Opposite prognostic roles of HIF1alpha and HIF2alpha expressions in bone metastatic clear cell renal cell cancer

BACKGROUND: Prognostic markers of bone metastatic clear cell renal cell cancer (ccRCC) are poorly established. We tested prognostic value of HIF1alpha/HIF2alpha and their selected target genes in primary tumors and corresponding bone metastases. RESULTS: Expression of HIF2alpha was lower in mRCC both at mRNA and protein levels (p/mRNA/=0.011, p/protein/=0.001) while HIF1alpha was similar to nmRCC. At the protein level, CAIX, GAPDH and GLUT1 were increased in mRCC. In all primary RCCs, low HIF2alpha and high HIF1alpha as well as CAIX, GAPDH and GLUT1 expressions correlated with adverse prognosis, while VEGFR2 and EPOR gene expressions were associated with favorable prognosis. Multivariate analysis confirmed high HIF2alpha protein expression as an independent risk factor. Prognostic validation of HIFs, LDH, EPOR and VEGFR2 in RNA-Seq data confirmed higher HIF1alpha gene expression in primary RCC as an adverse (p=0.07), whereas higher HIF2alpha and VEGFR2 expressions as favorable prognostic factors. HIF1alpha/HIF2alpha-index (HIF-index) proved to be an independent prognostic factor in both the discovery and the TCGA cohort. PATIENTS AND METHODS: Expressions of HIF1alpha and HIF2alpha as well as their 7 target genes were analysed on the mRNA and protein level in 59 non-metastatic ccRCCs (nmRCC), 40 bone metastatic primary ccRCCs (mRCC) and 55 corresponding bone metastases. Results were validated in 399 ccRCCs from the TCGA project. CONCLUSIONS: We identified HIF2alpha protein as an independent marker of the metastatic potential of ccRCC, however, unlike HIF1alpha, increased HIF2alpha expression is a favorable prognostic factor. The HIF-index incorporated these two markers into a strong prognostic biomarker of ccRCC

Less invasive treatment option for renal carcinoma with venous tumor thrombus

Aim To retrospectively analyze patients treated by renal tumor and venous tumor thrombus (VTT) removal and to introduce a less stressful and safer surgical method without thoracotomy in Neves level 3 cases. Methods From 2002 to 2011, 33 patients underwent surgery for renal cell cancer combined with tumor thrombus of the inferior vena cava. Preoperative symptoms, tumornode-metastasis classification of tumors, thrombus extension classified by Neves and Zincke system, types of surgical interventions, complications, postoperative management, and survival results were analyzed. Results Ten patients had level 1, 17 had level 2, and 6 had level 3 thrombi according to Neves and Zincke. In 5 patients with level 3 thrombi, the liver was mobilized without thoracotomy and in 1 patient endoluminal occlusion was utilized. There was no intraoperative mortality. The median survival time of 10 patients who died during follow-up period was 36.6 months (range, 0-121 months). Conclusion Renal cell cancer complicated with tumor thrombus without metastasis can be curable by performing a complete resection. The thrombus level determines the surgical approach and method. Our results confirm that level 3 caval vein tumor thrombus can be safely surgically treated by laparotomy with liver mobilization. Thoracotomy, use of cardiopulmonary bypass, and hypothermic circulatory arrest can be avoided with adequate liver-and vascular surgery methods. In 4%-15% of renal cell cancer cases, tumor thrombus is formed in the renal vein (RV) and later in the inferior vena cava (IVC), and in 1% the thrombus spreads into the right atrium (1-5). For advanced stage renal cell cancer a radical nephrectomy with removal of the tumor thrombus is required Zoltán MAteRIAL ANd MetHodS Patient population Between 2002 and 2011, at the Department of Urology, Semmelweis University 968 surgeries of renal cell cancer were performed. We studied the 33 cases in which renal cell cancer was combined with tumor thrombus of the RV and the ICV. Among them, there were 12 women (36.4%) and 21 men (63.6%), with the average age of 60.5 years (31-79 years, standard deviation 9.138). Preopeartive diagnostics Before each surgery, abdominal ultrasound and CT scan were performed, and in 21 cases MRI was performed (9-11). In level 2 cases, surgical procedure included the transperitoneal surgery through Chevron (subcostal)-incision: exploration, ligation of the renal artery, exclusion of the section above the IVC thrombus and the section below the renal veins followed by the exclusion of the intact renal vein, longitudinal cavotomy or the excision of the orifice of renal vein on the affected side, thrombectomy, flushing of the caval vein, de-gassing, lateral clamping of the cavotomy with Satinsky forceps, release of the exclusion, cavotomy closure with running suture, and nephrectomy. In level 1 cases, the cava was not involved, therefore the surgical intervention was less complicated, however in the level 3 cases the mobilization of the liver was required (11-13). The histological rating of the tumor was carried out according to the classification of Heidelberg, the staging was performed based on the 2010 tumor-node-metastasis (TNM) classification, and the histological grade was characterized according to Fuhrman (14, ReSuLtS Among 33 patients, there were 10 patients with level 1, 17 with level 2, and 6 with level 3. In these patients, Neves classification, number of cases, surgery type, and surgical time, the blood loss during surgery, intraoperative complications, reoperation and perioperative death was analyzed We surgically treated 6 patients with level 3 VTT. In 4 cases, the clamping was made bellow the hepatic veins. In these cases, there was no bleeding from the liver to the cavotomy. In 1 case, the tumor thrombus reached a higher position than in previous 4 cases, therefore the clamping was performed above the liver and the retrograde bleeding was reduced with the Pringle-maneuver. In 1 case, thrombectomy was performed using a Foley-catheter to overcome the endoluminal occlusion. The catheter easily passed by the solid tumor thrombus, there was no embolization, and the operative time was shorter than in other cases. The cavotomy, as well as the excision of the orifice of the affected renal vein, was closed with running suture using a Satinsky forceps for lateral clamping. There was no postoperative cava occlusion. Lymph node block dissection was performed in only 5 cases, in case of palpable enlarged lymph nodes. The infiltration of the caval vein wall was not observed in any of the cases, therefore cava resection was not needed. The average operative time was 3 hours and 34 minutes (2 hours-5 hours and 45 minutes). The median intraoperative blood loss was 1075 mL (200-3500 mL), which was substituted with 3.4 U (0-12 U) of red blood cell mass transfusion. Three reoperations were performed, one due to an injury of the contralateral ureter, one because of the bleeding from the removed kidney's bed, and one because of splenic injury. At the beginning of the less invasive surgical procedure, in 2 cases the clamping of vena cava was not performed, leading to pulmonary embolism. One occurred in the course of operation and the other at the time of the extubation. These patients received anticoagulant therapy and fully recovered. A patient, who suffered from multiple vascular disease, died on the second postoperative day. The cause of death was necrosis of the small bowel induced by the occlusion of the superior mesenteric artery. Other postoperative complications were not detected At the time of the operation, 11 patients (33.3%) had distant metastases, mostly in the lungs and the retroperitoneum. Other sites included the liver and the mediastinum. The maximum diameter of the renal tumor was on average 101 mm (50-280 mm). According to the TNM classification, 31 tumors were T3 and 2 cases were T4. Based on the Fuhrman staging there was 1 G1, 11 G2, 13 G3, and 8 G4-tumors. The median tumor thrombus length was 54 mm (10-130 mm). There was no intraoperative mortality. One patient died postoperatively (3%). The patients were monitored every 6 months after surgery. Serum creatinine, urea, and electrolyte levels were determined and abdominal ultrasound, chest, and abdominal CT examinations carried out. Survival time was determined in accordance with the date of death or the last follow-up date. The median follow-up period was 30 months (0-121 months). For RCC, the patients were treated with subcutaneous Interferon-1α 9 million units 3 times a week combined with 0.1 mg/kg body weight of intravenous vinblastine once a month. The duration of this therapy was determined by the general condition of the patients and the outcome of the disease -ideally it lasted for 1 year. In one case, due to the poor general condition of the patient, the postoperative oncologic treatment was disregarded. After 2008, 5 patients with distant metastases were treated with tyrosine kinase inhibitors. Seven of the 11 patients with distant metastases (33.3%) undergoing surgery died in an average of 12.1 months (3-19 months). Of the patients with no metastases at the time of surgery, 3 died, with median survival of 26.7 months (22-31 months). All deaths were caused by the postoperative progression of the underlying disease. Twenty-two patients (66.6%) were alive at the end of the follow-up. Four of them developed metastases following the surgery in an average time of 14.5 months (9-24 months). Eighteen patients without metastases had median survival time of 41.5 months (1-116 months) following surgery. The median survival rate for 33 patients calculated by the Kaplan-Meier survival was 18 months (range, 0-121) dIScuSSIoN The less invasive surgical approach used in this study reduced the complication rate, surgical time, and blood loss. In 5 cases, we preoperatively embolized the renal artery to reduce the tumor and the VTT size and to collapse the collateral veins (16-19). We did not notice complications like systemic reaction, embolization of another organ, and embolization of the tumor by disintegrating VTT published by other surgical teams (20,21). The surgical plan depends on the VTT level. Previously, the tumor thrombus levels 3 and 4 were treated using right thoracolaparotomy. Nowadays thoracolaparotomy is less frequent and the combination of median sternotomy and laparotomy is increasingly used instead. The Chevron-incision provides opportunity for liver mobilization, therefore the VC clamping can be done without thoracotomy. While initially the Chevron-incision was used only for the thrombi localized below the diaphragm, now it is also used for those localized above the diaphragm. As a result, moderate forms of tumor thrombus level 4 can be treated by laparotomy (12,13). The introduction of cardiopulmonary bypass (CPB) and hypothermic circulatory arrest (HCA) has allowed performing the dissection in a virtually blood-free area Our results show that level 3 caval vein tumor thrombus can be removed by a less aggressive surgical approach, underlining the benefits of a surgical intervention without thoracotomy. Acknowledgments We thank Dr Sandor G. Vari, MD, Director of the International Research and Innovation Management Program, Cedars-Sinai Medical Center, Los Angeles, CA, USA and President of the RECOOP HST Association for critical review and helpful comments

A szelektív monoaminoxidáz-B-gátlók helye a Parkinson-kór kezelési stratégiájában a marosvásárhelyi ideggyógyászati klinikák gyakorlatában = The role of selective monoamine oxidase B inhibitors in the therapeutic strategy of Parkinson’s disease in the neurology clinics of Tirgu Mures County Emergency Clinical Hospital

Absztrakt: Bevezetés: A Parkinson-kór kezelési stratégiájában a szelektív monoaminoxidáz-B-gátlóknak a betegség minden stádiumában jól meghatározott helyük van. Enyhe esetekben, főleg fiatal betegeknél, a szubsztitúciós terápia késleltetésének egyik hatékony eszközeként számolhatunk velük; előrehaladott Parkinson-kórban, a motoros komplikációk ellátásában, a levodopaterápia kiegészítői. Célkitűzés: Annak felmérése, hogy a marosvásárhelyi ideggyógyászati klinikákon alkalmazott terápiás stratégiákban mekkora szerep jut a szelektív monoaminoxidáz-B-gátlóknak. Módszer: Retrospektív tanulmányunkban 2003. január 1. és 2016. december 31. között a klinikákon vizsgált összes Parkinson-kóros beteg adatait elemeztük. A 2194 beteg zárójelentésében rögzített terápiás ajánlások alapján tanulmányoztuk a monoaminoxidáz-B-gátlók alkalmazásának sajátosságait. A Parkinson-kór megállapítása óta eltelt idő szerint öt éve, illetve több mint öt éve tartó betegségcsoportokat alkottunk. Eredmények: A vizsgált időszakban az öt éve vagy ennél rövidebb ideje diagnosztizált csoportban 1183 betegből 243 esetben szerepelt a kezelési stratégiában monoaminoxidáz-B-gátló: 12 esetben monoterápia, 52 esetben dopaminagonistával, illetve 61 esetben levodopával kombinálva. A többi 118 betegnél levodopa és dopaminagonista kombinációjához társítva kerültek alkalmazásra a monoaminoxidáz-B-gátlók. A több mint öt éve ismert 582 esetből 195-nél egészítették ki a terápiás stratégiát monoaminoxidáz-B-gátlóval (10 esetben szelegilin, 185 esetben rasagilin). Nem volt felhasználható adat a betegség kezdetét illetően 429 esetben (ezek közül öt esetben szelegilint, illetve 93 esetben rasagilint alkalmaztak). Következtetés: A vizsgált periódusban a monoaminoxidáz-B-gátlók alkalmazásának aránya hasonló az irodalomban talált adatokhoz. A betegséggel foglalkozó szakorvosoknak nagyobb bátorsággal kellene alkalmazniuk a rendelkezésre álló és az ajánlásokban szereplő készítményeket, jobban kihasználni a különböző gyógyszertársítások előnyeit, különösen, ha ez nem terheli anyagilag a beteget. Orv Hetil. 2017; 158(51): 2023–2028. | Abstract: Introduction: Selective monoamine oxidase B inhibitors have an accurate place in therapeutical strategy of Parkinsons’s disease. In the early stages of the disease, especially in younger patients with milder symptoms, the introduction of levodopa substitution could be efficacious in delaying; in advanced stages they are mainly used to treat motor complications, as an adjunct to levodopa. Aim: The evaluation of therapeutical strategies used in the neurology clinics of Tirgu Mures County Emergency Clinical Hospital in order to define the role of monoamine oxidase B inhibitors. Method: This retrospective study includes all records of patients with Parkinson’s disease hospitalized between 1 January 2003 and 31 December 2016. From the 2194 reports we used data focusing on the therapeutic recommendations. Regarding disease duration, we divided the patients in two groups: less than or equal to 5 years and more than 5 years. Results: From the 1183 patients in first group, 243 received monoamine oxidase inhibitors: 12 as monotherapy, 52 together with dopamine agonists, in 61 cases combined with levodopa. In 118 cases monoamine oxidase inhibitors were combined with levodopa and dopamine agonists. From 582 cases whith Parkinson’s disease for more than 5 years, 195 received monoamine oxidase B inhibitors (selegiline: 10 cases, rasagiline: 185 cases). In 429 cases we did not find accurate data regarding disease duration (selegiline: 5 cases, rasagiline: 93 cases). Conclusion: The use of monoamine oxidase B inhibitors was similar to those found in literature. The treating physicians should utilise more confidently the available therapeutical combinations. Orv Hetil. 2017; 158(51): 2023–2028

Opposite prognostic roles of HIF1α and HIF2α expressions in bone metastatic clear cell renal cell cancer

BACKGROUND Prognostic markers of bone metastatic clear cell renal cell cancer (ccRCC) are poorly established. We tested prognostic value of HIF1α/HIF2α and their selected target genes in primary tumors and corresponding bone metastases. RESULTS Expression of HIF2α was lower in mRCC both at mRNA and protein levels (p/mRNA/=0.011, p/protein/=0.001) while HIF1α was similar to nmRCC. At the protein level, CAIX, GAPDH and GLUT1 were increased in mRCC. In all primary RCCs, low HIF2α and high HIF1α as well as CAIX, GAPDH and GLUT1 expressions correlated with adverse prognosis, while VEGFR2 and EPOR gene expressions were associated with favorable prognosis. Multivariate analysis confirmed high HIF2α protein expression as an independent risk factor. Prognostic validation of HIFs, LDH, EPOR and VEGFR2 in RNA-Seq data confirmed higher HIF1α gene expression in primary RCC as an adverse (p=0.07), whereas higher HIF2α and VEGFR2 expressions as favorable prognostic factors. HIF1α/HIF2α-index (HIF-index) proved to be an independent prognostic factor in both the discovery and the TCGA cohort. PATIENTS AND METHODS Expressions of HIF1α and HIF2α as well as their 7 target genes were analysed on the mRNA and protein level in 59 non-metastatic ccRCCs (nmRCC), 40 bone metastatic primary ccRCCs (mRCC) and 55 corresponding bone metastases. Results were validated in 399 ccRCCs from the TCGA project. CONCLUSIONS We identified HIF2α protein as an independent marker of the metastatic potential of ccRCC, however, unlike HIF1α, increased HIF2α expression is a favorable prognostic factor. The HIF-index incorporated these two markers into a strong prognostic biomarker of ccRCC