Selpercatinib for treating recurrent mixed medullary and follicular cell-derived thyroid carcinoma: a case report.

BACKGROUND: Mixed medullary and follicular cell-derived thyroid carcinoma (MMFCC) is characterized by the coexistence of follicular and C cell-derived tumour cell populations within the same lesion. Due to its rarity, its etiology and clinical course remain unclear, and treatment for advanced or recurrent cases has not been established. CASE PRESENTATION: We report a case of MMFCC treated with selpercatinib. The patient was a 69-year-old male presenting with tumors in the right thyroid lobe and in the upper mediastinum. Fine-needle aspiration (FNA) cytology of the right thyroid lobe tumor revealed a medullary carcinoma; germline RET mutations were not detected. After resection of the right thyroid lobe with central node dissection, rapid intraoperative diagnosis of the mediastinal mass confirmed malignancy, leading to total thyroidectomy with excision of the upper mediastinal tumor. Histologically, the tumor in the right thyroid lobe and the pretracheal lymph node revealed a mixture of medullary and follicular carcinoma components, diagnosed as MMFCC. The mediastinal lymph node exhibited only medullary carcinoma components. At 11 months postoperatively, computed tomography scans showed enlargement of the right supraclavicular and upper mediastinal lymph nodes. FNA cytology of the right supraclavicular lymph node suggested the recurrence of medullary thyroid carcinoma. The gene panel testing (The Oncomine Dx Target Test Multi-CDx system®, Thermo Fisher SCIENTIFIC) of metastatic lymph node revealed RET somatic mutation (M918T). Treatment with selpercatinib was initiated, and both the cervical and mediastinal lymph nodes showed a reduction in size. CONCLUSIONS: We report a rare case of selpercatinib use for MMFCC. Since RET mutations may occur frequently in MMFCC, selpercatinib could be effective in treating MMFCC.

Left parathyroid carcinoma with secondary hyperparathyroidism: a case report.

BACKGROUND: Parathyroid carcinoma is a rare disease with a frequency of 0.005% of all malignancies [1, 2]. Various aspects of its pathogenesis, diagnosis, and treatment remain poorly understood. Furthermore, cases with secondary hyperparathyroidism are fewer. In this case report, we describe a case of left parathyroid carcinoma with secondary hyperparathyroidism. CASE PRESENTATION: The patient was a 54-year-old woman who had been on hemodialysis since the age of 40 years. At 53 years of age, her calcium levels were high, and she was diagnosed with drug-resistant secondary hyperparathyroidism and was referred to our hospital for surgical treatment. Blood tests revealed calcium levels of 11.4 mg/dL and intact parathyroid hormone (PTH) levels of 1007 pg/mL. Neck ultrasonography revealed a 22-mm large round hypoechoic mass, partially indistinct margins, and D/W ratio > 1 at the left thyroid lobe. Computed tomography scans revealed a 20-mm nodule at the left thyroid lobe. No enlarged lymph nodes or distant metastases were noted. 99mTc-hexakis-2-methoxyisobutylisonitrile scintigraphy revealed an accumulation at the superior pole of the left thyroid lobe. Laryngeal endoscopy revealed paralysis of the left vocal cord, signifying recurrent nerve palsy due to parathyroid carcinoma. Based on these results, a diagnosis of secondary hyperparathyroidism and suspected left parathyroid carcinoma was made, and the patient underwent surgery. Pathology results revealed hyperplasia in the right upper and lower parathyroid glands. The left upper parathyroid gland showed capsular and venous invasion, and the diagnosis was left parathyroid carcinoma. At 4 months post-surgery, calcium levels improved to 8.7 mg/dL and intact PTH levels to 20 pg/mL, with no signs of recurrence. CONCLUSIONS: We report a case of left parathyroid carcinoma associated with secondary hyperparathyroidism. Concomitant secondary hyperparathyroidism may cause mild hypercalcemia compared to parathyroid carcinoma alone due to the added modification of dialysis. Although our patient also presented with mild hypercalcemia, a D/W ratio > 1 on preoperative echocardiography and presence of recurrent nerve palsy on laryngoscopy led to the suspicion and treatment of parathyroid carcinoma preoperatively.

Clinical Significance of Cancer Stem Cell Markers in Primary and Metastatic Tissues in Patients With Breast Cancer.

BACKGROUND/AIM: This study aimed to examine the clinical significance of the protein expression of the cancer stem cell (CSC) markers ALDH1A1, CD133, CD44, and MSI-1 in primary and metastatic tissues of patients with breast cancer (BC). PATIENTS AND METHODS: ALDH1A1, CD133, CD44, and MSI-1 protein expression in pairs of primary and metastatic tissues of 55 patients with BC with metastases treated at Kanagawa Cancer Center between January 1970 and December 2016 were evaluated using immunohistochemical assay and their association with clinicopathological factors and survival was examined. RESULTS: There were no significant differences in CSC marker expression rates between primary and metastatic tissues for any CSC markers. Regarding the relationship between CSC marker expression in primary tissues and survival, patients with high CD133 expression had significantly lower recurrence-free survival (DFS) and overall survival. On multivariate analysis, they were also a poor independent predictor of DFS (hazard ratio=4.993, 95%CI=2.189-11.394, p=0.0001). In contrast, there was no significant association between the expression of any CSC marker in metastatic tissues and survival. CONCLUSION: CD133 expression in the primary BC tissue may be a useful risk factor for recurrence in patients with BC.

Validation of EZH2 Inhibitor Efficiency in Anaplastic Thyroid Carcinoma Cell Lines.

BACKGROUND/AIM: The prognosis of anaplastic thyroid carcinoma (ATC) is poor, and there is currently no established treatment to improve its outcome. We previously reported that enhancer of zeste homolog 2 (EZH2) was highly expressed in ATC, and may be a therapeutic target; however, the effects of EZH2 on ATC growth currently remain unknown. MATERIALS AND METHODS: We investigated the effects of an EZH2 inhibitor (DZNep) on four ATC cell lines (8305C, KTA1, TTA1 and TTA2). We performed a gene panel analysis of all ATC cell lines to identify differences in DZNep sensitivity between the cell lines. To investigate the effects of DZNep on the recovery of differentiation, we assessed changes in thyroid differentiation markers (TDMs) before and after the DZNep treatment using PCR. RESULTS: EZH2 was expressed in all ATC cell lines. The cell-reducing effects of DZNep were detected in all ATC cell lines, and were the strongest in KTA1 cells followed by TTA2 cells. The TTA1 and 8305C cell lines, which showed weak cell-reducing effects, had TP53 mutations. No changes in TDMs were observed in any ATC cell line. CONCLUSION: DZNep, an EZH2 inhibitor, exerted suppressive effects on the growth of ATC cell lines and has potential as a therapeutic strategy; however, its effects may be attenuated in ATC with TP53 mutations.

Parathyroid carcinoma with pancreatitis causing hypercalcaemic emergency treated with extracorporeal membrane oxygenation-assisted parathyroid resection.

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.

Phase II study of the efficacy and safety of lenvatinib for anaplastic thyroid cancer (HOPE).

PURPOSE: 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. PATIENTS AND METHODS: 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. RESULTS: 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%). CONCLUSION: 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.

Efficacy of Clinical Guidelines in Identifying All Japanese Patients with Hereditary Breast and Ovarian Cancer.

Clinical 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. We reviewed the medical records of 91 breast cancer patients who underwent genetic testing. 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 guidelines, 6 (12%) 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. The expansion of the NCCN criteria could benefit Japanese patients; however, larger studies are necessary to change clinical practice.

[A Case of Pregnancy-Associated Breast Cancer Which Underwent Surgical Treatment during Pregnancy and Chemotherapy after Delivery].

CASE: A 37-year-old pregnant woman arrived at our hospital with an abnormal mammogram. MEDICAL HISTORY: 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. DISCUSSION: 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.

TROP-2, Nectin-4, GPNMB, and B7-H3 Are Potentially Therapeutic Targets for Anaplastic Thyroid Carcinoma.

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.

Pneumatosis intestinalis associated with lenvatinib during thyroid cancer treatment: a case report.

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.

Long-Term Outcomes of a Randomized Study of Neoadjuvant Induction Dual HER2 Blockade with Trastuzumab and Lapatinib Followed by Weekly Paclitaxel Plus Dual HER2 Blockade for HER2-Positive Primary Breast Cancer (Neo-Lath Study).

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.

Inflammatory biomarkers and dynamics of neutrophil-to-lymphocyte ratio in lenvatinib treatment for anaplastic thyroid carcinoma.

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.

Quality Control of Breast Cancer Surgery Samples: Introducing Time Stamp Checking.

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.

Invasive procedures in patients undergoing treatment with lenvatinib for thyroid cancer.

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.

Prospective cohort study of febrile neutropenia in breast cancer patients administered with neoadjuvant and adjuvant chemotherapies: CSPOR-BC FN study.

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.

Preliminary Screening for Hereditary Breast and Ovarian Cancer Using a Chatbot Augmented Intelligence Genetic Counselor: Development and Feasibility Study.

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.

Membrane type 1 matrix metalloproteinase regulates anaplastic thyroid carcinoma cell growth and invasion into the collagen matrix.

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.

Occult Thyroid Carcinoma without Malignant Thyroid Gland Findings during Preoperative Examination: Report of Three Cases.

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.

EZH2 and MMSET Were Identified as Potentially Useful Therapeutic Targets in Metaplastic Breast Carcinoma.

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.

Evaluation of the 8th Edition TNM Classification for Anaplastic Thyroid Carcinoma.

BACKGROUND: The tumor-node-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 < 0.01). Sixty-three (58.3%) patients migrated from stage IV A to IV B by revision based on the existence of nodal involvement and 422 patients (55.7%) were stratified into stage IV 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 B compared to stage IV 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 A disease and categorized many heterogeneous patients in stage IV B.