Cerebrospinal Fluid Penetration and Combination Therapy of Entrectinib for Disseminated ROS1/NTRK-Fusion Positive Pediatric High-Grade Glioma.

Targeting oncogenic fusion-genes in pediatric high-grade gliomas (pHGG) with entrectinib has emerged as a highly promising therapeutic approach. Despite ongoing clinical studies, to date, no reports on the treatment of cerebrospinal fluid (CSF) disseminated fusion-positive pHGG exist. Moreover, clinically important information of combination with other treatment modalities such as intrathecal therapy, radiotherapy and other targeted agents is missing. We report on our clinical experience of entrectinib therapy in two CSF disseminated ROS1/NTRK-fusion-positive pHGG cases. Combination of entrectinib with radiotherapy or intrathecal chemotherapy appears to be safe and has the potential to act synergistically with entrectinib treatment. In addition, we demonstrate CSF penetrance of entrectinib for the first time in patient samples suggesting target engagement even upon CSF dissemination. Moreover, in vitro analyses of two novel cell models derived from one case with NTRK-fusion revealed that combination therapy with either a MEK (trametinib) or a CDK4/6 (abemaciclib) inhibitor synergistically enhances entrectinib anticancer effects. In summary, our comprehensive study, including clinical experience, CSF penetrance and in vitro data on entrectinib therapy of NTRK/ROS1-fusion-positive pHGG, provides essential clinical and preclinical insights into the multimodal treatment of these highly aggressive tumors. Our data suggest that combined inhibition of NTRK/ROS1 and other therapeutic vulnerabilities enhances the antitumor effect, which should be followed-up in further preclinical and clinical studies.

Technetium-99m-tetrofosmin in diagnosis of breast cancer and axillary lymph node involvement.

BACKGROUND: The aim of this study was to evaluate the accuracy of breast cancer seeking agent Tc-99m-Tetrofosmin in the detection of breast malignancy and axillary lymph node metastases. MATERIAL AND METHODS: Twenty-eight female patients (mean age 52.4) with 30 breast lesions suspected of malignancy were enrolled in the study. All the patients underwent clinical investigation, Tc-99m Tetrofosmin scintimammography (SMM), mammography (MM) and biopsy/surgery for final histopathologic diagnosis. Patients were injected intravenously with 555 MBq of Tc-99m Tetrofosmin, cubitally, in the contralateral arm to the side of suspicious lesion. Seven minute static scans or at least 2.0 million counts were obtained using single head gamma camera (Orbiter 75, Siemens). Planar images were acquired in left and right prone lateral view as well as in the supine position for an anterior view of chest and axillary region. RESULTS: SMM scans of 30 breast lesions were compared to the definitive histopathology findings (HP) using decision matrix. In the group of 23 patients with positive SMM scans 19 had breast malignancy: 15 infiltrating ductal cancer, three patients with one infiltrating lobular, one papillary, one colloidal cancer and one patient with cystosarcoma phyllodes-malignant type. SMM detected primary breast malignancy with 95% sensitivity, 60% specificity and 83% accuracy. Axillary dissection was performed in 19/20 with malignant disease. The number of lymph nodes extracted and HP evaluated varied from 4 to 23 per patient. Metastatic involvement was confirmed by HP in 9 out of 20 patients. SMM detected axillary metastases with 55% sensitivity and 80% accuracy. CONCLUSION: Our results showed that SMM might be useful as a complementary test to improve the sensitivity and specificity of conventional imaging modalities, although SMM in the staging of breast carcinoma was less reliable. Further studies to evaluate the role of SMM in metastatic node involvement are necessary.

[Breast carcinoma with melanocytic differentiation]. / Karcinom dojke sa melanocitnom diferencijacijom.

Azzopardi and Eusebi were the first to describe pigmented breast cancers in 1977. They postulated that the mammary cancer might become colonized by melanocytes at the expense of the epidermis, which was focally depleted of melanocytes, and that it occurred in most cases of breast cancers in which tumor cells reached the dermal-epidermal interface. Other authors suggested melanocytic differentiation of tumor cells. In this paper a case of a patient with ductal invasive breast cancer with partial melanocytic differentiation was presented, documented by HMB-45 and melan-A reactivity of tumor cells. Tumor was positive with antibodies for estrogen and progesterone receptors, pancytokeratin, negative with antibodies for S-100 protein and vimentin. Masson-Fontana reaction was negative. It was concluded that pigmented tumors should be differentiated from tumors with partial melanocytic differentiation, and that clinical significance of melanocytic differentiation should be analysed on larger number of cases.

[Diagnosis of the Mikulicz-Sjogren syndrome using biopsy of the minor salivary glands]. / Dijagnostika sindroma Mikulicz-Sjögren biopsijom malih pljuvacnih zlezda.

BACKGROUND: Sjögren's syndrome (SS) represents autoimmune disease characterized by chronic inflammation, destruction and insufficiency of exocrine glands, particularly salivary and lacrimal glands, accompanied by dryness of mouths and eyes. Diagnostic work-up involves clinical laboratory tests, radiography, scintigraphy and bioptic histopathological examination. Examination of small salivary glands in the biopsy of the lower lip represents a "golden standard" of diagnosis of SS, concerning the fact that the growth and the disfunction of salivary and lacrimal glands occurs in different pathologic states. METHODS: Resected specimens of the lower lip were obtained from 47 patients with clinical diagnosis of SS. After standard histopathological treatment, slices were hematoxylin and eosin stained. Immunohistochemistry against smooth muscle actin was performed using LSAB+ method (AHSMA-M7558, DAKO 1:50). On the basis of generally accepted histopathological diagnostic criteria the results were categorized as: findings suspicious for SS; findings compatible with the diagnosis of SS (mild, moderate and high degree of inflammation); nonspecific inflammatory reaction and nonrepresentative biopsy samples. RESULTS: Diagnosis of SS was confirmed in 32% of cases. In 2% of cases findings were suspected for SS, in 36% of cases findings were compatible with the diagnosis of nonspecific inflammation, and in 30% of cases material was not representative. CONCLUSIONS: By the biopsy of salivary glands of the lower lip the diagnosis of SS was confirmed in 50-60% of cases. Upon the precise diagnostic criteria it was also possible to determine the intensity of inflammation and tissue destruction in SS and identify other pathological conditions, which justified the biopsy. Surgical technique had to be adequate in order to obtain representative number of small salivary glands. In the presented material 30% of specimens were nonrepresentative which was very high percentage compared with literature data. This was most probably the reason why the diagnosis of SS was confirmed in only 32% of cases, i.e., in every third patient.