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BACKGROUND Variable chemotherapy exposure may cause toxicity or lack of efficacy. This study was initiated to validate pharmacokinetically (PK)-guided paclitaxel dosing in patients with advanced non-small-cell lung cancer (NSCLC) to avoid supra- or subtherapeutic exposure. PATIENTS AND METHODS Patients with newly diagnosed, advanced NSCLC were randomly assigned to receive up to 6 cycles of 3-weekly carboplatin AUC 6 or cisplatin 80 mg/m(2) either with standard paclitaxel at 200 mg/m(2) (arm A) or PK-guided dosing of paclitaxel (arm B). In arm B, initial paclitaxel dose was adjusted to body surface area, age, sex, and subsequent doses were guided by neutropenia and previous-cycle paclitaxel exposure [time above a plasma concentration of 0.05 µM (Tc>0.05)] determined from a single blood sample on day 2. The primary end point was grade 4 neutropenia; secondary end points included neuropathy, radiological response, progression-free survival (PFS) and overall survival (OS). RESULTS Among 365 patients randomly assigned, grade 4 neutropenia was similar in both arms (19% versus 16%; P = 0.10). Neuropathy grade ≥2 (38% versus 23%, P < 0.001) and grade ≥3 (9% versus 2%, P < 0.001) was significantly lower in arm B, independent of the platinum drug used. The median final paclitaxel dose was significantly lower in arm B (199 versus 150 mg/m(2), P < 0.001). Response rate was similar in arms A and B (31% versus 27%, P = 0.405), as was adjusted median PFS [5.5 versus 4.9 months, hazard ratio (HR) 1.16, 95% confidence interval (CI) 0.91-1.49, P = 0.228] and OS (10.1 versus 9.5 months, HR 1.05, 95% CI 0.81-1.37, P = 0.682). CONCLUSION PK-guided dosing of paclitaxel does not improve severe neutropenia, but reduces paclitaxel-associated neuropathy and thereby improves the benefit-risk profile in patients with advanced NSCLC. CLINICAL TRIAL INFORMATION NCT01326767 (https://clinicaltrials.gov/ct2/show/NCT01326767).

Background Genomic aberrations affecting the repair of DNA double-strand breaks by homologous recombination (HR) are found in various cancers and result in sensitivity to inhibitors of the DNA repair enzyme poly (ADP-ribose) polymerase (PARP). DNA double-strand breaks and activation of PARP can be induced by trabectedin, a cytotoxic agent used in soft-tissue sarcoma. In HR-deficient cancers that depend on PARP activity, trabectedin may thus increase the effect of PARP inhibitors such as olaparib. Next-generation sequencing techniques allow rapid identification of mutations in DNA repair pathways and mutational signatures that are generated by these aberrations. Trial design We present a randomized phase II trial comparing a combination of trabectedin and olaparib with treatment of physician’s choice in adult patients with advanced or metastatic tumors with genomic imprints of defective HR DNA repair (“BRCAness”), as determined by whole-exome or genome sequencing. A dedicated BRCAness score incorporates germline and somatic mutations in HR-relevant genes, mutational signatures, and measures of genomic instability; scores equal or above 3 allow for inclusion. Main exclusion criteria are hematologic and primary brain cancers, progressive/symptomatic brain metastases, ECOG PS > 1, severe organ insufficiencies, and prior treatment with a PARP inhibitor. Patients are randomized 1:1 to treatment with trabectedin (day 1) and olaparib (days 1-21) in a 21-day cycle vs. physician’s choice, both until disease progression. Cross-over upon disease progression is allowed. The primary endpoint is disease control (including CR, PR and SD according to RECIST v1.1) after 16 weeks. Secondary endpoints are tumor response, PFS, OS and quality of life. Efficacy evaluation involves a 2-group comparison between treatment arms in 102 patients. The statistical test used is a one-sided test of differences in disease control rates (alpha = 0.025). An interim analysis for futility will be conducted after 30% of patients are evaluable for the primary endpoint. The trial is active within the German Cancer Consortium, and thus far nine patients have been randomized. Clinical trial identification EudraCT: 2017-001755-31; NCT03127215. Legal entity responsible for the study Heidelberg University Hospital, Heidelberg, Germany. Funding AstraZeneca, ParmaMar and German Cancer Research Center (DKFZ). Disclosure C.E. Heilig: Honoraria (self), Travel / Accommodation / Expenses: PharmaMar; Travel / Accommodation / Expenses: Teva; Honoraria (institution), Travel / Accommodation / Expenses: Lilly; Travel / Accommodation / Expenses: Celgene; Travel / Accommodation / Expenses: Novartis. H. Kopp: Advisory / Consultancy: BMS; Advisory / Consultancy, Travel / Accommodation / Expenses: Merck-MSD; Advisory / Consultancy: Sanofi; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Novartis; Travel / Accommodation / Expenses: Boehringer-Ingelheim. K.H. Metzeler: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Celgene; Advisory / Consultancy: Novartis; Advisory / Consultancy: Jazz; Research grant / Funding (institution): Agios. S. Richter: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: PharmaMar; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (self), Travel / Accommodation / Expenses: Lilly. B. Hermes: Travel / Accommodation / Expenses: PharmaMar; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Lilly. N. von Bubnoff: Honoraria (self): AstraZeneca; Honoraria (self): Amgen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Novartis; Honoraria (self): BMS. T. Kindler: Advisory / Consultancy: Novartis; Travel / Accommodation / Expenses: PharmaMar. J. Siveke: Advisory / Consultancy: Baxalta; Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Celgene; Advisory / Consultancy, Travel / Accommodation / Expenses: Shire; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Research grant / Funding (self), Travel / Accommodation / Expenses: BMS. S. Wagner: Advisory / Consultancy: Takeda. S. Ochsenreither: Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy: Ipsen; Honoraria (self), Advisory / Consultancy: BMS; Advisory / Consultancy: AstraZeneca. B. Brors: Research grant / Funding (institution): SAP. D. Jager: Advisory / Consultancy: Amgen; Advisory / Consultancy: Bayer; Advisory / Consultancy: CureVac; Advisory / Consultancy: Definiens; Advisory / Consultancy: Roche; Advisory / Consultancy: BMS. C. Von Kalle: Advisory / Consultancy: Roche; Advisory / Consultancy: Genentech; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pfizer; Shareholder / Stockholder / Stock options: Genewerk. H. Glimm: Honoraria (self), Research grant / Funding (self): Bayer. S. Frohling: Honoraria (self), Travel / Accommodation / Expenses: Amgen; Honoraria (self), Travel / Accommodation / Expenses: PharmaMar; Honoraria (self), Travel / Accommodation / Expenses: Lilly; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: Bayer. R.F. Schlenk: Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony: Novartis; Research grant / Funding (institution): Pfizer; Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Daiichi Synkyo. All other authors have declared no conflicts of interest.

Background There is a need for novel therapies in metastatic STS, rendering checkpoint inhibitors (CPI) of interest in STS. Immune cell infiltrates are thought as a prerequisite for CPI efficacy and its role remains vague in STS. We analyzed whether the immune profile differed for STS treated within the phase II EPAZ study (NCT01861951). Methods RNA samples were measured using the PanCancer Immune Profiling Panel from the nCounter® Analysis System. FCF1, HDAC3, ZKSCAN5, MRPS5 and EIF2B4 were used as housekeeping genes. Samples were categorized in three groups based on their overall mRNA expression via unsupervised random forest analysis. Differences in gene expression were tested by T-tests or ANOVA, with correction for multiple testing. Ingenuity Pathway Analysis (IPA) were performed for activity prediction. K-M plots were used for survival estimates and log-rank analyses for comparisons. Results Specimens were available in 70/120 patients and 31 were assessable by immune profiling. 12 pts. received doxorubicin (DOX) and 18 pazopanib (PAZ). Median progression free survival (PFS) and median overall survival (OS) for the total cohort were 2.6 mo. and 11.6 mo., respectively. Patients were clustered in high (n = 4)/mixed (n = 20)/low (n = 7) mRNA profile expressions. While OS varied numerically between clusters (11.1/9.0/28.9 mo.), values were not significant (P = 0.5573). A similar pattern was detected for PFS (4.2/1.5/8.9 mo.; P = 0.4127). Conclusions Our study indicates that STS express a differential mRNA immune profile. However, clusters were not associated with outcome measures. A major limitation is the small sample size. Clinical trial identification NCT01861951. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure V. Grunwald: Honoraria (self), Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self): PharmaMar. M. Schuler: Research grant / Funding (institution): Novartis. P. Schoeffski: Honoraria (institution), Advisory / Consultancy: Daiichi; Honoraria (institution), Advisory / Consultancy: Eisai; Honoraria (institution), Advisory / Consultancy: Lilly; Honoraria (institution), Advisory / Consultancy: Medpace; Honoraria (institution), Travel / Accommodation / Expenses: Novartis; Honoraria (institution): Biovitrium; Honoraria (institution): 6th element capital; Advisory / Consultancy, Travel / Accommodation / Expenses: Adaptimmune; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bayer; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Blueprint; Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Advisory / Consultancy, Travel / Accommodation / Expenses: BoBoehringer Ingelheim; Advisory / Consultancy, Travel / Accommodation / Expenses: Cristal Therapeutics; Advisory / Consultancy, Travel / Accommodation / Expenses: Epizyme; Advisory / Consultancy, Travel / Accommodation / Expenses: Genzyme; Advisory / Consultancy, Travel / Accommodation / Expenses: Ipsen; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Loxo Oncology; Advisory / Consultancy, Travel / Accommodation / Expenses: Nektar; Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis. H. Kopp: Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Advisory / Consultancy, Travel / Accommodation / Expenses: Sanofi; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Novartis; Speaker Bureau / Expert testimony: LeoPharma; Speaker Bureau / Expert testimony: Pfizer; Travel / Accommodation / Expenses: Lilly; Travel / Accommodation / Expenses: Amgen. B. Kasper: Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: Novartis; Advisory / Consultancy: Eisai ; Honoraria (self), Research grant / Funding (institution): PharmaMar. L. Lindner: Advisory / Consultancy: Novartis; Honoraria (self): Lilly; Honoraria (self): Eisai; Honoraria (self): EZ Medconsultant; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: PharmaMar; Research grant / Funding (institution): Sennewald. J.M. Chemnitz: Honoraria (self): Ablynx; Advisory / Consultancy: Amgen; Advisory / Consultancy: Ablynx; Travel / Accommodation / Expenses: Amgen; Travel / Accommodation / Expenses: PharmaMar. G. Egerer: Honoraria (self): MSD; Advisory / Consultancy: MSD; Honoraria (self): PharmaMar; Travel / Accommodation / Expenses: MSD; Travel / Accommodation / Expenses: Astellas. All other authors have declared no conflicts of interest.

Background. Paratesticular liposarcomas are almost always mistakenly diagnosed as inguinal hernias subsequently followed by inadequate operation.Methods. 14 consecutive patients with paratesticular liposarcoma were retrospectively reviewed. Preoperative management was evaluated. Disease-free and overall survival were determined.Results. In 11 patients primary and in 3 patients recurrent liposarcoma of the spermatic cord were diagnosed. Regarding primary treatment in primary surgical intervention resection was radical (R0) in 7 of 14 (50%) patients, marginal (R1) in 6 (43%) patients, and incomplete with macroscopic residual tumour (R2) in 1 (7%) patient. Primary treatment secondary surgical intervention was performed in 4 patients: resection was radical (R0) in 3 (75%) patients and marginal (R1) in 1 (25%) patient. Regarding secondary treatment in recurrent disease resection was marginal (R1) in 3 patients (100%). Final histologic margins were negative in 10 patients with primary disease (71%) and positive in 4 patients with subsequent recurrent disease. After radical resection disease-free survival rates at 3 years were 100%. Overall survival at 4.5 years (54 (18–180) months) was 64%.Conclusion. An incomplete first surgical step increases the number of positive margins leading to local recurrences and adverse prognoses. Aggressive surgery should be attempted to attain 3-dimensional negative margins.

Megakaryocytes and platelets have been known to secrete angiogenic growth factors for a long time. However, there is little in vivo data on the regulation of angiogenesis by thrombopoietic cells. Both megakaryocytes and platelets are known to carry and release a multitude of both pro- and antiangiogenic mediators. Thus, it remained unknown how the “angiogenic phenotype” of thrombopoietic cells would be determined. Our group established that platelets contribute to angiogenesis as carriers of SDF-1, which is released by platelets in response to stimulation with hematopoietic cytokines. Indeed, even the action of VEGF-A seems to be mediated in part by the release of SDF-1 from stimulated platelets, thereby attracting proangiogenic hematopoietic cells. Moreover, the analysis of murine plasma and serum showed that similar to VEGF-A, SDF-1 is almost exclusively derived from platelets, and only trace amounts are detectable in platelet poor plasma. Because tumor patients' platelets have been shown to contain lower amounts of thrombospondin (Tsp), we generated Tsp-1 and Tsp-2 double knockout mice by crossing the single knockout lines. Interestingly, megakaryocytes and platelets derived from these mice confer a proangiogenic phenotype both in the bone marrow and in reperfusion of ischemic hindlimbs, thereby verifying the hypothesis of pro- and antiangiogenic platelet constituents “in balance.”

1. The effects of isosorbiddinitrate (ISDN) were tested on membrane currents and resting potential in Xenopus laevis oocytes which were either uninjected or injected with cRNA encoding for K+ channels from three distinct families (slowly activating I-sK channels, delayed- rectifying Kv1.1 or inwardly rectifying IRK1 K+ channels). 2. In uninjected oocytes ISDN (1 mM) resulted in a decrease of the holding current at potentials more positive than -100 mV and in an increase at potentials below -100 mV. Increasing extracellular K+ to 100 mM shifted the reversal potential for ISDN-mediated effects to approximately -12 mV, suggesting an inhibition of a K+ conductance by ISDN. 3. In current clamp studies ISDN (1 mM) and Ba2+ (3 mM) depolarized cell membrane. ISDN and Ba2+ had no additive effects on membrane potential when applied simultaneously. In voltage clamp studies, corresponding results were observed for the effects of ISDN and Ba2+ on the holding current with an apparent K-m of 0.21 and 0.08 mM, respectively. 4. In contrast to ISDN, the nitric oxide (NO) donors isosorbidmononitrate (ISMN) and S- nitrosocysteine (SNOC) had no effects on the holding currents in Xenopus oocytes. Moreover, the guanylate inhibitor LY 83583 did not affect ISDN-mediated holding current alterations, suggesting that ISDN acts independently of the second messenger NO. 5. ISDN inhibited exogenously expressed I-sK channels with an apparent K-m of 0.15 mM, but at 1 mM only weakly inhibited Kv1.1 and IRK1 channels. 6. It is concluded that ISDN inhibits an endogenous K+ conductance in Xenopus oocytes with a similar potency to that shown by expressed I-sK channels. These effects are independent of the second messenger NO.

Corrigendum: Cytokine-mediated deployment of SDF-1 induces revascularization through recruitment of CXCR4 + hemangiocytes

Permanent changes in the endocrine status of female SJL/J and CR mice were induced by masculinization, ablation of endocrine glands, inoculation of hormones, or feeding of the chemical carcinogen DMBA. All these procedures resulted in modification of the host hormonal milieu, as shown by blood hormone determination. Masculinization reduced drastically the onset of lymphosarcoma and increased the incidence of systemic neoplasms respectively in DMBA-treated female SJL/J and CR mice. Continued administration of gonadotrophins increased the incidence of systemic neoplasia in CR mice. A direct correlation is suggested between onset of lymphosarcoma or other tumours in mice and a specific shift to an abnormal hormonal environment.