[Successful pembrolizumab therapy in metastasized adenosquamous carcinoma of the colon]. / Erfolgreiche Pembrolizumab-Therapie bei metastasiertem adenosquamösem Karzinom des Kolons.

Adenosquamous carcinoma (ASqC) is an exceedingly rare subtype of colorectal cancer without any known special guidelines for treatment. The biological behaviour and molecular background are widely unknown, although a few case studies report a worse prognosis compared to ordinary colorectal adenocarcinoma. We herein report for the first time the successful immune checkpoint inhibitor therapy in a 40-year-old patient suffering from metastasized right-sided colonic ASqC with unique molecular features, after having previously progressed under standard chemotherapy.

Loss of PTEN is associated with elevated EGFR and HER2 expression and worse prognosis in salivary gland cancer.

BACKGROUND: Activity of the tumour-suppressor gene PTEN is reduced in different types of cancer and implicates non-responsiveness to targeted therapy. This study evaluates the gene and protein status of PTEN in salivary gland carcinomas. METHODS: A total of 287 carcinomas of the major and minor salivary glands were investigated for phosphatase and tensin homologue located on chromosome 10 (PTEN) deletion and loss of PTEN expression using fluorescence in situ hybridisation (FISH) and immunohistochemistry (IHC), respectively. Results were correlated to clinicopathological parameters, long-term survival, epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) (IHC and FISH) status of the tumours. RESULTS: Hemizygous deletions of PTEN were found in 35 out of 232 (15.1%) carcinomas, while homozygous deletions were observed in 17 out of 232 (7.3%) tumours. Phosphatase and tensin homologue located on chromosome 10 deletion was common in certain histological subtypes and especially homozygous deletion was associated with high-grade malignancy, lymph node metastases and unfavourable long-term prognosis (P<0.001). Loss of PTEN expression was present in 59 out of 273 (21.6%) carcinomas and was significantly correlated to genomic PTEN deletion, high-grade malignancy (P<0.001), increased tumour size (P=0.036), lymph node metastases (P=0.007) and worse disease-specific survival (P=0.002). Genomic PTEN deletion, in particular homogenous deletion (P<0.001) predominantly occurred in tumours with increased gene copy number of EGFR (60.0%) and/or amplification of HER2 (63.6%). Loss of PTEN expression was frequently found in tumours overexpressing EGFR (28.6%) and/or HER2 (52.6%). CONCLUSION: PTEN function is reduced in different types of salivary gland cancer indicating unfavourable prognosis. Its association with EGFR and HER2 signalling might affect targeted therapy.

[Salivary gland mucoepidermoid carcinoma: unusual variants with detection of the t(11,19)(q21;p13) translocation]. / Mukoepidermoidkarzinom der Speicheldrüse: Ungewöhnliche Varianten mit Nachweis der Translokation t(11,19)(q21;p13).

Mucoepidermoid carcinoma (MEC) represents the most common malignant salivary gland tumour. Based on the proportion of their constituent cell types, MECs may display a wide morphological spectrum, thereby mimicking diverse types of other primary salivary gland carcinomas. The correct diagnosis relies on demonstration of classical MEC features, assisted by histochemical and immunohistochemical stains in equivocal cases. The current article aims to demonstrate, on the basis of own observations, how the detection of the MEC-typical t(11, 19) translocation may be of great value in difficult-to-classify cases. The differential diagnosis includes squamous cell carcinoma, clear cell carcinoma and oncocytic neoplasms, as well as highly malignant adenocarcinomas which cannot be further classified.

Interaction between psychotropic drugs and thyroid hormone metabolism--an overview.

Psychotropic drugs can influence synthesis and metabolism of thyroid hormones at different sites. Generally, lithium, tricyclic antidepressants and phenothiazines lead to a reduction in synthesis and/or metabolism of thyroid hormones. The induction of autoimmune thyroid disorders by lithium and phenothiazines has been proven in animal studies and possibly can also be found in humans. Antipsychotic drugs generally exert their therapeutic effects through a modulation of the monoaminergic and serotoninergic system. At the hypothalamic level, thyrotropin releasing hormone (TRH) is controlled by the monoamonergic system and by serotonin. Depending on the specific species, there is a particular and different influence on the secretion of different hypothalamic-pituitary-thyroid (HPT)-axis hormones.

Plasma levels of parathyroid hormone-related peptide are elevated in hyperprolactinemia and correlated to bone density status.

Osteopenia is an important clinical manifestation of hyperprolactinemia. Bone loss in these patients has mainly been attributed to concomitant deficiency of gonadal hormones rather than to hyperprolactinemia per se. Parathyroid hormone-related peptide (PTHrP) is expressed in human mammary tissue, and elevated circulating PTHrP levels as well as concomitant hypercalcemia have been described during lactation. We sought to determine circulating PTHrP levels in patients with long-standing hyperprolactinemia and whether PTHrP may exert possible systemic effects on bone and mineral metabolism. We studied 45 patients (30 women and 15 men) with persisting hyperprolactinemia 6 +/- 4 years (mean +/- SD) after trans-sphenoidal surgery for prolactin-producing pituitary adenomas. PTHrP levels in 117 healthy controls were 10.6 +/- 7.3 pmol-eq/l (mean +/- SD). In hyperprolactinemic patients, plasma PTHrP was elevated to 30.3 +/- 13.4 pmol-eq/l (p < 0.001, n = 45), and in patients with humoral hypercalcemia of malignancy PTHrP levels were 52.9 +/- 29.6 (p < 0.001 to controls and hyperprolactinemic patients). Fifty-three percent of hyperprolactinemic patients (n = 24) had clearly elevated PTHrP levels (> 2 SD). Retrospective immunocytochemical studies of the removed pituitary adenomas from 19 patients generally showed a higher degree of immunoreactivity for PTHrP (1-34) in all but one case when compared with normal pituitary tissue. Patients with elevated circulating PTHrP levels showed in most instances strong immunoreactivity to PTHrP in 70-100% of tumor cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Changes induced by cadmium administration on thyroxine deiodination and sulfhydryl groups in rat liver.

The effects of cadmium on 5'-deiodination of thyroxine (T4) by rat liver and on the hepatic concentration of non-protein sulfhydryl groups (NPSH) were studied in Wistar rats of 200-250 g body weight. A group of ten rats was injected with cadmium chloride (300 micrograms/100 g body weight i.p.) daily for 4 days. Another group of six rats received, in addition, dithiothreitol (DTT; 1 mg/100 g body weight i.p.) daily for the same period. A group of eight normal untreated rats served as control. T4 deiodination was also determined in aliquots of liver from untreated rats, with cadmium (2 or 5 mmol/l) and with or without DTT (0, 2.5, 5 or 10 mmol/l) plus 1 microCi 125I-labelled T4. Hepatic NPSH were measured by a colorimetric method employing dithioldinitrobenzoic acid. Homogenates were incubated for 90 min at 37 degrees C and chromatographed in a tertiary amyl alcohol:hexane:ammonia (2 mol/l) (10:1:12) system. Cadmium-injected rats showed a significant (P < 0.01) decrease in T4 deiodination and in the generation of 125I (P < 0.01) and tri-iodothyronine (T3) (P < 0.02). NPSH were also decreased (P < 0.02). Administration of DTT restored T4 deiodination and NPSH to normal. In-vitro addition of cadmium or DTT to normal rat liver homogenates induced similar effects on the degradation of T4. Serum concentrations of T4 (P < 0.01) and T3 (P < 0.01) declined significantly in cadmium-injected rats, whereas DTT administration failed to normalize serum hormone levels. The data suggest that cadmium may have decreased 5'-deiodinating activity through binding to sulfhydryl groups of 5'-deiodinase as it does in other enzymes.(ABSTRACT TRUNCATED AT 250 WORDS)

Expression of various MHC class II molecules and of intracellular adhesion molecule-1 (ICAM-1) on focal clusters of dendritic cells in iodine deficiency goitres.

Thyroid sections from 18 consecutive euthyroid patients undergoing surgery for iodine deficiency goitre were investigated by means of immunohistochemistry and immunofluorescence, evaluating the expression of MHC class II antigens (HLA-DR, -DP, -DQ, and RFD1) and intercellular adhesion molecule-1 on the formerly described clusters of dendritic cells, as well as on thyrocytes. Eleven of 18 iodine deficiency goitres contained clusters of dendritic cells. These clusters appeared to express only HLA-DR in two cases; in nine of 12 cases they showed a differential expression of class II molecules in the following frequency: HLA-DR > DQ and/or -DP > RFD1. These dendritic cells also were ICAM-1+. In four of 18 iodine deficiency goitres, thyroid epithelial cells showed MHC class II expression in several combinations, but were ICAM-1-. In normal thyroids and in nodular goitres from inhabitants of the endemic area not having an actual iodine deficiency, only sparse clusters of dendritic cells were found; these cells were only HLA-DR+. Follicle lining cells were negative for the MHC class II molecules. In normal thyroids from an area with sufficient iodine supply, no clusters of dendritic cells were seen. The few dendritic cells observed were lying isolated in the interstitium and only positive for HLA-DR and ICAM-1; epithelial cells were negative for the studied markers. These data show clusters of dendritic cells in thyroids of inhabitants of an endemic area. When goitre is accompanied by iodine deficiency at the moment of operation, there appears to be activation of these dendritic cells and of thyroid epithelial cells.

[Primary and follow-up studies of patients with carcinoid metastases using indium 111 octreotide--rational use of Sandostatin]. / Primär- und Verlaufsuntersuchungen von Patienten mit Karzinoidmetastasen mittels Indium-111-Octreotid--Rationale Anwendung von Sandostatin.

Carcinoids may express Somatostatin receptors. Therefore, a Somatostatin-analogue, In-111 Octreotide (OctreoScan), was used for their demonstration. A total of 6 patients who presented with radiologically verified carcinoid-metastases was examined. In order to control tumor progress, 4 of these patients were reexamined within a period of 3 to 11 months. All of the radiological findings were confirmed scintigraphically, except some small retroperitoneally located lymph nodes. The follow-up examinations of 2 patients revealed additional metastases by scintigraphy only. There were no false positive results. The results of OctreoScan scintigraphy may be used for predicting the success of receptor-specific therapies and therefore, permit the rational and efficient application of Sandostatin.

Monoclonal antibodies specific for Clostridium difficile toxin B and their use in immunoassays.

Five mouse monoclonal antibodies (MAbs) against Clostridium difficile toxin B have been raised and characterized. Three of them were immunoglobulin M (IgM) antibodies (6B10, 6G3, and 10B9), and the other two were of the IgG1 isotype (9E5 and 17G2), recognizing specifically two distinct epitopes on the toxin B molecule. No MAb was able to neutralize cytotoxic activity significantly. The two IgG1 MAbs were purified and applied to various immunodiagnostic assays. MAbs coupled to latex beads were used for specific removal of toxin B from cytotoxic samples and for agglutination assay. An indirect sandwich enzyme-linked immunosorbent assay with MAb 9E5 or 17G2 as the capture antibody was established for identification of toxin B with a lower detection limit of 5 ng/ml.