Association between ERCC1 and XPA expression and polymorphisms and the response to cisplatin in testicular germ cell tumours.

BACKGROUND: Cisplatin cures over 80% of testicular germ cell tumours (TGCTs), and nucleotide-excision repair (NER) modifies the sensitivity to cisplatin. We explored the association between NER proteins and their polymorphisms with cisplatin sensitivity (CPS) and overall survival (OS) of patients with non-seminomatous (ns)-TGCTs. METHODS: The expression of ERCC1 and XPA and the presence of γH2AX were evaluated in cancer cell lines and in fresh ns-TGCTs. The ERCC1 protein was also determined in ns-TGCTs. The differences between CPS and non-CPS cell lines and patients were analysed by Student's t- or χ(2)-tests. The differences in OS were analysed using the log-rank test, and the hazard ratios (HRs) were calculated using the Cox model. RESULTS: High ERCC1 expression was observed in the non-CPS cells, and both ERCC1 and γH2AX expressions were augmented after cisplatin treatment. Increased ERCC1 expression was also identified in non-CPS patients. Neither polymorphism was associated with either CPS or OS. The presence of ERCC1 was associated with non-CPS (P=0.05) and adjusted in the prognosis groups. The HR in ERCC1-negative and non-CPS patients was >14.43, and in ERCC1-positive and non-CPS patients the HR was >11.86 (P<0.001). CONCLUSIONS: High levels of ERCC1 were associated with non-CPS, suggesting that ERCC1 could be used as a potential indicator of the response to cisplatin and prognosis in ns-TGCTs.

Brachytherapy versus radical hysterectomy after external beam chemoradiation with gemcitabine plus cisplatin: a randomized, phase III study in IB2-IIB cervical cancer patients.

BACKGROUND: The aim of the present study was to demonstrate that radical hysterectomy (RH) leads to improved survival outcomes in FIGO stage IB2-IIB cervical cancer when compared with standard brachytherapy (BCT) after identical external beam chemoradiation (EBRT-CT). PATIENTS AND METHODS: EBRT-CT treatment consisted of six courses of cisplatin at 40 mg/m² and gemcitabine at 125 mg/m² per week concurrent with 50.4 Gy of radiation. In the BCT arm, EBRT-CT was followed by BCT to reach a point A dose of 85 Gy, whereas in the experimental arm, a type III RH with bilateral pelvic lymph node dissection and para-aortic lymph node sampling (RH) was carried out within 4-6 weeks after EBRT-CT. RESULTS: Between May 2004 and June 2009, 211 patients were enrolled (BCT, 100 and RH, 111). At a median follow-up time of 36 months (3-80), progression-free survival (PFS) and overall survival (OS) rates were similar in both the arms. PFS rates were 74.8% and 71.7% in the BCT and RH arms [HR 0.6516 (95% confidence interval (CI) 0.3504-1.2116)], P = 0.186. OS rates were 76.3% in the BCT versus 74.5% in the surgical arm [HR 0.6981 (95% CI 0.3106-1.3439)], P = 0.236. No differences were observed in the pattern of local and systemic failures. CONCLUSIONS: This study failed to demonstrate that RH after EBRT-CT is superior to standard BCT.

Differential expression of the P2X7 receptor in ovarian surface epithelium during the oestrous cycle in the mouse.

Purinergic signalling has been proposed as an intraovarian regulatory mechanism. Of the receptors responsible for purinergic transmission, the P2X7 receptor is an ATP-gated cationic channel that displays a broad spectrum of cellular functions ranging from apoptosis to cell proliferation and tumourigenesis. In the present study, we investigated the functional expression of P2X7 receptors in ovarian surface epithelium (OSE). P2X7 protein was detected in the OSE layer of the mouse, both in situ and in primary cultures. In cultures, 2'(3')-O-(4-Benzoylbenzoyl)adenosine-5'-triphosphate (BzATP) activation of P2X7 receptors increased [Ca(2+)]i and induced apoptosis. The functionality of the P2X7 receptor was investigated in situ by intrabursal injection of BzATP on each day of the oestrous cycle and evaluation of apoptosis 24h using the terminal deoxyribonucleotidyl transferase-mediated dUTP-fluorescein nick end-labelling (TUNEL) assay. Maximum effects of BzATP were observed during pro-oestrus, with the effects being blocked by A438079, a specific P2X7 receptor antagonist. Immunofluorescence staining for P2X7 protein revealed more robust expression during pro-oestrus and in OSE regions behind the antral follicles, strongly supporting the notion that the differences in apoptosis can be explained by increased receptor expression, which is regulated during the oestrous cycle. Finally, P2X7 receptor expression was detected in the OSE layer of human ovaries, with receptor expression maintained in human ovaries diagnosed with cancer, as well as in the human ovarian carcinoma SKOV3 cell line.

Review of tubulocystic carcinoma of the kidney with focus on clinical and pathobiological aspects.

Tubulocystic carcinoma of the kidney (TCK) is a recently established entity in renal neoplastic pathology. This review aims to give an overview of the clinical and pathobiological aspects of TCK. Grossly, the TCKs are well-demarcated multicystic lesions giving a "wrapped bubble" or "spongy" appearance. Microscopically, the tumors are composed of multiple, variably sized cysts separated by thin fibrous septa lacking ovarian stroma or desmoplastic reaction. The cysts are lined by tumor cells with eosinophilic cytoplasm and nuclear atypia of variable, but not infrequently of high grade corresponding to Fuhrman grade 3. A frequent association with papillary tumors has been reported. Recent molecular genetic studies of TCK have revealed distinct features separating this subset of renal cell carcinomas (RCCs) from other types of renal tumors including collecting duct carcinoma of Bellini and renal medullary carcinoma as well as pointing towards a close kinship with papillary RCC. Tubulocystic carcinoma of the kidney generally pursues an indolent clinical course. However, several cases with aggressive clinical behavior have been reported. We strongly feel that there is enough clinicopathological evidence to corroborate TCK as a separate entity and that it should be incorporated into the next WHO classification of renal tumors as a separate neoplastic category.

Kca3.1 Activation Via P2y2 Purinergic Receptors Promotes Human Ovarian Cancer Cell (Skov-3) Migration.

Disorders in cell signaling mediated by ATP or histamine, activating specific membrane receptors, have been frequently associated with tumorigenesis. Among the elements of response to purinergic (and histaminergic) signaling, ion channel activation controls essential cellular processes in cancer, such as cell proliferation, motility, and death. Here, we studied the effects that ATP had on electrical properties of human ovarian adenocarcinoma cells named SKOV-3. ATP caused increase in intracellular Ca2+ concentration ([Ca2+]i) and, concurrently, it evoked a complex electrical response with a conspicuous outward component. This current was generated through P2Y2 receptor activation and opening of K+ channels, KCa3.1, as indicated by electrophysiological and pharmacological analysis, as well as by immunodetection and specific silencing of P2Y2 or KCa3.1 gene by esiRNA transfection. Low µM ATP concentration increased SKOV-3 cell migration, which was strongly inhibited by KCa3.1 channel blockers and by esiRNA-generated P2Y2 or KCa3.1 downregulation. Finally, in human ovarian tumors, the P2Y2 and KCa3.1 proteins are expressed and co-localized in neoplastic cells. Thus, stimulation of P2Y2 receptors expressed in SKOV-3 cells promotes motility through KCa3.1 activation. Since P2Y2 and KCa3.1 are co-expressed in primary tumors, our findings suggest that they may play a role in cancer progression.

Chromophobe renal cell carcinoma with microcystic and adenomatous arrangement and pigmentation--a diagnostic pitfall. Morphological, immunohistochemical, ultrastructural and molecular genetic report of 20 cases.

We present clinical, morphological, immunohistochemical, ultrastructural and molecular genetic features of 20 cases of a peculiar form of chromophobe renal cell carcinoma (CRCC) with morphology differing from that of conventional CRCC. Microscopically, the typical features of the tumors were microcystic arrangement and formation of adenomatous structures. Microcystic areas were composed of smaller eosinophilic and bigger pale cells having cytological appearance typical of conventional CRCC. Cytological features of the adenomatous structures were mostly different from those of conventional CRCC. They had a typical columnar arrangement with nuclei positioned at the base of the glandular structures and a small amount of a deeply eosinophilic cytoplasm often endowed with brush border facing the lumen of the glands. In addition, all the tumors showed a brown pigmentation. The pigmentation was located mostly extracellularly, where it formed pools of heavy deposits. Microscopic calcifications present in all cases formed psammoma bodies or else the calcifications were more extensive and amorphous in shape. Ultrastructurally, the cells showed features characteristic of CRCC: typical cytoplasmic vesicles were 100-700 nm in size and mitochondria had tubulovesicular, lamellar or circular cristae. Some tumor cells contained dark, variously sized electron-dense pigment granules. Neither melanosomes nor membrane-bound neurosecretory granules were seen. Using fluorescence in-situ hybridization probes for chromosomes 1, 2, 6, 10, 13, 17 and 21, the tumors revealed massive loss of tested chromosomes typical for conventional CRCC. Monosomy of chromosomes 1, 2, 6, 10, 13 and 21 was found in 100, 36, 91, 82, 82, 82 and 64% of cases, respectively. None of the cases showed mutation of exons 9, 11, 13 and 17 of the c-kit gene. The important feature of pigmented microcystic chromophobe renal cell carcinoma is a relatively benign biological behavior and the absence of distant metastases and sarcomatoid transformation.

Metastases to the breast.

AIM: The aim of this study was to report the clinico-pathological features of a series of patients with metastatic neoplasms to the breast. METHODS: A 10-year archive of surgical material was reviewed. A search was performed on all 10,650 breast neoplastic cases in the files of the Pathology Department from 1990 to 2000. RESULTS: There were 22 women and two men. The most common primary sites for solid tumours were cutaneous melanoma and ovarian carcinoma. Two of the 24 patients had no prior history of malignant disease. There was a solitary nodule in 17 cases; in seven cases there were multiple lesions in the same breast. Sixteen patients had a rapidly fulminating course and died of disease. Six patients are alive with disease and two patients were lost to follow-up. CONCLUSION: Recognition of these lesions as being metastatic may pre-empt radical surgery.

[Spindle cell and cuboidal renal cell carcinoma (loopoma). 10 case reports]. / Vretenobunecný a kuboidální renální karcinom (loopom). Popis 13 prípadu.

BACKGROUND: Current classification systems of neoplasms arising from renal parenchyma distinguish 5 categories of renal cell carcinoma (RCC), i.e. conventional RCC, papillary RCC, chromophobe RCC, collecting duct/medullary RCC and unclassified RCC. We present 13 cases of unusual and unclassified spindle and cuboidal renal cell carcinomas. METHODS AND RESULTS: The studied group consisted of 13 patients (7 men and 6 women). They ranged in age from 22 to 65 years (mean 57.3). Generally, the tumours were well circumscribed and confined to the kidney, whitish to grey on section with a diameter 4.5-13 cm (mean 8.6 cm). One patient was investigated for loin pain and nocturia. Three patients had staghorn nephrolithiasis and vague sonographic findings in renal parenchyma. In one patient the renal tumour was found when examined on follow-up examination for prostatic adenocarcinoma. None of our patients was known to have elevated levels of parathyroid hormone due to hyperplasia, adenoma or carcinoma of the parathyroid gland. Clinical follow-up of the patients ranged from 9 months to 8 years (mean 2.3 years). Microscopically, the tumours were composed of two main populations of cells: flattened, spindle cells with sparse cytoplasm and small cuboidal cells with clear to light eosinophilic cytoplasm. Eight patients are currently well without signs of recurrence or metastasis, one had metastasis in the regional lymph node at the time of nephrectomy, one died of unrelated cause, and three were lost to follow-up. CONCLUSIONS: We present 13 cases of unclassified RCC. Our cases were histologically, immunohistochemically and ultrastructurally similar to the hitherto reported case reports of this variant of RCC. It is obvious, that that variant of RCC should be recognised as a new subtype of RCC.

[Metanephric adenoma. 11 case reports and detection of collagen spherules in one tumor]. / Metanefrický adenom. Popis 11 prípadu s prukazem kolagenních sferul v jednom nádoru.

Eleven cases of metanephric adenoma are reported. The tumors were selected out of 6500 tumorous and pseudotumorous lesions of the kidney in our registry. Female to male ratio was 1:1.2. The average age of the patients was 48.3 years, with a range of 13-79 years. The mean size of the tumors was 7.2 cm. The tumors were spherical in shape, whitish to yellowish in colour. Histologically, they were arranged in a mainly tubular pattern with short pseudopapillae. The tumorous cells were deeply eosinophilic to basophilic with predominantly round nuclei. Psammomatous bodies were numerous. Immunohistochemically, they reacted positively with antibodies against cytokeratins, vimentin, and WT1. Ultrastructurally, the cytoplasm contained mitochondria, RER, and ribosomes. A collagenous spherulosis, identical with those in salivary gland and mammary tumors, was revealed in one case. The spherules were located mainly inside tubular structures. Ultrastructurally, they were composed of basement membrane-like material, which was surrounded by epithelial cells. Follow-up all of our patients was negative (if known) for 10 months to 4 years.

Primary malignant lymphoma of uterine cervix.

Primary malignant lymphoma of the uterine cervix is a rare disease. Malignant lymphoma can be clinically and histopathologically misdiagnosed for the infrequent presentation in this are. A case of 56-year-old woman with uterine cervical tumor with infiltration to both parametria is presented. A biopsy was performed and histopathological studies reported a large cell B lymphoma. After the diagnosis CT abdominal, pelvic and thoracic scan was performed and shows infiltration to posterior bladder without evidence of disease in lymph nodes or another organ. The patient was treated with chemotherapy and radiotherapy. Six month after finish the treatment is well and free of disease.

Spindle and cuboidal renal cell carcinoma, a tumour having frequent association with nephrolithiasis: report of 11 cases including a case with hybrid conventional renal cell carcinoma/ spindle and cuboidal renal cell carcinoma components.

AIMS: We present the largest series of an unclassified subtype of renal cell carcinoma, which seems to be a distinct morphological entity and which is sometimes designated as spindle and cuboidal renal cell carcinoma. METHODS AND RESULTS: Eleven cases of spindle and cuboidal renal cell carcinoma were found among 7000 primary renal cell tumours in Pilsen's routine and consultation files. The patients were five men and six women. They ranged in age from 22 to 65 years (mean 56.8). Microscopically, the tumours were composed of two main populations of cells. First, the preponderant type of cells was formed by flattened, spindle cells with sparse cytoplasm. The second cell type was a small cuboidal cell with clear to light eosinophilic cytoplasm. Spindle-shaped cells were arranged in a fascicular pattern often reminiscent of low-grade smooth muscle tumours. Solid areas of spindle cells were also present. Small cuboidal cells formed sparse tubular structures lined by a row of single cells. In addition to all previous published cases of spindle and cuboidal renal cell carcinoma we observed an association of nephrolithiasis in our cases. It was seen in 3/11 of our patients. A previously unreported feature is the occurrence of a conventional renal cell carcinoma component in one of our cases. Seven of our patients are currently well without signs of recurrence or metastasis, one had metastasis in a regional lymph node at the time of nephrectomy, one died of an unrelated condition, and two were lost to follow-up. CONCLUSIONS: We present 11 cases of spindle and cuboidal renal cell carcinoma, which is believed to be a distinctive morphological entity. Our cases were histologically, immunohistochemically and ultrastructurally similar to the previously reported cases of spindle and cuboidal renal cell carcinoma. In contrast to all previously reported cases of spindle and cuboidal renal cell carcinoma, we observed an association with nephrolithiasis in three of our cases; moreover, one of our tumours had a conventional renal cell carcinoma component and another revealed a metastatic focus in a regional lymph node. None of our patients died of the disease. This study confirms that spindle and cuboidal renal cell carcinoma has a low malignant potential.