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The present study investigated the association between local resection and cause of death in anaplastic thyroid carcinoma (ATC) patients with stage IVC disease.A total of 54 ATC patients with stage IVC disease were included in the study. Information including patient characteristics, laboratory data including complete blood count, treatment, and death were collected for analysis.The median overall survival (OS) for patients with or without resection was 8.4 [95% confidence interval (CI) 5.9-14.4)] and 4.2 (95% CI 2.5-6.2) months, respectively (p 0.001). No patients survived without resection at 1 year. Univariate analysis revealed that resection (p 0.001) and radiotherapy (p = 0.018) were significantly associated with OS. Multivariate analysis revealed that resection (hazard ratio 0.257; 95% CI 0.115-0.575; p 0.001) was the only independent prognostic factor of OS. In ATC patients with known resection status, the median OS for the patients with a resection status of R0/1 (n = 28) and R2 (n = 7) were 13.0 (95% CI 7.5-18.7) and 1.7 (95% CI 0.1-6.2) months, respectively (p 0.001). The most common specific cause of death was respiratory insufficiency (35%), followed by airway obstruction (25%) and cerebral cardiovascular-related death (5%). The frequency of airway obstruction was significantly lower in patients with resection (p = 0.018).Resection probably impacts on clinical course in ATC patients despite the presence of distant metastasis. However, R2 resection is likely to be harmful and surgeons should carefully consider the resectability of thyroid tumors.

Purpose This study aimed to analyze the clinical course of patients with differentiated thyroid cancer (DTC) who were treated by lenvatinib and investigate the specific criteria for the initiation of lenvatinib treatment in lung metastasis.MethodsA total of 111 patients with DTC treated by lenvatinib were included in the study. Patients were divided into two groups based on the target lesion for the initiation of lenvatinib treatment: lung metastasis group and other metastases group.ResultsIn the univariate analysis, the tumor size for the target lesion (p = 0.002) and target lesion (p < 0.001) were significantly associated with overall survival (OS). Multivariate analysis revealed that the target lesion [hazard ratio, 0.408; 95% confidence interval (CI), 0.206–0.810; p = 0.010] was the only independent prognostic factor of OS. Of the 53 patients in the lung metastasis group, 12 (23%) had lung metastasis-related finding such as pleural effusion (n = 12), hemoptysis (n = 2), and dyspnea (n = 1) at the initiation of lenvatinib treatment. The median OS in patients with or without lung metastasis-related findings were 41.0 [95% CI, 10.4–not available (NA)] months and 62.9 (95% CI, 53.0–NA) months, respectively (p = 0.022).ConclusionPatients with lung metastasis-related finding at the initiation of lenvatinib treatment had a poorer prognosis among the lung metastasis group. It is important to consider not only the tumor size but also the presence of lung metastasis-related findings when initiating lenvatinib treatment for DTC patients with lung metastasis.

Purpose This study aimed to estimate the proportion of patients with anaplastic thyroid carcinoma (ATC) at our institution who are likely to have the efficacy of immune checkpoint inhibitor (ICI) treatment by investigating programmed cell death ligand 1 (PD-L1) expression. Additionally, we investigated the association between PD-L1 expression and treatment outcomes of lenvatinib in patients with ATC. Methods The 19 lenvatinib-treated patients with ATC whose tissue samples available for immunohistochemistry were included in this study. The tumor proportion score (TPS) ≥1%was determined as positive for PD-L1 expression Results Of the 19 patients, 5 (26%) and 14 (74%) had a partial response to lenvatinib treatment and PD-L1 expression positivity, respectively. The median TPS was 30% in patients with positive PD-L1 expression. The median OS for all 19 patients was 4.8 (95% confidence interval [CI], 2.8–6.6) months with a 6-month OS rate of 36.8%. Furthermore, the median OS for patients with positive or negative PD-L1 expression was 5.3 (95% CI, 1.6–7.8) and 4.2 (95% CI, 1.1–not available) months, respectively (p = 0.277). Conclusion No correlation was observed between the PD-L1 expression in the ATC tissue samples and efficacy of lenvatinib. Furthermore, in our study, 14 (74%) of 19 patients with ATC had PD-L1 expression positivity. Although lenvatinib monotherapy may have limited efficacy, some patients with ATC have the possibility that the addition of ICI on lenvatinib is effective.

Background: Anaplastic thyroid cancer (ATC) is a very rare disease with a remarkably poor prognosis and with no established effective drug therapy. This study aimed to report the outcomes of lenvatinib single-agent therapy as an initial drug treatment in ATC and investigate its safety and efficacy. Methods: This retrospective cohort study included 56 patients with ATC with unresectable primary tumors of whom 36 were treated with lenvatinib and 12 with weekly paclitaxel (PTX), and 8 patients who refused any drug treatment received palliative care. Results: The average survival in the lenvatinib group is 5.8 months, which is significantly longer than 2.0 months in the PTX group (P = 0.005). The efficacy of lenvatinib in 36 patients with ATC, whose primary tumors were unresectable, was evaluated. The response rate was 33%, and the median overall survival was 5.0 months. A safety review indicated that lenvatinib should be used under the careful observation of local findings. Two patients, who showed a reduction with lenvatinib, underwent conversion surgery, which prolonged the prognosis in terms of avoiding events, such as asphyxia, fistula, and hemorrhage due to tumor growth; however, the surgical margins were positive, indicating that complete remission was impossible even if surgical resection was performed. Conclusions: Therefore, starting with lenvatinib treatment and finding a therapeutic drug based on the genomic analysis is an acceptable treatment strategy for ATC while halting the disease progression.

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.

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.

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.

Radioactive iodine (RAI) therapy has been the mainstay of treatment for papillary thyroid carcinoma (PTC) patients with distant metastasis (DM). Although tyrosine kinase inhibitors (TKIs) were introduced for the treatment of RAI refractory metastatic thyroid carcinoma several years ago, clinical outcomes for PTC patients with DM treated using RAI therapy remain unclear. We retrospectively examined 64 PTC patients (9 men, 55 women) with DM at diagnosis treated using RAI therapy without administration of any kind of chemotherapy or TKIs. Median age of patients was 58 years. Site of DM was the lungs (n = 59), bone (n = 3), and pleural dissemination (n = 2). No patients showed multiple-organ metastases at diagnosis. By the end of the study period, 21 patients had died of PTC. Cause-specific survival rates at 10, 15, and 20 years after initial surgery were 68.2%, 63.6% and 61.1%, respectively. Uni- and multivariate analyses identified age ≥55 years (HR 3.1, p = 0.023), site of DM other than the lungs (HR 13.4, p < 0.0001), and DM with no RAI avidity (HR 5.1, p = 0.0098) as factors independently associated with disease-related death. When analyses were restricted to patients with lung metastasis (n = 59), surgical non-curability was another independent risk factor (HR 5.2, p = 0.0047) in addition to age and RAI avidity. According to risk stratification analysis based on these risk factors, patients with site of DM other than the lungs or with lung metastasis showing ≥2 risk factors among age ≥55 years, DM with no RAI avidity, and surgical non-curability are expected to show higher mortality rates.

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.

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.

The present study evaluated the efficacy and safety of TJ-54 (Yokukansan; a traditional Japanese medicine) for the prevention and/or treatment of postoperative delirium in a randomized phase II trial of patients receiving surgery for gastrointestinal and lung malignancies. Patients ≥70 years of age who underwent surgery for gastrointestinal or lung malignancy were eligible for participation in the study. The 186 eligible patients were randomly assigned at a 1:1 ratio to receive TJ-54 or control during their peri-operative care (between 7 days prior to surgery and 4 days following surgery, except for the operation day). The signs and symptoms of delirium were assessed using the Diagnostic and Statistical Manual of Mental Disorders-IV by the investigator during the peri-operative period. A total of 186 eligible gastrointestinal or lung malignancy patients were analyzed (93, TJ-54; 93, control). There were no marked differences between the two randomized groups. The incidence of delirium was 6.5% (6 patients) in the TJ-54 group and 9.7% (9 patients) in the control group, with no significant difference (P=0.419). However, of the patients categorized with a mini-mental state examination (MMSE) score of ≤26, the incidence of postoperative delirium was 9.1% in the TJ-54 group and 26.9% in the control group [risk ratio, 0.338; 95% confidence interval (0.078-1.462), P=0.115]. Treatment with TJ-54 reduced the incidence of postoperative delirium compared with the control group. Although TJ-54 did not demonstrate any contribution to preventing or treating postoperative delirium in patients following surgery for gastrointestinal or lung malignancy, TJ-54 reduced the risk of postoperative delirium in the patients who were classified as MMSE ≤26. Further phase III studies with a larger sample size are required in order to clarify the effects of TJ-54 against postoperative delirium.

BACKGROUND Standard treatment for stage II/III gastric cancer is curative resection followed by adjuvant chemotherapy. However, the five-year survival remains unsatisfactory. Inhibin βA (INHBA) has been reported to be associated with cancer cell proliferation and chemoresistance. PATIENTS AND METHODS We studied the clinical significance of INHBA gene expression in 134 patients with stage II/III gastric cancer who received adjuvant chemotherapy with S-1. INHBA expression of specimens of cancer tissue and adjacent normal mucosa was measured by quantitative real-time, reverse-transcription polymerase chain reaction (RT-PCR). RESULTS INHBA expression levels were significantly higher in cancer tissue than in adjacent normal mucosa. High INHBA expression was associated with significantly poorer 5-year survival than was low expression. On multivariate analysis, INHBA expression was an independent prognostic factor. CONCLUSION INHBA gene expression in gastric cancer tissue is considered a useful independent predictor of outcomes in patients with stage II/III gastric cancer who receive adjuvant chemotherapy with S-1.

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

We report a Japanese pedigree with familial primary hyperparathyroidism due to a CDC73 mutation. To our knowledge, this is the first report of cinacalcet as a treatment for CDC73-related primary hyperparathyroidism. The proband had severe psychomotor retardation and received laryngotracheal separation surgery. At 19 yr of age, he developed acute pancreatitis. Hypercalcemia (12.2-13.8 mg/dL), elevated levels of intact PTH (86-160 pg/mL), and a tumor detected upon neck ultrasonography led to the diagnosis of primary hyperparathyroidism. Family history and biochemical examinations revealed that three family members (the proband's mother, elder brother, and maternal grandfather) had primary hyperparathyroidism. We identified a novel heterozygous mutation, c.240delT, p.Glu81Lysfs*28, in the CDC73 gene in three affected family members, excluding the proband's elder brother who refused genetic testing. Parathyroidectomy for the proband was considered as high-risk, because the tumor was located close to the tracheostomy orifice. After receiving approval from the institutional review board and obtaining the consent, we initiated cinacalcet treatment. At 22 yr of age, treatment with 100 mg of cinacalcet maintained serum calcium levels below 11.0 mg/dL with no apparent side effects. Our report presents the potential efficacy of cinacalcet as a treatment for CDC73-related primary hyperparathyroidism, in particularly inoperative cases.

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/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.

The 208 trial showed that lenvatinib has a significant antitumor effect on unresectable anaplastic thyroid cancer(ATC). Herein, we present a retrospective review of data from 7 patients with unresectable ATC who received lenvatinib in our hospital between May 2015 and October 2016. Two patients were men and 5 were women. The median age was 78(range, 72-85)years, and 1 patient had Stage IV A disease, 1 had Stage IV B, and 5 had Stage IV C at diagnosis, respectively. Three patients experienced a partial response and 1 patient experienced stable disease. The response rate was 43%, and the disease control rate was 57%. The median progression-free survival(PFS)was 4.1(range, 1.1-12.2)months. Grade 3 and Grade 4 gastrointestinal hemorrhage were observed in 2patients and Grade 3 anorexia was observed in 1 patient. Further clinical research seems to be needed to establish a treatment strategy involving lenvatinib for ATC.

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: Standard treatment for stage II/III gastric cancer is curative resection followed by adjuvant chemotherapy. However, the five-year survival remains unsatisfactory. Inhibin βA (INHBA) has been reported to be associated with cancer cell proliferation and chemoresistance. Patients and Methods: We studied the clinical significance of INHBA gene expression in 134 patients with stage II/III gastric cancer who received adjuvant chemotherapy with S-1. INHBA expression of specimens of cancer tissue and adjacent normal mucosa was measured by quantitative real-time, reverse-transcription polymerase chain reaction (RT-PCR). Results: INHBA expression levels were significantly higher in cancer tissue than in adjacent normal mucosa. High INHBA expression was associated with significantly poorer 5-year survival than was low expression. On multivariate analysis, INHBA expression was an independent prognostic factor. Conclusion: INHBA gene expression in gastric cancer tissue is considered a useful independent predictor of outcomes in patients with stage II/III gastric cancer who receive adjuvant chemotherapy with S-1.

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.

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.