A cukorbetegség és a daganatos thrombocytosis túlélésre gyakorolt hatásának vizsgálata emlőtumoros nőkben = Survival impact of diabetes and paraneoplastic thrombocytosis in women with breast cancer

Absztrakt: Bevezetés: Számos daganatban igazolták, hogy mind a thrombocytosis, mind a 2-es típusú cukorbetegség negatívan befolyásolja a tumoros betegek túlélését. A két tényező szerepét együttesen emlőtumorokban eddig még nem vizsgálták. Célkitűzés: Vizsgálatunk célja a Semmelweis Egyetem II. sz. Belgyógyászati Klinika, illetve az I. sz. Sebészeti Klinika szakambulanciáin 2014−2017 között emlőtumor miatt kezelt betegpopulációban a thrombocytosis és a 2-es típusú diabetes gyakoriságának és a daganatos betegség kimenetelére gyakorolt önálló és együttes hatásának felmérése volt. Vizsgáltuk az emlőtumor diagnózisakor a laboratóriumi és anamnesztikus adatokat a cukorbeteg és nem cukorbeteg csoportokban, túléléselemzéssel a thrombocytosis és/vagy a 2-es típusú cukorbetegség túlélést befolyásoló hatását. Módszer: Retrospektív vizsgálatunkban 274, emlőtumoros beteg adatait elemeztük. A betegeket legkésőbb 2018. 12. 31-ig, az utolsó egyetemi megjelenésükig vagy haláluk bekövetkeztéig követtük. Eredmények: Emelkedett thrombocytaszámokat (400 G/l feletti) a betegek ~5%-ában figyeltünk meg. A betegek közel ötöde 2-es típusú cukorbeteg volt (52 fő). A cukorbetegek szignifikánsan idősebbek voltak a tumor felismerésekor (nem cukorbeteg: 56,8 ± 13,8 év, cukorbeteg: 67,8 ± 11,0 év, p<0,0001). A nem cukorbetegeknél gyakoribb a tripla negatív (p = 0,0366), illetve a T1-es stádiumú tumor (50%), míg cukorbetegekben a T2-es stádium a leggyakoribb (51,9%). A túlélési modell alapján az emlőtumoros betegek rövidebb túlélési idejét prognosztizálja, ha 2-es típusú cukorbetegségben is szenvednek (p = 0,0032). Vizsgálatunkban a betegek túlélését a thrombocytosis nem befolyásolta. Következtetés: A 2-es típusú cukorbetegekben az emlőtumor diagnosztizálásakor súlyosabb klinikai stádium valószínűsíthető, és rövidebb túlélés prognosztizálható. Javasoljuk, hogy a cukorbeteg nők kontrollvizsgálata alkalmával a nők figyelmét fel kell hívni a mammográfiai szűrővizsgálatok fontosságára, illetve 30 éves kor felett a diabetest rizikótényezőnek kell tekinteni, és a betegek szűrővizsgálata legalább kétévente javasolt. Orv Hetil. 2019; 160(51): 2012–2020. | Abstract: Introduction: Thrombocytosis and type 2 diabetes have negative effect on the survival of tumor patients. Previously, their joint effect has not been studied in breast cancer. Aim: The aim of our retrospective study was to investigate the occurrence and effects of thrombocytosis and/or type 2 diabetes in breast cancer patients who attended the 2nd Department of Internal Medicine or the 1st Department of Surgery, Semmelweis University, between 2014 and 2017. Laboratory and anamnestic data were compared at the time of tumor diagnosis between diabetic and non-diabetic groups. Survival analysis was performed to study the effects of thrombocytosis and/or type 2 diabetes. Method: 274 study participants were followed until 31 December 2018, or until their last appearance at the University, or until their death. Results: 5% of the patients had elevated platelet counts (over 400 G/L), and 52 were diabetics. Diabetics were significantly older (non-diabetics: 56.8 ± 13.8 years, diabetics: 67.8 ± 11.0 years, p<0.0001). Triple negative subtype (p = 0.0366), and T1 stage (50%) were present more often in non-diabetics. Stage T2 was more common in diabetic patients (51.9%). Type 2 diabetes was associated with a shorter survival time (p = 0.0032). Thrombocytosis did not affect patient survival. Conclusion: At the diagnosis of breast cancer, existing type 2 diabetes is associated with a more severe clinicopathological stage and shorter survival. We recommend that during routine diabetes controls, women should be made aware of the importance of mammography screening. Moreover, diabetes should be considered as a risk factor; after 30 years of age, diabetics should be screened at least every two years. Orv Hetil. 2019; 160(51): 2012–2020

Colorectalis daganatokban a 2-es típusú cukorbetegség és a thrombocytosis előfordulása, a túlélésre gyakorolt hatásuk, a primer tumor műtéti eltávolítása előtt és után

Absztrakt: Bevezetés: Egyre több irodalmi adat utal a thrombocyták és a metasztatikus tumorsejtek kapcsolatára, illetve a pre- és posztoperatív thrombocytosis prediktív markerként való alkalmazhatóságára. Mind colorectalis daganatokban, mind 2-es típusú diabetesben jellemzőek a thrombocyták mennyiségi és/vagy minőségi károsodásai. 2-es típusú diabetesben a colorectalis tumorok emelkedett incidenciája ismert. Célkitűzés: Retrospektív vizsgálatunk célja a Semmelweis Egyetem II. Belgyógyászati Klinikájának Onkológiai Ambulanciáján az elmúlt három évben kezelt colorectalis tumoros betegekben a 2-es típusú diabetes gyakoriságának meghatározása, illetve a daganatos betegség felismerésekor és a primer daganat műtéti eltávolítását követően a thrombocytaszámok, valamint további laboratóriumi és anamnesztikus adatok felmérése, továbbá statisztikai modellek segítségével vizsgálni a cukorbetegség túlélést befolyásoló hatását. Módszer: 86, random kiválasztott colorectalis tumoros beteg pre- (86 fő) és posztoperatív (66 fő, műtétre alkalmas, párosított) adatait dolgoztuk fel. A betegeket legkésőbb 2017. szeptember 30-ig vagy haláluk bekövetkeztéig követtük. Eredmények: Emelkedett (400 giga/l feletti) thrombocytaszámokat figyeltünk meg a betegek 22,1%-ában (323,5 ± 128,63 giga/l, átlag ± SD), melyek a primer tumor műtéti eltávolítását követően 10,6%-ra csökkentek (χ2-teszt: p = 0,0351; 289,2 ± 82,45 giga/l, p = 0,0232). Az emelkedett thrombocytaszámokhoz rövidebb túlélési idők tartoztak (R: –0,35, p = 0,0085). Diabetes a betegek harmadában volt igazolható. A diabeteses és a nem diabeteses személyek vizsgált laboratóriumi paraméterei (például vérkép, vesefunkció, májenzimek) nem különböztek. A primer tumor sebészi eltávolítását követően a diabetes ötszörös kockázati tényezője a rövidebb túlélésnek (relatív kockázat: 5,1612, p = 0,0165). Az átlagos túlélési idő 30,6 ± 26,78 hónap. Következtetés: A következményes, tartósan fennálló thrombocytosis a műtét után kedvezőtlen túlélési időre utal. Megfigyeléseink alapján a colorectalis daganatok felismerésekor az emelkedett thrombocytaszám és a 2-es típusú diabetes prognosztikai markerek lehetnek. Orv Hetil. 2018; 159(19): 756–767. | Abstract: Introduction: The relationship between platelets and metastatic tumor cells is an ongoing research area. Pre- and postoperative thrombocytosis are suggested predictive survival markers. Colorectal cancer and type 2 diabetes are characterized by various changes to platelets. The occurrence of colorectal cancer is more frequent in diabetes. Aim: Our aim was to determine the occurrence of type 2 diabetes in colorectal cancer patients, who attended the Semmelweis University 2nd Department of Internal Medicine’s Oncology Department in the last three years. Further goals included the evaluation of anamnestic, pre- and postoperative laboratory data, and whether diabetes can be a significant survival factor. Method: A retrospective study was conducted with 86 randomly selected colorectal cancer patients’ preoperative (86 patients) and paired postoperative (66, who were operable) data. Patients were monitored no later than September 30, 2017 or until their death. Results: Preoperatively, elevated (over 400 Giga/L) platelet counts were present in 22.1% of the patients (323.5 ± 128.63 Giga/L, mean ± SD) which decreased to 10.6% postoperatively (χ2: p = 0.0351; 289.2 ± 82.45 Giga/L, p = 0.0232). Negative correlation was found between platelet counts and overall survival (R: –0.35, p = 0.0085). One third of the patients had diabetes. Laboratory results (i.e., blood counts, creatinine) between diabetic and non-diabetic patients were not significant. Diabetes is a significant five-fold postoperative risk factor for shorter overall survival (relative risk: 5.1612, p = 0.0165). Average survival was 30.6 ± 26.78 months. Conclusion: Persistent consequential postoperative thrombocytosis may indicate shorter survival time. Our observations suggest elevated platelet counts and type 2 diabetes as prognostic markers for survival at the recognition of colorectal tumors. Orv Hetil. 2018; 159(19): 756–767

Regular chromogranin A monitoring facilitated the early detection of a gastrointestinal neuroendocrine tumour in a patient with type 1 diabetes

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Personalized Indicator Thrombocytosis Shows Connection to Staging and Indicates Shorter Survival in Colorectal Cancer Patients with or without Type 2 Diabetes

Background: Pre- and postoperative thrombocytosis was reported to have significant effect on patient survival. However, the definition of thrombocytosis throughout the literature is not unified. Methods: A retrospective longitudinal observational study has been conducted with the inclusion of 150 colorectal cancer (CRC) patients and 100 control subjects. A new measure of platelet changes at an individual level, named personalized indicator thrombocytosis (PIT) was defined, including 4 anemia adjusted variants. Results: In concordance with the literature, PIT values of control subjects showed a slow decrease in platelet counts, while PIT values of CRC patients were significantly higher (p &lt; 0.0001). More advanced staging (p &lt; 0.0001) and both local (p &le; 0.0094) and distant (p &le; 0.0440) metastasis are associated with higher PIT values. Higher PIT values suggested shorter survival times (p &lt; 0.0001). Compared to conventional, a PIT-based definition resulted in approximately 3-times more patients with thrombocytosis. 28% and 77% of the deceased patients had conventional- and PIT-based thrombocytosis, respectively. Conclusions: Compared to conventional thrombocytosis, as an individual metric, PIT values may indicate the condition of patients more precisely. Possible future applications of PIT may include its usage in therapy decision and early cancer detection; therefore, further investigations are recommended

Histopathological Chromogranin A-Positivity Is Associated with Right-Sided Colorectal Cancers and Worse Prognosis

Background: Colorectal cancer (CRC) is known to be affected by paraneoplastic thrombocytosis and chromogranin A-positive neuroendocrine-cell differentiation (CgA+). Their combined effect has never been previously investigated. Methods: A prospective cohort pilot study of 42 CRC patients and 42 age- and sex-matched controls was carried out. Plasma interleukin-6, thrombopoietin, and serum chromogranin A and -B were measured; furthermore, tumor tissue was immunohistochemically stained for CgA+. Results: Twenty-seven and 15 patients were assigned to the chromogranin A-negative (CgA&minus;) and CgA+ groups, respectively. Within the CgA+ group, right-sided tumors were more frequent (18.5% vs. 53.3%), no stage I cancer was found, and patients of this group were in worse general condition. Compared to control subjects, chromogranin A level was higher in the CgA+ group (p = 0.0086), thrombopoietin (p = 0.0040) and chromogranin B (p = 0.0070) in the CgA&minus; group, while interleukin-6 was high in both tumor groups (p &le; 0.0090). Survival was significantly worse in the CgA+ group (hazard ratio: 5.73; p = 0.0378). Conclusions: Different thrombopoietin levels indicated distinct thrombocytosis types. Within the two CRC groups, serum levels of chromogranins changed in different directions suggesting two well-distinguishable pathophysiologies. Based on these observations we propose a new subtype of CRC, which can be characterized by chromogranin A-positive neuroendocrine-cell differentiation

Does Elevated Pre-Treatment Plasma PD-L1 Level Indicate an Increased Tumor Burden and Worse Prognosis in Metastatic Colorectal Cancer?

Background: Programmed death-ligand 1 (PD-L1) and programmed cell death protein 1 (PD-1) have been reported as possibly favorable prognostic factors in colorectal cancer (CRC). However, their longitudinal effect is unknown. Methods: A pilot study was performed to investigate whether baseline PD-1/PD-L1 levels are associated with further laboratory changes and/or shorter survival. Results: A total of 506 laboratory measurements from 37 metastatic CRC patients were analyzed. The baseline plasma PD-1 and PD-L1 levels were 27.73 &plusmn; 1.20 pg/mL and 16.01 &plusmn; 1.09 pg/mL, respectively. Disease progression (p = 0.0443) and baseline high-sensitivity C-reactive protein (p = 0.0011), aspartate transaminase (p = 0.0253), alanine transaminase (p = 0.0386), and gamma-glutamyl transferase (p = 0.0103) were associated with higher PD-L1 levels. Based on the baseline PD-1/PD-L1 levels, low and high PD-1/PD-L1 groups were created. Constant, pathological levels of complete blood count values, high-sensitivity C-reactive protein, serum albumin, high-density lipoprotein cholesterol, and lactate dehydrogenase were characteristic for patients with high baseline PD-L1. High PD-L1 levels were significantly associated with increased tumor burden. Disease-specific survival and progression-free survival were significantly shorter in patients with high PD-L1. Conclusions: Abnormal levels of laboratory parameters and intensified tumor burden can be expected if elevated baseline plasma PD-1/PD-L1 levels are found

Longitudinal Analysis of 1α,25-dihidroxyvitamin D₃ and Homocysteine Changes in Colorectal Cancer

Background: 1α,25-dihydroxycholecalciferol (1,25(OH)2D3) and homocysteine are known to play a role in the pathophysiology of colorectal cancer (CRC). In health, the two changes are inversely proportional to each other, but little is known about their combined effect in CRC. Methods: The serum 1,25(OH)2D3 and the homocysteine levels of eighty-six CRC patients were measured, who were enrolled into four cohorts based on the presence of metastases (Adj vs. Met) and vitamin D3 supplementation (ND vs. D). Results: 1,25(OH)2D3 was constant (Adj-ND), increased significantly (Adj-D, p = 0.0261), decreased (Met-ND), or returned close to the baseline after an initial increase (Met-D). The longitudinal increase in 1,25(OH)2D3 (HR: 0.9130, p = 0.0111) positively affected the overall survival in non-metastatic CRC, however, this effect was cancelled out in those with metastasis (p = 0.0107). The increase in homocysteine negatively affected both the overall (HR: 1.0940, p = 0.0067) and the progression-free survival (HR: 1.0845, p = 0.0073). Lower 1,25(OH)2D3 and/or higher homocysteine level was characteristic for patients with higher serum lipids, albumin, total protein, white blood cell and platelet count, male sex, and right-sided tumors. No statistically justifiable connection was found between the target variables. Conclusions: A measurement-based titration of vitamin D3 supplementation and better management of comorbidities are recommended for CRC

Szérum kromogranin A szint vizsgálata 2-es típusú cukorbetegségben [Serum chromogranin A level in patients with type 2 diabetes]

A kromogranin A (CgA) a granin fehérjecsaládba tartozó glükoprotein. E fehérje és a diabetes közötti szoros kapcsolatot 1-es típusú cukorbetegségben korábban több munkacsoport is igazolta. Jelen vizsgálatunk során a Semmelweis Egyetem, II. sz. Belgyógyászati Klinika Anyagcsere Ambulanciáján 2-es típusú cukorbetegek szérum kromogranin A szintjét határoztuk meg. Vizsgáltuk továbbá, hogy mely anamnesztikus és/vagy laboratóriumi paraméter függ össze a kromogranin A szinttel. Összesen 86 2-es típusú cukorbeteg személyt vontunk be a vizsgálatba. A betegekről felvett anamnesztikus adatok mellett éhgyomri vérvételt követően elemeztük a vérképet, a HbA1c-szintet, a vérzsírokat, a vesefunkciót, illetve a TSH-t. A szérum kromogranin A szint meghatározása radioimmunoassay módszerrel történt. A vizsgált személyek közül 6 főnél (6,98%) volt igazolható emelkedett szérum kromogranin A szint. A normális tartomány felső határértéke alapján 2 kohorszra osztottuk a betegeket (Normál CgA: 80 fő, szérum-CgA 50,43±21,73 ng/ml; Magas CgA: 6 fő, szérum-CgA 129,33±41,07 ng/ml; p<0,0001). A két vizsgálati kohorsz között sem a laboratóriumi paraméterekben, sem a HbA1c-értékekben, sem pedig az anamnesztikus adatokban nem igazoltunk különbséget. Eredményeink alapján 2-es típusú diabetesben a kromogranin A szint és a diabetes fennállási ideje, valamint az anyagcserehelyzet között nem igazolható összefüggés. | Chromogranin A (CgA) is a member of the granin glycoprotein family. Most important effects of the protein related to diabetes have been demonstrated in type 1 diabetes. In the present cohort study serum chromogranin A levels of patients with type 2 diabetes were analyzed, who attended the Metabolic Clinic of the 2nd Department of Internal Medicine, Semmelweis University. It was also investigated whether anamnestic or laboratory data has any relation to chromogranin A levels. Altogether 86 patients with type 2 diabetes were included. Anamnestic data were collected and fasting blood samples were taken. Complete blood count, HbA1c , lipids, renal function and TSH were analyzed. CgA values were measured via radioimmunoassay. At six of the 86 subjects (6,98%) had elevated serum chromogranin A levels. Patients were divided into two cohorts based on the serum CgA upper limit of normal (Normal CgA: 80 subjects, serum CgA 50,43±21,73 ng/ml; High CgA: 6 subjects, serum CgA 129,33±41,07 ng/ml; p<0,0001). No differences were found between study groups neither in laboratory parameters, nor in HbA1c values, nor in anamnestic data. Our results suggest that in type 2 diabetes there’s no connection between serum chromogranin A levels and the duration of diabetes, and it has no effect on glycemic control

Meta-Analysis of Modulated Electro-Hyperthermia and Tumor Treating Fields in the Treatment of Glioblastomas

Background: Glioblastoma is one of the most difficult to treat and most aggressive brain tumors, having a poor survival rate. The use of non-invasive modulated electro-hyperthermia (mEHT) and Tumor Treating Fields (TTF) devices has been introduced in the last few decades, both of which having proven anti-tumor effects. Methods: A meta-analysis of randomized and observational studies about mEHT and TTF was conducted. Results: A total of seven and fourteen studies about mEHT and TTF were included, with a total number of 450 and 1309 cases, respectively. A 42% [95% confidence interval (95% CI): 25–59%] 1-year survival rate was found for mEHT, which was raised to 61% (95% CI: 32–89%) if only the studies conducted after 2008 were investigated. In the case of TTF, 1-year survival was 67% (95% CI: 53–81%). Subgroup analyses revealed that newly diagnosed patients might get extra benefits from the early introduction of the devices (mEHT all studies: 73% vs. 37%, p = 0.0021; mEHT studies after 2008: 73% vs. 54%, p = 0.4214; TTF studies: 83% vs. 52%, p = 0.0083), compared with recurrent glioblastoma. Conclusions: Our meta-analysis showed that both mEHT and TTF can improve glioblastoma survival, and the most benefit may be achieved in newly diagnosed cases

Meta-Analysis of Modulated Electro-Hyperthermia and Tumor Treating Fields in the Treatment of Glioblastomas

Background: Glioblastoma is one of the most difficult to treat and most aggressive brain tumors, having a poor survival rate. The use of non-invasive modulated electro-hyperthermia (mEHT) and Tumor Treating Fields (TTF) devices has been introduced in the last few decades, both of which having proven anti-tumor effects. Methods: A meta-analysis of randomized and observational studies about mEHT and TTF was conducted. Results: A total of seven and fourteen studies about mEHT and TTF were included, with a total number of 450 and 1309 cases, respectively. A 42% [95% confidence interval (95% CI): 25&ndash;59%] 1-year survival rate was found for mEHT, which was raised to 61% (95% CI: 32&ndash;89%) if only the studies conducted after 2008 were investigated. In the case of TTF, 1-year survival was 67% (95% CI: 53&ndash;81%). Subgroup analyses revealed that newly diagnosed patients might get extra benefits from the early introduction of the devices (mEHT all studies: 73% vs. 37%, p = 0.0021; mEHT studies after 2008: 73% vs. 54%, p = 0.4214; TTF studies: 83% vs. 52%, p = 0.0083), compared with recurrent glioblastoma. Conclusions: Our meta-analysis showed that both mEHT and TTF can improve glioblastoma survival, and the most benefit may be achieved in newly diagnosed cases