CA19-9 producing locally advanced papillary thyroid carcinoma: a case report.

BACKGROUND: CA19-9 is a tumor marker for gastrointestinal and biliary-pancreatic adenocarcinomas; however, its association with thyroid cancer is unknown. Here, we report a case of CA19-9 producing locally advanced papillary thyroid carcinoma (PTC). CASE PRESENTATION: A 66-year-old woman who was identified with a thyroid tumor after a close examination of an elevated serum CA19-9 level, which was detected at health screening, was referred to our hospital. Ultrasonography revealed a 34 × 31 mm hypoechoic lesion in the lower pole of the left thyroid lobe. Computed tomography revealed a solid thyroid tumor with tracheal invasion without any distant metastases. Bronchoscopy revealed tumor exposure into the tracheal lumen on the left side of the trachea. Fine-needle aspiration cytology led to a diagnosis of papillary thyroid carcinoma (PTC). The patient underwent a total thyroidectomy, tracheal sleeve resection with end-to-end anastomosis, and lymph node dissection in the left cervical and superior mediastinal regions (D3c) with a reversed T-shaped upper sternotomy down to the third intercostal level. Histopathological analysis confirmed the diagnosis of PTC with tracheal invasion and no lymph node metastases (pT4a Ex2 N0). Immunohistochemical staining showed the expression of CA19-9 in cancer cells. Postoperatively, the serum CA19-9 level of the patient decreased to within the normal range. CONCLUSIONS: Some PTCs produce CA19-9, although less frequently. When elevated serum CA19-9 levels are observed, PTC should be included in the differential diagnosis for further investigation.

A Phase 2 Study of Encorafenib in Combination with Binimetinib in Patients with Metastatic BRAF-Mutated Thyroid Cancer in Japan.

Background: Driver mutations at BRAF V600 are frequently identified in papillary thyroid cancer and anaplastic thyroid cancer (ATC), in which BRAF inhibitors have shown clinical effectiveness. This Japanese phase 2 study evaluated the efficacy and safety of a BRAF inhibitor, encorafenib, combined with an MEK inhibitor, binimetinib, in patients with BRAF V600-mutated thyroid cancer. Methods: This phase 2, open-label, uncontrolled study was conducted at 10 institutions targeted patients with BRAF V600-mutated locally advanced or distant metastatic thyroid cancer not amenable to curative treatment who became refractory/intolerant to ≥1 previous vascular endothelial growth factor receptor-targeted regimen(s) or were considered ineligible for those. The primary endpoint was centrally assessed objective response rate (ORR). The secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Results: We enrolled 22 patients with BRAFV600E-mutated thyroid cancer: 17 had differentiated thyroid cancer (DTC), and 5 had ATC. At data cutoff (October 26, 2022), the median follow-up was 11.5 (range = 3.4-19.0) months. The primary endpoint of centrally assessed ORR was 54.5% (95% confidence interval [CI] 32.2-75.6; partial response in 12 patients and stable disease in 10). The ORRs in patients with DTC and ATC were 47.1% (8 of 17) and 80.0% (4 of 5), respectively. The medians for DOR and PFS by central assessment and for OS were not reached in the overall population, the DTC subgroup, or the ATC subgroup. At 12 months, the rate of ongoing response was 90.9%, and the PFS and OS rates were 78.8% and 81.8%, respectively. All patients developed ≥1 adverse events (AEs): grade 3 AEs in 6 patients (27.3%). No patients developed grade 4-5 AEs. The most common grade 3 AE was lipase increased (4 patients [18.2%]). Those toxicities were mostly manageable with appropriate monitoring and dose adjustment. Conclusions: Treatment with encorafenib plus binimetinib met the primary endpoint criteria and demonstrated clinical benefit in patients with BRAFV600E-mutated thyroid cancer regardless of its histological type, such as DTC or ATC, with no new safety concerns identified. Encorafenib plus binimetinib could thus be a new treatment option for BRAF V600-mutated thyroid cancer. Clinical Trial Registration number: Japan Registry of Clinical Trials: jRCT2011200018.

Clinical and immunological relevance of SLAMF6 expression in the tumor microenvironment of breast cancer and melanoma.

Compelling evidence shows that the frequency of T cells in the tumor microenvironment correlates with prognosis as well as response to immunotherapy. However, considerable heterogeneity exists within tumor-infiltrating T cells, and significance of their genomic and transcriptomic landscape on clinical outcomes remains to be elucidated. Signaling lymphocyte activation molecule 6 (SLAMF6) is expressed on intra-tumoral progenitor-exhausted T cells, which exhibit the capacity to proliferate, self-renew and produce terminally-exhausted T cells in pre-clinical models and patients. Here, we investigated the impact of SLAMF6 expression on prognosis in two immunologically different tumor types using publicly available databases. Our findings demonstrate that high SLAMF6 expression is associated with better prognosis, expression of TCF7 (encoding T-cell factor 1), and increased gene signatures associated with conventional type 1 dendritic cells and effector function of T cells in melanoma and breast cancer. Single-cell profiling of breast cancer tumor microenvironment reveals SLAMF6 expression overlaps CD8 T cells with a T-effector signature, which includes subsets expressing TCF7, memory and effector-related genes, analogous to progenitor-exhausted T cells. These findings illustrate the significance of SLAMF6 in the tumor as a marker for better effector responses, and provide insights into the predictive and prognostic determinants for cancer patients.

Eribulin promotes proliferation of CD8+ T cells and potentiates T cell-mediated anti-tumor activity against triple-negative breast cancer cells.

PURPOSE: Chemotherapeutic agents exert immunomodulatory effects on triple-negative breast cancer (TNBC) cells and immune cells. Eribulin favorably affects the immunological status of patients with breast cancer. However, the effects of eribulin on the immune cells remain unexplored. The aim of this study was to investigate the effects of eribulin on immune cells. METHODS: Peripheral blood mononuclear cells (PBMCs) from healthy donors and mouse splenocytes were stimulated with anti-CD3 and anti-CD28 antibodies. The effects of eribulin and paclitaxel on cell proliferation and differentiation status were analyzed using flow cytometry. RNA sequencing was performed to assess alterations in gene expression in CD8+ T cells following eribulin and paclitaxel treatment. Using TNBC cell lines (MDA-MB-231, Hs578T, and MDA-MB-157), the anti-tumor activity of CD3/CD28-stimulated T cells combined with eribulin or paclitaxel was evaluated. RESULTS: Eribulin did not affect CD3/CD28-stimulated PBMCs proliferation. However, eribulin significantly decreased the CD4/CD8 ratio in T cells, indicating that eribulin facilitates CD8+ T cell proliferation. Furthermore, eribulin significantly increased the frequency of less differentiated CD45RA+, CCR7+, and TCF1+ subsets of CD8+ T cells. RNA sequencing revealed that eribulin enhanced the expression of gene sets related to cell proliferation and immune responses. Moreover, eribulin augmented the anti-tumor effects of CD3/CD28-stimulated T cells against TNBC cells. These results were not observed in experiments using paclitaxel. CONCLUSIONS: Eribulin promoted CD8+ T cell proliferation, repressed effector T cell differentiation, and harnessed T cell-mediated anti-tumor effects. These mechanisms may be one of the cues that eribulin can improve the immunological status of tumor-bearing hosts.

Development of a predictive score for post-hemithyroidectomy hypothyroidism using skeletal muscle index, remnant thyroid index, and thyroid-stimulating hormone levels: a retrospective cohort study.

Background: Hypothyroidism is a major complication of hemithyroidectomy. Low remnant thyroid volume and high serum thyroid-stimulating hormone (TSH) levels are suggested as risk factors for post-hemithyroidectomy hypothyroidism. Reduced skeletal muscle mass is associated with a variety of postoperative complications. However, its impact on post-hemithyroidectomy hypothyroidism has not yet been studied. This study aimed to evaluate the association between skeletal muscle mass and the onset of post-hemithyroidectomy hypothyroidism and develop a predictive score using skeletal muscle mass in combination with previously reported risk factors. Methods: This study retrospectively analyzed 226 consecutive patients who underwent hemithyroidectomy at Shinshu University Hospital between January 2011 and December 2020. The skeletal muscle area at the fourth thoracic vertebral level and maximal remnant thyroid area were quantified using preoperative computed tomography and standardized by dividing them by the square of the patient's height, designated as the skeletal muscle index (SMI) and remnant thyroid volume index (RTI). Subclinical hypothyroidism was defined as a postoperative elevated serum TSH level (>5 µU/mL) with a normal free thyroxine (FT4) level (≥0.9 ng/dL), overt hypothyroidism as a postoperative increase in serum TSH level (>5 µU/mL) and a decrease in serum FT4 level (<0.9 ng/dL), and symptomatic hypothyroidism as an elevated serum TSH level (>5 µU/mL) with hypothyroidism-related symptoms. Logistic regression analysis was used to determine the factors associated with the onset of hypothyroidism. Results: Patients with euthyroid status had significantly higher SMI and RTI than those who developed post-hemithyroidectomy hypothyroidism (SMI, euthyroid: 12.0±2.4 vs. subclinical hypothyroid: 10.2±1.7, P<0.001, euthyroid vs. overt or symptomatic hypothyroid: 10.1±1.7, P<0.001, RTI, euthyroid: 1.19±0.41 vs. subclinical hypothyroid: 0.92±0.35, P<0.001, euthyroid vs. overt or symptomatic hypothyroid: 0.84±0.30, P<0.001). Multivariable analysis demonstrated that low SMI, low RTI [hazard ratio (HR): 3.35, P<0.001], and preoperative high serum TSH levels (HR: 2.54, P=0.003) were independent predictive factors for hypothyroidism. Patients who had low SMI, low RTI, and preoperative high serum TSH levels were more likely to develop hypothyroidism (68.8%) than those with either one (25.3%), two (47.8%), or none (15.2%) of these three factors. Conclusions: Preoperative evaluation of the SMI, RTI, and serum TSH levels may be useful in predicting the development of post-hemithyroidectomy hypothyroidism.

Epidemiological and therapeutic profiles of lung cancer patients in the Hokushin Region Japan: a retrospective hospital administrative database study.

OBJECTIVE: This study was performed to validate the epidemiology, initial treatment, and clinical practice of lung cancer patients in the Hokushin region, Japan. METHODS: We retrospectively surveyed data of 5503 newly diagnosed and registered lung cancer patients in 22 principal hospital-based cancer registries in Hokushin region linked with health insurance claims data for registered patients between 2016 and 2017. RESULTS: The patients consisted of 3677 (66.8%) men and 1826 (33.2%) women with a mean (range) age of 72.2 (27-103) years). Diagnoses were small cell lung cancer (n = 512, 9.4%), squamous cell carcinoma (n = 1083, 19.7%), and non-squamous non-small cell lung cancer (NSCLC; n = 3906, 70.9%). The population with stage I disease in Toyama prefecture (41.1%) was smaller than in the other three prefectures associated with reduced selection of initial surgical therapy and increased frequencies of stage IV disease (33.2%) and best supportive care (18.6%). Initial chemotherapy for stage IV non-squamous NSCLC consisted of tyrosine kinase inhibitors in 39.3% of cases for EGFR and 4% of cases for ALK-positive non-squamous NSCLC, followed by platinum compounds (25.9%) non-platinum compounds (12.9%), and immune checkpoint inhibitors (10.2%). Carboplatin was the commonly prescribed first-line cytotoxic chemotherapeutic agent (65.4% of patients under 75 years and in 96.7% of patients over 75 years). CONCLUSION: This study revealed real-world data on epidemiological and treatment status in lung cancer in four prefectures in Hokushin region, Japan. Simultaneous analysis of nationwide registry and insurance data could provide valuable insights for the development of lung cancer screening and medical treatment strategies. In addition, the comparative data analysis with other lesions or countries will be useful for evaluating the differences in clinical practice of cancer managements.

Significance of skeletal muscle index-to-body mass index ratio as a predictor of post-surgical bleeding after mastectomy in patients with breast cancer.

BACKGROUND: Post-surgical bleeding is a major complication of mastectomy in patients with breast cancer. However, the risk factors for post-surgical bleeding have not been well studied. Although obesity or reduced skeletal muscle mass is an indicator of cancer surgery complications, its impact on post-surgical bleeding after mastectomy remains unknown. METHODS: In total, 563 patients with breast cancer who underwent mastectomy were included in this study. We evaluated the preoperative body mass index (BMI), skeletal muscle index (SMI), and SMI-to-BMI ratio and analyzed the association between these values and the incidence of post-surgical bleeding. RESULTS: Post-surgical bleeding occurred in 33 (5.6%) patients. Mean BMI was significantly higher in the bleeding group (26.3 ± 4.7) than in the no-bleeding group (23.0 ± 4.1) (p < 0.001), whereas mean SMI was lower in the former group (45.0 ± 8.5) than in the latter group (48.0 ± 8.5) (p = 0.08). The bleeding group had significantly lower SMI-to-BMI ratio (1.71 ± 0.16) than the no-bleeding group (2.10 ± 0.23) (p < 0.001). Among these three parameters, SMI-to-BMI ratio had the highest area under the curve value in their receiver operating characteristic curves (0.73 for BMI, 0.59 for SMI, 0.92 for SMI-to-BMI ratio). Furthermore, on multivariate analysis, SMI-to-BMI ratio was an independent risk factor for post-surgical bleeding (hazard ratio, 38.4; 95% confidence interval, 13.9-136.2; p < 0.001). CONCLUSIONS: SMI-to-BMI ratio is a superior predictive factor of post-surgical bleeding after mastectomy to either BMI or SMI alone.

Neutrophil-to-Lymphocyte Ratio Is Associated With the Proportion of Poorly Differentiated Components in Papillary Thyroid Carcinoma.

INTRODUCTION: Diagnosis of poorly differentiated thyroid cancer (PDTC) requires ≥ 50% of poorly differentiated components (PDC) in Japan. However, the optimal cutoff percentage of PDC for PDTC diagnosis remains controversial. Although high neutrophil-to-lymphocyte ratio (NLR) correlates with the aggressiveness of papillary thyroid cancer (PTC), whether NLR is associated with the proportion of PDC in PTC remains unstudied. MATERIALS AND METHODS: Patients with the pure PTC (n = 664), PTC with < 50% PDC (n = 19), or PTC with ≥ 50% PDC (n = 26) who underwent surgery were retrospectively analyzed. Twelve-year disease-specific survival and preoperative NLR were compared among these groups. RESULTS: Twenty seven patients died from thyroid cancer. The PTC with ≥ 50% PDC group (80.7%) showed significantly worse 12-year disease-specific survival than the pure PTC group (97.2%) (P < 0.001); however, the < 50% PDC group (94.7%) did not (P = 0.91). The PTC with ≥ 50% PDC group had a significantly higher NLR than the pure PTC (P < 0.001) and the PTC with < 50% PDC groups (P < 0.001), whereas there was no significant difference in the NLR between the pure PTC and the PTC with < 50% PDC groups (P = 0.48). CONCLUSIONS: PTC with ≥ 50% PDC is more aggressive than either pure PTC or PTC with < 50% PDC, and NLR potentially reflects the PDC proportion. These results support the validity of 50% PDC as a cut-off for PDTC diagnosis and indicate the utility of NLR as a biomarker for PDC proportion.

Changes in the pathophysiology of primary hyperparathyroidism and analysis of postoperative recurrence cases at a regional core hospital in Japan: experience of 35 years in Shinshu University Hospital.

BACKGROUND: Since reoperation for recurrent primary hyperparathyroidism (PHPT) increases the risk of complications, such as recurrent laryngeal nerve palsy, it is vital to prevent recurrence as much as possible when performing the initial surgery. Therefore, we retrospectively analyzed the PHPT cases at Shinshu University Hospital from 1986 to 2020 for changes in the characteristics of PHPT over time and features of the recurrent cases to establish treatment strategies to prevent a postoperative recurrence. METHODS: Hereditary PHPT was diagnosed through endocrinological tests, systemic imaging, and/or genetic testing. Localization of swollen parathyroid glands was identified through neck ultrasonography (US), contrast-enhanced computed tomography, magnetic resonance imaging (MRI), and 99mTc-sestamibi scintigraphy. RESULTS: Among the 536 patients with PHPT (374 women and 162 men) with a mean age of 56.9±13.6 years, 90 (16.8%) had hereditary PHPT, while the other 446 (83.2%) had sporadic PHPT. Overall, 314 (58.6%) patients were asymptomatic, whereas 132 (24.6%) had symptoms related to PHPT. Asymptomatic PHPT was significantly more prevalent after 2001 (81.8%) than before 2001 (51.2%) (P<0.01), although the number of PHPT cases increased during the last decade. Resection of an enlarged parathyroid gland alone was performed for sporadic PHPT, while focused parathyroidectomy was performed after 2001. Total parathyroidectomy (TPTx) with autotransplantation was performed in patients with hereditary PHPT. In addition, the intraoperative rapid pathological diagnosis of the resected gland throughout the period and intraoperative serum intact parathyroid hormone (PTH) measurement from 2014 were used. Overall, 11 patients with hereditary PHPT (2.1%) developed recurrence. A recurrent parathyroid gland was identified in 10 of 11 cases through 99mTc-sestamibi scintigraphy. CONCLUSIONS: Although the incidence of asymptomatic PHPT has been increasing recently, focused parathyroidectomy is considered an appropriate procedure for sporadic PHPT that has been carefully examined preoperatively. Therefore, in the future, it will be necessary to conduct genetic testing for sporadic PHPT cases as much as possible to accurately diagnose the disease type and decide on a treatment strategy.

The Advantage of Using an Optical See-Through Head-Mounted Display in Ultrasonography-Guided Needle Biopsy Procedures: A Prospective Randomized Study.

An optical see-through head-mounted display (OST-HMD) can potentially improve the safety and accuracy of ultrasonography (US)-guided fine-needle aspiration. We aimed to evaluate the usefulness of an OST-HMD in US-guided needle-puncture procedures. We conducted a prospective randomized controlled study in which we compared the accuracy and safety of the US-guided needle puncture procedure and the stress on the practitioner when using OST-HMD versus standard US display (SUD). Inexperienced medical students were enrolled and randomly divided into two groups. A breast phantom was used to evaluate the required time and accuracy of the US-guided needle puncture. Practitioner stress was quantified using a visual analog scale (VAS). When the procedure was performed for the first time, the time required to reach the target lesion at a shallow depth was significantly shorter in the OST-HMD group (39.8 ± 39.9 s) than in the SUD group (71.0 ± 81.0 s) (p = 0.01). Using the OST-HMD significantly reduced the unintentional puncture of a non-target lesion (p = 0.01). Furthermore, the stress felt by the practitioners when capturing the image of the target lesion (p < 0.001), inserting and advancing the needle more deeply (p < 0.001), and puncturing the target lesion (p < 0.001) was significantly reduced in the OST-HMD group compared with that in the SUD group. Use of OST-HMD may improve the accuracy and safety of US-guided needle puncture procedures and may reduce practitioner stress during the procedure.

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.

Hypercalcemic crisis caused by primary hyperparathyroidism in a 11-year-old boy: a rare case report and review of the literature.

Background: Hypercalcemic crisis caused by primary hyperparathyroidism (PHPT) in pediatric patients is very rare, and appropriate treatment approach for this condition has not been well demonstrated. Here, we report a case of PHPT-induced hypercalcemic crisis in a boy. Case Description: An 11-year-old boy visited the clinic with abdominal pain and nausea that lasted for 3 months, but the cause of his symptoms could not be identified. As these symptoms worsened after 1 month, he was referred to a nearby hospital. The boy's albumin-corrected serum calcium level was very high (14.3 mg/dL). Treatment was immediately started with the administration of normal saline, furosemide, and calcitonin to lower his serum calcium levels. Based on elevated intact-parathyroid hormone (i-PTH) (405 pg/mL) level and enlargement of the right superior parathyroid on diagnostic imaging, he was diagnosed with hypercalcemic crisis due to PHPT. As his albumin-corrected serum calcium level increased to 16.5 mg/dL and he could not take almost any foods due to severe nausea, he was transferred to our hospital and treated with pamidronate. Although his albumin-corrected serum calcium level decreased to 14.0 mg/dL, his symptoms did not improve completely. Therefore, 2 days after transfer to our hospital, he underwent emergency surgery to resect the enlarged right superior parathyroid gland. Fifteen minutes after removal of the enlarged parathyroid gland, the serum intact-PTH level decreased to 41.7 pg/mL. The histopathological diagnosis of the enlarged parathyroid gland was adenoma. The boy became asymptomatic, and his albumin-corrected serum calcium level was maintained within the normal limits for 6 months post operatively. Genetic testing performed after the surgery did not detect any pathogenic mutations in the MEN1 and CDC73 genes, and no genetic predisposition has been identified to date. Conclusions: Emergency focused parathyroidectomy prior to genetic testing might be an appropriate strategy when the pediatric patient presents with a PHPT-induced hypercalcemic crisis.

Epidermal growth factor receptor activation confers resistance to lenvatinib in thyroid cancer cells.

Thyroid cancer is the most common endocrine malignancy. A multitargeted tyrosine kinase inhibitor, lenvatinib, has been used for the treatment of advanced thyroid cancer. To elucidate the mechanism of resistance to lenvatinib in thyroid cancer cells, we established lenvatinib-resistant sublines and analyzed the molecular mechanisms of resistance. Two thyroid cancer cell lines (TPC-1 and FRO) were used, and resistant sublines for lenvatinib (TPC-1/LR, FRO/LR) were established. In TPC-1/LR, the phosphorylation of epidermal growth factor receptor (EGFR), extracellular signal-regulated kinase (ERK), and Akt was enhanced whereas in FRO/LR, the phosphorylation of EGFR and downstream signal transduction molecules was not enhanced. The addition of epidermal growth factor decreased sensitivity to lenvatinib in TPC-1 and FRO. The combination of EGFR inhibitors lapatinib and lenvatinib significantly inhibited the growth of TPC-1/LR in both in vitro and mouse xenograft models. Short-term exposure to lenvatinib enhanced the phosphorylation of EGFR in six thyroid cancer cell lines regardless of their histological origin or driver gene mutations; however, phosphorylation of ERK was enhanced in all cells except TPC-1. A synergistic growth-inhibitory effect was observed in three thyroid cancer cell lines, including intrinsically lenvatinib-resistant cells. The results indicate that signal transduction via the EGFR pathway may be involved in the development of lenvatinib resistance in thyroid cancer cells. The inhibition of the EGFR pathway simultaneously by an EGFR inhibitor may have therapeutic potential for overcoming lenvatinib resistance in thyroid cancer.

Surgical resection of the primary tumor prevents an undesirable locoregional condition and improves the quality of life in patients with anaplastic thyroid cancer.

PURPOSE: Anaplastic thyroid cancer (ATC) is a highly aggressive tumor that invades surrounding tissues and rapidly metastasizes throughout the body. Growth of the primary tumor in the neck often causes serious conditions that decrease the quality of life (QOL) of patients. The objective of this study was to investigate the role of surgical resection in improving the QOL of patients with ATC. METHODS: This was a retrospective review of 62 patients with ATC treated at Shinshu University Hospital between January 2001 and June 2019. RESULTS: Fourteen patients underwent R0/R1 resection. Thirteen of the 14 patients received postoperative radiation, and 4 received chemotherapy. The mean survival period was 15.4 ± 18.2 (range, 2-75) months. Distant metastases appeared within 3.2 ± 2.3 months postoperatively in 12 patients. A permanent tracheostomy was required in six patients; however, eight patients did not show airway obstruction until death. Daily treatment for exudate or bleeding from tumors that eroded in the neck, which deteriorated the QOL, was unnecessary in 12 patients. CONCLUSIONS: As surgical resection can improve the QOL in patients with ATC, thyroid surgeons should promptly and carefully evaluate the resectability of the tumor and favor resection as much as possible.

Skeletal muscle loss during neoadjuvant chemotherapy predicts poor prognosis in patients with breast cancer.

BACKGROUND: The skeletal muscle index (SMI), which is calculated as the ratio of skeletal muscle area at the third lumbar vertebral level divided by height squared, has been considered a prognostic factor in patients with breast cancer. However, the prognostic impact of changes in SMI during treatment remains unclear. This study aimed to evaluate the influence of SMI changes in patients with breast cancer undergoing neoadjuvant chemotherapy (NAC). METHODS: We reviewed patients with breast cancer who underwent NAC and subsequent surgery for breast cancer between 2010 and 2017. The rate of SMI change during NAC was calculated, and the association between SMI changes and prognosis was retrospectively analyzed. RESULTS: In total, 141 patients were evaluated. 48 (34.0%), 53 (37.6%), and 40 (28.4%) patients exhibited increased (≥ 3%), maintained (- 3% <, < 3%), and decreased (- 3% ≥) SMI during NAC, respectively. The decreased SMI group showed significantly poorer disease-free survival than the maintained and increased SMI groups (hazard ratio [HR] 8.29, p <  0.001 for the decreased vs. increased SMI groups; HR 3.49, p <  0.001 for the decreased vs. maintained SMI groups). Moreover, decreased SMI was an independent risk factor for disease-free survival in multivariate analysis (HR 3.68, p <  0.01). CONCLUSIONS: Skeletal muscle loss during NAC predicts poor prognosis. Our results underscore the importance of monitoring and maintaining skeletal muscle mass during NAC.

Multi-institutional survey of malignant pleural mesothelioma patients in the Hokushin region.

BACKGROUND: Malignant pleural mesothelioma (MPM) is a major occupational and environmental neoplasm. The purpose of this study was to validate the clinical and epidemiological factors, diagnosis, and initial treatment among MPM patients in the Hokushin region. METHODS: We surveyed retrospective data from 152,921 cancer patients in 22 principal hospitals. RESULTS: A total of 166 MPM cases were newly diagnosed. These patients consisted of 136 men and 30 women, with a median age of 69 years. We estimated the incidence rate for MPM to be 0.55 cases per 100,000 person-years in this study. The ratio per 100,000 population-years was 0.39 in Fukui, 0.60 in Ishikawa, 1.02 in Toyama and 0.35 in Nagano. Forty-five patients were discovered when diagnosed incidentally in patients under observations for other diseases. Forty-six cases were diagnosed as localized disease, while 13 had accompanying regional lymph node metastasis. Furthermore, 44 cases showed infiltration into adjacent organs. A histo-cytological diagnosis was made in 164 cases (98.8%). A surgical approach, chemotherapy, and radiotherapy were performed for 33, 88, and 6 patients, respectively, while 44 patients (26.5%) received best supportive care. Multimodality therapy was conducted in just 3.0% of the MPM patients CONCLUSION: MPM has a tragically rapid progression if discovered under observations for other diseases. Workers in health-related fields should be on high alert for aggressive MPM. Better evaluation and multi-disciplinary approaches to MPM in these regions are needed to optimize multimodality therapy.

Multi-institutional survey of thymic carcinoma patients in Hokushin region.

BACKGROUND: Thymic carcinoma is a rare neoplasm, and its prognosis is very poor. The purpose of this study was to validate the clinical and epidemiological factors, diagnosis and initial treatment of thymic carcinoma among all patients diagnosed in the registered hospital group. METHODS: We surveyed retrospective data from 152,921 cancer patients in 22 principal hospitals. RESULTS: A total of 88 thymic carcinoma cases were newly diagnosed. These patients were 50 men and 38 women, with a median age of 66 years old. Eight patients were discovered in cancer screening, 9 in a voluntary setting, 14 at health checkups, 25 at follow-up of other diseases, and 32 cases by introduction from another hospital. Only 14 cases had been diagnosed with localized disease, but 5 cases were accompanied by regional lymph node metastasis. Furthermore, 12 cases showed infiltration into adjacent organs, and 24 cases had distant metastasis. Eighty-three cases were diagnosed by a pathological diagnosis. A surgical approach, chemotherapy, and radiotherapy were performed for 29, 35 patients, and 31 patients, respectively, while 17 patients received best supportive care. CONCLUSION: The diagnosis of thymic carcinoma is still difficult, and this disease has a tragically rapid progression if when discovered during follow-up of other diseases. An innovative modality for the early detection of thymic carcinoma is needed in modern medical society.

Fibroadenoma in a young male breast: A case report and review of the literature.

Fibroadenomas are the most common benign breast tumors in women, but rarely occur in men. Herein, we present a case of fibroadenoma occurring in a young, healthy male without hormonal alterations. This indicates that fibroadenoma should be regarded as differential diagnosis for tumors in the male breast.

Multicenter retrospective study on the use of Curebest™ 95GC Breast for estrogen receptor-positive and node-negative early breast cancer.

BACKGROUND: The benefits of postoperative chemotherapy in patients with estrogen receptor (ER)-positive breast cancer remain unclear. The use of tumor grade, Ki-67, or ER expression failed to provide an accurate prognosis of the risk of relapse after surgery in patients. This study aimed to evaluate whether a multigene assay Curebest™ 95GC Breast (95GC) can identify the risk of recurrence and provide more insights into the requirements for chemotherapy in patients. METHODS: This single-arm retrospective multicenter joint study included patients with ER-positive, node-negative breast cancer who were treated at five facilities in Japan and had received endocrine therapy alone as adjuvant therapy. The primary lesion specimens obtained during surgery were analyzed using the 95GC breast cancer multigene assay. Based on the 95GC results, patients were classified into low-risk (95GC-L) and high-risk (95GC-H) groups. RESULTS: The 10-year relapse-free survival rates were 88.4 and 59.6% for the 95GC-L and 95GC-H groups, respectively. Histologic grade, Ki-67, and PAM50 exhibited a significant relationship with the 95GC results. The segregation into 95GC-L and 95GC-H groups within established clinical factors can identify subgroups of patients using histologic grade or PAM50 classification with good prognosis without receiving chemotherapy. CONCLUSIONS: Based on the results of our retrospective study, 95GC could be used to evaluate the long-term prognosis of ER-positive, node-negative breast cancer. Even though further prospective validation is necessary, the inclusion of 95GC in clinical practice could help to select optimal treatments for breast cancer patients and identify those who do not benefit from the addition of chemotherapy, thus avoiding unnecessary treatment.

The mechanisms involved in the resistance of estrogen receptor-positive breast cancer cells to palbociclib are multiple and change over time.

PURPOSE: Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are widely used for the treatment of advanced estrogen receptor (ER)-positive breast cancer. To develop a treatment strategy for cancers resistant to CDK4/6 inhibitors, here, we established palbociclib-resistant sublines and analyzed their resistance mechanisms. METHODS: Palbociclib-resistant sublines were established from T47D and MCF7 cells. Sensitivity to other drugs was assessed via the WST assay. Altered expression/phosphorylation of proteins related to signal transduction and cell cycle regulation was examined using western blotting. Copy number alterations and mutations in the retinoblastoma (RB1) gene were also analyzed. RESULTS: Although an increase in CDK6 and decrease in retinoblastoma protein (Rb) expression/phosphorylation were commonly observed in the resistant sublines, changes in other cell cycle-related proteins were heterogeneous. Upon extended exposure to palbociclib, the expression/phosphorylation of these proteins became altered, and the long-term removal of palbociclib did not restore the Rb expression/phosphorylation patterns. Consistently a copy number decrease, as well as RB1 mutations were detected. Moreover, although the resistant sublines exhibited cross-resistance to abemaciclib, their response to dinaciclib was the same as that of wild-type cells. Of note, the cell line exhibiting increased mTOR phosphorylation also showed a higher sensitivity to everolimus. However, the sensitivity to chemotherapeutic agents was unchanged in palbociclib-resistant sublines. CONCLUSION: ER-positive breast cancer cells use multiple molecular mechanisms to survive in the presence of palbociclib, suggesting that targeting activated proteins may be an effective strategy to overcome resistance. Additionally, palbociclib monotherapy induces mutations and copy number alterations in the RB1 gene.