Management of germ cell tumors in children: Approaches to cure

The introduction of cisplatinum chemotherapy and current advances in the surgical treatment have resulted in a dramatic improvement of the prognosis of children with malignant germ cell tumors (GCT). Cisplatinum chemotherapy generally results in sufficient systemic tumor control, but local relapses may still occur in patients who did not receive adequate local treatment. Therefore, the therapeutic consideration must take into account age, primary site of the tumor, and its histology. In gonadal tumors, there is a high chance of primary complete resection since these tumors tend to be encapsulated, and particularly testicular GCT are often detected at a low tumor stage. In contrast, a primary complete resection may be impossible in large nongonadal tumors such as sacrococcygeal or mediastinal GCT. In these tumors, a neoadjuvant or pre-operative chemotherapy after clinical diagnosis by imaging and evaluation of tumor markers significantly facilitates complete resection on delayed surgery. In addition, the impact of chemotherapy on local tumor control may be enhanced by locoregional hyperthermia. In most intracranial GCT complete resection is impossible and may be associated with significant morbidity. Nevertheless, biopsy is essential for diagnosis in nonsecreting tumors. In intracranial GCT, radiotherapy significantly contributes to local tumor control, and doses are stratified according to histology. These general considerations have been integrated into national and international cooperative treatment protocols. In most current protocols, treatment is stratified according to an initial risk assessment that includes the parameters age, site, histology, stage, completeness of resection and the tumor markers alpha(1)-fetoprotein (AFP) and human choriogonadotropin (beta-HCG). With such modern protocols overall cure rates above 80% can be achieved. Moreover, the previously high-risk groups may now expect a favorable prognosis with this risk-adapted treatment, whereas an increasing number of low-risk patients are treated expectantly or with significantly reduced chemotherapy. As current biologic studies reveal distinct genetic patterns in childhood GCT, it can be expected that further combined clinical and genetic studies will be valuable for risk assessment of childhood GCT

NIR-quantum dots in biomedical imaging and their future

Fluorescence imaging has gathered interest over the recent years for its real-time response and high sensitivity. Developing probes for this modality has proven to be a challenge. Quantum dots (QDs) are colloidal nanoparticles that possess unique optical and electronic properties due to quantum confinement effects, whose excellent optical properties make them ideal for fluorescence imaging of biological systems. By selectively controlling the synthetic methodologies it is possible to obtain QDs that emit in the first (650–950 nm) and second (1000–1400 nm) near infra-red (NIR) windows, allowing for superior imaging properties. Despite the excellent optical properties and biocompatibility shown by some NIR QDs, there are still some challenges to overcome to enable there use in clinical applications. In this review, we discuss the latest advances in the application of NIR QDs in preclinical settings, together with the synthetic approaches and material developments that make NIR QDs promising for future biomedical applications

Treatment and outcomes of UK and German patients with relapsed intracranial germ cell tumors following uniform first-line therapy

We aimed to retrospectively assess treatments/outcomes, including the value of high-dose-chemotherapy and autologous-stem-cell-rescue (HDC + AuSCR) and re-irradiation, in a large, European patient-cohort with relapsed intracranial germ-cell-tumors (GCTs) receiving uniform first-line therapy, including radiotherapy as standard-of-care. Fifty-eight UK/German patients (48 male/10 female) with relapsed intracranial-GCTs [13 germinoma/45 non-germinomatous GCT (NGGCT)] treated 1996-2010 as per the SIOP-CNS-GCT-96 protocol were evaluated. For germinoma, six patients relapsed with germinoma and five with NGGCT (one palliative, one teratoma patient excluded). Five-year overall-survival (OS) for the whole-group (n = 11) was 55%. Four of six germinoma relapses and two of five relapsing with NGGCT were salvaged; patients were salvaged with either standard-dose-chemotherapy (SDC) and re-irradiation or HDC + AuSCR with/without re-irradiation. Of 45 relapsed NGGCT patients, 13 were excluded (three non-protocol adherence, five teratoma, five palliation). Five-year OS for the remaining 32 relapsed malignant NGGCT patients treated with curative intent was 9% (95%CI: 2-26%). By treatment received, 5-year OS for the 10 patients receiving SDC and 22 patients treated with intention for HDC + AuSCR was 0% (0-0%) and 14% (3-36%), respectively. The three relapsed NGGCT survivors had raised HCG markers alone; two received additional irradiation. Patients with relapsed germinoma had better 5-year OS than those with relapsed NGGCT (55 vs. 9%; p = 0.007). Patients with relapsed germinoma were salvaged both with SDC and re-irradiation or HDC + AuSCR with/without re-irradiation; both represent valid treatment options. Outcomes for malignant relapse following initial diagnosis of NGGCT were exceptionally poor; the few survivors received thiotepa-based HDC + AuSCR, which is a treatment option at first malignant relapse for such patients, with further surgery/irradiation where feasible

SIOP CNS GCT 96: final report of outcome of a prospective, multinational nonrandomized trial for children and adults with intracranial germinoma, comparing craniospinal irradiation alone with chemotherapy followed by focal primary site irradiation for patients with localized disease.

We conducted a nonrandomized international study for intracranial germinoma that compared chemotherapy followed by local radiotherapy with reduced-dose craniospinal irradiation (CSI) alone, to determine whether the combined treatment regimen produced equivalent outcome and avoided irradiation beyond the primary tumor site(s). Patients with localized germinoma received either CSI or 2 courses of carboplatin and etoposide alternating with etoposide and ifosfamide, followed by local radiotherapy. Metastatic patients received CSI with focal boosts to primary tumor and metastatic sites, with the option to be preceded with chemotherapy. Patients with localized germinoma (n 190) received either CSI alone (n 125) or combined therapy (n 65), demonstrating no differences in 5-year event-free or overall survival, but a difference in progression-free survival (0.97 0.02 vs 0.88 0.04; P .04). Seven of 65 patients receiving combined treatment experienced relapse (6 with ventricular recurrence outside the primary radiotherapy field), and only 4 of 125 patients treated with CSI alone experienced relapse (all at the primary tumor site). Metastatic patients (n 45) had 0.98 0.023 event-free and overall survival. Localized germinoma can be treated with reduced dose CSI alone or with chemotherapy and reduced-field radiotherapy. The pattern of relapse suggests inclusion of ventricles in the radiation field. Reduced-dose craniospinal radiation alone is effective in metastatic disease

Prostacyclin reverses platelet stress fibre formation causing platelet aggregate instability

Prostacyclin (PGI2) modulates platelet activation to regulate haemostasis. Evidence has emerged to suggest that thrombi are dynamic structures with distinct areas of differing platelet activation. It was hypothesised that PGI2 could reverse platelet spreading by actin cytoskeletal modulation, leading to reduced capability of platelet aggregates to withstand a high shear environment. Our data demonstrates that post-flow of PGI2 over activated and spread platelets on fibrinogen, identified a significant reduction in platelet surface area under high shear. Exploration of the molecular mechanisms underpinning this effect revealed that PGI2 reversed stress fibre formation in adherent platelets, reduced platelet spreading, whilst simultaneously promoting actin nodule formation. The effects of PGI2 on stress fibres were mimicked by the adenylyl cyclase activator forskolin and prevented by inhibitors of protein kinase A (PKA). Stress fibre formation is a RhoA dependent process and we found that treatment of adherent platelets with PGI2 caused inhibitory phosphorylation of RhoA, reduced RhoA GTP-loading and reversal of myosin light chain phosphorylation. Phospho-RhoA was localised in actin nodules with PKA type II and a number of other phosphorylated PKA substrates. This study demonstrates that PGI2 can reverse key platelet functions after their initial activation and identifies a novel mechanism for controlling thrombosis

Management of malignant dysgerminoma of the ovary

The evolution of treatment for malignant ovarian germ cell tumors has been one of the most successful in the history of gynecologic oncology, with dysgerminoma as the most common type of malignant ovarian germ cell tumors. Since the introduction of platinum-based chemotherapy in the 1980s, 5-year survival rates for early-stage dysgerminomas have been close to 100%, and as high as 98% for advanced stages. Despite this remarkable achievement, many questions remain in routine treatment. By performing a literature review, we aim to highlight both the current treatment of malignant dysgerminoma and unanswered questions in the modern management of this disease. These issues relate firstly to surgical therapy, such as the role of routine omentectomy and lymphadenectomy, the value of complete surgical resection, and the possibility of fertility-sparing surgery. Second, chemotherapy and the question of the possibility of de-escalation in early stages and the potential of neoadjuvant chemotherapy in advanced stages will be addressed. Finally, a brief overview of the current developments of new drug treatment regimens will be given

Studies on the actin-binding protein HS1 in platelets

<p>Abstract</p> <p>Background</p> <p>The platelet cytoskeleton mediates the dramatic change in platelet morphology that takes place upon activation and stabilizes thrombus formation. The Arp2/3 complex plays a vital role in these processes, providing the protrusive force for lamellipodia formation. The Arp2/3 complex is highly regulated by a number of actin-binding proteins including the haematopoietic-specific protein HS1 and its homologue cortactin. The present study investigates the role of HS1 in platelets using HS1^-/-mice.</p> <p>Results</p> <p>The present results demonstrate that HS1 is not required for platelet activation, shape change or aggregation. Platelets from HS1^-/-mice spread normally on a variety of adhesion proteins and have normal F-actin and Arp2/3 complex distributions. Clot retraction, an actin-dependent process, is also normal in these mice. Platelet aggregation and secretion is indistinguishable between knock out and littermates and there is no increase in bleeding using the tail bleeding assay.</p> <p>Conclusion</p> <p>This study concludes that HS1 does not play a major role in platelet function. It is possible that a role for HS1 is masked by the presence of cortactin.</p

Imaging response assessment for CNS germ cell tumours: consensus recommendations from the European Society for Paediatric Oncology Brain Tumour Group and North American Children's Oncology Group

Homogeneous and common objective disease assessments and standardised response criteria are important for better international clinical trials for CNS germ cell tumours. Currently, European protocols differ from those of North America (the USA and Canada) in terms of criteria to assess radiological disease response. An international working group of the European Society for Paediatric Oncology Brain Tumour Group and North American Children's Oncology Group was therefore established to review existing literature and current practices, identify major challenges regarding imaging assessment, and develop consensus recommendations for imaging response assessment for patients with CNS germ cell tumours. New clinical imaging standards were defined for the most common sites of CNS germ cell tumour and for the definition of locoregional extension. These new standards will allow the evaluation of response to therapy in patients with CNS germ cell tumours to be more consistent, and facilitate direct comparison of treatment outcomes across international studies