Two Cases of Distant Metastasis After Mastectomy for Breast Ductal Carcinoma In Situ.

While the prognosis for ductal carcinoma in situ (DCIS) of the breast is generally excellent, distant metastasis after appropriate local treatment is extremely rare. We experienced two cases of distant metastasis after mastectomy for breast ductal carcinoma in situ. In both cases, the surgical margins were negative, the sentinel nodes were negative for metastasis. The first case was a 67-year-old woman who developed lung metastases four years after mastectomy for high-grade DCIS. The second case was a 34-year-old woman with intermediate-grade DCIS who developed intraductal recurrence localized to the nipple two years after the initial nipple-sparing mastectomy and multiple lung and liver metastases six months later. Both cases developed distant metastases despite appropriate local treatment, without preceding or concurrent invasive local recurrence. Although the probability of distant recurrence is low, it is important to inform patients about the risk of recurrence.

Safety and Efficacy of Compression Therapy to Prevent Chemotherapy-Induced Peripheral Neuropathy in Lower Extremities of Breast Cancer Patients: A Pilot Study.

Background Chemotherapy-induced peripheral neuropathy (CIPN) is a problematic adverse event for breast cancer patients receiving taxane antimitotic agents. We evaluated the effectiveness of compression therapy against CIPN in the lower extremities of breast cancer patients receiving taxanes. Methods Eligible patients scheduled for perioperative treatment with taxanes for early-stage breast cancer were enrolled. Each patient wore latex-free surgical gloves and compression socks, putting on two layers of each 15 minutes before the administration of taxanes and removing them 15 minutes after administration. Peripheral neuropathy (PN) was evaluated using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 and the Patient Neurotoxicity Questionnaire (PNQ). The primary endpoint was the incidence of CTCAE version 4.0 grade 2 or higher CIPN in the lower extremities during the entire period of perioperative chemotherapy with taxanes. Results PN assessment by CTCAE in the lower extremities, the primary outcome, showed that 13.3% developed grade 2 sensory disturbances, and 8.3% developed grade 2 motor disturbances. The incidence of CTCAE grade 2 or higher PN in the hands was 26.7% for sensory disturbances and 13.3% for motor disturbances during the entire study period. No patient had grade 3 or higher PN. No adverse events due to compression therapy were observed. Conclusion Compression of the lower extremities with compression socks tended to reduce the incidence of CIPN compared to the general incidence. Compression therapy may help prevent the development of CIPN.

A Prospective Cohort Study Exploring the Effect of Lenvatinib Planned Drug Holidays in Treatment of Differentiated Thyroid Cancer.

Background: Although lenvatinib is the preferred treatment for unresectable radioactive iodine-refractory differentiated thyroid cancer (RR-DTC), this agent exerts considerable toxicities, which can lead to frequent dose interruptions and modifications. The adoption of planned drug holidays has been recently suggested as one means of minimizing or avoiding these severe adverse events. Our retrospective study demonstrated that planned drug holidays appear to be a promising strategy for continuing of lenvatinib. However, the benefits of planned drug holidays in a prospective study have yet to be clarified. Here, we investigated the impact of planned drug holidays on clinical outcomes in patients treated with lenvatinib in the COLLECT study. Methods: In COLLECT, a prospective observational study, patients with RR-DTC were treated with lenvatinib in a real-world clinical setting. Lenvatinib was administered orally at a dose of 24 mg daily. Dose modification for toxicities was permitted. Furthermore, planned drug holidays were allowed to avoid severe or intolerable toxicities. The present post hoc analysis focused on evaluating the impact of planned drug holidays on clinical outcomes, including overall survival (OS), time to treatment failure (TTF), time to failure strategy (TFS), and progression-free survival (PFS), in patients in the COLLECT study who were treated with lenvatinib. Results: In total, 262 patients were included. Of the 253 patients evaluable for efficacy, 73 undertook a planned drug holiday at the discretion of the attending physician. OS, TTF, TFS, and PFS were significantly longer in patients who used a planned drug holiday than in those who did not. The planned drug holiday group demonstrated notable clinical outcomes, with a 1-year OS of 95.8% and a 1-year PFS of 94.5%. Moreover, planned drug holidays demonstrated a clinically meaningful advantage in clinical outcomes. The planned drug holiday group had a significantly longer duration of administration at a dose of ≥10 mg. Conclusions: Planned drug holidays for lenvatinib were associated with significantly improved clinical outcomes compared to daily oral administration. Further investigation of the optimal treatment schedule for lenvatinib is warranted. Clinical Trial Registration: UMIN000022243.

Recurrent severe hypocalcemia following chemotherapy regimen changes in advanced breast cancer: two case reports.

BACKGROUND: As an oncologic emergency related to abnormalities in calcium metabolism, hypercalcemia associated with paraneoplastic syndrome and bone metastases is well known. Meanwhile, the incidence of hypocalcemia is low, except in cases associated with bone-modifying agents used for bone metastases. Hypocalcemia induced by bone-modifying agents typically occurs early after the initial administration, and its incidence can be significantly reduced by preventive administration of calcium and vitamin D3 supplements. CASE REPORT: We report two cases of recurrent severe hypocalcemia occurring during chemotherapy for metastatic breast cancer with multiple bone metastases. Case 1: A 35-year-old Japanese woman developed metastases in the bone, liver, and ovaries during postoperative endocrine therapy for invasive lobular carcinoma of the breast. She underwent chemotherapy and treatment with denosumab. She experienced recurrent episodes of severe hypocalcemia subsequent to a change in the chemotherapy regimen. Case 2: A 65-year-old Japanese woman encountered multiple bone metastases after postoperative anti-human epidermal growth factor receptor 2 therapy and during endocrine therapy for invasive ductal carcinoma of the breast. She underwent anti-human epidermal growth factor receptor 2 therapy and treatment with denosumab. She experienced recurrent severe hypocalcemia subsequent to a change in the chemotherapy regimen to letrozole + lapatinib, trastuzumab emtansine, and lapatinib + capecitabine. CONCLUSIONS: We observed two cases of recurrent severe hypocalcemia in patients with advanced breast cancer and bone metastases after modifications to their therapy regimens. These cases differed from the typical hypocalcemia induced by bone-modifying agents. It is possible that antitumor drugs affect calcium and bone metabolism associated with bone metastases. While these cases are rare, it is crucial for oncologists to be aware of hypocalcemia not only at the initiation of bone-modifying agents but also throughout the entire antitumor therapy, as hypocalcemia can lead to fatal outcomes.

Impact of the coronavirus disease 2019 pandemic on 20 representative surgical procedures in Japan based on the National Clinical Database: annual surveillance of 2021 by the Japan Surgical Society.

PURPOSE: The volume of surgical services has significantly reduced globally due to the coronavirus disease 2019 (COVID-19) pandemic. This study evaluated the level of recovery in terms of the number of operations performed in Japan in 2021, based on nationwide periodic surveillance. METHODS: Information on the weekly and annual volumes of 20 representative procedures in 6 surgical subspecialties in 2021 was extracted from the National Clinical Database. Statistical data for 2018 and 2019 (pre-pandemic era) were compared with those for 2020. Data on waves of infection, peak period, and high-prevalence areas (13 of 47 prefectures) were analyzed individually. RESULTS: The volumes of the 10 procedures, including gastrectomy, hepatectomy, valve replacement and valve plasty, coronary artery bypass grafting, infrarenal abdominal aorta replacement, ventricular septal defect closure, lung lobectomy, inguinal hernia repair (age < 16 years old), and appendectomy (age < 16 years old), did not reach 95% of that in the pre-pandemic era. The most striking decline in the surgical volume of these 10 procedures was observed during the peak period of wave 5 in high-prevalence areas. CONCLUSION: This near-complete enumeration survey identified the polarization of 20 representative procedures in terms of resumption of surgical service after the pandemic.

Local recurrence of breast cancer histologically resembling Paget disease presumably due to needle tract seeding: a case report.

Seeding of cancer cells along the needle tract during core needle biopsy is a well-known phenomenon, with a reported frequency of between 22 and 50% [Hoorntje et al. in Eur J Surg Oncol 30:520-525, 2004;Liebens et al. in Maturitas 62:113-123, 2009;Diaz et al. in AJR Am J Roentgenol 173:1303-1313, 1999;]. Local recurrence due to needle tract seeding is rare because the immune system eliminates the cancer cells in most cases. In addition, most local recurrences due to needle tract seeding occur as invasive carcinoma after diagnosis of invasive ductal carcinoma of the breast or mucinous carcinoma, and needle tract seeding due to noninvasive carcinoma is uncommon. We herein report a rare case of local breast cancer recurrence histologically resembling Paget disease, presumably due to needle tract seeding after core needle biopsy for diagnosis of ductal carcinoma in situ of the breast. After receiving a diagnosis of ductal carcinoma in situ, the patient underwent skin-sparing mastectomy and breast reconstruction with a latissimus dorsi musculocutaneous flap. The pathological study showed ER/PgR-negative ductal carcinoma in situ, and no postoperative radiation therapy or systemic therapy was administered. Six months after the surgery, the patient had a breast cancer recurrence histologically resembling Paget disease, presumably in the scar of her core needle biopsy. The pathological study showed Paget disease localized in the epidermis, no invasive carcinoma, and no lymph node metastasis. It was morphologically similar to the primary lesion and was diagnosed as a local recurrence due to needle tract seeding.

Virtual-freezing fluorescence imaging flow cytometry with 5-aminolevulinic acid stimulation and antibody labeling for detecting all forms of circulating tumor cells.

Circulating tumor cells (CTCs) are precursors to cancer metastasis. In blood circulation, they take various forms such as single CTCs, CTC clusters, and CTC-leukocyte clusters, all of which have unique characteristics in terms of physiological function and have been a subject of extensive research in the last several years. Unfortunately, conventional methods are limited in accurately analysing the highly heterogeneous nature of CTCs. Here we present an effective strategy for simultaneously analysing all forms of CTCs in blood by virtual-freezing fluorescence imaging (VIFFI) flow cytometry with 5-aminolevulinic acid (5-ALA) stimulation and antibody labeling. VIFFI is an optomechanical imaging method that virtually freezes the motion of fast-flowing cells on an image sensor to enable high-throughput yet sensitive imaging of every single event. 5-ALA stimulates cancer cells to induce the accumulation of protoporphyrin (PpIX), a red fluorescent substance, making it possible to detect all cancer cells even if they show no expression of the epithelial cell adhesion molecule, a typical CTC biomarker. Although PpIX signals are generally weak, VIFFI flow cytometry can detect them by virtue of its high sensitivity. As a proof-of-principle demonstration of the strategy, we applied cancer cells spiked in blood to the strategy to demonstrate image-based detection and accurate classification of single cancer cells, clusters of cancer cells, and clusters of a cancer cell(s) and a leukocyte(s). To show the clinical utility of our method, we used it to evaluate blood samples of four breast cancer patients and four healthy donors and identified EpCAM-positive PpIX-positive cells in one of the patient samples. Our work paves the way toward the determination of cancer prognosis, the guidance and monitoring of treatment, and the design of antitumor strategies for cancer patients.

Absolute Lymphocyte Count as an Independent Prognostic Factor in Metastatic Breast Cancer: A Retrospective Study.

INTRODUCTION: Recently, absolute lymphocyte count (ALC) and neutrophil-to-lymphocyte ratio (NLR) have been reported to be prognostic and/or predictive factors in breast cancer. However, most of the investigations on the relationship between systemic inflammatory markers and prognosis have been conducted perioperatively, with few studies reporting on patients with metastatic or recurrent breast cancer (MBC). Here, we investigated the role of ALC and NLR as prognostic factors of MBC. METHODS: This was a retrospective observational study of patients with MBC treated at the University of Tsukuba Hospital between 2013 and 2020. ALC and NLR clinical data were obtained from the patients' charts. Based on the previous reports, the cutoff value of ALC was set at 1,500/µL and that of NLR, at 3. We investigated the prognostic significance of ALC and NLR. RESULTS: About 80% of the 243 included patients were hormone receptor-positive, 20% were HER2-positive, and 10% were triple negative. The patients were grouped as follows: 114 (46.9%) and 129 (53.1%) in the high and low ALC groups and 145 (59.7%) and 98 (40.3%) in the high and low NLR groups, respectively. The group with high ALC at diagnosis of MBC showed significantly better prognosis (p = 0.002), and the median overall survival (OS) was 70.9 months, as compared with 40.2 months for the low ALC group. On multivariate analysis, visceral metastasis, subtype, and ALC were independent variables for OS; the NLR status was not correlated with OS. CONCLUSIONS: Analysis of real-world data suggests that ALC at diagnosis of MBC is an independent prognostic factor.

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.

Prevalence of Germline Variants in a Large Cohort of Japanese Patients with Pheochromocytoma and/or Paraganglioma.

The high incidence of germline variants in pheochromocytoma and paraganglioma (PPGL) has been reported mainly in Europe, but not among Japanese populations in Asia. We aimed to study the prevalence of germline variants in Japanese PPGL patients and the genotype-phenotype correlation. We examined 370 PPGL probands, including 43 patients with family history and/or syndromic presentation and 327 patients with apparently sporadic (AS) presentation. Clinical data and blood samples were collected, and the seven major susceptibility genes (MAX, SDHB, SDHC, SDHD, TMEM127, VHL, and RET) were tested using Sanger sequencing. Overall, 120/370 (32.4%) patients had pathogenic or likely pathogenic variants, with 81/327 (24.8%) in AS presentation. SDHB was the most frequently mutated gene (57, 15.4%), followed by SDHD (27, 7.3%), and VHL (18, 4.9%). The incidence of metastatic PPGL was high in SDHB carriers (21/57, 36.8%). A few unique recurrent variants (SDHB c.137G>A and SDHB c.470delT) were detected in this Japanese cohort, highlighting ethnic differences. In summary, almost a quarter of patients with apparently sporadic PPGL in Japan harboured germline variants of the targeted genes. This study reinforces the recommendation in Western guidelines to perform genetic testing for PPGL and genotype-based clinical decision-making in the Japanese population.

Investigation of the significance of population-based breast cancer screening among women aged under 40 years.

BACKGROUND: Owing to low incidence rates, population-based breast cancer screening is not recommended by many municipalities in Japan for women aged < 40 years. To evaluate the usefulness of screening in women aged < 40 years, we investigated the results of population-based breast cancer screening among young women performed in the Ibaraki Prefecture. METHODS: Data regarding histological characteristics, recall rates, cancer detection rates, positive predictive values, tumor categories, and status of lymph node metastases were obtained from population-based screening data from Ibaraki Health Service Association Institute. The "number needing to be screened" (NNS) was determined; using Pearson's chi-squared test, these data were compared between women aged < 40 years and > 40 years. RESULTS: The data of 428,560 women were evaluated. Cancer detection rates were significantly lower and the NNS and proportion of women with tumor category T2 or higher was significantly increased in women aged < 40 years than in those aged > 40 years (0.06% vs. 0.21%, 1505 vs. 281-439, and 28.9% vs. 6.3%, respectively; all, p < 0.05). The proportion of early-stage cancers was lower in women aged < 40 years than in those > 40 years, but this was not significant. CONCLUSIONS: These results suggest that population-based breast cancer screening should not be recommended for women aged < 40 years. To reduce the breast cancer-related mortality rate in young women and ensure efficient use of limited medical resources in Japan, a more efficient surveillance system, based on genetic propensity and family history, needs to be established.

Normocalcemic Primary Hyperparathyroidism Presenting with Muscle Weakness and Body Pain.

We herein report a 39-year-old woman who had aggravated body pain, waddling gait, and fatigability for the past 2 years. A neurological examination showed hyperreflexia and proximal muscle weakness. The serum calcium level was normal (10.1 mg/dL). However, serum alkaline phosphatase (3,855 IU/I) and parathyroid hormone (1,008 pg/mL) levels were remarkably high. Cervical ultrasonography revealed parathyroid goiter. The patient was diagnosed with hyperparathyroidism. Her muscle weakness and pain improved within three months after parathyroidectomy. Our findings suggest that clinicians should consider hyperparathyroidism as a differential diagnosis in patients with proximal muscle weakness, even if the serum calcium level is normal.

Neoantigen prediction in human breast cancer using RNA sequencing data.

Neoantigens have attracted attention as biomarkers or therapeutic targets. However, accurate prediction of neoantigens is still challenging, especially in terms of its accuracy and cost. Variant detection using RNA sequencing (RNA-seq) data has been reported to be a low-accuracy but cost-effective tool, but the feasibility of RNA-seq data for neoantigen prediction has not been fully examined. In the present study, we used whole-exome sequencing (WES) and RNA-seq data of tumor and matched normal samples from six breast cancer patients to evaluate the utility of RNA-seq data instead of WES data in variant calling to detect neoantigen candidates. Somatic variants were called in three protocols using: (i) tumor and normal WES data (DNA method, Dm); (ii) tumor and normal RNA-seq data (RNA method, Rm); and (iii) combination of tumor RNA-seq and normal WES data (Combination method, Cm). We found that the Rm had both high false-positive and high false-negative rates because this method depended greatly on the expression status of normal transcripts. When we compared the results of Dm with those of Cm, only 14% of the neoantigen candidates detected in Dm were identified in Cm, but the majority of the missed candidates lacked coverage or variant allele reads in the tumor RNA. In contrast, about 70% of the neoepitope candidates with higher expression and rich mutant transcripts could be detected in Cm. Our results showed that Cm could be an efficient and a cost-effective approach to predict highly expressed neoantigens in tumor samples.

Elevated Production of Mitochondrial Reactive Oxygen Species via Hyperthermia Enhanced Cytotoxic Effect of Doxorubicin in Human Breast Cancer Cell Lines MDA-MB-453 and MCF-7.

Hyperthermia (HT) treatment is a noninvasive cancer therapy, often used with radiation therapy and chemotherapy. Compared with 37 °C, 42 °C is mild heat stress for cells and produces reactive oxygen species (ROS) from mitochondria. To involve subsequent intracellular accumulation of DOX, we have previously reported that the expression of ATP-binding cassette sub-family G member 2 (ABCG2), an exporter of doxorubicin (DOX), was suppressed by a larger amount of intracellular mitochondrial ROS. We then hypothesized that the additive effect of HT and chemotherapy would be induced by the downregulation of ABCG2 expression via intracellular ROS increase. We used human breast cancer cell lines, MCF-7 and MDA-MB-453, incubated at 37 °C or 42 °C for 1 h to clarify this hypothesis. Intracellular ROS production after HT was detected via electron spin resonance (ESR), and DOX cytotoxicity was calculated. Additionally, ABCG2 expression in whole cells was analyzed using Western blotting. We confirmed that the ESR signal peak with HT became higher than that without HT, indicating that the intracellular ROS level was increased by HT. ABCG2 expression was downregulated by HT, and cells were injured after DOX treatment. DOX cytotoxicity enhancement with HT was considered a result of ABCG2 expression downregulation via the increase of ROS production. HT increased intracellular ROS production and downregulated ABCG2 protein expression, leading to cell damage enhancement via DOX.

Four cases of Trousseau syndrome associated with breast cancer that exhibited central nervous system manifestations.

Cancer-associated thrombosis is known as Trousseau syndrome (TS). Here, we report 4 cases of TS associated with advanced breast cancer that caused central nervous system (CNS) vascular events. All 4 patients experienced sudden onset of CNS symptoms. Imaging revealed multiple brain infarctions or intracranial hemorrhage and all 4 patients had leptomeningeal or brain metastasis. Laboratory findings showed hypercoagulability at diagnosis of TS. Of the 4 patients, 2 patients were treated with unfractionated heparin, while 2 patients could not undergo anticoagulant therapy. In all patients, once the TS occurred, the CNS symptoms progressed rapidly and the prognosis was very poor, 3 patients dying within about a month of diagnosis of TS. Therefore, the predictive factors of TS are important and standards and guidelines for administration of anticoagulants are needed.

High-Performance Liquid Chromatography for Therapeutic Drug Monitoring of Serum Lenvatinib.

BACKGROUND: Therapeutic drug monitoring (TDM) and dose adjustment of lenvatinib may be beneficial in the treatment of radioiodine-refractory thyroid cancer, by maximizing antitumor effects and minimizing adverse drug reactions. The aim of this study was, therefore, to develop and validate a high-performance liquid chromatography method using an ultraviolet detection system for routine serum lenvatinib detection in patients with thyroid cancer. METHODS: Serum specimens, spiked with an internal standard, were treated by a solid-phase extraction through an octadecylsilyl silica cartridge. Lenvatinib and internal standard were concomitantly separated from serum using a conventional octadecylsilyl silica column through isocratic elution, using a mobile phase consisting of 0.02 mol/L sodium phosphate (pH 6.7) and acetonitrile (50/50, vol/vol) at a flow rate of 1.0 mL/min. The detection wavelength was set at 244 nm. Serum samples from 5 patients were used for clinical validation of the method. RESULTS: The calibration curve for lenvatinib was linear (Pearson correlation coefficient, r = 0.9998) over the concentration range of 6.25-400 ng/mL, with a lower limit of quantification of 6.25 ng/mL. Extraction recoveries for lenvatinib were 97% or more, with coefficients of variation less than 2.2%. The coefficients of variation for intraday and interday assays were less than 4.7% and 6.0%, respectively. CONCLUSIONS: This sensitive high-performance liquid chromatography method can be used for lenvatinib therapeutic drug monitoring when liquid chromatography-tandem mass spectrometry facilities are unavailable.

Preoperative diagnosis of a giant cell tumor of soft tissue arising from the breast by ultrasound-guided core needle biopsy.

Giant cell tumors of soft tissue (GCT-ST) arising in the breast are extremely rare. Herein, we report a case of a 45-year-old woman with a 5-cm mass in her left breast. Ultrasonography revealed a mainly well-circumscribed mass that contained a cystic lesion. Magnetic resonance imaging showed a fibrous capsule-covered mass that contained a high-intensity area, suggesting hemorrhaging. Ultrasound-guided core needle biopsy (CNB) revealed mononuclear histiocytic cells with a round shape or spindled appearance that was mixed with multinucleated giant cells. Immunohistochemical analysis revealed CD68-positive staining in the mononuclear and giant cells but negative staining for pancytokeratin. Preoperatively, the tumor was highly suspected of being GCT-ST. Histopathological results after a left mastectomy showed similar findings to CNB. The final diagnosis was GCT-ST in the breast. To the best of our knowledge, this is the first case report of a GCT-ST arising in the breast diagnosed by ultrasound-guided CNB.

Cohort study exploring the effect of lenvatinib on differentiated thyroid cancer.

Lenvatinib is a molecular-targeting agent that was recently approved in Japan for treatment of curatively unresectable, radioactive iodine-refractory, progressive differentiated thyroid cancer (DTC). Because only a few Japanese patients have received lenvatinib in clinical trials, there are limited domestic data on its safety and efficacy or prognostic factors. Therefore, a prospective observational study has been designed to collect safety and efficacy data in at least 300 patients with curatively unresectable DTC receiving lenvatinib therapy (24 mg/day), in order to find predictors of antitumor activity and survival. Patients with progressive curatively unresectable DTC refractory to radioiodine therapy will be enrolled and the primary endpoint will be overall survival. This study is designed to estimate the 95% confidence intervals of the 1-year and 2-year survival rates with a two-sided width of less than 10%. Secondary endpoints will be the time to treatment failure, time to strategy failure, progression-free survival time with clinical progressive disease, response rate, quality of life, safety, and patient reports. The ultimate goal is to obtain information for developing evidence-based guidelines for treatment of DTC, including recommendations on patient selection, dosages, and duration of treatment. This study has been registered with the UMIN Clinical Trials Registry (UMIN000022243).

A Rare Coexistence of Pheochromocytoma and Parkinson's Disease With Diagnostic Challenges.

We herein report a case of pheochromocytoma occurring in the course of Parkinson's disease. The coexistence of these two disease is extremely rare, with only four cases hitherto reported across the public databases. It is also noteworthy that biochemical tests, which are critical for the diagnosis of pheochromocytoma, are severely confounded by dopaminergic medications for Parkinson's disease, highlighting the importance of image-based modalities in this setting. We further attempted to gain insight into the potential molecular mechanisms, proposing that hypoxia-inducible factor signaling could make these two diseases mutually exclusive, while excessive reactive oxygen species could enable their coexistence.

Effects of sorafenib and an adenylyl cyclase activator on in vitro growth of well-differentiated thyroid cancer cells.

Well-differentiated thyroid carcinomas have driver mutations involving growth factor receptor-tyrosine kinases (RTKs) or their intracellular signaling pathway, that is, the mitogen-activated protein kinase (MAPK) pathway. Sorafenib is a multikinase inhibitor of RTKs and the MAPK pathway and has recently been used for the treatment of unresectable well-differentiated thyroid carcinoma. In normal thyroid follicular cells, stimulation of the thyroid-stimulating hormone (TSH) receptor activates the cyclic adenosine monophosphate (cAMP) pathway and promotes cell growth as well as hormonal secretion. However, an adenylyl cyclase (AC) activator, forskolin, has been reported to suppress the growth of thyroid carcinoma cells. To clarify the roles of the MAPK and cAMP pathways in proliferation of well-differentiated thyroid carcinoma cells, we compared the effects of sorafenib and forskolin in in vitro models. Sorafenib inhibited constitutive activation of the MAPK pathway, cyclin-dependent kinase 4 (CDK4), and phosphorylated retinoblastoma protein (RB) in 3 well-differentiated carcinoma cell lines, but it did not show sufficiently effective suppression of cell growth. Forskolin significantly suppressed the growth of all 3 cell lines and also activated the cAMP pathway and inhibited expression of cyclin D1. Our results suggest that activation of the cAMP pathway could be more potent than activation of the MAPK pathway in suppressing proliferation of well-differentiated thyroid cancer cells. We postulate that the AC activator suppresses growth of thyroid carcinoma cells through undetermined mechanisms.