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Anaplastic thyroid cancer (ATC) is a rare and highly aggressive cancer for which effective systemic therapy has long been sought. Here, we assessed the efficacy and safety of lenvatinib in patients with unresectable ATC.The study was investigator-initiated and conducted under a multicenter, open-label, nonrandomized, phase II design. Eligibility criteria included pathologically proven ATC; unresectable measurable lesion as defined by RECIST 1.1; age 20 years or older; ECOG PS 0-2; and adequate organ function. The primary end-point was overall survival. Secondary end-points were progression-free survival, objective response rate, disease control rate, clinical benefit rate, and safety.Of 52 patients enrolled from 17 institutions, 42 patients who were confirmed to have ATC were included for efficacy analysis, and 50 patients were included for safety analysis. The estimated 1-year overall survival rate was 11.9% (95% CI, 4.4%-23.6%). One patient (2.4%) achieved complete response, four patients (9.5%) partial response, and 26 patients (61.9%) stable disease, including nine patients (21.4%) who demonstrated durable stable disease, giving an objective response rate of 11.9%, disease control rate of 73.8%, and clinical benefit rate of 33.3%. Adverse events of any grade were observed in 45 patients (90.0%), the most common of which of any grade included loss of appetite (48.0%), fatigue (48.0%), hypertension (44.0%), and palmar-plantar erythrodysesthesia syndrome (26.0%).Lenvatinib treatment resulted in disappointing survival for unresectable ATC patients. Although the number of responders was small, responses were durable, indicating that lenvatinib may be beneficial for selected patients. Further investigation to identify suitable candidates for lenvatinib monotherapy is needed.

Supplementary Figure 3 shows the activation of cell cycle-, and apoptosis-related proteins treated with lenvatinib or sorafenib in OCUT-1C and OCUT-2 cell subcutaneous tumors.

Supplementary Table 2 shows the production of angiogenesis-related cytokines in the supernatant of ATC cells.

Anaplastic thyroid carcinoma (ATC) is a rare but aggressive undifferentiated tumor that frequently metastasizes to the brain. The multiple kinase inhibitor lenvatinib and sorafenib have been approved to treat unresectable differentiated thyroid cancer, and lenvatinib has been approved in Japan to treat ATC. This study compared the effects of lenvatinib and sorafenib in mouse models of central nervous system metastases of ATC. Immunodeficient mice were inoculated with ATC cells, and the effects of lenvatinib and sorafenib were evaluated in subcutaneous- and brain metastasis–mimicking models. Drug distribution was evaluated by imaging tandem mass spectrometry (ITMS). Neither lenvatinib nor sorafenib affected the viability of ATC cell lines, whereas both inhibited VEGF secretion by ATC cells. In the subcutaneous tumor model, both lenvatinib and sorafenib inhibited growth and were associated with reduced tumor microvessel density. In the brain metastasis–mimicking model, lenvatinib, but not sorafenib, inhibited the growth of ATC cells and reduced microvessel density in brain lesions. ITMS showed that lenvatinib was well-distributed in both subcutaneous and brain lesions, whereas the distribution of sorafenib was lower in brain than in subcutaneous lesions. These results demonstrate that lenvatinib is well-distributed in mouse models of ATC, and inhibited the growth of ATC brain lesions predominantly by inhibiting angiogenesis, suggesting that lenvatinib is highly potent against ATC brain metastases.

Supplementary Figure S1. Copy number alteration profile for TERT locus in cell lines harboring homozygous TERT promoter mutations. Copy number changes are expressed as shades of red (gain) or blue (loss). Names of cell lines and log-ratio (lr) values are shown. Supplementary Figure S2. Genome-wide copy number alteration profile of PTC-derived cell lines (top) vs. ATC-derived cell lines (bottom). Chromosome numbers are shown on the top panel. Copy number changes are expressed as shades of red (gain) or blue (loss). Supplementary Figure S3. Representation of the chromosomal location for the 16 recurrent copy number alterations identified by GISTIC in 58 thyroid cancer cell lines. Supplementary Figure S4. Hierarchical clustering of gene expression profiles of thyroid cancer cell lines. Spearman correlation distance metric and Ward agglomeration method were used. Colors identify cell lines originating from tumors of different histologic subtypes. Font color indicates the histological type of the primary tumor from which these cell lines were generated, as follows: red= anaplastic; purple= poorly differentiated; green=follicular; blue= papillary thyroid cancer. Colored dots represent driver alteration: blue= BRAFV600E; orange= N-/H-/KRAS; purple= CCDC6-RET; green= NF1; yellow= MKRN1-BRAF; gray= FGFR2-OGDH; black= unknown. Supplementary Figure S5. Expression of individual genes in the thyroid differentiation signature. Supplementary Figure S6. Correlation of BRS calculated using our algorithm vs. the algorithm published by TCGA. The color of the circles indicates tumor genotype: blue- BRAFV600E, red- RAS gene mutation, green - neither BRAFV600E nor RAS mutation, orange - both BRAFV600E and RAS gene mutations present. Tumors with low BRS are BRAFV600E-like; tumors with high BRS are RAS-like. Supplementary Figure S7. Representative pictures of BAM files from MSK-IMPACT sequencing of CUTC5 specimens for three mutations: A. BRAF p.V600E; B. TP53 C135W; and C. ARID1A E1108*. Each panel shows the sequencing reads for the cell line (top) and primary tumor (bottom). The reference allele and protein translation is shown in the bottommost area, whereas the alternative allele is highlighted in the sequencing reads within each panel. Percentages on the left represent the frequency of the alternative allele in each of the samples tested. All three mutations are detected at low frequencies in the original pleural effusion sample, from which CUTC5 cell line was established. Supplementary Figure S8. Evolution of allelic frequencies from thyroid primary tumors to cell lines for A. TERT promoter; and B. TP53. Graphic representation of the alternative allele frequencies ("Alt Allele Freq"). Cell line names are color-coded on the right side of each graph. All TERT promoter mutations are the canonical c.-124C>T or c.-146C>T, whereas TP53 mutations are indicated. Supplementary Figure S9. Genome-wide copy number alteration profile of primary tumor/cell line and/or patient-derived xenograft (PDX) paired samples from 11 patients. Chromosome numbers are shown on the top panel. Copy number changes are expressed as shades of red (gain) or blue (loss). Colored dots indicate specimen types: cell line (green), primary tumor (orange) or PDX (purple). Cell line names are provided. Supplementary Figure S10. Global MSK-IMPACT copy number profile of THJ560 paired samples. Sample-centered representation of the copy number alterations, expressed as log2 ratios, for primary tumor (top panel), cell line (middle panel) and patient-derived xenograft (bottom panel). Table inserts show the top deletions, corresponding to the CDKN2A/CDKN2B locus for the cell line and xenograft, which are absent in the primary tumor.

Supplementary Table S1. Cell line authentication by Short Tandem Repeat Profiling (STR) Supplementary Table S2. Full list of genetic variants identified by MSK-IMPACT sequencing Supplementary Table S3. Details for identified high-confidence gene rearrangements resulting in in-frame fusion proteins Supplementary Table S4. Recurrent copy number alterations in thyroid cancer cell lines. Supplementary Table S5. Genes located within the recurrent copy number alteration regions. Supplementary Table S6. Differentially expressed genes, which are located within CNA regions. "Matching_CNA_type" column indicates whether the direction of the expression change corresponds to the CNA type (133 out of 134, overexpression for gene amplification and underexpression for gene deletions). Supplementary Table S7. Thyroid cancer cell lines gene expression data. Normalized gene expression values for all genes in the 44 cell lines assessed by Affymetrix expression microarray in this study ("CU" prefix, University of Colorado). Supplementary Table S8. Genes with differential expression in PTC vs. ATC cell lines. List of differentially expressed genes between PTC-derived vs. ATC-derived cell lines (limma, adjusted p-value

Supplementary Methods, Supplementary Figure and Table Legends

Purpose:Thyroid cancer cell lines are valuable models but have been neglected in pancancer genomic studies. Moreover, their misidentification has been a significant problem. We aim to provide a validated dataset for thyroid cancer researchers.Experimental Design:We performed next-generation sequencing (NGS) and analyzed the transcriptome of 60 authenticated thyroid cell lines and compared our findings with the known genomic defects in human thyroid cancers.Results:Unsupervised transcriptomic analysis showed that 94% of thyroid cell lines clustered distinctly from other lineages. Thyroid cancer cell line mutations recapitulate those found in primary tumors (e.g., BRAF, RAS, or gene fusions). Mutations in the TERT promoter (83%) and TP53 (71%) were highly prevalent. There were frequent alterations in PTEN, PIK3CA, and of members of the SWI/SNF chromatin remodeling complex, mismatch repair, cell-cycle checkpoint, and histone methyl- and acetyltransferase functional groups. Copy number alterations (CNA) were more prevalent in cell lines derived from advanced versus differentiated cancers, as reported in primary tumors, although the precise CNAs were only partially recapitulated. Transcriptomic analysis showed that all cell lines were profoundly dedifferentiated, regardless of their derivation, making them good models for advanced disease. However, they maintained the BRAFV600E versus RAS-dependent consequences on MAPK transcriptional output, which correlated with differential sensitivity to MEK inhibitors. Paired primary tumor-cell line samples showed high concordance of mutations. Complete loss of p53 function in TP53 heterozygous tumors was the most prominent event selected during in vitro immortalization.Conclusions:This cell line resource will help inform future preclinical studies exploring tumor-specific dependencies.

Hypoparathyroidism is a major complication of thyroid surgery. To avoid this complication, visual identification of the parathyroid glands is essential. However, its effectiveness depends heavily on the surgeon's expertise. Here, we describe a novel method, the gauze blotting technique, to immunochemically identify the parathyroid glands during thyroid surgery. Twenty-three patients who underwent thyroid lobectomy were enrolled in this study; 16 and 7 had benign and malignant thyroid diseases, respectively. After visually identifying candidate nodules for the parathyroid gland, a piece of dry gauze (5 mm × 10 mm) was applied to each tissue until it was moistened by exudates from the tissue. Pieces of gauze were also applied to the thyroid gland and adipose tissue located away from the candidate nodules. The gauze was immersed in saline, and the intact PTH (i-PTH) level of the supernatant was measured. The median PTH level for the parathyroid glands was 1,060 pg/mL, which was significantly higher than that for the thyroid gland (34 pg/mL) and adipose tissue (28 pg/mL) (p0.001). The cut-off value to distinguish the parathyroid gland from other tissues was 68 pg/mL with a positive predictive value, negative predictive value, sensitivity, and specificity of 84.6%, 88.8%, 86.8%, and 86.7%, respectively. A value ≥250 pg/mL yielded a 100% positive predictive value. Our novel gauze blotting technique can identify the parathyroid glands without damaging tissues during thyroid surgery.

The World Health Organization (WHO) classifies follicular thyroid carcinoma (FTC) into three categories: minimally invasive (mFTC), encapsulated angioinvasive (eaFTC), and widely invasive (wFTC). This study investigated whether this classification is appropriate. We enrolled 523 patients who underwent initial surgery at Kuma Hospital between 1998 and 2015 and were diagnosed with FTC. Capsular invasion (CI) was classified as none, minimal (microscopic), or wide (macroscopic) invasion. Vascular invasion (VI) was divided according to the number of invasive foci into three degrees: VI(-), VI(1+), and VI(2+). For 507 M0 patients, age ≥55 years (p = 0.004), non-oxyphilic histology (p = 0.043), and male sex (p0.001) predicted poor distant recurrence-free survival (DR-FS) on univariate analysis; however, tumor size4 cm and wide CI did not. The DR-FS rates significantly decreased from VI(-) to VI(2+) in a step-by-step fashion, including VI(-) vs. VI(1+) (p = 0.011) and VI(1+) vs. VI(2+) (p = 0.014). Multivariate analysis revealed that older age (p = 0.0004), non-oxyphilic histology (p = 0.041), male sex (p = 0.0052), VI(1+) (p = 0.017), and VI(2+) (p0.001) independently predicted distant recurrence. The DR-FS rates did not significantly differ among mFTC, wFTC/VI(-), and eaFTC/VI(1+). The DR-FS rate of eaFTC/VI(2+) was worse than that of eaFTC/VI(1+) (p = 0.042), but did not differ from that of wFTC/VI(1+/2+). Our findings suggest that subclassifying eaFTC according to the degree of VI and restricting wFTC to VI-positive cases would be better in the WHO classification. Revising the definition for wide CI is recommended.

Intrathyroidal thymic carcinoma (ITTC) is a rare malignancy of the thyroid. It is thought to originate from ectopic thymic tissue or embryonic thymic rest, in, or adjacent to, the thyroid. We analyzed the backgrounds, clinicopathological features, and prognosis of 20 patients with ITTC, treated at our hospital. Thirteen of the 15 patients (86%) who underwent ultrasonography were diagnosed as malignant, based on imaging findings. 16 of the 17 patients (93%) who underwent cytology, were diagnosed or suspected to be malignant. Locally curative surgery (thyroidectomy and lymph node dissection) was performed for 19 patients. Large tumor size (4 cm) was positively related to pathological node metastasis (p = 0.0389). Fourteen patients, including nine Ex-positive patients, underwent adjuvant external beam radiotherapy (EBRT) of the neck after surgery. Two patients showed recurrence of thyroid bed after and neither of them underwent adjuvant EBRT after surgery. Two patients who underwent EBRT showed recurrences of the lateral nodes (level V and level II), but they were easily dissected by re-operation. Ten- and 20-year local recurrence-free survival rates were 84.9% and 60.6%, respectively. To date, four patients showed distant recurrence, and 10- and 20-year distant recurrence-free survival rates were 75.0% and 75.0%, respectively. Our findings indicate that 1) the prognosis of ITTC is generally favorable, and 2) large tumor size is significantly related to lymph node metastasis. Two patients showing recurrence of the central region did not undergo EBRT; thus, further comparative studies are desirable to elucidate whether EBRT can prevent significant local recurrence.

Thyroid tumors arising from follicular cells can generally be divided into malignant and benign tumors. However, some cases are difficult to clearly diagnose whether they are benign or malignant. Therefore, in the most recent version of World Health Organization (WHO) classification, some borderline lesions such as follicular tumor of uncertain malignant potential (FT-UMP), well-differentiated tumor of uncertain malignant potential (WDT-UMP), and noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) were proposed. In this study, we investigated the clinical aspects, including the prognosis, of FT-UMP patients. We investigated the clinical features of 339 patients with FT-UMP. On ultrasound, 68% of the tumors were diagnosed as intermediate, and only 5% of those tumors were diagnosed as malignant. On cytology, 40% of the tumors were diagnosed as follicular neoplasm, and only 1% of these were suspected to be or diagnosed as malignancy. The diagnosis was based on questionable capsular invasion for 332 patients, questionable vascular invasion for 2 patients, and both for 5 patients. Eighty-six percent of the tumors showed low cell proliferation activity. To date, five patients (1%) have shown distant recurrence during postoperative follow-up and underwent various treatments such as radioactive iodine therapy, orthopedic surgery, and denosumab injection. None of these patients have died due to thyroid carcinoma. Our findings suggest that FT-UMP is generally an indolent disease, but some patients show distant recurrence. Physicians should carefully follow patients, although it remains unknown how long they should be observed after surgery.

PURPOSE The molecular subtype of breast cancer is an important component of establishing the appropriate treatment strategy. In clinical practice, molecular subtypes are determined by receptor expressions. In this study, we developed a model using deep learning to determine receptor expressions from mammograms. METHODS A developing data set and a test data set were generated from mammograms from the affected side of patients who were pathologically diagnosed with breast cancer from January 2006 through December 2016 and from January 2017 through December 2017, respectively. The developing data sets were used to train and validate the DL-based model with five-fold cross-validation for classifying expression of estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor 2-neu (HER2). The area under the curves (AUCs) for each receptor were evaluated with the independent test data set. RESULTS The developing data set and the test data set included 1,448 images (997 ER-positive and 386 ER-negative, 641 PgR-positive and 695 PgR-negative, and 220 HER2-enriched and 1,109 non–HER2-enriched) and 225 images (176 ER-positive and 40 ER-negative, 101 PgR-positive and 117 PgR-negative, and 53 HER2-enriched and 165 non–HER2-enriched), respectively. The AUC of ER-positive or -negative in the test data set was 0.67 (0.58-0.76), the AUC of PgR-positive or -negative was 0.61 (0.53-0.68), and the AUC of HER2-enriched or non–HER2-enriched was 0.75 (0.68-0.82). CONCLUSION The DL-based model effectively classified the receptor expressions from the mammograms. Applying the DL-based model to predict breast cancer classification with a noninvasive approach would have additive value to patients.

Parathyroid Lipoadenoma (PLA) contains abundant mature adipose tissue and is a rare cause of hyperparathyroidism. This study aimed to investigate the clinical features of PLA in nine patients with primary hyperparathyroidism, including two men and seven women, with ages ranging from 45-84 years (median 60 years). PLA accounted for 0.5% of all parathyroid tumors during the study period. One patient presented with anorexia due to hypercalcemia; however, the other eight patients were asymptomatic. The median preoperative serum intact-parathyroid hormone (iPTH) and calcium levels were 143 pg/mL (range, 102-378) and 10.8 mg/dL (range, 10.3-11.3), respectively. PLA was difficult to identify using ultrasonography (US) as it appears as a moderately hyperechoic nodule and is difficult to distinguish from the surrounding adipose tissues. Only 33% of the lesions (three out of nine lesions) were accurately identified. However, they could be distinctly differentiated from the surrounding tissue using computed tomography (CT). All PLAs were also detected using the sesta-methoxyisobutylisonitrile single-photon emission-computed tomography (SPECT). All the patients were treated by a single gland extirpation. The median size and weight of the PLA were 14 mm (range, 10-22) and 567 mg (range, 200-1,533), respectively. In conclusion, the clinical manifestations of PLA are similar to those of ordinal parathyroid adenomas, except for their unique US and CT images. PLA should be considered as a potential etiologic factor in cases of hyperparathyroidism when the lesions are demonstrated as hyperechoic nodules or unidentified by US but detected by CT or SPECT imaging.

Older age is recognized as a predictor of poor prognosis in papillary thyroid carcinoma (PTC) patients. However, young age is associated with disease progression of PTC measuring 1 cm or smaller in patients on active surveillance. In this study, we investigated the relationship between patient age and prognosis of PTC belonging to very low-, low-, and intermediate-risk groups based on the guidelines published by the Japan Association of Endocrine Surgery in 2018. We enrolled 4,870 PTC patients with no high-risk features and assigned each to one of three categories: very low risk (N = 1,161), low risk (N = 1,746), and intermediate risk (N = 1,963). In very low-risk patients, the local recurrence-free survival (RFS) rate of young patients (55 years) was significantly worse (p = 0.0437) than that of older patients (≥55 years). In low-risk patients, although age did not affect local recurrence, older patients were more likely to show distant recurrence on univariate (p = 0.0005) and multivariate analyses (p = 0.0017). In the intermediate-risk series, the local RFS rate of older patients tended to be poor (p = 0.0538), and older age was significantly associated with distant RFS (univariate, p = 0.0356; multivariate, p = 0.0439) and carcinoma death (univariate, p0.0001; multivariate, not done because of no other suitable factors). The prognostic significance of patient age depends on risk classification: younger age significantly predicts local recurrence in very low-risk PTC, while older age predicts worse prognosis in low- and intermediate-risk patients. These findings indicate that young age is related to rapid growth in early-phase PTC.

Background/aim Radioactive iodine-refractory differentiated thyroid carcinoma (RR-DTC) has been treated with multi-kinase inhibitors (MKIs), e.g., sorafenib (SOR) and lenvatinib (LEN). We analyzed the outcomes of RR-DTC patients who underwent SOR or LEN treatment at Kuma Hospital. Patients and methods We enrolled 21 and 18 patients treated with SOR and LEN, respectively. Results The incidence of partial response in the LEN group was significantly higher than that in the SOR group. Serum thyroglobulin significantly decreased from the beginning of treatment to 1 month later in the LEN group (not in the SOR group). The neutrophil-lymphocyte ratio (NLR) was significantly decreased at 1 month later in both groups. An NLR ≥3 at the start of MKI treatment had a prognostic impact. Conclusion For RR-DTC, LEN could be more effective than SOR, at least in the short term. The first-line drug should be selected based on other factors (e.g., adverse events, patient background).

Background/aim To date, thyroglobulin-doubling rate (Tg-DR) and tumor volume-doubling rate (TV-DR) of metastatic lesions have been identified as dynamic prognostic factors for differentiated thyroid carcinoma (DTC). In this study, we investigated the prognostic impact for another dynamic factor, the neutrophil-to-lymphocyte ratio (NLR), for DTC with distant metastasis. Patients and methods We enrolled 321 patients in total, and NLR at the first detection of distant metastasis (initial NLR) was collected for 312. Results Patients with initial NLR >3 had a significantly poorer cause-specific survival than those with initial NLR ≤3. On multivariate analysis, initial NLR >3 was recognized as an independent prognostic factor together with Tg-DR >1/year, TV-DR >1/year, radioactive iodine-refractory distant metastasis, and distant metastasis to organs other than the lung. Conclusion Careful observation and active therapies, including multitarget kinase inhibitors, are recommended for patients with NLR >3 at the first detection of distant metastasis or during follow-up.

The Japan Associations of Endocrine Surgeons has developed the revised version of the Clinical Practice Guidelines for Thyroid Tumors. This article describes the guidelines translated into English for the 35 clinical questions relevant to the therapeutic management of thyroid cancers. The objective of the guidelines is to improve health-related outcomes in patients with thyroid tumors by enabling users to make their practice evidence-based and by minimizing any variations in clinical practice due to gaps in evidential knowledge among physicians. The guidelines give representative flow-charts on the management of papillary, follicular, medullary, and anaplastic thyroid carcinoma, along with recommendations for clinical questions by presenting evidence on the relevant outcomes including benefits, risks, and health conditions from patients' perspective. Therapeutic actions were recommended or not recommended either strongly (◎◎◎ or XXX) based on good evidence (😊)/good expert consensus (+++), or weakly (◎, ◎◎ or X, XX) based on poor evidence (😣)/poor expert consensus (+ or ++). Only 10 of the 51 recommendations given in the guidelines were supported by good evidence, whereas 35 were supported by good expert consensus. While implementing the current guidelines would be of help to achieve the objective, we need further clinical research to make our shared decision making to be more evidence-based.

Active surveillance for papillary thyroid microcarcinomas (PTMCs) initiated in Japan is becoming adopted worldwide as a management option. However, it remains unclear how to manage newly appearing PTMCs in the remnant thyroid after hemithyroidectomy. We investigated the outcomes of similar observational management (OM) for PTMCs appearing in the remnant thyroid after hemithyroidectomy for papillary thyroid carcinoma (PTC) and benign thyroid nodules. Eighty-three patients were newly diagnosed with PTMC in the remnant thyroid between January 1998 and March 2017. Of these, 42 patients underwent OM with3 times ultrasound examinations. Their initial diagnoses were PTC (initially malignant group) in 37 patients and benign nodule (initially benign group) in 5 patients. We calculated the tumor volume doubling rate (TV-DR) during OM for each PTMC. The TV-DR (/year) was-0.1, -0.1-0.1, 0.1-0.5, and0.5 in 12, 19, 5, and 6 patients, respectively. The TV-DRs in both groups did not statistically differ, but six patients (16%) in the initially malignant group showed moderate growth (TV-DR0.5/year). They underwent conversion surgery and none of them had further recurrence. The remaining 36 patients retained OM without disease progression. The TV-DR in the initially malignant group was not significantly associated with patients' backgrounds or their initial clinicopathological features. None of the patients in this study showed distant metastases/recurrences or died of thyroid carcinoma. Although a portion of PTMCs appearing after hemithyroidectomy for thyroid malignancy are moderately progressive, OM may be acceptable as a management option for PTMCs appearing in the remnant thyroid after hemithyroidectomy.

Objectives The objective of this study was to develop and validate a state-of-the-art, deep learning (DL)-based model for detecting breast cancers on mammography. Methods Mammograms in a hospital development dataset, a hospital test dataset, and a clinic test dataset were retrospectively collected from January 2006 through December 2017 in Osaka City University Hospital and Medcity21 Clinic. The hospital development dataset and a publicly available digital database for screening mammography (DDSM) dataset were used to train and to validate the RetinaNet, one type of DL-based model, with five-fold cross-validation. The model’s sensitivity and mean false positive indications per image (mFPI) and partial area under the curve (AUC) with 1.0 mFPI for both test datasets were externally assessed with the test datasets. Results The hospital development dataset, hospital test dataset, clinic test dataset, and DDSM development dataset included a total of 3179 images (1448 malignant images), 491 images (225 malignant images), 2821 images (37 malignant images), and 1457 malignant images, respectively. The proposed model detected all cancers with a 0.45–0.47 mFPI and had partial AUCs of 0.93 in both test datasets. Conclusions The DL-based model developed for this study was able to detect all breast cancers with a very low mFPI. Our DL-based model achieved the highest performance to date, which might lead to improved diagnosis for breast cancer.

Some thyroid tumors that are cytologically diagnosed as benign may be pathologically diagnosed as malignant. Here, we investigated the long-term outcomes of patients with thyroid tumors with benign cytology, and the factors for malignancy. We retrospectively reviewed the cases of 3,102 patients with thyroid tumors1 cm cytologically diagnosed as benign at our hospital during a 1-year period from January 2007. The median follow-up duration for all patients was 68.7 (range 0.0-168.7) months. Immediate surgery and delayed surgery were performed in 393 and 148 patients, respectively. Eventually, 541 (17.4%) of the 3,102 patients underwent a thyroidectomy, and 2,561 (82.6%) were observed without surgery. Among the surgically treated patients, the tumors of 525 (97.0%) and 16 (3.0%) were pathologically diagnosed as benign and malignant, respectively. There was no significant difference in age, gender, tumor size, serum thyroglobulin level at surgery, or the tumor volume-doubling rate (TV-DR) between the benign and malignant cases. Only the ultrasonographic findings based on our hospital's classification system were directly and significantly linked to pathological diagnosis (p0.01). Among the tumors of the 667 patients who were followed without surgery for10 years, 89.9% remained unchanged and 7.2% were reduced in size. Ultrasonographic evaluation provides important information for therapeutic decision-making regarding surgery versus observation for cytologically benign tumors.

A 52-year-old woman experienced right breast pain and detected a mammary tumor 6 months ago. She then noticed rapid enlargement of the tumor, which was suspected to be a borderline malignant phyllodes tumor. The tumor size was approximately 15 cm and presented with skin congestion but without infiltration. The tumor showed internal heterogeneous echo and rich blood flow signals on breast ultrasonography. Ultrasonography also showed swelling of the axillary lymph node. Lymph node cytology revealed the presence of atypical cells in the lymph node, and CT scan showed lymph node metastasis in the right axilla and no distant metastases. We performed mastectomy with lymph node sampling. Pathological examination of the specimens confirmed a malignant phyllodes tumor and a metastatic lymph node. One month later, a subcutaneous mass and multiple pulmonary nodules were identified on a chest CT scan. Chest wall irradiation(45 Gy)and chemotherapy were performed, but the number of pulmonary nodules, pleural effusion, and size of the subcutaneous mass continued to increase. Although she underwent another chemotherapeutic treatment, she died 5 months after the surgery. Thus, we report a case of a malignant phyllodes tumor with an extremely rare lymph node metastasis, which rapidly progressed even though multimodal therapy was performed.

Objective We evaluated the utility of continuous intraoperative neuromonitoring (CIONM) during surgery for thyroid cancer (TC) in an educational university hospital. Study Design Prospective observational study. Methods During the period April 2016 to March 2017, 43 patients who underwent standardized surgery with CIONM were prospectively included: 5 men and 38 women, 24-87 years old (median 52 years); 23 lobectomies and 20 total thyroidectomies with node dissection were conducted. Thirty-six operations were performed by a supervising surgeon, and seven were performed by trainees. Results Temporal vocal cord paresis (VCP) was identified in 9 of 63 nerves at risk (14.3%) by postoperative laryngoscopy. VCP was not related to clinical factors including the surgeon's experience or the severe nerve stress demonstrated by CIONM. A significant relation only between VCP and loss of signal (LOS) was demonstrated (P = .002). The recovery of VCP was rapid (

Purpose: Thyroid cancer cell lines are valuable models but have been neglected in pancancer genomic studies. Moreover, their misidentification has been a significant problem. We aim to provide a validated dataset for thyroid cancer researchers. Experimental Design: We performed next-generation sequencing (NGS) and analyzed the transcriptome of 60 authenticated thyroid cell lines and compared our findings with the known genomic defects in human thyroid cancers. Results: Unsupervised transcriptomic analysis showed that 94% of thyroid cell lines clustered distinctly from other lineages. Thyroid cancer cell line mutations recapitulate those found in primary tumors (e.g., BRAF, RAS, or gene fusions). Mutations in the TERT promoter (83%) and TP53 (71%) were highly prevalent. There were frequent alterations in PTEN, PIK3CA, and of members of the SWI/SNF chromatin remodeling complex, mismatch repair, cell-cycle checkpoint, and histone methyl- and acetyltransferase functional groups. Copy number alterations (CNA) were more prevalent in cell lines derived from advanced versus differentiated cancers, as reported in primary tumors, although the precise CNAs were only partially recapitulated. Transcriptomic analysis showed that all cell lines were profoundly dedifferentiated, regardless of their derivation, making them good models for advanced disease. However, they maintained the BRAFV600E versus RAS-dependent consequences on MAPK transcriptional output, which correlated with differential sensitivity to MEK inhibitors. Paired primary tumor-cell line samples showed high concordance of mutations. Complete loss of p53 function in TP53 heterozygous tumors was the most prominent event selected during in vitro immortalization. Conclusions: This cell line resource will help inform future preclinical studies exploring tumor-specific dependencies.

The purpose of this study was to compare the efficacy of the pre-prescription of garenoxacin mesylate hydrate (GRNX) with that of moxifloxacin hydrochloride (MFLX) in the management of breast cancer patients with low-risk febrile neutropenia. Data from female patients who had been instructed to take previously prescribed oral GRNX or MFLX for 3 days during adjuvant and neoadjuvant chemotherapy if their body temperature exceeded 38 °C were analyzed. This study compared the effectiveness between these fluoroquinolones using a propensity score matching analysis. The 330 patients received 1192 administrations of chemotherapy between May 2007 and April 2014 and 136 (41.2%) patients had a total of 212 (17.8%) febrile episodes. The frequencies of febrile episodes were 19.5% (113/579) and 16.2% (99/613) in the GRNX and MFLX groups, respectively. After propensity score matching, 384 episodes were matched in each group. Febrile events occurred in 80 and 56 cases in the GRNX and MFLX groups, respectively. Treatment success was identified in 80.0% (64/80) of cases in the GRNX group and 64.3% (36/56) of cases in the MFLX group (P = 0.0494). Additionally, the therapeutic use of granulocyte-colony stimulating factor was 6.3% (5/80) of cases in the GRNX group and 17.9% (10/56) of cases in the MFLX group (P = 0.0498). There were few differences in the frequency of adverse effects between the two groups. These results indicate that the pre-prescription of GRNX may be a more effective option for the management of low-risk febrile neutropenia during adjuvant and neoadjuvant chemotherapy for breast cancer.

Widely invasive follicular thyroid carcinoma (wi-FTC) is regarded as having an aggressive character and a dire prognosis, but it has not been known whether all wi-FTCs have a dire prognosis. Herein we retrospectively analyzed the cases of 133 patients with wi-FTCs to determine the prognostic significance of vascular invasion and cell-proliferation activity based on the Ki-67 labeling index (LI). Of the 119 patients without distant metastasis (M0), 11 (9.2%) showed recurrence during the postoperative follow-up. In a univariate analysis, the recurrence-free survival (RFS) rates of the M0 patients with vascular invasion and those with a Ki-67 LI ≥5% were significantly poorer (p = 0.0013 and p = 0.0268, respectively) than those of the patients without vascular invasion or with a Ki-67 LI5%. Other clinicopathological factors such as patient age, gender, tumor size, and oxyphilic tumor were not significantly related to the patients' RFS. In a multivariate analysis, positive vascular invasion independently affected the RFS (p = 0.0133), but Ki-675% did not (p = 0.1348). To date, only five patients have died of their thyroid carcinoma; four cases were M1. In conclusion, although M0 wi-FTC generally has a favorable prognosis, cases with positive vascular invasion or a high Ki-67 LI are likely to recur, and careful postoperative follow-up is necessary.

A 59-year-old female was performed a left mastectomy with axillary lymph node dissection. Final diagnosis of the surgical specimen was left breast cancer pT2N1M0, Stage ⅡB, Luminal type. She was treated with adjuvant endocrine therapy, however, chest wall recurrence was identified at 1 year and 3 months after surgery, and curative resection of this tumor and radiotherapy were performed. Nine months later, she was admitted to the hospital for cervical pain and dyspnea, and magnetic resonance imaging showed bone metastasis in cervical vertebra which compressed spinal cord. Although cervical fusion therapy was performed, she died 39 days later. Metastasis spinal cord compression in breast cancer patients may result in irreversible spinal cord injury if treatment is delayed. Rapid diagnosis and systemic treatment for oncologic emergency are significant.

The patient was 54 years old, female. She was aware of gradually worsening right peri-eyelid swelling 2 years before the first presentation to our dermatology department. She underwent biopsy of eyelid skin 2 times. Nevertheless, definitive diagnosis was not obtained. Two months after the initial examination, right anterior thoracic swelling appeared, and right axillary, right subclavian, and interpectoral lymphadenopathy were detected. She was referred to our department for diagnosing metastatic breast cancer. Ultrasonography showed hypoechoic lesion with distortion(largest lesion2 cm)in right breast, which was suspected to be a breast cancer. The results of breast core needle biopsy, the third time's eyelid skin biopsy and additional imaging studies confirmed T2N3M1, Stage Ⅳ right mammary invasive lobular carcinoma with metastasis to the eyelid skin, right axillary lymph nodes, right subclavian lymph nodes and the subcutaneous tissue of the right back. Immunohistochemical studies showed ER-positive, PgR-negative, HER2-negative, and low Ki-67 expression. Endocrine therapy with letrozole was initiated, which maintained stable disease without compromising the quality of life.

Seventy years old woman noticed a mass in her right breast before 3 years. Since she had ulcer bleeding, she visited our hospital. In physical findings, a hemorrhagic about 8 cm mass with an ulcer was found in the upper right breast. Breast ultrasonography revealed a large tumor of approximately 8 cm in the right A area, and needle biopsy revealed invasive ductal carcinoma(ER positive, PgR positive, HER2 positive, Ki-67 low expression). Right axillary lymph node metastasis was confirmed, but no clear distant metastasis was observed. Pretreatment diagnosis was right breast cancer, cT4bN1M0, Stage ⅢB, Luminal HER. Chemotherapy was started with pertuzumab, trastuzumab, and docetaxel, and the tumor was reduced after 6 cycles. Due to side effects, the drug was changed to a molecular targeted drug only and the treatment was continued. However, redness was observed in the entire right breast, and breast cancer skin metastasis was suspected. Since the dermatitis caused by metronidazole gel was also distinguished, the redness was improved when the application was stopped. When confirmed by a patch test, a reaction to metronidazole gel was observed, leading to the diagnosis of dermatitis caused by metronidazole gel.

Anaplastic thyroid cancer (ATC) is a rarely occurring refractory disease. While recent clinical trials have demonstrated the efficacy of tyrosine kinase inhibitor (TKI) therapy for ATC, evidence is scarce in clinical practice. In this study, we reviewed our initial experiences with TKI treatment in ATC patients with the aim of revealing the efficacy and safety of the same in clinical practice. We retrospectively reviewed our experiences with TKI treatment use in ATC patients diagnosed at our institute from 2014 to 2019. Changes in the patients' neutrophil-to-lymphocyte ratio (NLR) by TKI therapy introduction as well as their clinical factors to indicate the efficacy were examined. Seven patients showed no indication for TKI treatment, while 13 (65%) received treatment. The median duration of TKI treatment was 1.9 months. All patients died, and the overall survival period from diagnosis was 4.7 (95% confidence interval: 2.0-11.5) months. Adverse events ≥Grade 3 were observed commonly (92.3%), and resulted in the termination of TKI treatment in six cases (46.1%). Existence of multiple unfavorable characteristics (higher Prognostic Index) was associated with poor survival. The NLR decreased after the introduction of TKIs and increased again when treatment failed. The response rate to TKI among the ATC patients were approximately 30% in practice. Although the duration of the response was short, several patients demonstrated long survival durations when TKI treatment was provided after successful multidisciplinary treatment to control local disease. Decreases in high NLR values during treatment may suggest the continued effect of TKIs.

To demonstrate how artificial intelligence (AI) can expand radiologists’ capacity, we visualized the features of invasive ductal carcinomas (IDCs) that our algorithm, developed and validated for basic pathological classification on mammograms, had focused on. IDC datasets were built using mammograms from patients diagnosed with IDCs from January 2006 to December 2017. The developing dataset was used to train and validate a VGG-16 deep learning (DL) network. The true positives (TPs) and accuracy of the algorithm were externally evaluated using the test dataset. A visualization technique was applied to the algorithm to determine which malignant findings on mammograms were revealed. The datasets were split into a developing dataset (988 images) and a test dataset (131 images). The proposed algorithm diagnosed 62 TPs with an accuracy of 0.61–0.70. The visualization of features on the mammograms revealed that the tubule forming, solid, and scirrhous types of IDCs exhibited visible features on the surroundings, corners of the masses, and architectural distortions, respectively. We successfully showed that features isolated by a DL-based algorithm trained to classify IDCs were indeed those known to be associated with each pathology. Thus, using AI can expand the capacity of radiologists through the discovery of previously unknown findings.

Background/aim Infusion reactions (IRs) often occur with trastuzumab. Although premedication by non-steroidal anti-inflammatory drugs can be effective to a certain extent, IRs are still common and infrequently severe. Therefore, a predictive marker that can select patients requiring further prophylaxis is useful for appropriate prevention, but remains unclear. Patients and methods We conducted a retrospective analysis for 136 consecutive female inpatients aged 18 years and older who received 8 mg/kg of the initial trastuzumab administration for breast cancer with a 25-mg dose of rectal diclofenac before trastuzumab infusion between May 2007 and April 2019, in order to assess IRs. Results Overall, 57 patients were eligible for inclusion in the study. IRs were observed in 17.5% (10/57) of the patients. Univariate analysis showed that patients with a low eosinophil percentage (≤2%) were associated with IRs (p=0.016). Conclusion A low eosinophil percentage can be a useful new predictive marker for trastuzumab-induced IRs in patients with breast cancer.