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Background: We assessed the efficacy and safety of tadalafil, a phosphodiesterase type 5 inhibitor, in patients with heart failure with preserved ejection fraction and combined postcapillary and precapillary pulmonary hypertension., Methods: In the double-blind PASSION study (Phosphodiesterase-5 Inhibition in Patients With Heart Failure With Preserved Ejection Fraction and Combined Post- and Pre-Capillary Pulmonary Hypertension), patients with heart failure with preserved ejection fraction and combined postcapillary and precapillary pulmonary hypertension were randomized 1:1 to receive tadalafil at a target dose of 40 mg or placebo. The primary end point was the time to the first composite event of adjudicated heart failure hospitalization or all-cause death. Secondary end points included all-cause mortality and improvements in New York Heart Association functional class or ≥10% improvement in 6-minute walking distance from baseline., Results: Initially targeting 372 patients, the study was terminated early because of disruption in study medication supply. At that point, 125 patients had been randomized (placebo: 63; tadalafil: 62,). Combined primary end-point events occurred in 20 patients (32%) assigned to placebo and 17 patients (27%) assigned to tadalafil (hazard ratio, 1.02 [95% CI, 0.52-2.01]; P =0.95). There was a possible signal of higher all-cause mortality in the tadalafil group (hazard ratio, 5.10 [95% CI, 1.10-23.69]; P =0.04). No significant between-group differences were observed in other secondary end points. Serious adverse events occurred in 29 participants (48%) in the tadalafil group and 35 (56%) in the placebo group., Conclusions: The PASSION trial, terminated prematurely due to study medication supply disruption, does not support tadalafil use in patients with heart failure with preserved ejection fraction and combined postcapillary and precapillary pulmonary hypertension, with potential safety concerns and no observed benefits in primary and secondary end points., Registration: URL: https://www.clinicaltrialsregister.eu/; Unique identifier: 2017-003688-37. URL: https://drks.de; Unique identifier: DRKS -DRKS00014595., Competing Interests: Dr Hoeper has received fees for lectures and/or consultations from Acceleron, Actelion, AOP Health, Bayer, Ferrer, GossamerBio, Janssen, Keros, and MSD. Max Wissmüller has received lecture fees from Janssen. Hanno Leuchte has received fees for consultations and/or lectures from Acceleron, Jansse-Cilag, Bayer, Boehringer-Ingelheim, Ferrer, MSD, and Pfizer. Michael Halank has received fees for lectures and/or consultations from AstraZeneca, Janssen-Cilag, and MSD. In addition, he has received support for attending meetings and/or travel from AOP Health and Janssen-Cilag. Hans-Jürgen Seyfarth has received fees for lectures and/or consultations from Janssen-Cilag and MSD. Stephan Baldus has received fees for lectures and/or consultations from Abbott, Edwards, Jenavalve, AstraZeneca, Bayer, Daiicho Sankyo, and Amgen, as well as research grants from Abbott, AstraZeneca, and Daiichi Sankyo. Johann Bauersachs has received fees for lectures and/or consultations from Amgen, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Cardior, Corvia, CVRx, Edwards, Norgine, Novartis, Pfizer, Roche and Vifor. In addition, institutional grants have been provided by Abiomed, CVRx, Norgine, Roche, and Zoll. He holds patents for microRNA and downstream targets for diagnostics and therapeutic purposes (PCT/EP2007/008772 and PCT/EP2009/051986). Michael Böhm is supported by the Deutsche Forschungsgemeinschaft (German Research Foundation; TTR 219, project No. 322900939) and reports personal fees from Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Medtronic, Novartis, ReCor, Servier and Vifor. Hossein-Ardeschir Ghofrani has received honoraria for consultations and/or speaking at conferences from Bayer HealthCare AG, Actelion, Encysive, Pfizer, Ergonex, Lilly, and Novartis. He is member of the Advisory Board for Acceleron, Bayer HealthCare AG, Pfizer, GSK, Actelion, Lilly, Merck, Encysive, and Ergonex. He has also received governmental grants from the German Research Foundation, Excellence Cluster Cardiopulmonary Research, State Government of Hessen, and the German Ministry for Education and Research. Stavros Konstantinides reports personal lecture/advisory fees and research grants to his institution from Bayer AG, Boston Scientific, Daiichi-Sankyo, LumiraDx, and Penumbra, as well as personal lecture/advisory fees from MSD and Pfizer–Bristol-Myers Squibb. Karen M. Olsson has received fees for lectures and/or consultations from Acceleron, Actelion, Bayer, Ferrer, GSK, Janssen, MSD, Pfizer, and United Therapeutics. Rolf Wachter has received fees for lectures and/or consultation from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Medtronic, Novartis, Pfizer, Pharmacosmo, Sciarc, Servier, and Vifor. His institution has received research grants from Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, European Union, and Medtronic. Carolyn S.P. Lam is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from NovoNordisk and Roche Diagnostics; has served as consultant or on the Advisory Board/ Steering Committee/ Executive Committee for Alleviant Medical, Allysta Pharma, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Biopeutics, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, CardioRenal, Cytokinetics, Darma Inc, EchoNous Inc, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research & Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc, Quidel Corp, Radcliffe Group Ltd, Recardio Inc, ReCor Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, and Us2.ai; and serves as cofounder and non–executive director of Us2.ai. Stephan Rosenkranz has received fees for lectures and/or consultations from Abbott, Acceleron, Actelion, Aerovate, AOP, AstraZeneca, Bayer, Boehringer-Ingelheim, Edwards, Ferrer, Gossamer, Janssen, MSD, and United Therapeutics. His institution has received research grants from Actelion, AstraZeneca, Bayer, Janssen, and Lempo. The other authors report no conflicts.

With more novel drugs being approved for the treatment of ovarian carcinoma, the question remains to what extent patients benefit from antiangiogenic treatment with bevacizumab, either in combination with poly-(ADP-ribose) polymerase inhibitors or as single-agent maintenance. As fibroblast growth factor receptors and their ligands (FGFRs/FGFs) are key players in angiogenic signaling and have been linked to resistance to several drugs, we investigated the prognostic or predictive potential of FGFs/FGFRs signaling in the context of bevacizumab treatment within the prospective phase III AGO-OVAR11/ICON-7 study. FGFR1, FGFR2, FGFR3, FGFR4, FGF1, and FGF19 gene expressions were determined in 380 ovarian carcinoma tumor samples collected from German centers in the multicenter phase III AGO-OVAR11 trial/ICON-7 trial. All patients received carboplatin and paclitaxel, administered every 3 weeks for 6 cycles, and were randomized to bevacizumab. Expressions of FGFR1, FGFR2, FGF1, and FGF19 were associated with progression-free survival in both uni- and multivariate (FGFR1: HR, 1.6, P < .001; FGFR2: HR, 1.6, P = .002; FGF1: HR, 2.3, P < .001; and FGF19: HR, 0.7; P = .007) analysis. A signature built by FGFR1, FGFR4, and FGF19 defined a subgroup (n = 62) of patients that derived the greatest bevacizumab-associated improvement of progression-free survival (HR, 0.3; P = .004). In this exploratory analysis of a prospective randomized phase III trial, we provide evidence that the expression of FGFRs/FGFs might have independent prognostic values. An FGFR/FGF-based gene signature identified in our study appears to predict long-term benefit from bevacizumab. This observation is hypothesis-generating and requires validation on independent cohorts., (Copyright © 2024. Published by Elsevier Inc.)

Purpose: Although thrombocytosis in patients with primary ovarian cancer has been widely investigated, there are only very few data about the role of thrombocytosis in recurrent ovarian cancer. The aim of our study was to investigate the impact of pretreatment thrombocytosis prior to chemotherapy on clinical outcome in patients with recurrent platinum eligible ovarian cancer., Methods: In our retrospective analysis we included 300 patients who were treated by AGO Study Group Centers within three prospective, randomized phase-III-trials. All patients included had been treatment-free for at least 6 months after platinum-based chemotherapy. We excluded patients who underwent secondary cytoreductive surgery before randomization to the trial. Thrombocytosis was defined as a platelet count of ≥ 400⋅10 9 /L., Results: Pretreatment thrombocytosis was present in 37 out of 300 (12.3%) patients. Patients with thrombocytosis responded statistically significantly less to chemotherapy (overall response rate 35.3% and 41.6%, P = 0.046). The median progression-free survival (PFS) for patients with thrombocytosis was 6.36 months compared to 9.00 months for patients without thrombocytosis (hazard ratio [HR] = 1.19, 95% confidence interval [CI] = 0.84-1.69, P = 0.336). Median overall survival (OS) of patients with thrombocytosis was 16.33 months compared to 23.92 months of patients with a normal platelet count (HR = 1.46, 95% CI = 1.00-2.14, P = 0.047)., Conclusions: The present analysis suggests that pretreatment thrombocytosis is associated with unfavorable outcome with regard to response to chemotherapy and overall survival in recurrent ovarian cancer.

Background: Previous data suggest that the incidence of hypoparathyroidism after surgery for Graves disease (GD) is lower after subtotal thyroidectomy compared to total thyroidectomy (TT). The present study evaluated the incidence of postoperative hypoparathyroidism after near-total (NTT) versus TT in GD., Methods/design: In a multicenter prospective randomized controlled clinical trial, patients with GD were randomized intraoperatively to NTT or TT. Primary endpoint was the incidence of transient postoperative hypoparathyroidism. Secondary endpoints were permanent hypoparathyroidism, transient recurrent laryngeal nerve palsy (RLNP), reoperations for bleeding, inadvertently removed parathyroid glands, and recurrent hyperthyroidism after 12 months., Results: Eighteen centers randomized 205 patients to either TT (n = 102) or NTT (n = 103) within 16 months. According to intention-to-treat postoperative transient hypoparathyroidism occurred in 19% (20/103) patients after NTT and in 21% (21 of 102) patients after TT (P = 0.84), which persisted >6 months in 2% and 5% of the NTT and TT groups (P = 0.34). The rates of parathyroid autotransplantation (NTT 24% vs TT 28%, P = 0.50) and transient RLNP (NTT 3% vs TT 4%, P = 0.35) was similar in both groups. The rate of reoperations for bleeding tended to be higher in the NTT group (3% vs 0%, P = 0.07) and the rate of inadvertently removed parathyroid glands was significantly higher after NTT (13% vs 3%, P = 0.01). An existing endocrine orbitopathy improved in 35% and 24% after NTT and TT (P = 0.61). Recurrent disease occurred in only 1 patient after TT (P = 0.34)., Conclusion: NTT for GD is not superior to TT regarding transient postoperative hypoparathyroidism.

Background: Superficial wound infections after gastrointestinal surgery markedly impair the affected patients' quality of life. As it is still unknown which method of skin closure is best for the reduction of wound infections in elective gastrointestinal sur- gery, we compared the frequency of wound infections after intracutaneous suturing versus skin stapling., Methods: In a prospective, randomized, single-center study, patients undergoing elective gastrointestinal surgery were intraoperatively randomized to skin closure either with an intracutaneous suture or with staples. The primary endpoint-the occurrence of a grade A1 wound infection within 30 days of surgery-was evaluated according to the intention-to-treat principle., Results: Out of a total of 280 patients, 141 were randomized to intracutaneous suturing and 139 to stapling. The groups did not differ significantly with respect to age, sex, or ASA classification. 19 of the 141 patients in the intracutaneous suturing group (13.5%) had a grade A1 wound infection, compared with 23 of 139 in the stapling group (16.6%) (odds ratio [OR]: 0.79; 95% confidence interval: [0.41; 1.52]; p = 0.47). A multiple regression analysis revealed that the type of surgery (colorectal vs. other), the approach, and the incision length were independent risk factors for a grade A1 wound infection. When wound dehiscences were additionally considered, wound complications were found to have arisen significantly more often in the stapling group than in the intracutaneous suturing group (16.3% [23/141] versus 30.2% [42/139], OR: 0.45 [0.25; 0.80]; p = 0.006)., Conclusion: In elective gastrointestinal surgery, intracutaneous suturing was not found to be associated with a lower rate of superficial wound infections than skin stapling, but fewer wound dehiscences occurred in the intracutaneous suturing group.

Background: Somatostatin analogs have been shown to control the growth of well-differentiated metastatic neuroendocrine tumors. Their effect on overall survival is a matter of debate. We analyzed the prognostic significance of early treatment with octreotide LAR and of hepatic tumor load in the PROMID trial cohort., Patients and Methods: Between 2001 and 2008, 85 treatment-naïve patients were randomly assigned to monthly octreotide LAR 30 mg or placebo until tumor progression or death. Post-study treatment was at the discretion of the investigator. Upon disease progression, 38 out of 43 placebo patients (88.4%) received octreotide LAR. For survival, patients were followed until May 2014., Results: Forty-eight out of 85 patients (56.5%) died. In 38 patients (79.2%), death was tumor related. The median overall survival (84.7 and 83.7 months) was only slightly different in patients assigned to octreotide and placebo [HR = 0.83 (95% CI: 0.47-1.46); p = 0.51]. The median overall survival was 84.7 months for all 85 patients, 107.6 months in the low-tumor-load (n = 64) and 57.5 months in the high-tumor-load (n = 21) subgroups [HR = 2.49 (95% CI: 1.36-4.55); p = 0.002]. There was a trend towards improved overall survival in patients with a low hepatic tumor load receiving octreotide compared to placebo ['median not reached' and 87.2 months; HR = 0.59 (95% CI: 0.29-1.2); p = 0.142]., Conclusion: The extent of tumor burden is a predictor for shorter survival. Overall survival was similar in patients receiving octreotide LAR or placebo treatment at randomization. Crossover of the majority of placebo patients to octreotide LAR may have confounded the data on overall survival., (© 2016 S. Karger AG, Basel.)

Aim: Despite promising preclinical findings regarding clinical utility of farnesyltransferase inhibitors (FTI), such as lonafarnib, success of clinical trials is limited. A multicentre AGO-OVAR-15 phase II trial reported an unfavourable effect of lonafarnib on the outcome of patients with advanced ovarian cancer. This study was performed as a genetic subgroup analysis of the AGO-OVAR-15 trial, and investigated the utility of the promoter polymorphism rs11623866 of the farnesyltransferase ß-subunit gene (FNTB) in predicting the clinical effectiveness of lonafarnib., Methods: The influence of rs11623866 (c.-609G > C) on FNTB promoter activity was investigated by electrophoretic-mobility-shift assay, luciferase-reporter assay and RT-qPCR. A total of 57 out of 105 patients from the AGO-OVAR-15 trial, treated with carboplatin and paclitaxel ± lonafarnib, was genotyped for rs11623866 by restriction fragment length polymorphism analysis. Genotype-dependent survival analysis was performed by Kaplan-Meier analysis., Results: The presence of the G allele was associated with increased FNTB promoter activity compared with the C allele. An unfavourable effect of lonafarnib was limited to patients carrying a GG genotype (HRPFS 6.2, 95%CI = 2.01, 19.41, P = 0.002; HROS 9.6, 95%CI = 1.89, 48.54, P = 0.006). Median progression free survival (PFS) for patients with the GG genotype in the lonafarnib treated arm was 10 months, whereas median PFS without FTI-treatment was 40 months. Median overall survival (OS) in the lonafarnib-treated group was 19 months, whereas median OS was not reached in the untreated group., Conclusions: Discrepancies between preclinical success and clinical failure may be due to the patients' genetic variability of FNTB. Therefore, our results may encourage retrospective evaluation of FNTB polymorphisms in previous FTI studies, especially those reporting positive FTI response., (© 2015 The British Pharmacological Society.)

Purpose: Somatostatin analogs are indicated for symptom control in patients with gastroenteropancreatic neuroendocrine tumors (NETs). The ability of somatostatin analogs to control the growth of well-differentiated metastatic NETs is a matter of debate. We performed a placebo-controlled, double-blind, phase IIIB study in patients with well-differentiated metastatic midgut NETs. The hypothesis was that octreotide LAR prolongs time to tumor progression and survival., Patients and Methods: Treatment-naive patients were randomly assigned to either placebo or octreotide LAR 30 mg intramuscularly in monthly intervals until tumor progression or death. The primary efficacy end point was time to tumor progression. Secondary end points were survival time and tumor response. This report is based on 67 tumor progressions and 16 observed deaths in 85 patients at the time of the planned interim analysis., Results: Median time to tumor progression in the octreotide LAR and placebo groups was 14.3 and 6 months, respectively (hazard ratio [HR] = 0.34; 95% CI, 0.20 to 0.59; P = .000072). After 6 months of treatment, stable disease was observed in 66.7% of patients in the octreotide LAR group and 37.2% of patients in the placebo group. Functionally active and inactive tumors responded similarly. The most favorable effect was observed in patients with low hepatic tumor load and resected primary tumor. Seven and nine deaths were observed in the octreotide LAR and placebo groups, respectively. The HR for overall survival was 0.81 (95% CI, 0.30 to 2.18)., Conclusion: Octreotide LAR significantly lengthens time to tumor progression compared with placebo in patients with functionally active and inactive metastatic midgut NETs. Because of the low number of observed deaths, survival analysis was not confirmatory.

Purpose: Venous thromboembolism (VTE) has been associated with negative prognosis in cancer patients. Most series reporting on VTE have included different tumor types not differentiating between recurrent or primary disease. Data regarding the actual impact of VTE on primary advanced ovarian cancer (AOC) are limited., Patients and Methods: Between 1995 and 2002, the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study group (AGO-OVAR) recruited 2,743 patients with AOC in three prospectively randomized trials on platinum paclitaxel-based chemotherapy after primary surgery. Pooled data analysis was performed to evaluate incidence, predictors, and prognostic impact of VTE in AOC. Survival curves were calculated for the VTE incidence. Univariate analysis and Cox regression analysis were performed to identify independent predictors of VTE and mortality., Results: Seventy-six VTE episodes were identified, which occurred during six to 11 cycles of adjuvant chemotherapy; 50% of them occurred within 2 months postoperatively. Multivariate analysis identified body mass index higher than 30 kg/m(2) and increasing age as independent predictors of VTE. International Federation of Gynecology and Obstetrics stage and surgical radicality did not affect incidence. Overall survival was significantly reduced in patients with VTE (median, 29.8 v 36.2 months; P = .03). Multivariate analysis identified pulmonary embolism (PE), but not deep vein thrombosis alone, to be of prognostic significance. In addition, VTE was not identified to significantly affect progression-free survival., Conclusion: Patients with AOC have their highest VTE risk within the first 2 months after radical surgery. Only VTE complicated by symptomatic PE have been identified to have a negative impact on survival. Studies evaluating the role of prophylactic anticoagulation during this high risk postoperative period are warranted.