Benefit of pazopanib in advanced gastrointestinal stromal tumours: results from a phase II trial (SSG XXI, PAGIST).

BACKGROUND: Patients with advanced gastrointestinal stromal tumours (GISTs) resistant to the tyrosine kinase inhibitors imatinib and sunitinib may be treated with regorafenib, which resulted in a median progression-free survival (PFS) of 4.8 months in the GRID trial. Also, pazopanib, another tyrosine kinase inhibitor, has been studied in a randomized, placebo-controlled trial (PAZOGIST) in the third line, which showed a PFS of 45.2% 4 months after study entry, but patients intolerant to sunitinib were also included. We designed another trial evaluating pazopanib, enrolling only patients with progression on both imatinib and sunitinib. PATIENTS AND METHODS: Since all eligible patients had progressive disease, we preferred a non-randomized, phase II multicentre trial so that all patients could receive a potentially active drug. Patients had a progressive metastatic or locally advanced GIST and were ≥18 years of age, with a performance status of 0-2, and sufficient organ functions. The primary endpoint was disease control rate (defined as complete remission + partial remission + stable disease) at 12 weeks on pazopanib. A Simon's two-stage analysis was used with an interim analysis 12 weeks after enrollment of the first 22 patients, and if passed, there was a full enrolment of 72 patients. GIST mutational analysis was done, and most patients had pazopanib plasma concentration measured after 12 weeks. RESULTS: Seventy-two patients were enrolled. The disease control rate after 12 weeks was 44%, and the median PFS was 19.6 weeks (95% confidence interval 12.6-23.4 weeks). Pazopanib-related toxicity was moderate and manageable. No statistically significant differences were found related to mutations. Plasma concentrations of pazopanib had a formal but weak correlation with outcome. CONCLUSION: Pazopanib given in the third line to patients with GIST progressing on both imatinib and sunitinib was beneficial for about half of the patients. The PAGIST trial confirms the results from the PAZOGIST trial, and the median PFS achieved seems comparable to the PFS achieved with regorafenib in the third-line setting.

Epithelioid hemangioendothelioma, an ultra-rare cancer: a consensus paper from the community of experts.

Epithelioid hemangioendothelioma (EHE) is an ultra-rare, translocated, vascular sarcoma. EHE clinical behavior is variable, ranging from that of a low-grade malignancy to that of a high-grade sarcoma and it is marked by a high propensity for systemic involvement. No active systemic agents are currently approved specifically for EHE, which is typically refractory to the antitumor drugs used in sarcomas. The degree of uncertainty in selecting the most appropriate therapy for EHE patients and the lack of guidelines on the clinical management of the disease make the adoption of new treatments inconsistent across the world, resulting in suboptimal outcomes for many EHE patients. To address the shortcoming, a global consensus meeting was organized in December 2020 under the umbrella of the European Society for Medical Oncology (ESMO) involving >80 experts from several disciplines from Europe, North America and Asia, together with a patient representative from the EHE Group, a global, disease-specific patient advocacy group, and Sarcoma Patient EuroNet (SPAEN). The meeting was aimed at defining, by consensus, evidence-based best practices for the optimal approach to primary and metastatic EHE. The consensus achieved during that meeting is the subject of the present publication.

Diagnosis and management of tropomyosin receptor kinase (TRK) fusion sarcomas: expert recommendations from the World Sarcoma Network.

Sarcomas are a heterogeneous group of malignancies with mesenchymal lineage differentiation. The discovery of neurotrophic tyrosine receptor kinase (NTRK) gene fusions as tissue-agnostic oncogenic drivers has led to new personalized therapies for a subset of patients with sarcoma in the form of tropomyosin receptor kinase (TRK) inhibitors. NTRK gene rearrangements and fusion transcripts can be detected with different molecular pathology techniques, while TRK protein expression can be demonstrated with immunohistochemistry. The rarity and diagnostic complexity of NTRK gene fusions raise a number of questions and challenges for clinicians. To address these challenges, the World Sarcoma Network convened two meetings of expert adult oncologists and pathologists and subsequently developed this article to provide practical guidance on the management of patients with sarcoma harboring NTRK gene fusions. We propose a diagnostic strategy that considers disease stage and histologic and molecular subtypes to facilitate routine testing for TRK expression and subsequent testing for NTRK gene fusions.

Rivaroxaban versus aspirin for secondary prevention of ischaemic stroke in patients with cancer: a subgroup analysis of the NAVIGATE ESUS randomized trial.

BACKGROUND AND PURPOSE: Cancer is a frequent finding in ischaemic stroke patients. The frequency of cancer amongst participants in the NAVIGATE ESUS randomized trial and the distribution of outcome events during treatment with aspirin and rivaroxaban were investigated. METHODS: Trial participation required a recent embolic stroke of undetermined source. Patients' history of cancer was recorded at the time of study entry. During a mean follow-up of 11 months, the effects of aspirin and rivaroxaban treatment on recurrent ischaemic stroke, major bleeding and all-cause mortality were compared between patients with cancer and patients without cancer. RESULTS: Amongst 7213 randomized patients, 543 (7.5%) had cancer. Of all patients, 3609 were randomized to rivaroxaban [254 (7.0%) with cancer] and 3604 patients to aspirin [289 (8.0%) with cancer]. The annual rate of recurrent ischaemic stroke was 4.5% in non-cancer patients in the rivaroxaban arm and 4.6% in the aspirin arm [hazard ratio (HR) 0.98, 95% confidence interval (CI) 0.78-1.24]. In cancer patients, the rate of recurrent ischaemic stroke was 7.7% in the rivaroxaban arm and 5.4% in the aspirin arm (HR 1.43, 95% CI 0.71-2.87). Amongst cancer patients, the annual rate of major bleeds was non-significantly higher for rivaroxaban than aspirin (2.9% vs. 1.1%; HR 2.57, 95% CI 0.67-9.96; P for interaction 0.95). All-cause mortality was similar in both groups. CONCLUSIONS: Our exploratory analyses show that patients with embolic stroke of undetermined source and a history of cancer had similar rates of recurrent ischaemic strokes and all-cause mortality during aspirin and rivaroxaban treatments and that aspirin appeared safer than rivaroxaban in cancer patients regarding major bleeds. www.clinicaltrials.gov (NCT02313909).

Photon iso-effective dose for cancer treatment with mixed field radiation based on dose-response assessment from human and an animal model: clinical application to boron neutron capture therapy for head and neck cancer.

Boron neutron capture therapy (BNCT) is a treatment modality that combines different radiation qualities. Since the severity of biological damage following irradiation depends on the radiation type, a quantity different from absorbed dose is required to explain the effects observed in the clinical BNCT in terms of outcome compared with conventional photon radiation therapy. A new approach for calculating photon iso-effective doses in BNCT was introduced previously. The present work extends this model to include information from dose-response assessments in animal models and humans. Parameters of the model were determined for tumour and precancerous tissue using dose-response curves obtained from BNCT and photon studies performed in the hamster cheek pouch in vivo models of oral cancer and/or pre-cancer, and from head and neck cancer radiotherapy data with photons. To this end, suitable expressions of the dose-limiting Normal Tissue Complication and Tumour Control Probabilities for the reference radiation and for the mixed field BNCT radiation were developed. Pearson's correlation coefficients and p-values showed that TCP and NTCP models agreed with experimental data (with r > 0.87 and p-values >0.57). The photon iso-effective dose model was applied retrospectively to evaluate the dosimetry in tumours and mucosa for head and neck cancer patients treated with BNCT in Finland. Photon iso-effective doses in tumour were lower than those obtained with the standard RBE-weighted model (between 10% to 45%). The results also suggested that the probabilities of tumour control derived from photon iso-effective doses are more adequate to explain the clinical responses than those obtained with the RBE-weighted values. The dosimetry in the mucosa revealed that the photon iso-effective doses were about 30% to 50% higher than the corresponding RBE-weighted values. While the RBE-weighted doses are unable to predict mucosa toxicity, predictions based on the proposed model are compatible with the observed clinical outcome. The extension of the photon iso-effective dose model has allowed, for the first time, the determination of the photon iso-effective dose for unacceptable complications in the dose-limiting normal tissue. Finally, the formalism developed in this work to compute photon-equivalent doses can be applied to other therapies that combine mixed radiation fields, such as hadron therapy.

Plasma levels of hepatocyte growth factor and placental growth factor predict mortality in a general population: a prospective cohort study.

BACKGROUND: Circulating levels of growth factors involved in leucocyte production and angiogenesis could be indicative of underlying aberrations of tissue homeostasis and therefore be utilized as predictors of risk for all-cause cardiovascular disease (CVD) or cancer mortality. METHODS: Baseline plasma levels of a range of growth factors were measured in two cohorts of the population-based FINRISK study (1997 Discovery cohort, N = 8444, aged 25-74; 2002 Replication cohort, N = 2951, aged 51-74 years) using a multiplexed bead array methodology and ELISA. Participants were followed up by linking them to registry data. RESULTS: In the Discovery cohort (653 deaths; 216 CVD-related, 231 cancer-related), fully adjusted Cox proportional hazard regression models showed that increased plasma hepatocyte growth factor (HGF) and placental growth factor (PlGF) were associated with higher risk of 10-year mortality (HR, 1.29 [95% confidence interval (CI), 1.18-1.41] and HR, 1.23 [95% CI, 1.14-1.32], respectively). In the Replication cohort (259 deaths; 83 CVD-related, 90 cancer-related), baseline HGF levels also predicted all-cause mortality (HR, 1.2 [95% CI, 1.08-1.32]; PlGF data not available). By including HGF levels in a CVD mortality model, 9% of all CVD deaths were correctly reclassified in the Discovery cohort (categorical net reclassification improvement [NRI] for events, P = 4.0 × 10-4 ). Moreover, adding HGF to all-cause and CVD mortality models resulted in an overall clinical NRI of 0.10-0.18 in the Discovery cohort and meta-analyses (P < 0.05 for all tests). CONCLUSION: Blood levels of HGF and PlGF may serve as new biomarkers for predicting increased risk of death in the general population.

Breast cancer prognosis and isolated tumor cell findings in axillary lymph nodes after core needle biopsy and fine needle aspiration cytology: Biopsy method and breast cancer outcome.

BACKGROUND: It is unknown whether performing a core needle biopsy (CNB) to diagnose breast cancer increases the incidence of isolated tumor cells (ITC) in the axillary sentinel lymph nodes. METHODS: Patients diagnosed with unilateral invasive pT1 breast cancer (≤2 cm in diameter, n = 1525) at a single center between February 2001 and August 2005 were included in this prospective observational cohort study. The patients were categorized into two groups according to the type of the preoperative breast needle biopsy performed, the CNB and the fine needle aspiration cytology (FNAC) groups, and followed up for a median of 9.5 years after breast surgery. RESULTS: 868 (56.9%) patients had FNAC and 657 (43.2%) CNB. In the subset of patients with no axillary metastases (pN0, n = 1005) 70 patients had ITC, 37 (4.3%) out of the 546 patients in FNAC group and 33 (5.0%) out of the 459 patients in the CNB group (p = 0.798). The type of tumor biopsy did not influence breast cancer-specific survival (p = 0.461) or local recurrence-free survival (p = 0.814) in univariable survival analyses. Overall, survival favored the CNB group in a univariable analysis, but no difference in survival emerged in a multivariable analysis (p = 0.718). CONCLUSIONS: CNB was not associated with a greater incidence of ITC in axillary lymph nodes as compared with FNAC, and did not have an adverse effect on survival outcomes in a patient population treated with modern adjuvant therapies.

Deregulated hepsin protease activity confers oncogenicity by concomitantly augmenting HGF/MET signalling and disrupting epithelial cohesion.

Hepsin belongs to a family of cell-surface serine proteases, which have sparked interest as therapeutic targets because of the accessibility of extracellular protease domain for inhibitors. Hepsin is frequently amplified and/or overexpressed in epithelial cancers, but it is not clear how enhanced hepsin expression confers a potential for oncogenicity. We show that hepsin is consistently overexpressed in more than 40% of examined breast cancers, including all major biological subtypes. The effects of doxycycline-induced hepsin overexpression were examined in mammary epithelial organoids, and we found that induced hepsin acutely downmodulates its cognate inhibitor, hepatocyte growth factor (HGF) activator inhibitor type 1 (HAI-1). Hepsin-induced depletion of cellular HAI-1 led to a sharp increase in pericellular serine protease activity. The derepressed hepsin proteolytically activated downstream serine proteases, augmented HGF/MET signalling and caused deterioration of desmosomes and hemidesmosomes; structures important for cell cohesion and cell-basement membrane interaction. Moreover, chronic induction of hepsin considerably shortened the latency of Myc-dependent tumourigenesis in the mouse mammary gland. The serine protease and uPA system inhibitor WX-UK1, identified as a micromolar range hepsin inhibitor, prevented hepsin from augmenting HGF/MET signalling and disrupting desmosomes and hemidesmosomes. The findings suggest that the oncogenic activity of hepsin arises not only from elevated expression level but also from depletion of HAI-1, events which together trigger gain-of-function activity impacting HGF/MET signalling and epithelial cohesion. Thus, hepsin overexpression is a major oncogenic conferrer to a serine protease activity involved in breast cancer dissemination.

Biokinetic analysis of tissue boron (¹°B) concentrations of glioma patients treated with BNCT in Finland.

A total of 98 patients with glioma were treated with BPA-F-mediated boron neutron capture therapy (BNCT) in Finland from 1999 to 2011. Thirty-nine (40%) had undergone surgery for newly diagnosed glioblastoma and 59 (60%) had malignant glioma recurrence after surgery. In this study we applied a closed 3-compartment model based on dynamic (18)F-BPA-PET studies to estimate the BPA-F concentrations in the tumor and the normal brain with time. Altogether 22 patients with recurrent glioma, treated within the context of a clinical trial, were evaluated using their individual measured whole blood (10)B concentrations as an input to the model. The delivered radiation doses to tumor and the normal brain were recalculated based on the modeled (10)B concentrations in the tissues during neutron irradiation. The model predicts from -7% to +29% (average, +11%) change in the average tumor doses as compared with the previously estimated doses, and from 17% to 61% (average, 36%) higher average normal brain doses than previously estimated due to the non-constant tumor-to-blood concentration ratios and considerably higher estimated (10)B concentrations in the brain at the time of neutron irradiation.