An Orally Efficacious Thyrotropin Receptor Ligand Inhibits Growth and Metastatic Activity of Thyroid Cancers.

CONTEXT: Thyroid-stimulating hormone (or thyrotropin) receptor (TSHR) could be a selective target for small molecule ligands to treat thyroid cancer (TC). OBJECTIVE: We report a novel, orally efficacious ligand for TSHR that exhibits proliferation inhibitory activity against human TC in vitro and in vivo, and inhibition of metastasis in vivo. METHODS: A35 (NCATS-SM4420; NCGC00241808) was selected from a sublibrary of >200 TSHR ligands. Cell proliferation assays including BrdU incorporation and WST-1, along with molecular docking studies were done. In vivo activity of A35 was assessed in TC cell-derived xenograft (CDX) models with immunocompromised (NSG) mice. Formalin-fixed, paraffin-embedded sections of tumor and lung tissues were observed for the extent of cell death and metastasis. RESULTS: A35 was shown to stimulate cAMP production in some cell types by activating TSHR but not in TC cells, MDA-T32, and MDA-T85. A35 inhibited proliferation of MDA-T32 and MDA-T85 in vitro and in vivo, and pulmonary metastasis of MDA-T85F1 in mice. In vitro, A35 inhibition of proliferation was reduced by a selective TSHR antagonist. Inhibition of CDX tumor growth without decreases in mouse weights and liver function showed A35 to be efficacious without apparent toxicity. Lastly, A35 reduced levels of Ki67 in the tumors and metastatic markers in lung tissues. CONCLUSION: We conclude that A35 is a TSHR-selective inhibitor of TC cell proliferation and metastasis, and suggest that A35 may be a promising lead drug candidate for the treatment of differentiated TC in humans.

Diagnostic yield of Bronchoscopic techniques in evaluating primary lung cancer: The Philippine General Hospital (PGH) experience

Objectives@#To determine the overall diagnostic yield of bronchoscopy-guided sampling methods in detecting lung cancer at the University of the Philippines, Philippine General Hospital. The diagnostic yield, equivalent to sensitivity, is defined as the number of bronchoscopic sampling or biopsy procedures with a diagnosis of malignancy divided by the total number of confirmed malignant cases. @*Methods@#This is a cross-sectional, retrospective sensitivity study involving bronchoscopy procedures from January 2014 to December 2018. Surgical Pathology and Cytology Reports of eligible cases were accessed through the institutional Laboratory Information System. Sensitive patient information was omitted, and each case was assigned a unique code. The overall diagnostic yield/sensitivity of bronchoscopy and the diagnostic yield/sensitivity of each technique were calculated. @*Results@#A total of 100 patients satisfied the inclusion and exclusion criteria. Primary lung malignancies are more common in males and the elderly. The most common primary lung cancer is adenocarcinoma (33%). Bronchoscopy, regardless of whether single or multiple techniques were used, has a diagnostic yield of 86% (CI: 77.6-92.1%). Of the individual techniques, those that obtain solid tissues (endobronchial and transbronchial biopsies; 88.2% [CI: 78.1-94.8%] and 80.0% [CI: 28.4-99.5%], respectively) have higher yields compared to techniques that obtain cytologic samples (bronchial washing and brushing; 54.2% [43.7-64.4%] and 70.1% [58.6-80%], respectively). @*Conclusion@#Bronchoscopy, as a diagnostic procedure for pulmonary malignancies, has relatively high sensitivity and may be used for lesions located centrally and can be inspected visually. A multidisciplinary approach to patient selection for bronchoscopy helps improve the utility of the various bronchoscopic techniques.

Intracapsular carcinoma ex pleomorphic adenoma

@#<p style="text-align: justify;">This is the case of a 37-year-old female patient presenting with a 10-year history of a gradually enlarging right infra-auricular mass. A parotidectomy was performed. The surgical pathology specimen consisted of an 18 cm diameter encapsulated nodular mass with a homogenous, cream-tan solid surface. Microscopic section showed an encapsulated neoplasm with abundant chondromyxoid stroma and tubular epithelial elements characteristic of a pleomorphic adenoma. (Figure 1) Randomly scattered within the tumor were foci of haphazard and complex glands. (Figure 2) These glands exhibited nuclear pleomorphism, luminal necrosis, and mitoses compatible with an adenocarcinomatous proliferation. (Figure 3) Based on these features, the case was signed out as an intracapsular carcinoma ex pleomorphic adenoma.</p><p style="text-align: justify;">Carcinoma ex pleomorphic adenoma is a carcinoma arising from a pre-existing pleomorphic adenoma. The antecedent benign tumor may either be a long-standing one, often with a history measured in decades, or characterized by a protracted history of excisions and multiple recurrences.1,2 The carcinoma on the other hand is either epithelial or myoepithelial in derivation. By morphologic sub-type, the most commonly reported carcinoma arising in a pleomorphic adenoma is a salivary duct carcinoma or an adenocarcinoma that is not otherwise specified (NOS).1,3 Residual pleomorphic adenoma tissue is identifiable either in its typical morphology, a chondromyxoid stroma, or a hyalinized sclerotic nodule.1</p><p style="text-align: justify;">Aside from the type of carcinoma arising from the pleomorphic adenoma, another parameter that has to be reported is the extent of involvement by the carcinomatous component. A carcinoma that is entirely limited to within the parent tumor that is still enclosed by a complete capsule is termed an "intracapsular" or "non-invasive" carcinoma ex pleomorphic adenoma.1,2 Once the carcinoma breaches the capsule and infiltrates the surrounding tissue, then it is considered invasive. If the invasion is less than 4 - 6 mm beyond the capsular border, the tumor is termed "minimally invasive". Carcinomatous elements that extend beyond this threshold is termed "widely invasive".1 This threshold is greater than the previous threshold of 1.5 mm recommended in an earlier edition of the WHO classification although the present edition does state that this threshold is preliminary and requires further validation.1,2,4 It has to be pointed out though that quantifying invasion may not always be possible in tumors that have positive margins, those that are intrinsically unencapsulated such as minor salivary gland tumors, and those with complex multinodular growth patterns such as in recurrent pleomorphic adenoma.1 This difficulty has to be stated in the report and what conditions preclude quantifying the degree of invasion.</p><p style="text-align: justify;">Non-invasive carcinoma ex pleomorphic adenoma has quite a good outcome with very low reported rates of recurrence or regional metastasis. In a review of thirty cases and a report of an additional three cases, only one case showed recurrence or metastasis.3 This favorable outcome certainly contrasts with that of the widely invasive type where metastasis is reported to occur in up to 70% of cases.1 Another review of ten cases showed one case developing metastasis, and recommended that non-invasive cases should thus still be followed up closely after primary treatment because regional or distant metastasis can occur.2 </p><p style="text-align: justify;">To the best of our knowledge, there are no published local data on the incidence of early malignant transformation of pleomorphic adenomas in the Filipino population. Hence, we take this opportunity to report this case. Awareness of the entity and prudent liberal sampling of these tumors may help address this gap.</p><p style="text-align: justify;"> </p>