologists, and explored whether DCNN could augment the diagnostic accuracy of six radiologists. Pathological diagnosis was the reference standard.
For DCNN to detect ovarian cancer, AUC was 0·911 (95% CI 0·886–0·936) in the internal dataset, 0·870 (95% CI 0·822–0·918) in external validation dataset 1, and 0·831 (95% CI 0·793–0·869) in external validation dataset 2. The DCNN model was more accurate than radiologists at detecting ovarian cancer in the internal dataset (88·8% vs 85·7%) and external validation dataset 1 (86·9% vs 81·1%). Accuracy and sensitivity of diagnosis increased more after DCNN-assisted diagnosis than assessment by radiologists alone (87·6% 85·0–90·2 vs 78·3% 72·1–84·5, p<0·0001; 82·7% 78·5–86·9 vs 70·4% 59·1–81·7, p<0·0001). The average accuracy of DCNN-assisted evaluations for six radiologists reached 0·876 and were significantly augmented when they were DCNN-assisted (p<0·05).
The performance of DCNN-enabled ultrasound exceeded the average diagnostic level of radiologists matched the level of expert ultrasound image readers, and augmented radiologists’ accuracy. However, these observations warrant further investigations in prospective studies or randomised clinical trials.
National Key Basic Research Program of China, National Sci-Tech Support Projects, and National Natural Science Foundation of China.
The value of intensity-modulated radiation therapy (IMRT) after doxorubicin-based chemotherapy in primary mediastinal large B-cell lymphoma (PMBCL) is unknown. We assessed the dosimetric parameters, ...treatment outcomes, and toxicity of IMRT in PMBCL.
Forty-one PMBCL patients underwent mediastinal IMRT after doxorubicin-based chemotherapy. Thirty-eight patients had stage I-II disease, and 3 patients had stage III-IV disease. Most patients presented with bulky mediastinal disease (65.9%) and local invasion (82.9%). The dose-volume histograms of the target volume and critical normal structures were evaluated.
The average planning target volume (PTV) mean dose was 39 Gy. Only 0.5% and 1.4% of the PTV received <90% and <95% of the prescribed dose, respectively, indicating excellent target coverage. The median mean lung dose and percentage lung volume receiving 20 Gy (V20) were 16.3 Gy and 30.6%. The 5-year overall survival (OS) and local control (LC) were 95.1% and 89.8%. After chemotherapy, consolidation radiation therapy in patients with complete/partial response resulted in significantly better survival than salvage radiation therapy in patients with stable/progressive disease (3-year OS 100% vs 75%; 3-year LC 96.6% vs 62.5%). No grade 4 or 5 acute or late toxicities occurred.
Mediastinal IMRT after doxorubicin-based chemotherapy can be safely and efficiently delivered, and it provides favorable outcomes in PMBCL patients with a large target volume and high-risk features.
Improved markers for predicting recurrence are needed to stratify patients with localised (stage I–III) renal cell carcinoma after surgery for selection of adjuvant therapy. We developed a novel ...assay integrating three modalities—clinical, genomic, and histopathological—to improve the predictive accuracy for localised renal cell carcinoma recurrence.
In this retrospective analysis and validation study, we developed a histopathological whole-slide image (WSI)-based score using deep learning allied to digital scanning of conventional haematoxylin and eosin-stained tumour tissue sections, to predict tumour recurrence in a development dataset of 651 patients with distinctly good or poor disease outcome. The six single nucleotide polymorphism-based score, which was detected in paraffin-embedded tumour tissue samples, and the Leibovich score, which was established using clinicopathological risk factors, were combined with the WSI-based score to construct a multimodal recurrence score in the training dataset of 1125 patients. The multimodal recurrence score was validated in 1625 patients from the independent validation dataset and 418 patients from The Cancer Genome Atlas set. The primary outcome measured was the recurrence-free interval (RFI).
The multimodal recurrence score had significantly higher predictive accuracy than the three single-modal scores and clinicopathological risk factors, and it precisely predicted the RFI of patients in the training and two validation datasets (areas under the curve at 5 years: 0·825–0·876 vs 0·608–0·793; p<0·05). The RFI of patients with low stage or grade is usually better than that of patients with high stage or grade; however, the RFI in the multimodal recurrence score-defined high-risk stage I and II group was shorter than in the low-risk stage III group (hazard ratio HR 4·57, 95% CI 2·49–8·40; p<0·0001), and the RFI of the high-risk grade 1 and 2 group was shorter than in the low-risk grade 3 and 4 group (HR 4·58, 3·19–6·59; p<0·0001).
Our multimodal recurrence score is a practical and reliable predictor that can add value to the current staging system for predicting localised renal cell carcinoma recurrence after surgery, and this combined approach more precisely informs treatment decisions about adjuvant therapy.
National Natural Science Foundation of China, and National Key Research and Development Program of China.
Abstract Background Comprehensive health economic evaluation, a key component of the Cancer Screening Program in Urban China (CanSPUC), was expected to support government policy-making on screening ...initiatives for common cancers (lung, breast, colorectal, oesophageal, liver, and stomach cancer) in urban China. Estimation of expenditure for cancer diagnosis and treatment from a societal perspective was an essential component. The aim of this study was to estimate direct medical and non-medical expenditure and to discern the resultant financial burden. Methods A multicentre cross-sectional survey of patients with target cancers or precancerous lesions was conducted in 37 tertiary hospitals in 13 provinces across China, from 2012 to 2014. Each patient was interviewed with a structured questionnaire for sociodemographic, clinical, and expenditure information. Expenditure data was converted to 2014 values and presented as US$. Expenditure and financial burden were quantified as a whole and by subgroups. Findings Of the included 14 594 patients with cancer (mean age 56·7 years, 58% male), annual household income was $8607. Mean expenditure per patient was $9739 (95% CI 9612–9866), and non-medical expenditure accounted for 9·3%. Expenditure per patient with colorectal, oesophageal, lung, stomach, liver or breast cancer was $10 978 (10 636–11 321), $10 506 (10 199–10 813), $9970 (9664–10 276), $9891 (9606–10 176), $8668 (8358–8977) and $8532 (8234–8831), respectively. Expenditure increased from stage I to stage IV for colorectal, stomach, and breast cancer (p<0·0001). Out-of-pocket expenditure of newly diagnosed cancer (2 months before and 10 months after diagnosis) per cancer patient was $4947 (4875–5020), accounting for 57·5% of annual household income, presenting 77·6% of families with an unmanageable financial burden. Apart from cancer site and stage, hospital type, education, occupation, insurance type, and previous years' household income were also significant predictors of expenditure (F=247·9, 56·3, 29·7, 12·8, and 28·7, respectively; all p<0·0001) as well as self-reported financial burden (χ2 =130·4, 495·1, 1112·2, 1009·4, and 1848·2, respectively; all p<0·0001). In addition, for the included 1532 precancerous patients, mean expenditure was $3221 (3055–3387), a third of expenditure for patients with cancer. Interpretation Expenditure for diagnosis and treatment seemed catastrophic for patients with cancer in China, and non-medical expenditure was substantial. Expenditure and financial burden varied within subgroups, especially between patients with different degrees of lesions, suggesting that cancer screening might be cost-effective in China. Funding National Health and Family Plan Committee of China.
Abstract Background The measurement of quality-adjusted life-years (QALYs) forms a key component of cost–utility evaluation in cancer intervention; however, detailed data for utility weights by ...cancer type and health status are still scarce both in China and other regions. The aim of this study was to systematically evaluate utility scores in relation to the most common six cancers in China in 2012 (lung, breast, colorectal, oesophageal, liver, and stomach cancer). Methods As a part of a Screening Program in Urban China (CanSPUC) supported by the central government of China, we undertook a cross-sectional survey in 13 provinces across China from 2013 to 2014. Two generic instruments, EQ-5D (EuroQol 5-dimensions) and SF-12 (12-item Short Form Health Survey), and a cancer-specific instrument, FACTs (Function Assessment of Cancer Therapy) were applied. 46 394 participants were interviewed in five groups: general population (n=11 699, group A), individuals who had attended single cancer screening (n=11 805, group B), individuals who had attended multiple screenings (n=6838, group C), patients with precancerous lesions (n=1942, group D), and patients with cancer (n=14 110, group E). All participants had no psychosis and provided written consent to participate in the study. The survey was approved by the Institutional Review Board of the Cancer Hospital of Chinese Academy of Medical Sciences. Findings The EQ-5D utility scores were 0·96 (95% CI 0·96–0·96) for group A, 0·94 (0·94–0·94) for group B, 0·94 (0·94–0·94) for group C, 0·85 (0·84–0·86) for group D, and 0·77 (0·77–0·77) for group E. Cancer-specific analysis showed that EQ-5D utility scores were 0·77 (0·76–0·78) for lung cancer, 0·78 (0·77–0·79) for breast cancer, 0·75 (0·74–0·76) for colorectal cancer, 0·75 (0·74–0·76) for oesophageal cancer, 0·80 (0·79–0·81) for liver cancer, and 0·76 (0·75–0·77) for stomach cancer. The utility scores for cancer at different clinical stages also differed; for example, the scores for patients with breast cancer were estimated as 0·79 (0·77–0·80) at stage I, 0·79 (0·78–0·80) at stage II, 0·77 (0·76–0·79) at stage III, and 0·69 (0·65–0·72) at stage IV. Compared with data from EQ-5D, results from SF-12 on differences among subgroups seemed narrower; for example, the utility score among the six cancers ranged from 0·60 to 0·62. Interpretation These data will be applied to future cost–utility evaluation on various cancer screening strategies in China, and could contribute more precise evaluation of burden of disease related to disability-adjusted life-years globally. Funding The National Health and Family Plan Committee of China.
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