Sensitivity and specificity of mammography and adjunctive ultrasonography to screen for breast cancer in the Japan Strategic Anti-cancer Randomized Trial (J-START): a randomised controlled trial.

BACKGROUND: Mammography is the only proven method for breast cancer screening that reduces mortality, although it is inaccurate in young women or women with dense breasts. We investigated the efficacy of adjunctive ultrasonography. METHODS: Between July, 2007, and March, 2011, we enrolled asymptomatic women aged 40-49 years at 42 study sites in 23 prefectures into the Japan Strategic Anti-cancer Randomized Trial (J-START). Eligible women had no history of any cancer in the previous 5 years and were expected to live for more than 5 years. Randomisation was done centrally by the Japan Clinical Research Support Unit. Participants were randomly assigned in 1:1 ratio to undergo mammography and ultrasonography (intervention group) or mammography alone (control group) twice in 2 years. The primary outcome was sensitivity, specificity, cancer detection rate, and stage distribution at the first round of screening. Analysis was by intention to treat. This study is registered, number UMIN000000757. FINDINGS: Of 72,998 women enrolled, 36,859 were assigned to the intervention group and 36,139 to the control group. Sensitivity was significantly higher in the intervention group than in the control group (91·1%, 95% CI 87·2-95·0 vs 77·0%, 70·3-83·7; p=0·0004), whereas specificity was significantly lower (87·7%, 87·3-88·0 vs 91·4%, 91·1-91·7; p<0·0001). More cancers were detected in the intervention group than in the control group (184 [0·50%] vs 117 [0·32%], p=0·0003) and were more frequently stage 0 and I (144 [71·3%] vs 79 [52·0%], p=0·0194). 18 (0·05%) interval cancers were detected in the intervention group compared with 35 (0·10%) in the control group (p=0·034). INTERPRETATION: Adjunctive ultrasonography increases sensitivity and detection rate of early cancers. FUNDING: Ministry of Health, Labour and Welfare of Japan.

A randomized controlled trial to verify the efficacy of the use of ultrasonography in breast cancer screening aged 40-49 (J-START): 76 196 women registered.

OBJECTIVE: The objective of the Japan Strategic Anti-cancer Randomized Trial was to verify the efficacy of the use of ultrasonography in breast cancer screening among women aged 40-49 years. The purpose of this paper was to report the design and recruitment result of this study. METHODS: In this study of women in their 40s, the participants were divided into two groups, one of which (the intervention group) was subjected to mammography and ultrasonography (using a standardized ultrasonography examination), while the other (the control group) was examined with mammography, in a randomized controlled trial, with the objective of verifying the accuracy and efficacy of examinations by comparing the two groups. RESULTS: The cumulative total number of participants registered in the study was 76 196 (38 313 in the intervention group and 37 883 in the control group). 71.0% of participants registered to the study were under individual randomized controlled trial, 25.0% were under cluster randomized controlled trial and 3.9% were under non-randomized controlled group. The study was designed so that participants registered at their first examination underwent examinations by the same method for the subsequent two years. 74.1% of participants scheduled for a second examination had undertaken it, while information regarding the presence of interval cancer had been obtained from a further 20.6% using a questionnaire. At July 2013, the status of 5.3% of all participants was unclear. CONCLUSIONS: It was the first large-scale randomized controlled trial carried out in Japan. The scheduled second examinations were completed at the end of fiscal 2012. Once the proportion of participants whose status is unclear has fallen to ≤5%, the authors plan to collate the data relating to the primary end points, and publish the results.

The Japan Society of Ultrasonics in Medicine guidelines on non-mass abnormalities of the breast.

It is possible to appropriately diagnose non-mass abnormalities by elucidating ultrasound non-mass abnormality findings and sharing the concept. If non-mass abnormalities can be diagnosed early, the number of curable cases could increase, leading to fewer breast cancer deaths. The Japan Society of Ultrasonics in Medicine (JSUM) Terminology/Diagnostic Criteria Committee has classified non-mass abnormalities into five subtypes: hypoechoic area in the mammary gland, abnormalities of the ducts, architectural distortion, multiple small cysts, and echogenic foci without a hypoechoic area. We herein define the findings for each of these subtypes and present a summary of the JSUM guidelines on non-mass abnormalities of the breast generated based on those findings.

Overall assessment system of combined mammography and ultrasound for breast cancer screening in Japan.

Mammography is the only screening method with evidence in support of reduced breast cancer mortality, but yields poor accuracy outcomes in women with dense breast tissue. The Japan Strategic Anti-cancer Randomized Trial (J-START) was conducted as part of the measures implemented to deal with women with dense breast tissue. Although the sensitivity was increased, the specificity was significantly lower in the intervention group because further examination was required in all positive cases classified by either mammography or ultrasound in the J-START. To address the issue, an overall assessment system of combined mammography and adjunctive ultrasound for breast cancer screening has been developed in Japan. The basic concept is based on a comprehensive assessment that includes a mammography assessment followed by an adjunctive assessment for ultrasound similar to the clinical setting. Currently, mammography alone is recommended for population-based breast cancer screening in Japan, but additional ultrasonography is extensively available for women, especially for women with dense breasts with shared decision-making for personalized breast cancer screening. The overall assessment system is recommended for use in Japan when breast cancer screening is conducted using both mammography and ultrasonography. In this article, we summarize the advantages of the overall assessment and the simultaneous mammography/ultrasound method, the basic approach used in Japan to assign the overall assessment category for breast cancer screening, and we outline the future directions of adjunctive screening ultrasound.

Investigation of the significance of population-based breast cancer screening among women aged under 40 years.

BACKGROUND: Owing to low incidence rates, population-based breast cancer screening is not recommended by many municipalities in Japan for women aged < 40 years. To evaluate the usefulness of screening in women aged < 40 years, we investigated the results of population-based breast cancer screening among young women performed in the Ibaraki Prefecture. METHODS: Data regarding histological characteristics, recall rates, cancer detection rates, positive predictive values, tumor categories, and status of lymph node metastases were obtained from population-based screening data from Ibaraki Health Service Association Institute. The "number needing to be screened" (NNS) was determined; using Pearson's chi-squared test, these data were compared between women aged < 40 years and > 40 years. RESULTS: The data of 428,560 women were evaluated. Cancer detection rates were significantly lower and the NNS and proportion of women with tumor category T2 or higher was significantly increased in women aged < 40 years than in those aged > 40 years (0.06% vs. 0.21%, 1505 vs. 281-439, and 28.9% vs. 6.3%, respectively; all, p < 0.05). The proportion of early-stage cancers was lower in women aged < 40 years than in those > 40 years, but this was not significant. CONCLUSIONS: These results suggest that population-based breast cancer screening should not be recommended for women aged < 40 years. To reduce the breast cancer-related mortality rate in young women and ensure efficient use of limited medical resources in Japan, a more efficient surveillance system, based on genetic propensity and family history, needs to be established.

B-mode ultrasound diagnostic flowchart for solid breast masses: JABTS BC-01 study.

PURPOSE: Breast ultrasound has been widely used as an essential examination for diagnosing breast cancer. However, standardized diagnostic criteria are as yet lacking. This study aimed to develop a simple diagnostic flowchart for beginners learning breast ultrasonography. The diagnostic flowchart was developed based on the recall criteria widely used in Japan. METHODS: We conducted a multicenter study to examine recall criteria usefulness in the diagnostic phase of breast disease. Women with ultrasound-visible breast masses who underwent B-mode breast ultrasound examination were recruited from 22 hospitals in Japan between September 2009 and January 2010. B-mode images were evaluated by members of the centralized image interpretation committee. We developed the new diagnostic flowchart based on the results. The usefulness of the diagnostic flowchart was assessed by employing datasets from the current study and another study which we conducted (BC-04 study). RESULTS: We evaluated 1045 solid masses (malignant: 495, benign: 550). Multivariate analysis showed that shape, margin, echogenic halo, interruption of the mammary gland interface, and depth width ratio were significant findings for distinguishing between benign and malignant masses. We modified the recall criteria and developed our novel diagnostic flowchart using these findings. The sensitivity and specificity of the new flowchart (current study: 0.97, 0.45; BC-04 study dataset: 0.95, 0.45) were similar to those of experts (current study: 0.96, 0.54; BC-04 study dataset: 0.98, 0.38). CONCLUSION: We developed a simple diagnostic flowchart for breast ultrasound. This flowchart is anticipated to be applicable to educating beginners learning breast ultrasound.

Multicenter Prospective Study of Color Doppler Ultrasound for Breast Masses: Utility of Our Color Doppler Method.

The use of color Doppler ultrasound (CD) for distinguishing between benign and malignant breast lesions remains controversial. This study (JABTS BC-04 study) was aimed at confirming the usefulness of our CD diagnostic criteria. We evaluated ultrasound images of 1408 solid breast masses from 16 institutions in Japan (malignant: 839, benign: 569). Multivariate analysis indicated that vascularity (amount of blood flow), vascular flow pattern ("surrounding marginal flow" or "penetrating flow") and the incident angle of penetrating flow were significant findings for distinguishing between benign and malignant lesions. However, the sensitivity and specificity of B-mode alone did not improve significantly with CD addition (97.6% → 97.9%, 38.3% → 41.5%, respectively). We explored the causes of these negative results and found that age should have been considered when evaluating vascularity. Simulation experiments suggested that specificity is significantly improved when age is taken into consideration (38.3% → 46.0%, p < 0.001) and we thereby improved our diagnostic criteria.

Proton beam therapy for hepatocellular carcinoma adjacent to the porta hepatis.

PURPOSE: To evaluate the efficacy and safety of proton beam therapy (PBT) for patients with hepatocellular carcinoma (HCC) located adjacent to the porta hepatis. METHODS AND MATERIALS: Subjects of the study were 53 patients with HCC located within 2 cm of the main portal vein. All patients had tumor confined to the radiation field with no evidence of metastatic disease. All patients had hepatic function levels of a Child-Pugh score of 10 or less, Eastern Cooperative Oncology Group performance status of 2 or less, and no uncontrolled ascites. Patients underwent PBT of 72.6 GyE in 22 fractions from Sept 2001 to Dec 2004. RESULTS: After 3 years, the actuarial survival rate was 45.1% and local control rate was 86.0%. Prognostic factors for survival included Child-Pugh score, number of tumors, and alpha-fetoprotein levels. No late treatment-related toxicity of Grade 2 or higher was observed. CONCLUSIONS: The PBT delivering 72.6 GyE in 22 fractions appears to be effective and safe for HCC adjacent to the porta hepatis.

Proton beam therapy for aged patients with hepatocellular carcinoma.

PURPOSE: To investigate the safety and efficacy of proton beam therapy for aged patients with hepatocellular carcinoma (HCC). METHODS AND MATERIALS: Twenty-one patients aged > or =80 years with HCC underwent proton beam therapy. At the time of irradiation, patient age ranged from 80 to 85 years (median, 81 years). Hepatic tumors were solitary in 17 patients and multiple in 4. Tumor size ranged from 10 to 135 mm (median, 40 mm) in maximum diameter. Ten, 5, and 6 patients received proton beam irradiation with total doses of 60 Gy in 10 fractions, 66 Gy in 22 fractions, and 70 Gy in 35 fractions, respectively, according to tumor location. RESULTS: All irradiated tumors were controlled during the follow-up period of 6-49 months (median, 16 months). Five patients showed new hepatic tumors outside the irradiated volume, 2-13 months after treatment, and 1 of them also had lung metastasis. The local progression-free and disease-free rates were 100% and 72% at 3 years, respectively. Of 21 patients, 7 died 6-49 months after treatment; 2 patients each died of trauma and old age, and 1 patient each died of HCC, pneumonia, and arrhythmia. The 3-year overall, cause-specific, and disease-free survival rates were 62%, 88%, and 51%, respectively. No therapy-related toxicity of Grade > or = 3 but thrombocytopenia in 2 patients was observed. CONCLUSIONS: Proton beam therapy seems to be tolerable, effective, and safe for aged patients with HCC. It may contribute to prolonged survival due to tumor control.

Proton beam therapy for hepatocellular carcinoma with inferior vena cava tumor thrombus: report of three cases.

Three patients with hepatocellular carcinoma (HCC) and inferior vena cava tumor thrombus (IVCTT) were treated using proton beam therapy at the University of Tsukuba, Japan. A total dose of 50-70 Gy in 10-35 fractions was given to the primary tumor and IVCTT. All the patients survived for more than 1 year from the beginning of proton beam therapy (13-55 months) and no treatment-related toxicity of grade 3 or higher was observed. These cases suggest that proton beam therapy is safe and effective for patients with HCC associated with IVCTT.

Ultrasound Image Classification of Ductal Carcinoma In Situ (DCIS) of the Breast: Analysis of 705 DCIS Lesions.

The Japan Association of Breast and Thyroid Sonology (JABTS) proposed, in 2003, a conceptual classification system for non-mass abnormalities to be applied in addition to the conventional concept of masses, to facilitate detecting ductal carcinoma in situ (DCIS) lesions. The aim of this study was to confirm the utility of this system and to clarify the distribution of these findings in DCIS lesions. Data on 705 surgically treated DCIS lesions from 16 institutions in Japan were retrospectively reviewed. All 705 DCIS lesions could be classified according to the JABTS classification system. The most frequent findings were hypo-echoic areas in the mammary gland (48.6%), followed by solid masses (28.0%) and duct abnormalities (10.2%) or mixed masses (8.1%). Distortion (1.3%), clustered microcysts (1.4%) and echogenic foci without a hypo-echoic area (2.5%) were uncommon. These results suggest that the concept of non-mass abnormalities is useful in detecting DCIS lesions.

Detection of intraductal component around invasive breast cancer using ultrasound: correlation with MRI and histopathological findings.

PURPOSE: The purpose of this study was preoperatively to diagnose the intraductal component, which is indispensable in planning for breast conservation therapy, and also to minimize local recurrence. This study investigated the efficacy of ultrasound (US) in the detection of intraductal component in comparison with magnetic resonance imaging (MRI) and histopathological findings. PATIENTS AND METHODS: In 47 patients with invasive breast cancer, US features of the intraductal component were classified as (a) solid ductal dilatation radiating from the tumor, (b) presence of satellite lesion in the same segment without ductal dilatation, and (c) ductal dilatation between the main tumor and satellite lesion. MRI depicted intraductal extension as the most enhanced area during the first or second phase of the dynamic study. Other criteria for the detection of the intraductal component by MRI were as follows: (a) a satellite lesion around the main tumor, (b) bridging enhancement between the main tumor and satellite lesions. The extent of the intraductal component was measured and classified as mimimal (0-5 mm), moderate (6-15 mm) or wide (>15 mm). RESULTS: In 28 of 47 (60.0%) patients, a wide intraductal component of more than 15 mm was proved histopathologically. Of 28 patients, US and MRI could accurately detect wide intraductal components in 16 patients and 14 patients, respectively. Sensitivity, specificity, and accuracy were 57.1%, 84.2%, and 68.1% respectively for US and 50.0%, 89.5% and 65.9% for MRI, respectively. When both US and MRI results were combined, sensitivity, specificity, and accuracy were 75.0%, 84.2%, and 78.7%. CONCLUSION: Current US examination depicted the intraductal component of breast cancer more accurately than MRI. Further, our study suggests that the use of both US and MRI together is complementary and offers more advantage than US alone.

Establishment of seminars to improve the diagnostic accuracy and effectiveness of breast ultrasound.

PURPOSE: To improve the ability of technicians and physicians to find and diagnose breast lesions in breast ultrasound screening. METHODS: Seminars were organized for technicians and physicians engaged in breast ultrasound screening, and tests were carried out to evaluate the usefulness of the seminars. Each seminar lasted 2 days and comprised lectures and group activities. Pretests and post-tests conducted before and after each seminar, respectively, consisted of 100 questions: 50 about animated images, and 50 about static images. The tests required the participant to find lesions in animated images and estimate the probability of malignancy from static images. RESULTS: In the animated image tests, sensitivity was greater after the seminar, although specificity did not change significantly. In the static image tests, sensitivity increased, and a significant increase was also observed in the receiver operating curve analysis for degree of certainty in diagnosing cancer. CONCLUSION: The seminars improved the participants' ability to find and diagnose breast lesions during ultrasound screening.

The essence of the Japan Radiological Society/Japanese College of Radiology Imaging Guideline.

Diagnostic imaging is undoubtedly important in modern medicine, and final clinical decisions are often made based on it. Fortunately, Japan has the highest numbers of diagnostic imaging instruments, such as CT and MRI devices, and boasts easy access to them as well as a high level of diagnostic accuracy. In consequence, a very large number of imaging examinations are performed, but diagnostic instruments are installed in so many medical facilities that expert management of these examinations tends to be insufficient. Particularly, in order to avoid risks, clinicians have recently become indifferent to indications of imaging modalities and tend to rely on CT or MRI resulting in increasing the number of imaging examinations in Japan. This is a serious problem from the viewpoints of avoidance of unnecessary exposure and medical economy. Under these circumstances, the Japan Radiological Society and Japanese College of Radiology jointly initiated the preparation of new guidelines for diagnostic imaging. However, the field of diagnostic imaging is extremely wide, and it is impossible to cover all diseases. Therefore, in drafting the guidelines, we selected important diseases and focused on "showing evidence and suggestions in the form of clinical questions (CQs)" concerning clinically encountered questions and "describing routine imaging techniques presently considered to be standards to guarantee the quality of imaging examinations". In so doing, we adhered to the basic principles of assuming the readers to be "radiologists specializing in diagnostic imaging", "simultaneously respecting the global standards and attending to the situation in Japan", and "making the guidelines consistent with those of other scientific societies related to imaging". As a result, the guidelines became the largest ever, consisting of 152 CQs, nine areas of imaging techniques, and seven reviews, but no other guidelines in the world summarize problems concerning diagnostic imaging in the form of CQs. In this sense, the guidelines are considered to reflect the abilities of diagnostic radiologists in Japan. The contents of the guidelines are essential knowledge for radiologists, but we believe that they are also of use to general clinicians and clinical radiological technicians. While the number and contents of CQs are still insufficient, and while chapters such as those on imaging in children and emergency imaging need to be supplemented, the guidelines will be serially improved through future revisions. Lastly, we would like to extend our sincere thanks to the 153 members of the drafting committee who authored the guidelines, 12 committee chairpersons who coordinated their efforts, six members of the secretariat, and affiliates of related scientific societies who performed external evaluation.

Monitoring of hepatocellular carcinoma, following proton radiotherapy, with contrast-enhanced color Doppler ultrasonography.

BACKGROUND: We have reported that proton radiotherapy for hepatocellular carcinoma (HCC) is a safe and effective therapeutic option. However, it is difficult to evaluate its effect in certain cases. Recently, it has been reported that the usage of contrast-enhanced color Doppler ultrasonography (CECDU) can improve diagnostic accuracy, both in terms of the presence of hepatic tumor and in the evaluation of treatment. The aim of this study was to determine the usefulness of CECDU in assessing the therapeutic response of HCC treated with proton radiotherapy. METHODS: Twenty-two patients treated with the proton radiotherapy were studied. We inspected HCC lesions by CECDU, before and after the irradiation, over time. The magnitude of blood flow in the HCC was quantified on still images by CECDU. The ratio of the number of color pixels against that of the total number of pixels in the tumor area was defined as the tumor blood flow ratio (TBFR). RESULTS: Immediately after the proton treatment, a transient increase of blood flow in the tumor was recognized in more than half of the patients, while the TBFR was unchanged or decreased in the remaining patients. At longer periods after irradiation, the TBFR in all HCCs gradually decreased, and this reduction of TBFR was statistically significant from 9 months after irradiation. These findings are consistent with those obtained previously by computed tomography (CT) as well as magnetic resonance imaging (MRI). CONCLUSIONS: We propose CECDU as a useful diagnostic option for the evaluation of HCC treated with proton radiotherapy.

Distinct diagnostic criteria for ultrasonographic examination of papillary thyroid carcinoma: a multicenter study.

Recent advances permitting high-resolution ultrasonography have made ultrasonographic examination of nodular thyroid diseases an accessible examination for routine practice. However, diagnostic criteria for ultrasonographic examination of thyroid nodules are not surely established. To identify the optimal strategy for well standardized differential diagnosis of papillary thyroid carcinoma and benign nodules, we evaluated the significance of individual ultrasonographic characteristics of thyroid nodules in a multicenter study. Ten characteristics in ultrasonograms from 53 patients scored by 17 investigators from 15 centers were analyzed by t tests and logistic regression analyses. Between benign and papillary thyroid cancer groups, all characteristics but not size or multiplicity of strong echoes, which suggest calcifications, were significant parameters. Logistic regression analyses showed that border character, shape, and internal echo level are highly significant parameters (p < 0.0005). A multiple logistic regression showed to be the most important predictors of pathologic diagnosis. The diagnostic criterion with border character and internal echo level yielded 93% sensitivity and 92% specificity. In conclusion, univariate and multivariate analyses identified border character, shape, internal echo level, but not strong echoes (calcifications), as important characteristics in differentiating papillary thyroid carcinoma from benign nodules. These results will contribute to standardization of accurate ultrasonographic diagnosis of papillary thyroid carcinoma.

Ultrasound (US) diagnosis of nonpalpable breast cancer.

BACKGROUND: Ultrasound (US) is a standard modality to diagnose breast diseases. To elucidate the usefulness of US in the diagnosis of nonpalpable breast cancers, we reviewed the cases that were treated at our institution. METHODS: Of the 106 cancers that were operated upon at the Tsukuba University Hospital between February 2004 and March 2005, 12 cancers were nonpalpable. We reviewed their US findings, results of US-guided fine needle aspiration cytology (FNAC), core biopsy results, and histological diagnoses. RESULTS: On US, 9 tumors appeared as masses. The US observations were valuable, but a confirmatory diagnosis could not be made. US-guided FNAC was performed in 8 cases; malignancy was suspected in 6 cases. US-guided core biopsy was performed in 9 cases, and it was diagnostic in 7 cases. CONCLUSIONS: Nonpalpable breast cancers can be effectively detected by US, and the diagnosis can be confirmed by US-guided FNAC or core biopsy.

Quantitative evaluation of diagnostic information around the contours in ultrasound images.

PURPOSE: To develop a new contour extraction method for identifying abnormal tissue. METHODS: We combined two techniques: logarithmic K distribution of a scattering model (method 1) and regional discrimination using the characteristics of local ultrasound images (method 2) into an integrated method (method 3) that provides accurate contours, which are essential for quantitizing border information. RESULTS: The diagnostic tissue information around the border of an image can be characterized by its shape and texture statistics. The degrees of circularity and irregularity and the depth-width ratio were calculated for the extracted contours of breast tumors. In addition, gradients, separability, and variance between the two regions along the contour and the area and variance of the internal echoes, were calculated as indices of diagnostic criteria of breast tumors. The quantitized indices were able to discriminate among cysts, fibroadenomas, and cancer. CONCLUSION: In many ultrasound images of breast tumors, the combined techniques, the variance ratio of the logarithmic K distribution to the logarithmic Rayleigh distribution and the multilevel technique with local image information can effectively extract abnormal tissue contours.