Prognostic markers in rectal neuroendocrine tumors

M1 - 87 s. + liitteet Helsingin yliopistoNeuroendocrine tumors of the rectum were regarded as benign, when Oberndorfer originally described the entity in 1907. Later, he acknowledged that some neuroendocrine tumors (or carcinoids, the term at that time) behave in a more aggressive manner, and a few of them even had the potential to metastasize with poor outcome. In the novel World Health Organization (WHO) classification launched in 2010, all neuroendocrine tumors of the gastrointestinal (GI) tract are malignant. In this classification, tumors of every part of the GI tract are graded uniformly according to proliferation index and mitotic frequency, whereas the TNM-classification (tumor, node, metastasis) is specific for each site. Around 10% of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) occur in the rectum. The tumor series comprised 73 rectal NETs, with the main objective being to study the prognostic value of the WHO 2010 classification in rectal NETs: additionally, as the WHO classification has been used for a rather short time, tumor markers were tested to find a good, reliable prognostic tool. The WHO 2010 had excellent prognostic significance; none of the G1- NETs (grade 1) metastasized, whereas G2-NETs were often disseminated, some of them at initial presentation. Metastatic NETs have a poor prognosis. Cell-cycle antigen cyclin A also correlated with prognosis, and G2-NETs with high cyclin A expression were all metastatic. Transcription factor prospero homeobox 1 (PROX1) was immunohistochemically positive in a significant proportion of rectal NETs, and showed a correlation with metastatic potential and survival. It was also possible to conclude that the novel stem cell-associated factor HES77 (human embryonic stem cell factor 77) correlated well with rectal NETs metastatic potential and prognosis. These results support the validity of the WHO 2010 classification in rectal NETs. In view of this study, for patients with a rectal G1-NET, one follow-up endoscopy to exclude local recurrence might suffice. Intensive follow-up does not seem indicated, as metastatic potential is very low. As to G2-NETs, a thorough work-up is recommended, since most of these tumors disseminate eventually, some after several years, and a standard 5-year follow-up may not suffice. PROX1-positivity suggests that colorectal adenocarcinoma and rectal NET may, to some extent, share the same pathway in oncogenesis, which could lead to future therapeutic applications

Soijalisä ja ekvolin tuotto vaihdevuosi-ikäisillä tibolonia käyttävillä naisilla : vaikutukset sydän- ja verisuonisairauksien merkkiaineisiin

Tibolone, a synthetic steroid, is effective in the treatment of postmenopausal symptoms. Its cardiovascular safety profile has been questioned, because tibolone reduces the levels of high-density lipoprotein (HDL) cholesterol. Soy-derived isoflavones may offer health benefits, particularly as regards lipids and also other cardiovascular disease (CVD) risk factors. The soy-isoflavone metabolite equol is thought to be the key as regards soy-related beneficial effects. We studied the effects of soy supplementation on various CVD risk factors in postmenopausal monkeys and postmenopausal women using tibolone. In addition, the impact of equol production capability was studied. A total of 18 monkeys received casein/lactalbumin (C/L) (placebo), tibolone, soy (a woman s equivalent dose of 138 mg of isoflavones), or soy with tibolone in a randomized order for 14 weeks periods, and there was a 4-week washout (C/L) in between treatments. Postmenopausal women using tibolone (N=110) were screened by means of a one-week soy challenge to find 20 women with equol production capability (4-fold elevation from baseline equol level) and 20 control women, and treated in a randomized cross-over trial with a soy powder (52 g of soy protein containing 112 mg of isoflavones) or placebo for 8 weeks. Before and after the treatments lipids and lipoproteins were assessed in both monkeys and women. In addition, blood pressure, arterial stiffness, endothelial function, sex steroids, sex hormone-binding globulin (SHBG), and vascular inflammation markers were assessed. A 14% increase in plasma low-density lipoprotein (LDL) + very low-density lipoprotein (VLDL) cholesterol was observed in tibolone-treated monkeys vs. placebo. Soy treatment resulted in a 18% decrease in LDL+VLDL cholesterol, and concomitant supplementation with tibolone did not negate the LDL+VLDL cholesterol-lowering effect of soy. A 30% increase in HDL cholesterol was observed in monkeys fed with soy, whereas HDL cholesterol levels were reduced (48%) after tibolone. Interestingly, Soy+Tibolone diet conserved HDL cholesterol levels. Tibolone alone increased the total cholesterol (TC):HDL cholesterol ratio, whereas it was reduced by Soy or Soy+Tibolone. In postmenopausal women using tibolone, reductions in the levels of total cholesterol and LDL cholesterol were seen after soy supplementation compared with placebo, but there was no effect on HDL cholesterol, blood pressure, arterial stiffness or endothelial function. Soy supplementation decreased the levels of estrone in equol producers, and those of testosterone in the entire study population. No changes were seen in the levels of androstenedione, dehydroepiandrosterone sulfate, or SHBG. The levels of vascular cell adhesion molecule-1 increased, and platelet-selectin decreased after soy treatment, whereas C-reactive protein and intercellular adhesion molecule-1 remained unchanged. At baseline and unrelated to soy treatment, equol producers had lower systolic, diastolic and mean arterial pressures, less arterial stiffness and better endothelial function than non-producers. To conclude, soy supplementation reversed the tibolone-induced fall in HDL cholesterol in postmenopausal monkeys, but this effect was not seen in women taking tibolone. Equol production capability was associated with beneficial cardiovascular changes and thus, this characteristic may offer cardiovascular benefits, at least in women using tibolone.Soijalisä ja ekvolin tuotto vaihdevuosi-ikäisillä tibolonia käyttävillä naisilla: vaikutukset sydän- ja verisuonisairauksien merkkiaineisiin Suomessa noin 20 000 naista käyttää tibolonia vaihdevuosioireiden hoitoon. Tiboloni on keinotekoinen valmiste, joka muistuttaa vaikutuksiltaan monin tavoin perinteistä vaihdevuosien hormonihoitoa. Tiboloni voi kuitenkin pienentää hyvän HDL-kolesterolin pitoisuutta veressä. Samanaikaisesti tibolonin kanssa monet naiset käyttävät myös vaihtoehtoisia hoitoja, joista tavallisimpia ovat kasviestrogeenejä sisältävät soijavalmisteet. Aasialainen ravinto sisältää runsaasti soijaperäisiä kasviestrogeenejä, minkä on ajateltu pienentävän sydän- ja verisuonisairauksien vaaraa. Tarkoin ei tiedetä, miten kasviestrogeenit toimivat, mutta noin 30%:lla ihmisistä suoliston bakteerifloora muuttaa niitä ekvoliksi, joka voi viime kädessä olla se vaikuttava aine. Tutkin soijalisän vaikutusta eräisiin sydän- ja verisuonisairauksien riskiä mittaaviin tekijöihin vaihdevuosi-ikäisissä apinoissa (n=18) ja naisissa (n=40) tiboloni-hoidon aikana. Soija esti apinoilla tibolonin aiheuttaman hyvän HDL-kolesterolin laskun ja vaikutti suotuisasti muutenkin veren rasva-aineisiin. Naisilla sen sijaan soija ei nostanut tibolonin aiheuttamaa hyvän HDL-kolesterolin laskua, vaikkakin se jonkin verran laski kokonaiskolesterolia ja huonoa LDL-kolesterolia. Naisilla soijalisä ei vaikuttanut myöskään verenpaineeseen tai verisuonen seinämän toimintaan. Sen sijaan se muutti naisen omien sukupuolihormonien pitoisuuksia tavalla, jonka saattoi katsoa sydän- ja verisuonitautiriskin kannalta hyödylliseksi. Tämä vaikutus oli voimakkain naisilla, joiden suolistossa soija muuttui ekvoliksi; näillä naisilla myös verenpaine oli matalampi ja verisuonen seinämän muukin toiminta oli parempi. Näiden tulosten perusteella voidaan sanoa, että soijalisä vaikuttaa vain vähän tai ei juuri ollenkaan verisuonen seinämän toimintaan terveillä tibolonia käyttävillä naisilla. Ne naiset (noin 30% kaikista), jotka pystyvät muuttamaan soijaa ekvoliksi, voivat saada mahdollista suojaa sydän- ja verisuonisairauksia vastaan

Sentinel node tumor burden in prediction of prognosis in melanoma patients

Recent data have demonstrated no survival benefit to immediate completion lymph node dissection (CLND) for positive sentinel node (SN) disease in melanoma. It is important to identify parameters in positive SNs, which predict prognosis in melanoma patients. These might provide prognostic value in staging systems and risk models by guiding high-risk patients' adjuvant therapy in clinical practice. In this retrospective study of university hospital melanoma database we analyzed tumor burden and prognosis in patients with positive SNs. Patients were stratified by the diameter of tumor deposit, distribution of metastatic focus in SN, ulceration and number of metastatic SNs. These were incorporated in Cox proportional hazard regression models. Predictive ability was assessed using Akaike information criterion and Harrell's concordance index. A total of 110 patients had positive SN and 104 underwent CLND. Twenty-two (21%) patients had non-SN metastatic disease on CLND. The 5-year melanoma specific survival for CLND-negative patients was 5.00 years (IQR 3.23-5.00, range 0.72-5.00) compared to 3.69 (IQR 2.28-4.72, range 1.01-5.00) years in CLND-positive patients (HR 2.82 (95% CI 1.17-6.76, p = 0.020).The models incorporating distribution of metastatic focus and the largest tumor deposit in SN had highest predictive ability. According to Cox proportional hazard regression models, information criterions and c-index, the diameter of tumor deposit > 4 mm with multifocal location in SN despite of number of metastatic SN were the most important parameters. According to the diameter of tumor deposit and distribution of metastatic focus in SN, adequate stratification of positive SN patients was possible and risk classes for patients were identified.Peer reviewe

Correction to: Maternal complications in twin pregnancies in Finland during 1987–2014 : a retrospective study

An amendment to this paper has been published and can be accessed via the original article

Perinatal outcomes in Finnish twins : a retrospective study

Background To establish the changes in perinatal morbidity and mortality in twin pregnancies in Finland, a retrospective register research was conducted. Our extensive data from a 28-year study period provide important information on the outcome of twin pregnancies in Finland that has previously not been reported to this extent. Methods All 23,498 twin pregnancies with 46,996 children born in Finland during 1987-2014 were included in the study. Data were gathered from the Medical Birth Register and the Hospital Discharge Register (Finnish Institute for Health and Welfare, Finland) regarding perinatal mortality (PNM) and morbidity. For statistical analysis, binomial regression analysis and crosstabs were performed. The results are expressed in means, percentages and ranges with comparison to singletons when appropriate. Odds ratios from binomial regression analysis are reported. A p-value Results There were 46,363 liveborn and 633 stillborn twins in Finland during 1987-2014. Perinatal mortality decreased markedly, from 45.1 to 6.5 per 1000 for twin A and from 54.1 to 11.9 per 1000 for twin B during the study period. Yet, the PNM difference between twin A and B remained. Early neonatal mortality did not differ between twins, but has decreased in both. Asphyxia, respiratory distress syndrome, need for antibiotics and Neonatal Intensive Care Unit (NICU) stay were markedly more common in twin B. Conclusions In Finland, PNM and early neonatal mortality in twins decreased significantly during 1987-2014 and are nowadays very low. However, twin B still faces more complications. The outline provided may be used to further improve the monitoring and thus perinatal outcome of twins, especially twin B.Peer reviewe

Perinatal outcomes in Finnish twins : a retrospective study

Background To establish the changes in perinatal morbidity and mortality in twin pregnancies in Finland, a retrospective register research was conducted. Our extensive data from a 28-year study period provide important information on the outcome of twin pregnancies in Finland that has previously not been reported to this extent. Methods All 23,498 twin pregnancies with 46,996 children born in Finland during 1987-2014 were included in the study. Data were gathered from the Medical Birth Register and the Hospital Discharge Register (Finnish Institute for Health and Welfare, Finland) regarding perinatal mortality (PNM) and morbidity. For statistical analysis, binomial regression analysis and crosstabs were performed. The results are expressed in means, percentages and ranges with comparison to singletons when appropriate. Odds ratios from binomial regression analysis are reported. A p-value Results There were 46,363 liveborn and 633 stillborn twins in Finland during 1987-2014. Perinatal mortality decreased markedly, from 45.1 to 6.5 per 1000 for twin A and from 54.1 to 11.9 per 1000 for twin B during the study period. Yet, the PNM difference between twin A and B remained. Early neonatal mortality did not differ between twins, but has decreased in both. Asphyxia, respiratory distress syndrome, need for antibiotics and Neonatal Intensive Care Unit (NICU) stay were markedly more common in twin B. Conclusions In Finland, PNM and early neonatal mortality in twins decreased significantly during 1987-2014 and are nowadays very low. However, twin B still faces more complications. The outline provided may be used to further improve the monitoring and thus perinatal outcome of twins, especially twin B.Peer reviewe

Characteristics and Trends of Cutaneous Squamous Cell Carcinoma in a Patient Cohort in Finland 2006-2015

The incidence of cutaneous squamous cell carcinoma is increasing worldwide. In most epidemiological studies, only the first case of cutaneous squamous cell carcinoma is registered, underestimating the burden of the disease. To determine the frequency and detailed characteristics of cutaneous squamous cell carcinoma in a Finnish patient cohort, we performed a retrospective 10-year study taking into account multiple tumours in one patient. On the pathology database search and medical record review we identified 774 patients with a total of 1,131 cutaneous squamous cell carcinomas. The crude incidence increased from 18.6/100,000 persons in 2006 to 28.1 in 2015. The location of tumours differed between men and women: the greatest difference concerned cutaneous squamous cell carcinoma of the ear, with 93% of cases occurring in men. One fourth (24%) of patients had more than one tumour. A small shift from poorly to well-differentiated tumours was seen. In conclusion, the incidence of cutaneous squamous cell carcinoma increased, with many patients presenting with multiple tumours.Peer reviewe

Correction to: Perinatal outcomes in Finnish twins : a retrospective study

An amendment to this paper has been published and can be accessed via the original article