Evidence for a functional role of calsequestrin 2 in mouse atrium.

AIM: Several genetically modified mice models were studied so far to investigate the role of cardiac calsequestrin (CSQ2) for the contractile function of the ventricle and for the occurrence of ventricular tachycardia. Using a CSQ2 knockout mouse, we wanted to study also the atrial function of CSQ2. METHODS: The influence of CSQ2 on atrial function and, for comparison, ventricular function was studied in isolated cardiac preparations and by echocardiography as well as electrocardiography in mice with deletion of CSQ2. RESULTS: Using deletion of exon 1, we have successfully generated a constitutive knockout mouse of the calsequestrin 2 gene (CSQ2-/- ). CSQ2 protein was absent in the heart (atrium, ventricle), but also in oesophagus and skeletal muscle of homozygous knockout mice. In 6-month-old CSQ2-/- mice, relative left atrial weight was increased, whereas relative heart weight was unchanged. The staircase phenomena in paced left atrial preparations on force of contraction and the post-rest potentiation were different between wild type and CSQ2-/- indicative for a decreased sarcoplasmic Ca2+ load and supporting an important role of CSQ2 also in the atrium. The incidence of arrhythmias was increased in CSQ2-/- . In 2-year-old CSQ2-/- mice, cardiac hypertrophy and heart failure were noted possibly as a result of chronically increased cytosolic Ca2+ levels. CONCLUSION: These data suggest a functional role of CSQ2 not only in the ventricle but also in the atrium of mammalian hearts. Loss of CSQ2 function can cause not only arrhythmias, but also cardiac hypertrophy and heart failure.

Statement by the Kommission Ovar of the AGO: The New FIGO and WHO Classifications of Ovarian, Fallopian Tube and Primary Peritoneal Cancer.

More than 25 years after the last revision, in 2012 the FIGO Oncology Committee began revising the FIGO classification for staging ovarian, Fallopian tube and primary peritoneal cancers. The new classification has become effective with its publication at the beginning of 2014. Following recent findings on the pathogenesis of ovarian, Fallopian tube and primary peritoneal cancer and reflecting standard clinical practice, the three entities have now been classified uniformly. The histological subtype is included (high-grade serous - HGSC; low-grade serous - LGSC; mucinous - MC; clear cell - CCC; endometrioid - EC). Stages III and IV have been fundamentally changed: stage IIIA now refers to a localized tumor limited to the pelvis with (only) retroperitoneal lymph node metastasis (formerly classified as IIIC). Stage IV has been divided into IVA and IVB, with IVA defined as malignant pleural effusion and IVB as parenchymatous or extra-abdominal metastasis including inguinal and mediastinal lymph node metastasis as well as umbilical metastasis. A new WHO classification was published almost concurrently. The classification of serous tumors addresses the issue of the tubal carcinogenesis of serous ovarian cancer, even if no tubal precursor lesions are found for up to 30 % of serous high-grade cancers. The number of subgroups was reduced and subgroups now include only high-grade serous, low-grade serous, mucinous, seromucinous, endometrioid, clear cell and Brenner tumors. The category "transitional cell carcinomas" has been dropped and the classification "seromucinous tumors" has been newly added. More attention has been focused on the role of borderline tumors as a stage in the progression from benign to invasive lesions.

Surgical staging and prognosis in serous borderline ovarian tumours (BOT): a subanalysis of the AGO ROBOT study.

BACKGROUND: Incomplete surgical staging is a negative prognostic factor for patients with borderline ovarian tumours (BOT). However, little is known about the prognostic impact of each individual staging procedure. METHODS: Clinical parameters of 950 patients with BOT (confirmed by central reference pathology) treated between 1998 and 2008 at 24 German AGO centres were analysed. In 559 patients with serous BOT and adequate ovarian surgery, further recommended staging procedures (omentectomy, peritoneal biopsies, cytology) were evaluated applying Cox regression models with respect to progression-free survival (PFS). RESULTS: For patients with one missing staging procedure, the hazard ratio (HR) for recurrence was 1.25 (95%-CI 0.66-2.39; P=0.497). This risk increased with each additional procedure skipped reaching statistical significance in case of two (HR 1.95; 95%-CI 1.06-3.58; P=0.031) and three missing steps (HR 2.37; 95%-CI 1.22-4.64; P=0.011). The most crucial procedure was omentectomy which retained a statistically significant impact on PFS in multiple analysis (HR 1.91; 95%-CI 1.15-3.19; P=0.013) adjusting for previously established prognostic factors as FIGO stage, tumour residuals, and fertility preservation. CONCLUSION: Individual surgical staging procedures contribute to the prognosis for patients with serous BOT. In this analysis, recurrence risk increased with each skipped surgical step. This should be considered when re-staging procedures following incomplete primary surgery are discussed.

[Histological grading of epithelial ovarian cancer. Review and recommendation]. / Histologische Malignitätsgraduierung des Ovarialkarzinoms. Überblick und Empfehlung.

Histological grading of ovarian cancer has prognostic relevance and implications for treatment decisions. No standardized grading system has been established so far. Several grading systems are currently being used, including the FIGO, WHO, and Silverberg grading systems which cannot be directly translated into each other. Furthermore, individual grading criteria are not uniformly applicable to different histological subtypes. For serous ovarian cancer a binary grading system is now in use as the distinction between low-grade versus high-grade carcinomas reflects the different pathogenesis of these entities. Uniform guidelines for grading ovarian cancer are necessary and should ideally reflect the prognosis. This article provides an overview of commonly used grading systems and their prognostic value. The article demonstrates that a type-specific grading of ovarian cancer should be performed and recommendations for grading the various histological subtypes are given.

Age-dependent differences in borderline ovarian tumours (BOT) regarding clinical characteristics and outcome: results from a sub-analysis of the Arbeitsgemeinschaft Gynaekologische Onkologie (AGO) ROBOT study.

BACKGROUND: Approximately one-third of all borderline ovarian tumours (BOT) are diagnosed in patients with child-bearing potential. Detailed information regarding their specific characteristics and prognostic factors is limited. METHODS: Clinical parameters of BOT patients treated between 1998 and 2008 in 24 German centres were retrospectively investigated. Central pathology review and prospective follow-up were carried out. Patients <40 versus ≥40 years were analysed separately and then compared regarding clinico-pathological variables and prognosis. RESULTS: A total of 950 BOT patients with a median age of 49.1 (14.1-91.5) years were analysed [280 patients <40 years (29.5%), 670 patients ≥40 years (70.5%)]. Fertility-preserving surgery was carried out in 53.2% (149 of 280) of patients <40 years with preservation of the primarily affected ovary in 32 of these 149 cases (21.5%). Recurrence was significantly more frequent in patients <40 years (19.0% versus 10.1% 5-year recurrence rate, P < 0.001), usually in ovarian tissue, whereas disease-specific overall survival did not differ between the subgroups. In case of recurrent disease, malignant transformation was less frequent in younger than in older patients (12.0% versus 66.7%, P < 0.001), mostly presenting as invasive peritoneal carcinomatosis. Multivariate analysis for patients <40 years identified advanced International Federation of Gynecology and Obstetrics (FIGO) stage and fertility-sparing approach as independent prognostic factors negatively affecting progression-free survival (PFS) while, for patients ≥40 years, higher FIGO stage and incomplete staging was associated with impaired PFS. CONCLUSIONS: Despite favourable survival, young BOT patients with child-bearing potential are at higher risk for disease recurrence. However, relapses usually remain BOT in the preserved ovaries as opposed to older patients being at higher risk for malignant transformation in peritoneal or distant localisation. Therefore, fertility-sparing approach can be justified for younger patients after thorough consultation.

The heterogeneity of ovarian cancer.

Ovarian cancer carries the worst prognosis of all gynecological malignancies. This is mainly due to its resistance against commonly used cytostatic drugs as well as the lack of a screening method for its detection at an early stage. Both basic and translational research have shown over the past decades that ovarian cancer as a medical term includes several types of tumors with different phenotypes, molecular biology, etiology, tumor progression, and even different prognosis. In this issue of Archives of Gynecology and Obstetrics, J. Dietel presents a review article about novel findings of the etiopathogenesis of ovarian cancer and the role that fallopian tubes may play. He also outlines the implied clinical consequences. Here, we give a brief overview of the heterogeneity of ovarian cancer to introduce the topic.

Peritoneal carcinosis in apparently benign cortisol producing adrenal adenoma ≥ 5 cm in diameter: the need of regular postoperative surveillance.

BACKGROUND: Clinical and histopathological distinction between benign and malignant adrenocortical tumors can be a challenge.Report on 2 patients with cortisol producing apparently benign adrenal adenomas ≥ 5 cm in diameter with local malignant recurrence and peritoneal carcinomatosis after endoscopic surgery. RESULTS: Case 1: The 59-year-old male presented with adrenal hypercortisolism due to a 5.0 cm large adrenal tumor on the left side. A retroperitoneoscopic total adrenalectomy was performed. Histologically, a benign adrenal adenoma (Weiss score 1, Ki-67 < 2%) was found. 6 months later, the patient developed clinically and biochemically recurrent disease with recurrent tumor in the left adrenal region and peritoneal carcinomatosis. The patient died 5 months after second surgery. Case 2: The 32-year-old female was pregnant in 27th week when presenting with adrenal hypercortisolism due to a 5.5 cm large adrenal tumor on the left side. She was operated on using a laparoscopic approach and a total adrenalectomy was carried out. Histological examination revealed a benign adrenocortical adenoma (Weiss score 1, Ki-67 < 5%). 4 years later, the patient came back with clinically and biochemically recurrent disease. Imaging showed a 10 cm large tumor in the left retroperitoneum and a diffuse peritoneal carcinomatosis. The patient died 2 months after diagnosis. CONCLUSION: Cortisol producing adrenal tumors ≥ 5 cm in diameter are at risk to be misdiagnosed as apparently benign. Regular surveillance should be considered in patients presenting with large cortisol producing tumors.

Mitochondrial dysfunction: an early event in Alzheimer pathology accumulates with age in AD transgenic mice.

Recent evidence suggests mitochondrial dysfunction as a common early pathomechanism in Alzheimer's disease integrating genetic factors related to enhanced amyloid-beta (Ass) production and tau-hyperphosphorylation with aging, as the most relevant sporadic risk factor. To further clarify the synergistic effects of aging and Ass pathology, we used isolated mitochondria of double Swedish and London mutant APP transgenic mice and of non-tg littermates. Pronounced mitochondrial dysfunction in adult Thy-1 APP mice, such as a drop of mitochondrial membrane potential and reduced ATP-levels already appeared at 3 months when elevated intracellular but not extracellular Ass deposits are present. Mitochondrial dysfunction was associated with higher levels of reactive oxygen species, an altered Bcl-xL/Bax ratio and reduction of COX IV activity. We observed significant decreases in state 3 respiration and FCCP-uncoupled respiration in non-tg mice after treatment with extracellular Ass. Similar deficits were seen only in aged Thy-1 APP mice, probably due to compensation within the respiratory chain in young animals. We conclude that Ass dependent mitochondrial dysfunction starts already at 3 months in this AD model before extracellular deposition of Ass and progression accelerates substantially with aging.

Free bone cement fragments after minimally invasive unicompartmental knee arthroplasty: an underappreciated problem.

The minimally invasive implantation of unicompartmental knee arthroplasty (UKA) leads to excellent functional results, but due to the reduced intraoperative visibility the removal of excessive cement may be difficult. In a retrospective study we assessed radiologically the incidence of loose and excess bone cement in 120 UKAs and correlated it to the thickness of the tibial cement layer. In 25 cases loose or attached excess cement was seen. Two of these patients with loose cement bodies required revision surgery. An additional 2 patients not operated at our institution required revision because of pain and loss of motion. The average thickness of the tibial cement layer was 3.1 (1.7-5.0) mm in all the patients. But it was significantly higher in the group with excess cement bodies [3.3 (2.3-5.0) mm] compared to the group without excess cement [3.0 (1.7-4.1) mm] (P < 0.05). Symptomatic free cement bodies need to be removed immediately, if necessary arthroscopically, in order to avoid damage to the implants. To avoid this problem in minimally invasive UKA, intraoperative fluoroscopy, a dental mirror or a nerve hook seem to be useful tools to identify and remove loose or excess cement.

Prediction of lateral lymph node metastases in medullary thyroid cancer.

BACKGROUND: In medullary thyroid cancer (MTC), there is a concordance between central and lateral neck involvement, but this relationship has not been assessed quantitatively. METHODS: After compartment-oriented lymphadenectomy for untreated MTC, the numbers of central lymph node metastases with ipsilateral (195 patients) and contralateral (185 of 195 patients) lateral lymph node metastases were analysed retrospectively. RESULTS: With one to three positive central lymph nodes, involvement of the ipsilateral lateral neck increased from 10.1 per cent (with no central node involvement) to 77 per cent, and from a mean of 0.6 to 3.7 nodal metastases (P < 0.001). With four or more central nodes, the rate was 98 per cent, with 10.7 nodal metastases (P = 0.001). A weaker increase was observed in the contralateral lateral neck: with one to nine positive central nodes, contralateral lateral neck involvement increased from 4.9 to 38 per cent, and from a mean of 0.6 to 2.3 nodal metastases (P = 0.011). With ten or more positive central nodes, the rate rose to 77 per cent, with 6.2 nodal metastases (P = 0.009). With one exception, contralateral lateral nodal metastases coexisted with metastases in the central and ipsilateral lateral neck. CONCLUSION: These data may lay the groundwork for more informed decision-making regarding dissection of the lateral neck compartments.

Referral bias in thyroid cancer surgery: direction and magnitude.

AIM: This study was conducted to clarify the impact of referral bias in thyroid cancer surgery. METHODS: Analysis of 1419 consecutive patients with papillary (n=653), follicular (n=248), and medullary thyroid cancer (n=518) referred to a specialist center for initial surgery or reoperation. RESULTS: With increasing travel distance (successive postal code areas), mean age decreased among patients referred for initial surgery (from 53 to 35 years for papillary cancer, 65 to 49 years for sporadic medullary cancer, and 40 to 23 years for hereditary medullary cancer, all p< or =0.001; and from 65 to 54 years for follicular cancer, p=0.26). The significant decline in mean age continued among patients reoperated on for papillary cancer (from 53 to 43 years, p<0.001), but was lost among patients reoperated on for medullary cancers. For patients with differentiated, but not medullary cancers, greater travel distance was associated with higher frequencies of extrathyroidal extension at initial surgery (from 17% to 63% for follicular cancer, p=0.003) and reoperation (from 18% to 47% for papillary, and 5% to 44% for follicular cancer, all p<0.001), and higher frequencies of lymph node metastasis at initial surgery (from 23% to 58% for papillary, and 17% to 50% for follicular cancer, p< or =0.008) and reoperation (from 27% to 77% for papillary, and 0% to 35% for follicular cancer, all p<0.001). CONCLUSION: Referral bias in thyroid cancer surgery can include two components working in opposite directions: age and extent of disease. Controlling for these components should reduce the impact of referral bias on thyroid cancer research.

Proximal loading of the femur leads to low subsidence rates: first clinical results of the CR-stem.

INTRODUCTION: A new femoral stem was developed with a design that leads to compression of cancellous bone in the calcar region which results in proximal loading. The cross-sectional design of the implant provides rotational stability. MATERIALS AND METHODS: In the first clinical investigation ten patients underwent uncemented total hip arthroplasty between January 1999 and May 1999 using the CR-stem((R)) (Implantcast GmbH, Buxtehude, Germany). Results were investigated using the Harris-hip-score (HHS) and antero-posterior and lateral radiographs. Migration was evaluated with the EBRA-FCA-method with a follow-up of 7 years. RESULTS: We demonstrated a mean subsidence rate of 2.23 +/- 1.13 mm 7 years after implantation thus providing basic data for extensive testing in a clinical environment. DISCUSSION: As small subsidence rates are regarded as predictor for superior long-term results in uncemented total hip arthroplasty according to the literature, the CR-stem shows promise for excellent long-term results.

Expression of the RNA-binding protein IMP1 correlates with poor prognosis in ovarian carcinoma.

The IMP (IGFII mRNA-binding protein) family comprises a group of three RNA-binding proteins involved in the regulation of cytoplasmic mRNA-fate. Recent studies identified IMP proteins as oncofetal factors in various neoplasias, but knowledge of a potential role in ovarian carcinomas is still lacking. The immunohistochemical analysis of 107 ovarian carcinomas, 30 serous borderline tumors of the ovary and five normal ovaries revealed de novo synthesis of IMP1 in 69% of ovarian carcinomas. Elevated IMP1 expression was observed preferentially in high-grade and high-stage cases and was a significant prognostic indicator for reduced recurrence-free and overall survival. Phenotypic studies in ovarian carcinoma-derived ES-2 cells demonstrated that IMP1 knockdown affects proliferation and cell survival. Reduced proliferation was associated with decreased c-myc mRNA half-life, suggesting IMP1 as an oncogenic factor that is involved in promoting elevated proliferation by stabilizing the c-myc mRNA in ovarian carcinoma cells.

Stem cell-associated genes are extremely poor prognostic factors for soft-tissue sarcoma patients.

Cancer stem cells can play an important role in tumorigenesis and tumor progression. However, it is still difficult to detect and isolate cancer stem cells. An alternative approach is to analyse stem cell-associated gene expression. We investigated the coexpression of three stem cell-associated genes, Hiwi, hTERT and survivin, by quantitative real-time-PCR in 104 primary soft-tissue sarcomas (STS). Multivariate Cox's proportional hazards regression analyses allowed correlating gene expression with overall survival for STS patients. Coexpression of all three stem cell-associated genes resulted in a significantly increased risk of tumor-related death. Importantly, tumors of patients with the poorest prognosis were of all four tumor stages, suggesting that their risk is based upon coexpression of stem cell-associated genes rather than on tumor stage.

[Differential diagnosis of ovarian metastases]. / Differenzialdiagnostik ovarieller Metastasen.

Ovarian metastases comprise 7-10% of all malignant ovarian tumors. The detection of ovarian metastases is difficult because primary ovarian tumors are a morphologically very heterogeneous group, and metastases can simulate an primary ovarian tumor perfectly. A correct diagnosis, however, is most important in order to avoid an unnecessary and ineffective chemotherapy. Therefore, every morphologically unusual ovarian tumor should raise doubts. In addition, mucinous and endometrioid tumors may also be metastatic in nature. Immunohistochemistry, as well as knowledge on the patient's history, will clarify most of the suspicious cases.

Expression of the stem cell self-renewal gene Hiwi and risk of tumour-related death in patients with soft-tissue sarcoma.

Self-renewal is considered as a common property of stem cells. Dysregulation of stem cell self-renewal is likely a requirement for the development of cancer. Hiwi, the human Piwi gene, encodes a protein responsible for stem cell self-renewal. In this study, we investigated the expression of Hiwi at the RNA level by real-time quantitative PCR in 65 primary soft-tissue sarcomas (STS) and ascertained its impact on prognosis for STS patients. In a multivariate Cox's proportional hazards regression model, we found that an increased expression of Hiwi mRNA is a significant negative prognostic factor for patients with STS (P=0.017; relative risk 4.6, 95% confidence interval (CI) 1.3-16.1) compared to medium expression of Hiwi transcript. However, a low expression of Hiwi transcript is correlated with a 2.4-fold (CI 0.7-8.0) increased risk, but this effect was not significant (P=0.17). Altogether, high-level expression of Hiwi mRNA identifies STS patients at high risk of tumour-related death. This is the first report showing a correlation between expression of a gene involved in stem cell self-renewal and prognosis of cancer patients.