TAK-960, a novel, orally available, selective inhibitor of polo-like kinase 1, shows broad-spectrum preclinical antitumor activity in multiple dosing regimens

Polo-like kinase 1 (PLK1) is a serine/threonine protein kinase involved in key processes during mitosis. Human PLK1 has been shown to be overexpressed in various human cancers, and elevated levels of PLK1 have been associated with poor prognosis, making it an attractive target for anticancer therapy. TAK-960 [4-[(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino]-2-fluoro-5-methoxy-N-(1-methylpiperidin-4-yl) benzamide] is a novel, investigational, orally bioavailable, potent, and selective PLK1 inhibitor that has shown activity in several tumor cell lines, including those that express multidrug-resistant protein 1 (MDR1). Consistent with PLK1 inhibition, TAK-960 treatment caused accumulation of G(2)-M cells, aberrant polo mitosis morphology, and increased phosphorylation of histone H3 (pHH3) in vitro and in vivo. TAK-960 inhibited proliferation of multiple cancer cell lines, with mean EC(50) values ranging from 8.4 to 46.9 nmol/L, but not in nondividing normal cells (EC(50) >1,000 nmol/L). The mutation status of TP53 or KRAS and MDR1 expression did not correlate with the potency of TAK-960 in the cell lines tested. In animal models, oral administration of TAK-960 increased pHH3 in a dose-dependent manner and significantly inhibited the growth of HT-29 colorectal cancer xenografts. Treatment with once daily TAK-960 exhibited significant efficacy against multiple tumor xenografts, including an adriamycin/paclitaxel-resistant xenograft model and a disseminated leukemia model. TAK-960 has entered clinical evaluation in patients with advanced cancers.     

Development of subclinical hyperthyroidism due to Graves' disease in a hypothyroid woman who had undergone hemithyroidectomy for adenomatous goiter and radiotherapy for nasopharyngeal cancer

A variety of thyroid disorders develop following external radiation to head and neck cancers. Hypothyroidism is the most common clinical consequence of the radiotherapy and lifelong thyroid hormone replacement is required in many cases. Patients who received both hemithyroidectomy and the external radiation to the neck are at especially high risk for permanent hypothyroidism. Here we report an unusual case with radiation-induced hypothyroidism who had undergone hemithyroidectomy for adenomatous goiter 8 years before the radiotherapy for nasopharyngeal cancer and subclinical hyperthyroidism due to Graves' disease developed during thyroxine replacement therapy. Thus subclinical hyperthyroidism due to Graves' disease can develop in patients with radiation-induced hypothyroidism even if they have undergone hemithyroidectomy for thyroid nodules. Therefore careful and periodic evaluation of thyroid function is required even on adequate thyroxine replacement therapy.     

Intraductal papillary-mucinous carcinoma of the pancreas with tumor thrombus in the portal vein: a report of two cases

Intraductal papillary-mucinous carcinoma (IPMC) is a recently recognized pancreatic tumor and this is the first report to present two patients with IPMC complicating tumor thrombi in the portal vein. Two women, a 74- and a 55-year-old, each revealed a round, cystic and well-demarcated tumor of the pancreas in an abdominal computed tomography (CT). However, the inner lumen of the splenic and portal veins was insufficiently stained during iv-infusion of the contrast medium, suggesting the presence of tumor thrombi. Owing to this information, the presence of tumor thrombus was investigated and correctly identified during laparotomy, and it was completely removable together with the primary pancreatic tumor. The resected tumors showed expansive growth because mucin and tumor tissues rose up when they were cut. Microscopically, the tumor was diagnosed as adenocarcinoma without ovarian-like stroma, and the final diagnosis of branch type of IPMC was made for the two patients. However, within one postoperative year, both patients developed liver metastasis. Although IPMC is known as having a lower potential for metastasis or invasion, the tumor thrombi can form when it reveals an expansive growth suggesting a high inner pressure. In addition, a higher possibility for subsequent liver metastasis should be anticipated after the tumor forms a thrombus in the portal vein.     

Prognosis of patients who develop cervical lymph node recurrence following curative resection for thoracic esophageal cancer

Patients with esophageal cancer often display relapse at cervical nodes after surgery, but their prognosis and a suitable therapy remains unknown. We retrospectively reviewed the records for 35 patients who underwent esophagectomy with lymphadenectomy who then displayed relapse at the cervical lymph nodes alone between 1985 and 2003 in order to observe the prognostic factors for such patients. Median survival time from the date of recurrence for all 35 patients was 12 months with 1-year, 2-year, 3-year and 5-year survival rate of 47.2%, 26.5%, 17.7% and 8.8%, respectively. With regard to the initial treatment against cervical node recurrence, 15 patients were treated by radiotherapy alone, eight by chemoradiotherapy, 11 by surgery and one by chemotherapy alone. Univariate analysis revealed that cervical node dissection at the prior esophagectomy (yes/no, P = 0.0178), time to recurrence (> 9 months or < 9 months, P = 0.0497) and the number of relapsed nodes (solitary/multiple, P = 0.0029) were significant prognostic factors. Among these factors, the number of relapsed nodes (solitary/multiple) was found to be the only significant prognostic factor with an odds ratio of 2.409 and 95% confidence interval of 1.033-5.619 by multivariate analysis. In conclusion, cervical node metastasis is generally considered to be distant organ metastasis. However, if it is a solitary node recurrence, substantial survival can be attained by appropriate loco-regional therapy.     

The prevalence of non-syndromic orofacial clefts and associated congenital heart diseases of a tertiary hospital in Riyadh,Saudi Arabia

BackgroundOrofacial clefts are considered one of the most common birth defects and are frequently associated with other malformations. Congenital heart disease is one of the most prevalent congenital malformation.ObjectiveTo investigate the prevalence of congenital heart diseases associated with non-syndromic orofacial clefts in the Saudi population.MethodsElectronic files of non-syndromic orofacial cleft patients who visited the Oral and Maxillofacial Surgery Department in King Abdulaziz Medical City of Riyadh, Saudi Arabia from January 2015 to December 2018 were retrospectively reviewed. Data were recorded in an excel sheet and analyzed using SPSS via frequency tests.ResultsIn the cleft children identified, the prevalence of non-syndromic orofacial clefts was (77%). Orofacial clefts showed a male predominance (62%). The most common orofacial phenotype was unilateral cleft lip and palate (34%). The prevalence of associated congenital malformations with orofacial clefts was (41%). The most prevalent congenital malformation was congenital heart disease (35%), mainly found in unilateral cleft lip and palate patients (33%). The prevalence of associated congenital heart disease with orofacial clefts was (19%). The most frequent type of congenital heart disease was atrial septal defect (37%).ConclusionThis study highlights the recognition of the associated congenital heart disease with non-syndromic orofacial cleft patients. Global screening protocols designed for newborns with non-syndromic orofacial cleft are needed to eliminate late diagnosis of critical congenital heart diseases which might present operative risks of anesthesia and/or surgical procedures.     

Influence of type of final restoration on the fracture resistance and fracture mode of endodontically treated premolars with occluso-mesial cavities

IntroductionThe aim of this study was to compare the fracture resistance of endodontically treated premolars after the application of three restorative materials (i.e., direct composite, indirect composite, and computer aided design/computer aided manufacturing CAD/CAM ceramic inlays) to restore a conservative occluso-mesial cavity preparation.Materials and methodssixty sound maxillary premolars were divided into four experimental groups; group A: the control group, where neither root canal treatment nor preparation were performed; group B: teeth were restored with a direct Filtek Z250 composite restorative material; group C: teeth were restored with an indirect inlay Filtek Z250 composite restorative material; group D: teeth were restored with IPS E.Max CAD/CAM monolithic ceramic inlays. Access cavities and root canal treatment procedures were conducted using standard techniques. Then, the cavities were restored with direct composite restorative materials following manufacturer’s instructions. Each group received mesial-occlusal cavities and restored according to the designated group.Teeth from all groups were exposed to a thermocycling regimen of 500 cycles in water baths at 5–55 °C. Then, each specimen was mounted on a special fixture on a computer controlled Instron Universal Testing Machine. An axial compressive load was applied to the palatal cusp up to failure at an angle of 45°. The force was applied at the rate of 2 mm/min until visible or audible evidence of fracture was observed. The force at fracture was measured in MPa, and the fracture mode was recorded as either favorable [restorable adhesive fracture above the cemento-enamel junction (CEJ)] or unfavorale (non-restorable fractures under CEJ). The obtained data were analyzed using the SPSS version 21.0 statistical software. One-way ANOVA and Tukey's test were used to compare the mean values of maximum load of the four groups. Pearson's Chi-square test was used to compare the distribution of failure mode among the four groups. The p-value of ≤ 0.05 was used to report the statistical significance of results.     

Erythrocyte zinc concentration as an indicator to distinguish painless thyroiditis-associated transient hypothyroidism from permanent hypothyroidism

Red blood cell (RBC) zinc (Zn) concentration reflects a patient's mean thyroid hormone level over the preceding several months. The aim of this study was to examine whether RBC Zn level can be used as an indicator to distinguish painless thyroiditis-associated transient hypothyroidism (TH) from permanent hypothyroidism (PH). RBC Zn level was measured in 30 untreated PH patients with Hashimoto's thyroiditis and 7 untreated TH patients with painless thyroiditis in whom preceding transient thyrotoxicosis had been confirmed. RBC Zn concentration was significantly lower in TH patients than that in PH patients. There was a positive correlation between RBC Zn and serum TSH, and the latter was clearly lower in TH patients than that in PH patients. However, RBC Zn level was again significantly lower in TH patients than PH patients despite of the comparable serum TSH levels in both groups when RBC Zn was evaluated in patients with serum TSH levels of less than 50 mU/L. Thus TH patients could be identified with RBC Zn measurement, allowing us avoidance of unnecessarily prolonged T4 administration to them.     

Follicular cholangitis mimicking cholangiocarcinoma treated with right hepatectomy: A case report and review of published works

Follicular cholangitis is a new, rare disease that causes severe biliary stricture. We herein describe the findings from a resected case of follicular cholangitis, suggesting a distinct disease entity that causes benign biliary stricture. A 60‐year‐old man who was referred to our hospital due to elevated γ‐glutamyl transpeptidase levels and dilatation of the B8 bile duct. Although bile juice cytology and bile duct brushing cytology showed no malignancy, the dilatation was progressive. Therefore, right hepatectomy combined with caudate lobectomy was carried out on suspicion of intrahepatic cholangiocarcinoma. The wall of the resected bile duct was markedly thickened due to severe fibrosis under the mucosal layer. Histology of the mucosal epithelium indicated no malignancy. Infiltration of plasma cells characterized by remarkable formation of lymphoid follicles with germinal centers was observed around the bile ducts. The patient was diagnosed with follicular cholangitis based on histological findings. We thus observed a rare case of follicular cholangitis. This case and review of published reports suggest that, despite its rarity, follicular cholangitis should be considered at the differential diagnosis of biliary stricture. This case report could contribute to a better understanding of how to address this disease.     

Real-time endobronchial ultrasound-guided transbronchial needle aspiration is useful for diagnosing sarcoidosis

BACKGROUND AND OBJECTIVE: Several studies of real-time endobronchial ultrasound (EBUS)-guided transbronchial needle aspiration (TBNA) have reported a sensitivity of approximately 90% in the diagnosis of mediastinal and hilar malignancies. However, few studies have addressed its role in the diagnosis of sarcoidosis. The aim of the present study was to assess the utility of EBUS-TBNA in confirming a pathological diagnosis of sarcoidosis. METHODS: Fifteen consecutive patients with suspected sarcoidosis and mediastinal and/or hilar lymphadenopathy were investigated prospectively. EBUS-TBNA with an echo-bronchoscope and a dedicated echogenic 22-gauge needle was carried out in patients under conscious sedation, followed by conventional TBNA of the same lesion using a 19-gauge needle. RESULTS: EBUS-TBNA and/or TBNA demonstrated non-caseating epithelioid cell granulomas in 14 of 15 patients (93%). All 14 patients with a pathological diagnosis of sarcoidosis were considered to have sarcoidosis based on subsequent clinical assessments. The single patient with a negative EBUS-TBNA and TBNA had a malignant melanoma diagnosed following surgical biopsy. EBUS-TBNA confirmed a diagnosis of sarcoidosis in 13 of the 14 patients (93%) by identifying non-caseating epithelioid cell granulomas in 18 of 23 lymph nodes (78%) sampled. When two needle aspirates of one or two lymph nodes were carried out, the percentage positive pathological diagnosis for sarcoidosis for (i) EBUS-TBNA; (ii) TBNA; and (iii) the combination of EBUS-TBNA and TBNA were 93% (13 of 14 patients), 93% (13 of 14 patients) and 100% (14 of 14 patients), respectively. There were no complications associated with the procedures. CONCLUSION: EBUS-TBNA is less invasive and acceptably sensitive as a method for obtaining pathological confirmation of sarcoidosis.