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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.

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.

Summary Emergencies due to malignancies usually have a severe clinical course and require urgent treatment. These scenarios are dubbed ‘oncologic emergencies’. Parathyroid tumours often cause hypercalcaemia but not oncologic emergencies. We present a case of parathyroid carcinoma with severe hypercalcaemia and pancreatitis, resolved by surgical resection of the tumour assisted by extracorporeal membrane oxygenation (ECMO). A 66-year-old woman presented to our hospital because of haematuria. Laboratory findings were as follows: white blood cell count: 30 000, C-reactive protein: 17.7, calcium: 21.9, creatine kinase: 316, creatine kinase-myoglobin binding: 20, troponin I: 1415.8, amylase: 1046, lipase: 499, blood urea nitrogen: 57, and creatinine: 2.42. ECG was unremarkable. CT revealed a 4-cm low-density irregular tumour in the left lobe of the thyroid gland and severe pancreatitis. We diagnosed hypercalcaemia and pancreatitis due to parathyroid carcinoma. Volume expansion with isotonic saline was started immediately. Calcitonin, followed by denosumab, calcimimetic agents, and continuous hemodiafiltration were administered. The patient’s general condition worsened due to uncontrolled hypercalcaemia. Urgent tumour resection was planned, assisted with ECMO for cardiopulmonary support and surgical field venous pressure reduction. Tumour histology was suggestive of parathyroid carcinoma. Hypercalcaemia and the patient’s general condition improved gradually postoperatively. Hypercalcaemia is one of the oncologic emergency symptoms, commonly occurring because of lytic bone metastasis. However, reports about parathyroid carcinoma-causing life-threatening hypercalcaemia and pancreatitis are scarce; the fatality of this condition is estimated to be 30–70%. We report a case of survival of hypercalcaemia of malignancy. Learning points Parathyroid carcinoma is relatively rare and sometimes causes emergent conditions such as hypercalcaemia and severe pancreatitis. General therapy for hypercalcaemia including aggressive saline dehydration, administration of furosemide, calcitonin, zoledronic acid, and evocalcet, and dialysis is sometimes ineffective for parathyroid carcinoma. Therefore, careful planning of therapy in case of exacerbation is important. During an emergency, rapid surgical treatment despite high calcium level is the best potential therapeutic strategy.

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.

A 37-year-old pregnant woman arrived at our hospital with an abnormal mammogram.Mammography performed in June 2018 revealed an abnormal shadow on the left breast. Cytology from the 6-mm tumor in the left upper-outer quadrant revealed a malignancy. At the same time, a transvaginal echo revealed cysts, and the patient was diagnosed at 5 weeks gestation. Needle biopsy revealed a luminal A-like cStage Ⅰ, cT1bN0M0 invasive ductal carcinoma (IDC). Tumor resection and sentinel lymph node biopsy were performed under local anesthesia at 12 weeks gestation, and post-delivery adjuvant therapy was planned. Histologic examination of the resected tumor revealed that it was HER2-positive( immunohistochemistry score 3+); therefore, we had to reconsider the use of trastuzumab and decided to administer it to the patient after childbirth. The patient gave birth by cesarean section, and weekly paclitaxel plus trastuzumab was initiated 7 months after surgery. The patient is currently alive without recurrence.We faced several difficulties during the treatment of this patient. Postoperative adjuvant therapy is recommended to be administered 8 weeks after the surgical resection of the tumor. However, in our case, given that the tumor was HER2-positive, we could administer adjuvant therapy with trastuzumab only after delivery. Although the prevalence of breast cancer in women below the age of 40 years in Japan is currently as low as 4-6%, the incidence of pregnancy-associated breast cancer is predicted to increase as the number of elderly primigravida increases due to later marriage.

PurposeClinical screening using the National Comprehensive Cancer Network (NCCN) testing criteria may fail to identify all patients with hereditary breast and ovarian cancers. Thus, this study aimed to evaluate the strategy of expanding target patients for genetic testing among Japanese patients. Patients and MethodsWe reviewed the medical records of 91 breast cancer patients who were genetically tested.Results Among 91 patients, eight were diagnosed with pathogenic or likely pathogenic variants: BRCA1 (n=4) and BRCA2 (n=4). Among 50 patients meeting the testing criteria of the guideline, six (12%, 95% confidence interval; 4.5–24.3%) were diagnosed with pathogenic or likely pathogenic variants. The sensitivity and specificity of screening using the testing criteria were 75% and 47%, respectively. Expanding the NCCN criteria to include all women diagnosed with breast cancer aged ≤ 65 years achieved 88% sensitivity but 8% specificity. ConclusionsThe expansion of the NCCN criteria could benefit Japanese 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.

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.

Anaplastic thyroid carcinoma (ATC) is one of the most aggressive cancer types; however, the molecular mechanism contributing to the aggressive characteristics remain unclear. Membrane type 1 matrix metalloproteinase (MT1-MMP) plays an important role in cancer invasion and has been associated with a poor prognosis in various malignant neoplasms. In this study, we investigated the relationship between MT1-MMP expression and the proliferation and invasion of ATC cells, along with the association with clinicopathologic factors in patients with ATC. Suppression of MT1-MMP reduced the proliferation and invasion of ATC cells, and suppressed ERK activity, indicating a role in cancer cell proliferation in collagen matrix culture conditions. The expression of MT1-MMP was detected in 29 of 34 (85.3%) surgical specimens from ATC patients. In addition, the expression of MT1-MMP in the tumor lesion was higher than that of normal and stromal tissues. Collectively, these results suggest that elevated MT1-MMP expression plays a role in the pathogenesis of ATC, which may promote its aggressive characteristics such as proliferation and invasion, highlighting a potential new therapeutic target.

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.

Background: Anaplastic thyroid carcinoma (ATC) is a highly aggressive thyroid tumor with a poor prognosis. However, there are limited choices for ATC treatment. Recently, the effectiveness of antibody–drug conjugates has been demonstrated in various carcinomas. Whether the targets of antibody–drug conjugates are expressed in anaplastic thyroid carcinoma remains unclear. Methods: Fifty-four patients with ATC were enrolled in this study. Tissue microarrays were constructed using the archives of formalin-fixed paraffin-embedded tissue blocks. All sections were stained with the following antibody–drug conjugate targets: human epidermal growth factor receptor 2 (HER2), nectin-4, trophoblast cell surface antigen 2 (TROP-2), glycoprotein non-metastatic B (GPNMB), and B7-H3. Results: HER2 was negative in all tissues, whereas GPNMB and B7-H3 were expressed in most ATC tissues. TROP-2 and nectin-4 were expressed in 65% and 59% of ATC tissues, respectively. TROP-2 was expressed at significantly higher levels in ATC undifferentiated from papillary thyroid carcinoma than in ATC undifferentiated from follicular thyroid carcinoma and de novo ATC. In contrast, nectin-4 expression was markedly higher in patients with de novo ATC than in those with papillary and follicular thyroid carcinoma. Conclusions: TROP-2 and nectin-4 are potential therapeutic targets for ATC undifferentiated from papillary thyroid carcinoma and de novo ATC, respectively. GPNMB and B7-H3 potential for treating all types of ATC.

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.

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

Overall survival remains unsatisfactory in stage II/III gastric cancer, even after curative surgery and adjuvant chemotherapy. Platelet-derived growth factor receptor-β (PDGFR-β) is associated with the proliferation of cancer cells. The present study therefore investigated the association of PDGFR-β gene expression with patient outcome in 134 stage II/III gastric cancer patients who received adjuvant chemotherapy with S-1. Relative PDGFR-β gene expression was measured in surgical cancer tissue and adjacent normal mucosa specimens by reverse transcription-quantitative polymerase chain reaction. The PDGFR-β gene expression levels were found to be significantly higher in the cancer tissues compared with the adjacent normal mucosa. A high level of PDGFR-β gene expression was associated with a significantly poorer 5-year overall survival rate compared with a low level of PDGFR-β expression. Upon multivariate analysis, PDGFR-β gene expression was found to be an independent predictor of survival. Overall, the study indicates that PDGFR-β overexpression in gastric cancer tissues is a useful independent predictor of outcome in patients with stage II/III gastric cancer who receive adjuvant chemotherapy with S-1.

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.