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Background: Analytical information obtained from clinical tissue samples has recently become more important due to recent advancements in the clinical practice of medicine, for example, gene panel testing. However, acquiring and managing the sample quality, which greatly influences the analyses, are not sufficient and hence requires immediate attention. We introduced time stamp (TS) recording and documentation using the Standard PREanalytical Code (SPREC) for breast cancer surgery samples to monitor and control their quality. Materials and Methods: The TS recording used SPREC for quality control of each sample by recording seven factors: type of sample, type of collection, warm ischemia time (WIT), cold ischemia time (CIT), fixation type, fixation time (FT), and long-term storage. The responsibilities to record each factor were assigned among group members (breast surgeons, anesthesiologists, pathologists, operating room nurses, and medical technologists in pathology). Results: Records based on SPREC were recorded for 393 surgical cases of first-time breast cancer patients performed at the Kanagawa Cancer Center from May 2018 to April 2019. The vascular clamp time was defined as when skin flap formation was completed, regardless of the surgical procedure. An anesthesiologist recorded the vascular clamp time and sample collection time, and the pathologist recorded the fixation start time and fixation end time. WIT was 23 (3-116) minutes (breast-conserving surgery, 11 [3-38] minutes; mastectomy, 26 [5-116] minutes; and nipple-sparing mastectomy, 39 [31-43] minutes), CIT was 37 (3-1052) minutes, and FT was 43 (17-115) hours. The median CIT and FT were significantly shortened after introducing the TS system, and the variabilities were reduced. Conclusion: A TS system for quality control of breast cancer surgical sample functions well due to the establishment of highly versatile WIT and a working group consisting of multiple members of different occupations who shared roles.

Background As Asians are more vulnerable to febrile neutropenia (FN) than Caucasians, evaluations of FN incidence and risk factors in Asians are important for the appropriate use of primary pegfilgrastim (PEG-G). Patients and methods Japanese breast cancer patients receiving standard adjuvant chemotherapies were prospectively enrolled in multicenter institutions from August 2015 to July 2017. FN was evaluated from 2 treatment policies: true FN (T-FN): ≥37.5 °C, grade 4 neutropenia, mandatory hospital visit (visiting); surrogate FN (S-FN): ≥37.5 °C, oral antibiotic, no mandatory visit (non-visiting). PEG-G was used at the physicians’ discretion. The primary endpoint was FN incidence during all cycles. Multivariate logistic regression analysis was performed to identify T-FN risk factors. Results Of 1005 enrolled patients, 980 women treated with FEC, E(A)C, and TC were analyzed. The FN incidence proportions in all patients were 22.5%, 27.5%, and 33.9% for FEC, E(A)C, and TC, respectively. Those of T-FN were 27.7%, 22.4%, and 36.6%; those of S-FN were 17.3%, 32.4%, and 31.5% with more frequent primary PEG-G usage. The relative dose intensity (RDI) of the 3 regimens was ≥0.85 in both groups. In the analysis of risk factors, TC (odds ratio = 2.67), age ≥ 65 years (2.24), and pretreatment absolute neutrophil count (ANC)/1000 μl (0.8) remained significant. Conclusions FN incidences were above 20% in the 3 regimens, with TC showing the highest. RDI was maintained at a high level in both visiting and non-visiting groups. Patient-related risk factors were age and pretreatment ANC., Highlights • This study compared febrile neutropenia (FN) incidences of 3 breast cancer regimens. • FN incidences were >20% in the 3 regimens (FEC, E(A)C; TC); TC showed the highest. • The relative dose intensities in visiting and non-visiting groups were at high level. • Age and pretreatment absolute neutrophil count were found as significant FN factors.

Occult thyroid carcinoma preceded by clinical manifestations and findings from extrathyroidal tumors is rare. The lack of malignant findings in the thyroid during the preoperative examination makes diagnosis difficult. We encountered a 71-year-old man with a primary ectopic thyroid carcinoma causing superior vena cava syndrome. Although no malignant findings were found in the thyroid gland, biopsy of bone metastases led to the diagnosis of thyroid cancer. HE staining of bone metastases revealed nuclear features of papillary carcinoma, and immunostaining was positive for thyroglobulin and PAX-8. The second case involved an 84-year-old man with a mediastinal tumor and suspected thyroid cancer because of high thyroglobulin levels in blood. The pathological tumor finding was papillary thyroid cancer. The last case was that of a 56-year-old woman lacking preoperative thyroid examination malignant findings, but with cervical lymph node metastasis. The thyroglobulin level of the lymph node puncture fluid was useful for preoperative diagnosis. We performed total thyroidectomy plus bilateral modified neck dissection. Pathology revealed a 1 mm papillary carcinoma in the left lobe. All of these cases were difficult to diagnose. However, we combined the results of various tests such as radiographic imaging, blood tests, and immunohistological tests to diagnose our patients.

Background/aim Metaplastic breast carcinoma (MBC) is a rare malignancy, which is often triple-negative for the hormone receptors and human epidermal growth factor receptor 2, and thus, does not benefit from targeted therapy. In this study, we examined the expression of methylation and demethylation enzymes by immunostaining MBC and the adjacent normal tissues or triple-negative ductal carcinoma (TNDC), and identified alterations that may be used as therapeutic targets. Materials and methods We retrospectively studied surgical specimens from 15 patients who underwent surgery for MBC at Kanagawa Cancer Center between 2005 and 2016, and similarly from 14 patients with TNDC. The frequencies of high methylation/demethylation enzyme expression were compared among them. Results The frequencies of high enhancer of zeste homolog 2 (EZH2) and multiple myeloma SET domain (MMSET) expression were significantly higher in both MBC and TNDC than in normal tissue. Conclusion EZH2 and MMSET may be useful therapeutic targets in MBC.

Background: Febrile neutropenia (FN) is one of the greatest concerns when maintaining chemotherapy dosage for early breast cancer patients. However, the incidence proportion of FN remains unclear because of the empirical prescription of oral antibiotics, the use of G-CSF, and the absence of body temperature examination and hematology test. Therefore, we performed a prospective cohort study of FN in breast cancer patients receiving adjuvant or neoadjuvant chemotherapy. Methods: Breast cancer patients were prospectively enrolled from August 2015 to July 2017. The regimens included 4 cycles of FEC (epirubicin 100 mg/m²), E(A)C (epirubicin 90 mg/m² or doxorubicin 60 mg/m²), and TC (docetaxel 75 mg/m²). Considering the current practice of empirically prescribing oral antibiotics without hematology tests, we followed 2 groups and surveyed FN using 2 different definitions: true FN (T-FN): ≥ 37.5°C and grade 4 neutropenia by a hematologic test with a visit to the hospital (visiting group), and surrogate FN (S-FN): ≥ 37.5°C and oral antibiotic intake without a mandatory visit to the hospital (non-visiting group). The primary objective was to investigate the FN incidence of each regimen during the first 4 cycles. The overall incidence proportion of FN was calculated as (patients with T-FN or S-FN) / (total patients). The proportion of T-FN or S-FN in each group was also examined. In the secondary analysis, the risk factors of FN and the safety of FN management in the non-visiting group were investigated. Multiple logistic regression analysis was performed to assess the risk factors. As we assumed that FN occurs in 20% of the patients by these regimens, the planned sample size based on the confidence intervals was 1000. This trial was registered as UMIN 000017857. Results: A total of 1005 female patients with Stage I to III breast cancer were enrolled. Of these patients, 25 were excluded because of incomplete treatments or other regimens administered. There were 477 patients in the visiting group and 503 patients in the non-visiting group. The numbers of patients in each regimen were 338 in FEC, 335 in E(A)C, and 307 in TC. The overall incidence proportions of FN were 22.5%, 27.5%, and 33.9% in FEC, E(A)C, and TC, respectively. The incidence proportions of T-FN were 27.7%, 22.4%, and 36.6%; those of S-FN were 17.3%, 32.4%, and 31.5%. Pegfilgrastim (PEG-G) was used in the 1st cycle more frequently in the non-visiting group than in the visiting group: in FEC, E(A)C, and TC, 39.0%, 11.8%, and 52.1% in the non-visiting group; 4.71%, 1.82%, and 14.1% in the visiting group, respectively. The risk factors of FN were regimen (TC: OR: 2.67, 95%CI: 1.36-5.26), age (> 65 OR: 2.24, 95%CI: 1.34-3.75), neutrophil count at registration (/1000/μl: OR: 0.8, 95%CI: 0.67-0.95), pre-/post-operation (pre-: OR: 0.51, 95%CI: 0.29-0.88), and PEG-G (OR: 0.04, 95%CI: 0.01-0.34). There were no significant differences in the frequency of grade 3 adverse events, hospitalization, intake of oral antibiotics, and relative dose intensity between the visiting group and the non-visiting group. Therapeutic daily G-CSF was more frequently used in the visiting group than in the non-visiting group. Conclusions: FN occurred at a rate higher than 20% in these 3 regimens, most frequently in TC. Neutrophil count at registration was found to be one of the risk factors of FN. The current practice of prescribing antibiotics without hematologic tests is acceptable for FN management because the outcomes were not significantly different between the visiting group and the non-visiting group. Citation Format: Takashi Ishikawa, Kentaro Sakamaki, Kazutaka Narui, Hideki Nishimura, Takafumi Sangai, Kentaro Tamaki, Yoshie Hasegawa, Ken-ichi Watanabe, Nobuyasu Suganuma, Shintaro Michishita, Sadatoshi Sugae, Tomohiko Aiharya, Koichiro Tsugawa, Hiroshi Kaise, Hirofumi Mukai. Prospective cohort study of febrile neutropenia in breast cancer patients with neoadjuvant and adjuvant chemotherapy: CSPOR-BC FN Study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-14-09.

Fibroblast growth factor receptor 4 (FGFR4) expression has association with tumor malignancy. In thyroid cancers, FGFR4 has been reported to be characteristically expressed in aggressive thyroid tumors, such as anaplastic thyroid carcinoma (ATC). We investigated FGFR4 expression in patients with ATC and analyzed their clinical responses to lenvatinib. Primary tumor samples were obtained from 12 patients with ATC who underwent surgery or core needle biopsy. FGFR4 protein expression in all ATC samples was analyzed via immunohistochemistry, and the treatment efficacy of lenvatinib was evaluated. The proportion of FGFR4-positive cells in the samples ranged from 0 to 50%. Four patients had partial responses, and three patients had stable diseases as a best clinical response to lenvatinib. The median PFS durations of patients with none, weak, and moderate intensity were 0.5, 3.2 (95% CI 1.1–not estimable [NE]), and 4.6 (95% CI 1.1–NE) months, respectively (p = 0.003). Because FGFR4 was expressed in ATC tissues, the FGFR4 expression might be associated with the treatment efficacy of lenvatinib in a part of ATC patients. To clarify whether FGFR4 can serve as a prognostic or predictive factor for lenvatinib therapy, more cases must be accumulated.

Background Pneumatosis intestinalis is a rare disease characterized by gas-filled cysts within the submucosa or serosa of the intestinal tract. In recent years, pneumatosis intestinalis was reported in patients undergoing cancer treatment, and some case reports exist that report that pneumatosis intestinalis occurs during administration of vascular endothelial growth factor inhibitors, such as bevacizumab and sunitinib. Here, we report the first case of pneumatosis intestinalis during lenvatinib treatment. Case presentation A 77-year-old Japanese man presented to our hospital with a chief complaint of numbness in the right leg and weakness of the lower limbs 9 years after right thyroid lobectomy. Computed tomography showed a tumor 90 mm in size from the lumbar spine to the sacrum, causing spinal cord compression. Blood tests showed that the patient’s thyroglobulin level was increased to 11,600 ng/ml. We diagnosed him with thyroid cancer with bone metastases. External beam radiotherapy (39 Gy/13 Fr) was performed on the bone metastases, followed by total thyroidectomy and radioactive iodine therapy. Four months after radioactive iodine therapy, lenvatinib was introduced because the symptoms of numbness and weakness recurred. Lenvatinib was introduced at dose of 24 mg, and then it was reduced to 14 mg owing to Common Terminology Criteria for Adverse Event grade 3 paronychia of the right foot. Although no further significant adverse events occurred, a scheduled computed tomography image showed pneumatosis intestinalis of the ascending colon 14 weeks after the introduction of lenvatinib. No abdominal or digestive symptoms were observed; therefore, we selected conservative treatment. We discontinued lenvatinib for a week, but we were required to restart lenvatinib as the numbness in the right leg worsened after withdrawal. Since the introduction of lenvatinib, 3 years and 5 months passed; we continued lenvatinib treatment, and the therapeutic effect remains partial response. There has been no recurrence of pneumatosis intestinalis. Conclusions Although rare, it is important to recognize that pneumatosis intestinalis can occur in association with lenvatinib and should be differentiated from intestinal perforation. Pneumatosis intestinalis association with lenvatinib can be improved by withdrawal.

Despite the excellent prognosis associated with pathological complete response (pCR) to neoadjuvant chemotherapy (NAC), some patients still develop recurrence. Here, we investigated the outcomes of breast cancer patients with pCR, as well as the clinical and pathological predictors of cancer recurrence in these patients.Of the 1599 breast cancer patients treated with NAC, we evaluated 394 patients who achieved pCR between January 2007 and December 2016. pCR was defined as no evidence of invasive cancer in breast. Residual in situ ductal and axillary lymph node diseases were not considered. We analyzed the outcomes using the Kaplan-Meier method. We assessed the association of clinical and pathological predictors with cancer recurrence using the cox proportional hazards regression model.The median follow-up time was 63 months. The 5-year disease-free survival rate was 92.3%. Cancer recurrence was observed in 28 patients (7.1%): local recurrence 8 patients (2.0%), visceral metastasis 10 patients (2.5%), and brain metastasis 10 patients (2.5%). Brain metastases were found in patients with HER2 type breast cancer. The significant predictors of cancer recurrence were HER2 positivity (p = 0.04), clinical tumor size (p 0.01), and lymph node metastasis (p 0.01) before NAC on univariate analysis and only lymph node metastasis on multivariate analysis.Patients achieving pCR to NAC showed excellent outcomes. Advanced clinical stage, large tumor size, presence of lymph node metastasis, and HER2 positivity before NAC were identified as significant predictors of cancer recurrence. Residual in situ ductal and lymph node diseases after NAC were not significant predictors.

[Background] JBCRG-16 (NeoLath) study is a five-arm study to evaluate the efficacy and safety of lapatinib and trastuzumab (6 weeks) followed by lapatinib and trastuzumab plus weekly paclitaxel (12 weeks) with/without prolongation of anti-HER2 therapy prior to chemotherapy (18 vs. 6 weeks), and with/without endocrine therapy in patients with HER2+ and/or estrogen receptor (ER)+ disease. The primary endpoint was pathological complete response (pCR) rate and pCR rate was 47.9% (Masuda N, et al. Breast Cancer, 2018). It is recently reported that microRNAs (miRNAs) are stably present in serum and potentially useful in the diagnosis and evaluation of treatment of cancer. We performed exploratory analysis of detecting pCR by comprehensive analysis of serum miRNAs. [Materials and Methods] Serum samples were obtained from study participants who received neoadjuvant systemic therapy with trastuzumab, lapatinib and paclitaxel. Before profiling of miRNAs, the overall serum samples were randomly devided in two sets, namely the training set and the testing set with pCR or non-pCR. Pathological complete response (pCR) was defined as the absence of residual invasive cancer of the resected breast specimen and all sampled regional lymph nodes. Total RNA was extracted from a 300 ul serum sample using 3D-Gene® RNA extraction reagent from a liquid sample kit. A comprehensive quantitative expression analysis of miRNA was performed using the by DNA chip 3D-Gene®, which was designed to detect 2565 miRNA sequences registered in miRBase release 21 (http://www.mirbase.org/). The expression level of miRNAs were normalized by internal control (miR-2861, miR-149-3p and miR-4463). Clinicopathological data was retrieved from trial data. [Results] A total of 112 samples were obtained. Seventy were used in the training set and others were used in the testing set. Median age was 54 years (range 26-70). Sixty-five (58%) patients were pre-menopausal. ER was positive in 59 patients (52.7%). Fourteen (12.5%) were T1c, 78 (69.6%) were T2 and 20 (17.9%) were T3. Fifty-seven (50.9%) patients were node-positive. Fifty-nine (52.7%) patients achieved pCR. The formula with the combination of three miRNAs (miR-A, miR-B, miR-C) was found to be able to predict pCR. This set had a sensitivity of 62.5%, specificity of 86.7% and accuracy of 71.8% in the testing cohort. Area under curve of receiver operationg characteristic curve was 0.753. [Conclusion] The combination of three miRNAs has potential to predict pCR in patients who received neoadjuvant combination therapy of trastuzumab, lapatinib and paclitaxel in HER2-positive primary breast cancer. The further analysis of changing expression of miRNAs during neoadjuvant therapy is underway and further results will be presented in the symposium. Citation Format: Shimomura A, Masuda N, Kawauchi J, Takizawa S, Ichikawa M, Matasuzaki J, Kuroi K, Hara H, Yamamoto N, Inoue K, Suganuma N, Aogi K, Ohno S, Tamura K, Ochiya T, Toi M. Predicting pathological complete response by the combination of microRNAs in patients with HER2-positive primary breast cancer who received neoadjuvant combination therapy of trastuzumab, lapatinib and paclitaxel: Results from JBCRG-16 (NeoLath) study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-10-16.

BACKGROUND Neoadjuvant chemotherapy (NAC) has become a common practice in breast cancer care since it not only expands the opportunity for breast conservation surgery, but also allows in vivo assessment of individual cancer biology. Patients who achieved pathological complete response (pCR) after NAC are known to have significantly improved outcomes than those who did not. To date, there has been no large study of factors that associate with tumor recurrence after patients had pCR following NAC. To identify such factors, we examined a cohort of 394 patients. METHODS Patients diagnosed during 2007-16 with clinical stage I-III breast cancer who achieved pCR following NAC were identified from clinical records at four hospitals in urban Japan. Nearly 70% of patients received standard NAC regimen, which was a combination of anthracycline and taxane, with trastuzumab added as needed. pCR was defined as no pathological evidence of invasive cancer in the breast; residual ductal carcinoma in situ (DCIS) and residual axillary lymph node metastasis were included in this study. The median follow-up time was 63 months (range = 16-161 months). Outcomes were assessed by 5-year disease-free survival (DFS) and 5-year overall survival (OS). RESULTS Among the 394 patients with pCR, the breast cancer subtype was as follows: Luminal – 49 (12.4%), Luminal-HER2 – 97 (24.6%), HER2 – 117 (29.7%), and TNBC – 131 (33.2%). During follow up, 28 (7.1%) of the 394 patients had experienced tumor recurrence. In univariate Cox regression analysis, each of HER2-receptor status, pre-NAC tumor size, and pre-NAC axillary lymph node status were associated with recurrence. The hazard ratios, and their 95% confidence intervals (CI) and P values for these significant factors were as follows. HER2-receptor negative vs. positive: 2.5 (CI = 1.0-5.8; P = 0.036); cT1/2 vs. cT3/4: 2.2 (CI = 1.3-6.1; P = 0.008); cN0 vs. cN1-3: 9.5 (2.2-40.7; P = 0.002). However, age ( CONCLUSION Axillary lymph node metastasis before rather than after NAC, and HER2-receptor positivity are associated with tumor recurrence in patients who achieved pCR in breast cancer. HER2-receptor positive patients had higher risk for brain metastasis and shorter survival. Given the extreme rarity of local recurrence after pCR, we cannot help but speculate that omitting surgical removal of pCR tissue may be permissible when pCR has been diagnosed accurately. Citation Format: Asaoka M, Narui K, Suganuma N, Chishima T, Yamada A, Kawai S, Uenaka N, Sato E, Katsuta E, Kawaguchi T, Takabe K, Ishikawa T. Axillary lymph node metastasis and HER2-receptor positivity significantly associate with recurrence and worse survival in breast cancer patients who achieved pathological complete response after neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-15-12.

We conducted the Neo-LaTH study in which patients were randomized to different lengths of neoadjuvant induction anti-HER2 therapy with lapatinib and trastuzumab followed by weekly paclitaxel plus the anti-HER2 therapy, and in estrogen receptor (ER)-positive patients, with or without concurrent endocrine therapy. The use of endocrine therapy did not affect the response, comprehensive pathological complete response (CpCR) plus ypN0 rate was 57.6% and 30.3% in ER-negative and ER-positive patients, respectively. After surgery, patients received an anthracycline-based regimen based on physician’s choice, followed by trastuzumab for 1 year, and in ER-positive patients, endocrine therapy for 5 years. Here, we report the 5-year survival outcomes. Among the followed-up patients (n = 212), the 5-year disease-free survival (DFS), distant DFS, and overall survival rates were 87.8% [95% confidence interval (CI), 82.5–91.6%], 93.7% (95% CI, 89.3–96.3%), and 95.6% (95% CI, 91.7–97.7%), respectively, with no difference between ER-negative and ER-positive patients. The 5-year DFS rate was significantly higher in patients who had a CpCR plus ypN0 after neoadjuvant treatment than in those who did not (91.7% vs. 85.1%, p = 0.0387). The stratified analysis showed better survival outcomes in patients who had CpCRypN0 than in those who did not after neoadjuvant treatment, regardless of use of adjuvant anthracycline therapy.

Background Inflammatory biomarkers have been reported to be associated with anticancer drug efficacy in various cancers. This study aimed to investigate the associations between baseline inflammatory biomarkers or dynamics of neutrophil-to-lymphocyte ratio (NLR) and treatment outcomes of lenvatinib in ATC. Methods Twenty ATC patients whose complete blood count were available were included in this study. Patients characteristics, overall survival (OS), and the associations between baseline inflammatory biomarkers or dynamics of NLR and treatment outcomes of lenvatinib were investigated. Results All 20 patients had a median baseline NLR of 4.5 (range, 1.4-19.7), a median platelet-to-lymphocyte ratio (PLR) of 169.9 (range, 66.8-671.1), and a median lymphocyte-to-monocyte ratio (LMR) of 2.6 (range, 0.5-5.5). The median OS was 4.2 (95% CI: 1.1-10.3) months in patients with baseline NLR ≤4.5 and 3.1 (95% CI: 1.1-8.3) months in patients with baseline NLR >4.5 (P=0.681). The median OS was 4.2 (95% CI: 1.1-7.8) months in patients with baseline PLR ≤169.9 and 3.9 (95% CI: 0.6-8.3) months in patients with baseline PLR >169.9 (P=0.822). The median OS was 3.7 (95% CI: 1.1-9.8) months in patients with baseline LMR ≤2.6 and 4.2 (95% CI: 0.6-5.4) months in patients with baseline LMR >2.6 (P=0.421). NLR was increased more than the standard deviation of the baseline NLR after lenvatinib initiation in two of 16 patients with follow-up NLR data available. The median OS was 2.0 (95% CI: 1.1- not estimable) months in the increased group but was 5.3 (95% CI: 3.1-9.8) months in the non-increased group (P=0.003). Conclusions There was seemed to be no association between prognosis or treatment efficacy of lenvatinib and baseline inflammatory biomarker values in our cases with ATC. However, we possibly estimate prognosis for ATC during lenvatinib treatment by observing the dynamics of NLR.

Lenvatinib is a multi-tyrosine kinase inhibitor that inhibits angiogenesis and is currently in use for the treatment of refractory thyroid cancer. Therapy using this agent can be prolonged in patients, although serious complications may ensue among those who require surgical procedures. To the best of our knowledge, the safety of invasive surgical procedures in patients undergoing treatment with lenvatinib has not been fully evaluated. A total of 94 patients were treated with lenvatinib for thyroid cancer between June 2015 and August 2019 at the Kanagawa Cancer Center. Of this cohort, 14 invasive procedures were performed on 11 patients. A total of 8 of these procedures were performed under local anesthesia and 6 under general anesthesia; 3 belonging to the latter group were emergency procedures. No primary wound complications were observed among the patients in the cohort; however, one case of delayed healing secondary to placement of a thoracic drain for acute pneumothorax was reported in the present study. Lenvatinib was initially discontinued in this patient, but it was reintroduced 17 days later due to hypoxemia that may have been related to lung metastases. Hypoxemia improved, although wound healing spanned 14 weeks. Therapy was discontinued prior to percutaneous endoscopic gastrostomy in a patient with local progression; while no wound complications were observed, the patient ultimately died from exacerbation of neoplastic disease. In the current study, which focused on surgical interventions performed on patients undergoing lenvatinib treatment, 1 in 14 wound complications improved conservatively. However, it is critical to recognize that disease progression may occur if drugs are withdrawn prior to performing invasive procedures.

Background Breast cancer is the most common form of cancer in Japan; genetic background and hereditary breast and ovarian cancer (HBOC) are implicated. The key to HBOC diagnosis involves screening to identify high-risk individuals. However, genetic medicine is still developing; thus, many patients who may potentially benefit from genetic medicine have not yet been identified. Objective This study’s objective is to develop a chatbot system that uses augmented intelligence for HBOC screening to determine whether patients meet the National Comprehensive Cancer Network (NCCN) BRCA1/2 testing criteria. Methods The system was evaluated by a doctor specializing in genetic medicine and certified genetic counselors. We prepared 3 scenarios and created a conversation with the chatbot to reflect each one. Then we evaluated chatbot feasibility, the required time, the medical accuracy of conversations and family history, and the final result. Results The times required for the conversation were 7 minutes for scenario 1, 15 minutes for scenario 2, and 16 minutes for scenario 3. Scenarios 1 and 2 met the BRCA1/2 testing criteria, but scenario 3 did not, and this result was consistent with the findings of 3 experts who retrospectively reviewed conversations with the chatbot according to the 3 scenarios. A family history comparison ascertained by the chatbot with the actual scenarios revealed that each result was consistent with each scenario. From a genetic medicine perspective, no errors were noted by the 3 experts. Conclusions This study demonstrated that chatbot systems could be applied to preliminary genetic medicine screening for HBOC.

A 63-year-old man was diagnosed with multiple lung metastases from anaplastic thyroid cancer and received lenvatinib. Follow-up computed tomography on day 34 of lenvatinib treatment showed pneumothorax. The pneumothorax was temporarily improved with chest drainage. However, pleurodesis was performed to treat a relapse of the pneumothorax. Pneumothorax during chemotherapy for a malignant tumor is considered a relatively rare complication. This case is the first documentation that pneumothorax may develop during lenvatinib treatment. The possible development of pneumothorax should be considered when lenvatinib is used in patients with lung metastasis.

Highlights • Undifferentiated pleomorphic sarcoma constitutes, Introduction Undifferentiated pleomorphic sarcoma (UPS) constitutes less than of all sarcomas in adults and rarely involves the breast. We herein present a patient with UPS of the breast with lung and bone metastases. This case was treated by eribulin as first chemotherapy, and performed mastectomy for local control. Case presentation A 55-year-old female presented a tumor measuring over 5 cm with pain in the right breast. Pathology of the incisional biopsy specimen led to a diagnosis of UPS. Computed tomography revealed a right tumor, right pubic tumor with osteolysis, and multiple lung metastases. She was started on eribulin; however, the tumor grew in size, indicating progressive disease, and the patient underwent simple mastectomy for local control. Pathological evaluation of the excised tumor was consistent with UPS. The patient elected palliative treatment and died due to respiratory failure caused by multiple lung metastases that exacerbated four months after surgery. Discussion Soft tissue sarcomas with distant metastases are treated with chemotherapy; however, there are currently no effective chemotherapeutic agents for UPS of the breast. Given the potential efficacy of eribulin in soft tissue tumors and the easy management of associated side effects, the patient was treated with eribulin, which however was insufficient for disease control. Conclusion The prognosis of UPS with distant metastasis remains poor. Treatment approaches including chemotherapy and surgery should be considered based on the patient's general condition, prognosis, and expectations on quality of life.

Surgical biopsy of metastatic lesions followed by pathological confirmation for the investigation of biomarkers is occasionally proposed as an effective strategy in the treatment of metastatic breast cancer. However, few reports have examined Ki-67 immunohistochemical expression in distant metastatic lesions of breast cancer patients. This study aimed to investigate the clinicopathological significance of subtypes and Ki-67 immunohistochemical expression in metastatic breast cancer lesions. We retrospectively studied surgical specimens of primary breast cancer tumors and their corresponding metastatic lesions from patients (n = 68) who underwent surgery for primary breast cancer tumors between December 1977 and March 2013. Tissue microarrays were constructed using primary and metastatic lesions, and were stained with antibodies against estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, and Ki-67. We also examined the clinicopathological characteristics and outcome measures of patients with metastatic breast cancer using primary and paired metastatic lesions. Compared with the primary lesions, there was no significant difference in subtypes in the metastatic lesions according to metastatic sites. Metastatic lesions of the brain, viscera, and bone exhibited slightly higher levels of Ki-67 immunohistochemical expression compared with primary lesions. A Cox proportional hazards model using multivariate analysis demonstrated that high Ki-67 immunohistochemical expression in distant metastatic lesions was associated with poorer overall survival outcomes after biopsy of recurrence lesion (hazard ratio 2.307; 95% confidence interval 1.207–4.407, P = 0.011). High Ki-67 immunohistochemical expression levels in distant metastatic lesions were independently associated with poorer overall survival outcomes after biopsy of recurrence lesion in breast cancer patients.

Background: The tumor&ndash, node&ndash, metastasis (TNM) classification system to categorized anaplastic thyroid cancer (ATC) was revised. Methods: The revised system was evaluated using a large database of ATC patients. Results: A total of 757 patients were analyzed. The proportion and median overall survival values (OS: months) for each T category were T1 (n = 8, 1.1%, 12.5), T2 (n = 43, 5.7%, 10.9), T3a (n = 117, 15.5%, 5.7), T3b (n = 438, 57.9%, 3.9), and T4 (n = 151, 19.9%, 5.0). The OS of the N0 and N1 patients were 5.9 and 4.3, respectively (log-rank p &lt, 0.01). Sixty-three (58.3%) patients migrated from stage IV&thinsp, A to IV&thinsp, B by revision based on the existence of nodal involvement and 422 patients (55.7%) were stratified into stage IV&thinsp, B, without a worsening of their OS (6.1), leaving 45 patients (5.9%) in stage IV A with fair OS (15.8). The hazard ratios for the survival of the patients of stage IV&thinsp, B compared to stage IV&thinsp, A increased from 1.1 to 2.1 by the revision. No change was made for stage IV C (n = 290, 38.8%, 2.8). Conclusion: The revised TNM system clearly indicated the prognoses of ATC patients by extracting rare patients with fair prognoses as having stage IV&thinsp, A disease and categorized many heterogeneous patients in stage IV&thinsp, B.

Anaplastic thyroid cancer (ATC) is an orphan disease with extremely poor prognosis. In particular, unresectable stage IVC ATC is extremely difficult to treat and is associated with a survival of only a few months, even when treated with irradiation and/or chemotherapy. In 2015, lenvatinib was approved for the treatment of ATC in Japan. The aim of the present study was to evaluate the efficacy of lenvatinib for stage IVC ATC. A total of 32 patients with pathologically confirmed stage IVC ATC who were treated at the Kanagawa Cancer Center between 2011 and 2018 were included in the present study, of whom 16 patients were treated with lenvatinib (L group). The remaining 16 patients received palliative therapy (P group), of whom 7 were treated with weekly paclitaxel, 2 received external radiation for tumor reduction 5 days per week until treatment completion, and 2 underwent tracheostomy to avoid the risk of asphyxiation. The survival curves of both groups were analyzed using the log-rank test. The median overall survival time of the L and P groups was 4.2 and 2.0 months, respectively. A significant survival benefit was observed in the L group compared with that in the P group (P=0.00298). A reduction in tumor size by ≥30% (clinical partial response) within 1 month after treatment was observed in 5 patients (31.3%) in the L group and in no patients in the P group. Therefore, lenvatinib treatment yielded a median survival benefit of ~2 months compared with palliative therapy in stage IVC ATC. However, although a reduction in tumor size by ≥30% was confirmed in 5 patients who received lenvatinib treatment, 2 of those patients succumbed to massive necrosis and bleeding. These results suggest that an appropriate lenvatinib dose reduction is necessary.

Summary Anaplastic transformation of a primary thyroid tumor whose process can be followed is rare. The objective this study is to report a case of anaplastic transformation of locally advanced papillary thyroid carcinoma after treatment with lenvatinib. A 74-year-old woman consulted a local physician because of cough and bloody sputum. Thyroid cancer with tracheal invasion was suspected on computed tomography (CT) imaging, and she visited our hospital for treatment. We suspected anaplastic thyroid cancer (ATC) and core needle biopsy was performed. Histologic sections of the core needle biopsy showed that the tumor formed a papillary structure, and we diagnosed papillary thyroid carcinoma. Surgery would have been difficult, and we initiated lenvatinib at a low dose of 8 mg/day. CT on day 40 of lenvatinib treatment revealed that the thyroid tumor had shrunk remarkably. CT on day 111 revealed that tumor regrowth and tracheal invasion had been exacerbated. Core needle biopsy was performed, and histologic sections of the core needle biopsy that was performed after regrowth of the tumor showed that individual cancer cells had large, irregular nuclei, and necrosis was also observed. The immunohistochemical findings were negative for thyroglobulin, and only a few cells were positive for thyroid transcription factor 1, and we diagnosed ATC. Anaplastic transformation of the target lesion may be one of the causes of lenvatinib treatment failure in differentiated thyroid carcinoma. Learning points: Anaplastic transformation of a primary thyroid tumor whose process can be followed is rare. The resistance mechanism of lenvatinib in treatment for differentiated thyroid carcinoma has not been clarified. Anaplastic transformation of the target lesion may be one of the causes of lenvatinib treatment failure in differentiated thyroid carcinoma.

Summary The objective this study is to report two cases of thyroid gland invasion by upper mediastinal carcinoma. Mediastinal tumors are uncommon and represent 3% of the tumors seen within the chest. In reports on mediastinal masses, the incidence of malignant lesions ranged from 25 to 49%. The thyroid gland can be directly invaded by surrounding organ cancers. We report these cases contrasting them to the case of a thyroid cancer with mediastinal lesions. Case 1 was a 73-year-old woman who was diagnosed with papillary thyroid carcinoma, and she underwent surgery and postoperative radioactive iodine. Case 2 was a 74-year-old man who was diagnosed with non-small-cell lung carcinoma, favor squamous cell carcinoma, and he underwent chemoradiotherapy. Case 3 was a 77-year-old man who was diagnosed a thymic carcinoma based on pathological findings and referred the patient to thoracic surgeons for surgical management. The images of the three cases were similar, and the differential diagnoses were difficult and required pathological examination. Primary thyroid carcinoma and invading carcinoma originating from the adjacent organs need to be distinguished because their prognoses and treatment strategies are different. It is important to properly diagnose them by images and pathological findings. Learning points: The thyroid gland in the anterior neck can be directly invaded by surrounding organ cancers. Primary thyroid carcinoma and invading carcinoma originating from the adjacent organs need to be distinguished because their prognoses and treatment strategies are different. It is important to properly diagnose by images and pathological findings.

Some patients with differentiated thyroid cancer (DTC) may require an initial low dose (LD) of lenvatinib. However, few studies have investigated the efficacy of LD lenvatinib. We compared the efficacy and tolerability of lenvatinib at an initial LD to those of the standard initial dose of 24 mg in patients with DTC. In this cross-sectional study, records of patients with DTC treated with lenvatinib were retrospectively reviewed. Patients were divided into 2 groups based on the initial dose of lenvatinib: a full-dose (FD) group that received an initial dose of 24 mg/d and a LD group that received an initial dose of less than 24 mg/d. Categorical variables were compared with the Fisher exact test and continuous variables with Student t test. A progression-free survival (PFS) curve was constructed with the Kaplan–Meier method. A probability (P) value of

Anaplastic thyroid cancer (ATC) is a rare and extremely aggressive malignancy, with a median survival of less than 6 months due to rapid progression and resistance to multimodal therapies. Effective treatment strategies have not been identified. A prospective clinical study was performed to objectively evaluate outcomes of treatment with paclitaxel.An investigator-initiated, multicenter, nonrandomized, open-label, single-arm study to evaluate the feasibility and efficacy of weekly paclitaxel (80 mg/m(2)) administration for patients with pathologically confirmed ATC was conducted in a nationwide organization.Feasibility was analyzed in 56 patients. More than one course of treatment was performed in 52 (93%) patients retaining sufficient dose intensity (84%). No patient had to terminate the treatment because of an adverse event. The median overall survival was 6.7 months [confidence interval 4.4-9.0]. The 6-month survival was 54%. Among the 42 patients with an evaluable lesion, none demonstrated complete remission, 9 (21%) showed partial remission, 22 (52%) achieved stable disease, and 8 (19%) exhibited progressive disease; 3 did not complete the initial treatment course. The objective response rate was 21%, and the clinical benefit rate was 73%. The median time to progression was 1.6 months. Statistically, no additional effect of concomitant radiation was demonstrated in 6 patients receiving combined therapy. Eight patients, in whom a complete post-treatment surgical removal of the tumor was feasible, survived significantly longer (median 7.6 months [CI 8.1-23.0]) than the other 34 patients in whom the tumor could not be completely removed after chemotherapy (5.4 months [CI 3.0-7.8], p = 0.018).The study demonstrates objective and accurate information concerning the feasibility and efficacy of a standardized treatment with weekly paclitaxel administration for ATC patients.Weekly paclitaxel administration for ATC patients can be of clinical benefit in a neo-adjuvant setting.

The occurrence of renal tumors originating from thyroid cancer is extremely rare with a few effective treatments for renal metastases. Here, we report the cases of two patients with differentiated thyroid cancer who underwent nephrectomy for a metastatic kidney tumor. Case 1 was a 74-year-old man who was diagnosed with right kidney tumor 10 years after initial surgery for papillary thyroid cancer (PTC). Right nephrectomy was performed, and the pathology was metastatic PTC. Case 2 was a 68-year-old woman who was diagnosed with left kidney tumor 24 years after surgery for follicular thyroid carcinoma (FTC). Left nephrectomy was performed, and the pathology was metastatic FTC. Nephrectomy for single renal metastasis could be considered a treatment option if the patients’ general condition is positive.

In patients with distant metastasis, treatment for differentiated thyroid cancer (DTC) includes complete total thyroidectomy, followed by radioactive iodine (RAI) therapy for metastatic lesions. Tyrosine kinase inhibitor (TKI) treatment is the final treatment option for metastatic lesions, which is incurable with surgery/RAI therapy. The present study examined whether treatment outcomes for DTC in patients with distant metastasis improved following TKI treatment. This study included 147 patients (median age, 71; range, 33-91 years) who underwent surgery in our hospitals and were diagnosed with distant metastasis. Disease progression was observed in 70 patients, of whom 56 were treated with TKI (TKI group); 14 refused TKI treatment or showed no treatment indication [untreated (UT) group]. Disease progression and treatment outcomes were assessed using imaging evaluations. The present study investigated thyroglobulin doubling time (Tg-DT) and Tg antibody presence/absence and their relation to disease progression. Overall survival following disease progression between the two groups was compared. The study included 22 cases of sorafenib, 49 of lenvatinib, and 15 involving TKIs. The mean dosing period for sorafenib was 153 days and for lenvatinib was 462 days. In the TKI group, 16, 26, and 9 patients exhibited partial responses (PRs), stable disease (SD), and progressive disease (PD), respectively, whereas 5 patients were not evaluable. The disease control rate (DCR) (PR+SD) was 75.0%. A total of 16 patients died in the TKI group, whereas 10/14 patients in the UT group died. Survival curves for the groups were significantly different. TKI treatment improved the prognosis of patients with distant metastasis and PD.

Anaplastic thyroid cancer (ATC) is associated with an extremely poor prognosis and is resistant to the majority of chemotherapies. In 2015, lenvatinib was approved for treating ATC in Japan. The present study aimed to evaluate the overall survival (OS) of patients with ATC treated with lenvatinib. A total of 23 patients with a definitive histological diagnosis of ATC who were treated at Kanagawa Cancer Center (Yokohama, Kanagawa. Japan) were enrolled. Surgical treatment was possible in 10 patients (including one debulking surgery), and lenvatinib treatment was postoperatively started. The remaining 13 patients were not eligible for debulking surgery; thus, lenvatinib was promptly approved as a life-saving treatment. The therapeutic effect was determined according to the Response Evaluation Criteria In Solid Tumors criteria (ver.1.1). The patients exhibited a lenvatinib response rate of 17.4% and a disease control rate of 43.5%. However, lenvatinib was associated with a 100% incidence of treatment-related adverse events (AEs), with hypertension being the most common AE (91.3%). Additionally, dose interruptions and reductions were required due to the development of tumor fistulas or other tumor-related AEs, and 9 (39.1%) patients discontinued treatment due to grade 3 or higher AEs. The median OS time was 166 days. Overall, the present study demonstrated the effectiveness of lenvatinib against ATC, which is often chemotherapy-resistant. Successful treatment of fistulas developing due to tumor necrosis at the site of the primary lesion is crucial for improving the patient outcome. The response to lenvatinib in patients with ATC varies on a case-by-case basis and requires further investigation in future studies.

Angiogenesis plays a crucial role in the development, growth, and metastasis of carcinomas, and studies have reported conflicting evidence regarding the VEGFR expression in anaplastic thyroid cancer. We investigated the expression of VEGFR2 in patients with anaplastic thyroid cancer (ATC) and analyzed the clinical response to the VEGFR inhibitor lenvatinib. This cross-sectional study included primary tumor samples obtained from 12 patients with ATC, including 5 males and 7 females (age range 63–89 years) who underwent surgery or core needle biopsy for a thyroid tumor in the Department of Breast and Endocrine Surgery at Kanagawa Cancer Center in Kanagawa, Japan. VEGFR2 protein expression in the ATC samples was analyzed by immunohistochemistry in all patients, and the therapeutic effect of lenvatinib was evaluated in seven patients who underwent tissue biopsy and lesion evaluation. VEGFR expression was not detected in any of the samples from the 12 patients. Four of the 12 patients treated with lenvatinib had partial response, the three patients achieved stable disease, and the five patients were not examined. There was no correlation between the expression of VEGFR2 in tumor tissue and the clinical response to lenvatinib among patients with ATC. Further studies are necessary to elucidate the mechanism underlying the response to lenvatinib.

Background The usefulness of re-sentinel node biopsy (re-SNB) is unclear in the management of patients with ipsilateral recurrent breast cancer. Methods We retrospectively reviewed 52 patients with locally recurrent breast cancer who underwent re-SNB from July 2012 to March 2019. Both radioactive colloid and indocyanine green were used in all cases. Results Forty-four patients were after SNB and 8 were after axillary lymph node dissection(ALND). SLNs were successfully visualized by lymphoscintigraphy in 94.2% (49/52) of cases (95.4% post-SNB vs. 87.5% post-ALND, Fisher’s exact test, p = 0.401). Among post-SNB patients with successful mapping, 50% had SLNs only in ipsilateral axilla(I) and 50% had at least one SLN in other regions(contralateral axilla [C] and/or parasternal region [P])with or without SLN in (I), compared to 28.6% and 71.4% in post-ALND cases respectively(p = 0.424). Among post-SNB cases with prior breast irradiation (n = 37), 44.4% had SLN only in (I) and 55.6% had at least one SLN in other regions, compared to 83.3% and 16.7% in cases without prior irradiation (n = 7) (p = 0.184), respectively. While these differences were not significant, a lower rate of visualization and higher frequency of aberrant lymphatic flow in post-ALND than those in post-SNB was noted, and prior irradiation might affect lymphatic flow. We tried re-SNB for 47 cases and SLNs were successfully removed in 45 (95.7%) patients (92.8% in post-SNB, 100% in post-ALND). Re-SNB for (I) was performed for all cases with hot spots in (I) and one case without hot spot. Re-SNB for (C) or (P) were decided based on physician’s judgment. The SLN identification rates by site were 92.1% (35/38) for (I), 90.0% (9/10) for (C), and 100% (3/3) for (P). Sentinel node metastasis was found in three cases, all of which were in (I). ALND was performed in one case with macrometastasis but was omitted in two cases with micrometastases. The median follow-up duration after re-SNB was 22 months and no recurrence was observed. Conclusions Sentinel node identification was possible with high detection rates among patients with recurrent breast cancer after prior breast-conserving and axillary surgery. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure T. Yamanaka: Honoraria (self): Chugai; Honoraria (self): Eisai; Honoraria (self): Novartis Pharma; Honoraria (self): Taiho; Honoraria (self): Phizer Japan. T. Yamashita: Honoraria (self), Research grant / Funding (institution): Chugai; Honoraria (self): Eisai; Honoraria (self): Novartis Pharma; Honoraria (self): Taiho; Honoraria (self), Research grant / Funding (institution): Nippon Kayaku; Honoraria (self): AstraZeneca; Honoraria (self), Research grant / Funding (institution): Kyowa kirin; Honoraria (self): Phizer Japan; Honoraria (self): Takeda. N. Suganuma: Honoraria (self): Eisai; Honoraria (self): Novartis Pharma; Honoraria (self): Taiho; Honoraria (self): Kyowa kirin; Honoraria (self): Phizer Japan. All other authors have declared no conflicts of interest.

BACKGROUND/AIM Enhancer of zeste homolog 2 (EZH2) is a member of the polycomb group of genes, which are key factors in the regulation of cell proliferation and differentiation. EZH2 is overexpressed in many malignancies. We analyzed EZH2 protein expression levels in different histological subtypes of thyroid cancer to examine its utility as a prognostic factor. MATERIALS AND METHODS We examined EZH2 protein expression by immunohistochemistry in tissue samples from 67 cases of poorly differentiated (PDTC) and 48 cases of anaplastic thyroid carcinoma (ATC), and in samples of adjacent normal and differentiated thyroid carcinoma (DTC). We examined differences in expression of EZH2 among various histological types of thyroid cancer, and the relationship between EZH2 expression and patient outcome. RESULTS EZH2 protein was expressed in PDTC and ATC, but not in normal thyroid gland or DTC. EZH-positivity increased in the order of DTC, PDTC, and ATC (p

Most substernal goiters can be managed through the transcervical approach, but a sternotomy is required in some cases. This report is about a large substernal goiter, which was resected via a transcervical and full sternotomy approach. The patient was a 57-year-old female, who visited our hospital for surgical treatment for a large substernal goiter. Computed tomography of the neck and chest revealed that the substernal goiter extended to both sides of the thorax and had compressed the trachea. We performed total thyroidectomy safely via a transcervical and full sternotomy approach. No postoperative complications occurred, except transient hypocalcemia. A histopathological examination did not reveal any malignancy, and the lesion was diagnosed as an adenomatous goiter. Most substernal goiters can be managed through the transcervical approach, but a full sternotomy is required when a substernal goiter extends to both sides of the thorax and/or has a larger diameter than the thoracic inlet or airway constriction is revealed. A full sternotomy provides excellent exposure and can help reduce the risk of complications, such as recurrent laryngeal nerve palsy and injuries to major blood vessels.

Background Thyroid dysfunction is occasionally reported after the administration of nivolumab. We report on the incidence of and risk factors for nivolumab-induced thyroid dysfunction in patients with non-small lung cancer. Patients and methods A total of 82 patients who received nivolumab between January 2016 and December 2016 at the Kanagawa Cancer Center were included. Prior to nivolumab treatment, 72 patients had normal thyroid function. Results Among the 72 patients with normal thyroid function prior to nivolumab treatment, the incidence of thyroid dysfunction was 19.5%. There were no significant differences between patients in whom thyroid dysfunction had occurred regarding sex, age, nivolumab dose, or thyroid function prior to nivolumab administration. However, the total number of doses of nivolumab was significantly greater in patients who developed thyroid dysfunction after nivolumab treatment (p=0.03). Conclusion The total number of doses administered may be a risk factor for the development of thyroid dysfunction after nivolumab therapy.

Background Non-functioning parathyroid carcinoma is a rare disease that is difficult to distinguish from other diseases based on the lack of hyperparathyroidism. This is a report of non-functioning parathyroid carcinoma diagnosed by reverse transcription polymerase chain reaction (RT-PCR) targeting parathyroid hormone (PTH) messenger RNA. Case Presentation The patient is a 67-year-old male who visited our hospital for the chief complaint of hoarseness. A 5-cm mass was observed in the right lobe of the thyroid gland, and poorly differentiated thyroid carcinoma was suspected according to the fine-needle biopsy results. The laboratory data for thyroid functions, thyroglobulin, anti-thyroglobulin antibodies, calcium, phosphorus, and intact-PTH were all within the normal range. Right recurrent nerve paralysis was observed preoperatively. The patient was diagnosed with poorly differentiated thyroid carcinoma, and total thyroidectomy and central node dissection with partial resection of the right recurrent nerve and esophageal muscle were performed. The pathological findings revealed atypical cells containing clear cells in solid and alveolar structures with broad fibrosis. Mitosis, focal coagulative necrosis, and vascular and capsular invasions were observed. A slightly positive PTH immunohistochemical stain was noted, whereas the RT-PCR results were positive. We finally diagnosed this tumor as non-functioning PTC. No distant metastasis occurred, and the patient is still alive. Conclusions This is a report of a patient with non-functioning parathyroid carcinoma, which is clinically very rare. We diagnosed this tumor as non-functioning parathyroid carcinoma using RT-PCR for PTH mRNA.

Background In metastatic breast cancer, the status of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), as well as the Ki-67 index sometimes change between primary and metastatic lesions. However, the change in expression levels of enhancer of zeste homolog 2 (EZH2) between primary and metastatic lesions has not been determined in metastatic breast cancer. Methods Ninety-six metastatic breast cancer patients had biopsies or resections of metastatic lesions between September 1990 and February 2014 at the Kanagawa Cancer Center. We evaluated ER, PR, HER2, Ki-67, and EZH2 in primary lesions and their corresponding metastatic lesions using immunohistochemistry. We examined the change in expression of EZH2 between primary and metastatic lesions, the correlation between the expression of EZH2 and the expression of other biomarkers, and the relationship between EZH2 expression and patient outcome in metastatic breast cancer. Results EZH2 expression was significantly higher in metastatic lesions compared with primary lesions. EZH2 expression was highly correlated with Ki-67 expression in primary and metastatic lesions. High-level expression of EZH2 was associated with poorer disease-free survival (DFS) outcomes in patients with primary lesions (P

In 2014/2015, tyrosine kinase inhibitors (TKIs) were introduced as a secondary treatment for refractory differentiated thyroid cancer (DTC) in Japan. While renal dysfunction is an adverse event of TKI, data on this adverse event in TKI-treated DTC remains insufficient. Here, we investigated renal function in patients undergoing TKI treatment for DTC and evaluated the efficacy of dose reduction/withdrawal for cases of renal dysfunction. A total of 73 cases of radioactive iodine-refractory DTC treated with sorafenib (n = 22) or lenvatinib (n = 51) were included. Patient data evaluated were TKI treatment period, estimated glomerular filtration rate (eGFR) before and after TKI therapy, incidence and degree (maximum value at time of TKI treatment) of proteinuria, and albumin levels before and after TKI therapy were compared. The mean ΔeGFR was −6.75% with lenvatinib and +5.90% with sorafenib. It was not significant (P = .15). The mean Δalbumin was −8.90% and −5.85% with lenvatinib and sorafenib, respectively; there was no significant difference between the lenvatinib and sorafenib groups (P = .77). According to our program of TKI dose reduction and withdrawal, all patients except 2 with diabetes were successfully continuing treatment. Overall, the present results demonstrated that renal function is negatively affected by long-term TKI treatment for RAI-refractory DTC. However, heightened proteinuria, decreased eGFR and albumin levels, and significant but apparently reversible renal dysfunction were more frequent with lenvatinib than sorafenib.

Background/Aims: Changes in estradiol that inhibits bone resorption were examined to investigate the in vivo defensive response to progression of bone disorder after gastric cancer surgery. Materials and Methods: Women who might show effects of menstruation were excluded because estradiol was examined. The subjects were 17 men with a mean age of 60.4 years who had undergone gastrectomy because of gastric cancer and were followed as outpatients. Microdensitometry was used to evaluate bone disorder. The duration after surgery until bone assessment was a mean of 3.5 years. The surgical procedure was total gastrectomy with Roux-Y reconstruction in 4 patients and subtotal gastrectomy with Billroth-I reconstruction in 9 patients and with Billroth-II reconstruction in 4 patients. Results: Bone disorder requiring treatment was observed in 6 out of the 17 patients (35.3%). Estradiol showed higher than normal values in 10 patients (58.8%). The incidence of bone disorder was high in patients with high estradiol levels, but the difference was not significant. Blood levels of estradiol in patients with bone disorder requiring treatment were high but again the difference was not significant (P = 0.119). Conclusions: Although the difference was not statistically significant, the increase in estradiol observed in patients with progressive bone disorder suggested to be caused by in vivo inhibition of enhanced bone metabolism after gastric cancer surgery.

Several studies from other countries have reported that patients with screen-detected breast cancer have better survival than those with symptomatic breast cancer. However, no such comparison has been performed in Japan. Therefore, we aimed to compare the clinicopathological characteristics and survival rates between symptomatic and screen-detected breast cancer in Japanese women. From January 2000 to December 2004, 977 and 182 women with symptomatic or screen-detected breast cancer, respectively, underwent surgery at a single Japanese hospital. We retrospectively reviewed these patients’ clinicopathological data. Likelihood of death was estimated using the Kaplan–Meier method and the log-rank test. Multivariate analysis including mode of detection, tumor size, lymph node status, hormone receptor status, and adjuvant therapy administration was performed using the Cox proportional hazards model. Screen-detected breast cancer was associated with increased rate of breast-conserving surgery, non-invasive carcinoma, smaller tumor size, decreased lymph node involvement, increased hormone receptor positivity, and decreased adjuvant chemotherapy administration. Compared to women with symptomatic tumors, those with screen-detected tumors had improved overall and breast cancer-specific survival rates. Factors associated with survival in univariate analysis were screen detection, tumor size, lymph node status, progesterone receptor status, and adjuvant chemotherapy administration. Breast cancer screening in Japanese women has led to increases in the rates of breast-conserving surgery, hormone receptor positivity, and survival rates along with reductions in axillary lymph node dissection and adjuvant chemotherapy administration.

Background: Neoadjuvant chemotherapy (NAC) is a widely accepted treatment not only for locally advanced breast cancer, but also for earlier-stage operable disease. The main purpose of it is to downstage the tumor and to avoid the extensive operation and increase breast conservation surgery. Recent studies have indicated that patients who achieve a pathologic complete response (pCR) after NAC show better outcomes than patients with residual disease in breast cancer (non-pCR). On the other hand, there are some cases in which cancer recurred despite achieving pCR (pCR-rec). This retrospective study investigates the clinical profiles and outcome associated with the patients whose tumor recurred after achieving pCR after NAC. Patients and Methods: All the clinical and pathologic data were collected from 4 institutions in Japan: Yokohama City University Hospital, Kanagawa Cancer Center, Yokohama Rosai Hospital and Tokyo Medical University Hospital. Total of 1,599 operable breast cancer patients who underwent NAC were enrolled. The median follow-up period was 41 months. Vast majority of the patients were treated with anthracycline followed by taxane-based chemotherapy, with or without trastuzumab as neoadjuvant therapy. We defined pCR as no residual invasive cancer in the breast and axially nodes, and non-pCR was divided into 2 groups as Grade 1 (no to mild response) and Grade 2 (moderate response). Results: Of 1,599 patients enrolled in the study, 363 patients achieved pCR (22.7%). Among the pCR patients, 41 were Luminal type, 93 were Luminal-HER2 type, 109 were HER2 type, and 120 were triple-negative (TN) type (pCR rate was 5.94%, 30.4%, 49.3% and 31.3%, respectively). Cancer recurrence after resection was observed in 18 patients (pCR-rec, 4.9%). Axial nodal metastasis diagnosed before NAC associated to cancer recurrence among the pCR patients (p= 0.0003). pCR patients showed significantly better outcome compared to non-pCR, consistent with the previous reports among all patients. However, pCR-rec showed significantly worse DFS compared to those with Grade 1, Grade 2, or pCR (P Conclusions: Although achieving pCR after NAC improved outcome, patients with cancer recurrence after pCR show significantly unfavorable outcome even compared to non-pCR patients. In further study, identifying these patients before treatment could improve their poor survival. Citation Format: Mariko Asaoka, Takashi Ishikawa, Eiichi Sato, Kazutaka Narui, Takashi Chishima, Akimitsu Yamada, Nobuyasu Suganuma, Tsutomu Kawaguchi, Kazuaki Takabe. Clinical profile and outcome associated with breast cancer recurrence after pathologic complete response to neoadjuvant chemotherapy: A multicenter study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 591.

Introduction: The pathological complete response (pCR) rate is approaching to 50% particularly in patients with hormone-receptor negative disease by neoadjuvant chemotherapy (NAC). If the disease is not recurred locally in cases with pCR and pCR could be accurately diagnosed preoperatively, it is possible to treat some population of patients without surgery after NAC. We conducted two studies to examine: 1) outcomes of patients who had achieved pCR by NAC with a special attention to local recurrence. 2) diagnostic accuracy of pCR with core needle biopsy (CNB) for cases obtained clinical complete response (cCR) by NAC. Methods: 1) Clinical outcomes were retrospectively investigated in 395 patients who achieved pCR from 1599 patients with primary operable breast cancer treated by NAC (overall pCR rate of 24.7%: 395/1599). The association of clinic-pathological factors with recurrence was investigated. 2) Ultrasound-guided CNB was performed prospectively for 86 cases who achieved cCR by MRI after NAC. The concordance of pathological results between CNB and surgical specimens was examined. The pathological diagnosis was categorized as no carcinoma (pCR), carcinoma in situ (CIS) and invasive carcinoma (INV). Results: 1) 395 pCR cases consisted of 50 Luminal type (pCR rate: 7.2%), 98 Luminal-HER2 type (32.1%), 116 HER2 type (52.5%), and 131 triple negative (TN) type (34.2%). The median follow-up was 41 months. Recurrent diseases including local recurrence or distant metastasis were found in 5.80% (23/395). According to subtypes, these were 2.00% (1/50) for Luminal type, 4.08% (4/98) for Luminal-HER2 type, 10.3% (12/116) for HER2 type, and 4.58% (6/131) for TN type. Local recurrence was found in 1.2% of cases (5/395). Risk factors of recurrence were clinical stage before NAC and nodal status after NAC in the univariate analysis, and only clinical stage remained statistically significant in the multivariate analysis. 2) Pathology of surgical specimen revealed pCR in 41 cases (48%), CIS in 17 cases (20%) and INV in 28 cases (32%). Discordant cases: pCR in CNB, but CIS and INV in surgical specimens were found in 24 cases (14 CIS and 10 INV). The false negative rate (FNR) and accuracy of CNB to predict INV were 22.2% and 88.4%, respectively. Conclusion: Except HER2 type, recurrence was not frequent particularly in cases with an early clinical stage. Local recurrence was rarely observed in any subtype. However, ultrasound-guided CNB for cCR cases diagnosed by MRI was not reliable enough to predict pCR. Thus, imaging diagnosis and biopsy methods need to be improved to achieve 10% of FNR and 90% of accuracy for predicting pCR and to proceed to an observational study without performing surgery. Citation Format: Takashi Ishikawa, Mariko Asaoka, Kazutaka Narui, Akimitsu Yamada, Nobuyasu Suganuma, Takashi Chishima, Takahiko Kawate, Kana Miyahara, Kazuaki Takabe, Yasushi Ichikawa, Eiichi Sato. Clinical studies to treat without surgery for breast cancer cases who achieved clinical complete response by neoadjuvant chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1601.

Lung cancer associated with Sweet's syndrome is extremely rare. There are only seven reports of such cases. As far as could be determined from a comprehensive search, there is no reported operative case of lung cancer with this syndrome in the world literature. A 75-year-old Japanese man was diagnosed as having Sweet's syndrome. A chest computed tomography (CT) scan to screen for malignant lesions associated with this syndrome revealed an abnormal shadow in the lung. Although [(18)F]2-fluoro-2-deoxy-D: -glucose positron emission tomography showed no abnormal uptake, lung cancer was most strongly suspected by chest CT. His erythema improved rapidly with steroid therapy and he underwent a segmentectomy (S(6)) of the right lower lobe. A pathological examination revealed lung adenocarcinoma (pT1N0M0: Stage Ia). The patient was discharged from the hospital without any worsening of Sweet's syndrome. We herein report a first operative case of an early stage lung adenocarcinoma with this syndrome.

OBJECTIVE To investigate the differences in the pattern of glucose transporter (GLUT) gene expression between normal and tumour tissues and among histological subtypes of renal cell carcinomas (RCCs), as malignant cells are characterized by increased glucose uptake and use. MATERIALS AND METHODS Enhanced glucose uptake probably depends on the overexpression of GLUT, usually GLUT1 and/or GLUT3, but there are few comprehensive studies to evaluate the relative expression pattern and level of GLUT in normal and tumour kidney tissues, especially of the recently identified GLUT genes. In all, 71 kidney surgical samples were evaluated using reverse transcriptase-polymerase chain reaction (RT-PCR) for GLUT1–14 in normal and tumour (clear cell, papillary and chromophobe RCC, and oncocytoma) tissues. The expression levels for GLUT1–5, 9, 10 and 12 were quantified by real-time quantitative PCR. RESULTS The RT-PCR results showed that normal kidney tissue expresses all the GLUT isoforms. In clear cell RCC GLUT1 expression increased (P

This study aimed to analyse whether age, metastasis, extrathyroidal invasion and size (AMES) risk definition is valuable for Japanese patients with differentiated thyroid carcinoma (DTC). Methods: Two hundred and fifteen Japanese DTC patients (43 men, 172 women; mean age, 51.0 years; mean follow-up, 102 months) treated surgically at our institutions between 1981 and 2001 were retrospectively analysed. Clinicopathological features were compared between high-risk and low-risk patients by AMES criteria. Various risk factors were also evaluated for each group of patients. Results: There were 57 high-risk and 158 low-risk patients. Recurrence and mortality rates were 43.9% and 24.6% in high-risk patients and 7.6% and 0.6% in low-risk patients, respectively (p < 0.0001). Disease-specific survival rates at 5, 10 and 15 years were 84.3%, 74.0% and 63.5% in high-risk patients and 100%, 100% and 98.3% in low-risk patients, respectively (p < 0.0001). Univariate analysis revealed that curative resection, local recurrence and distant metastasis were risk factors for mortality in the high-risk group. Multivariate analysis revealed that curative resection (hazard ratio [HR], 4.68; 95% confidence interval [CI], 1.23-17.83; p = 0.024) and distant metastasis (HR, 4.79; 95% CI, 1.24-18.40; p = 0.023) were significantly related to mortality in high-risk patients. Conclusion: AMES can identify high-risk and low-risk Japanese patients. Distant metastasis and curative resection are prognostic factors for disease-specific death.

The aim of this study was to evaluate microscopic nodal status in papillary thyroid carcinoma (PTC) with and without lymphadenopathy and its relation to outcomes.We retrospectively analyzed 134 patients with PTC who underwent initial thyroidectomy. Forty-two patients with lymphadenopathy underwent therapeutic modified neck dissection (MND) and 92 without lymphadenopathy underwent prophylactic MND. The frequencies, numbers, and percentages of lymph node metastasis (LNM) were determined to evaluate nodal status; then, whether each nodal status influence to outcomes was analyzed. Disease-free survival (DFS) and disease-specific survival (DSS) were assessed (Kaplan-Meier method and log-rank test).Lymphadenopathy was significantly related to local recurrence and DFS, but not DSS. The frequency (100 vs 67.4%), number (15.8 vs 2.7), and percentage (49.7 vs 17.8%) were significantly higher in patients with lymphadenopathy than in those without lymphadenopathy (p0.0001). Similarly, these were significantly higher in patients who developed recurrence than in those who did not. Recurrence was frequent in older patients with lymphadenopathy. The frequency, number, and percentage were also higher in older patients who developed local recurrence.Lymphadenopathy and microscopic nodal status are significantly related to recurrence. Only a few nodes seem to be involved pathologically when no lymphadenopathy.

症例は36歳の女性. 出産を契機に全身性エリテマトーデス (systemic lupus erythematosus : SLE) を発症, 治療経過中に両側肺化膿症を合併した. 左肺病変は舌区域気管支の胸膜腔への開存による気胸となり, さらに膿胸へと進展した. 胸水培養からはStaphylococcus aureus (MRSA) が検出された. 胸腔ドレーンを挿入し, 抗生剤による洗浄を繰り返したが改善を認めず, 当科を紹介された. 手術を施行し, 術後9病日に胸腔ドレーンを抜去, その後退院した. SLEに合併した膿胸に対する1手術例を報告する.

The aim of this study is to evaluate the outcome of different modes of resection in papillary thyroid carcinoma (PTC) with laryngotracheal invasion. Sixty-four primary PTCs with laryngotracheal invasion between 1964 and 2003 were retrospectively analyzed (17 men and 47 women; mean age, 61.6 years; mean follow-up, 92.3 months). Thirteen curative resections included six pharyngolaryngoesophagectomies, two total laryngectomies, and five circumferential resections (complete surgery). Eighteen patients who were candidates for curative resection refused to undergo complete surgery to avoid functional impairment, especially laryngeal function (incomplete surgery). Thirty-three patients with minimal invasion underwent shave or partial resection (conservative surgery). Clinical outcomes were compared between the three groups. The influence of different types of surgery and invasion was also evaluated by Cox proportional hazard analysis. Three (23.1%) complete, 17 (94.4%) incomplete, and 4 (13.8%) conservative surgery patients died of disease (P