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Background Histone mutant gliomas (HMG) with histone H3 K27 and G34 mutations are recognized as biologically discrete entities with distinct anatomical locations, younger age at presentation (in comparison to the most common high-grade gliomas, IDH wildtype glioblastoma), and poor prognosis. There is a paucity of data regarding the management of adult HMG patients and no consensus on management. This study aims to identify current patterns of Australian and US neuro-oncology clinical practice for this entity. Methods Following institutional approvals, patterns of care questionnaire designed to capture relevant clinical variables was circulated through the Cooperative Trials Group for Neuro-Oncology (COGNO) in Australia and the Caris Precision Oncology Alliance in the United States (US). Results Between 4/2021 and 10/2021, 43 responses were collected. 33% (n = 14) of responders tested all patients for HMGs routinely; 40.92% (n = 18) tested in select patients 26% (n = 11) did not test for HMGs. The common indications for testing selected patients were midline anatomic location (n = 18) and age (n = 11) (<50 years). 23 used molecular sequencing, 22 used IHC at their centers. Nine participants stated knowledge of histone H3 mutations did not affect their management of these gliomas, 11 said it affected their management at the time of recurrence, 23 stated it affected the management of midline K27M patients, 11 participants stated it affected the management of K27M mutant gliomas in other locations, and 3 felt it affected the management of G34R/V mutant gliomas. Conclusion Here we present a description of how the discovery of a new molecular subtype of primary glial tumors, histone mutated gliomas in adults, is being introduced into clinical practice. [ABSTRACT FROM AUTHOR]

There is unmet need for additional biomarkers to better select patients with non-small cell lung cancer (NSCLC) that are likely to benefit from immunotherapy in order to improve patient outcomes, reduce patient toxicity, and relieve the growing burden of healthcare costs. In this issue of the JCI, Hayashi and colleagues evaluated soluble forms of the immune checkpoint molecules PD-L1, PD-1, and CTLA-4 in the plasma of patients with advanced NSCLC who had been treated with anti-PD-1/L1 therapy. The findings suggest that these soluble immune-checkpoint factors may provide a complementary biomarker to PD-L1 IHC, although application into the clinic may not be straightforward. [ABSTRACT FROM AUTHOR]

Faced with unique immunobiology and marked heterogeneity, treatment strategies for glioblastoma require therapeutic approaches that diverge from conventional oncological strategies. The selection and prioritization of targeted and immunotherapeutic strategies will need to carefully consider these features and companion biomarkers developed alongside treatment strategies to identify the appropriate patient populations. Novel clinical trial strategies that interrogate the tumor microenvironment for drug penetration and target engagement will inform go/no-go later-stage clinical studies. Innovative trial designs and analyses are needed to move effective agents toward regulatory approvals more rapidly. [ABSTRACT FROM AUTHOR]

Neuroendocrine neoplasms (NENs) are relatively rare neoplasms occurring predominantly in the gastrointestinal tract and pancreas. Their heterogeneity poses challenges for diagnosis and treatment. There is a paucity of markers for characterisation of NEN tumours. For routine diagnosis, immunohistochemistry of the NEN-specific markers CgA and synaptophysin and the proliferation marker Ki-67 are used. These parameters, however, are qualitative and lack the capacity to fully define the tumour phenotype. Molecules of epithelial–mesenchymal transition (EMT) are potential candidates for improved tumour characterisation. Using qRT-PCR, we measured mRNA levels of 27 tumour markers, including 25 EMT-associated markers, in tumour tissue and matched non-tumour tissues for 13 patients with pancreatic NENs. Tissue from patients with three different grades of tumour had distinctly different mRNA profiles. Of the 25 EMT-associated markers analysed, 17 were higher in G3 tissue relative to matched non-tumour tissue, including CD14, CD24, CD31, CD44, CD45, CD56, CK6, CK7, CK13, CK20, NSE, CDX2, CgA, DAXX, PCNA, laminin and Ki-67. The differences in levels of seven EMT-associated markers, Ki-67, DAXX, CD24, CD44, vimentin, laminin and PDX1 plus CgA and NSE (neuroendocrine markers) enabled a distinct molecular signature for each tumour grade to be generated. EMT molecules differentially expressed in three tumour grades have potential for use in tumour stratification and prognostication and as therapeutic targets for treatment of neuroendocrine cancers, following validation with additional samples. [ABSTRACT FROM AUTHOR]

Neurocognitive impairment is being increasingly recognized as an important issue in patients with cancer who develop cognitive difficulties either as part of direct or indirect involvement of the nervous system or as a consequence of either chemotherapy-related or radiotherapy-related complications. Brain radiotherapy in particular can lead to significant cognitive defects. Neurocognitive decline adversely affects quality of life, meaningful employment, and even simple daily activities. Neuroprotection may be a viable and realistic goal in preventing neurocognitive sequelae in these patients, especially in the setting of cranial irradiation. Lithium is an agent that has been in use for psychiatric disorders for decades, but recently there has been emerging evidence that it can have a neuroprotective effect. This review discusses neurocognitive impairment in patients with cancer and the potential for investigating the use of lithium as a neuroprotectant in such patients. [ABSTRACT FROM AUTHOR]

Summary: Neurological complications of systemic cancer—those arising outside the nervous system—can be distressing, disabling, and sometimes fatal. Diagnosis is often difficult because different neurological disorders may present with similar signs and symptoms. Furthermore, comorbid neurological illnesses, common in elderly patients with cancer, can complicate diagnosis. Early diagnosis and aggressive treatment can improve neurological symptoms and can substantially enhance a patient''s quality of life. We approach the problem of neurological complications of systemic cancer as would a neurologist: first by identifying the anatomical area or areas that are affected (ie, brain, spinal cord, peripheral nerve), then by evaluating the diagnostic approach, considering the symptoms and signs and including appropriate laboratory tests, and finally, by recommending treatment. We focus on disorders that are difficult to diagnose, need neurological consultation, and for which effective treatments exist. [Copyright &y& Elsevier]

Thrombocytopenia in patients with solid malignancy can be caused by bone marrow involvement or toxicity from anticancer therapy; however, it could rarely be the first presentation of a tumor such as breast cancer or lymphoma. Hematological paraneoplastic syndromes such as paraneoplastic thrombocytopenia and/or immune thrombocytopenic purpura (ITP) are well described as secondary findings simultaneously with malignancies such as breast cancer and lymphoma. Other hematological conditions such as severe amegakaryocytic thrombocytopenia, thrombotic thrombocytopenic purpura (TTP), and myelodysplastic syndromes (MDS) have also rarely been described as a possible paraneoplastic process complicating solid tumors. On the one hand, occult disseminated malignancy may mimic ITP and TTP, leading to diagnostic and therapeutic problems. On the other hand, thrombocytopenia could be the first manifestation of cancer. [ABSTRACT FROM AUTHOR]

Despite the important evolution of immunotherapeutic agents, brain tumors remain, in general, refractory to immune therapeutics. Recent discoveries have revealed that the glioma microenvironment includes a wide variety of immune cells in various states that play an important role in the process of tumorigenesis. Anti-tumor immune activity may be occurring or induced in immunogenic hot spots or at the invasive edge of central nervous system (CNS) tumors. Understanding the complex heterogeneity of the immune microenvironment in gliomas will likely be the key to unlocking the full potential of immunotherapeutic strategies. An essential consideration will be the induction of immunological effector responses in the setting of the numerous aspects of immunosuppression and evasion. As such, immune therapeutic combinations are a fundamental objective for clinical studies in gliomas. Through immune profiling conducted on immune competent murine models of glioma and ex vivo human glioma tissue, we will discuss how the frequency, distribution of immune cells within the microenvironment, and immune modulatory processes, may be therapeutically modulated to lead to clinical benefits. [ABSTRACT FROM AUTHOR]

Background Isocitrate dehydrogenase (IDH) is commonly mutated (mIDH) in gliomas, and this mutant enzyme produces the oncometabolite 2-hydroxyglutarate (2HG). 2HG promotes gliomagenesis and is implicated in epileptogenesis. Ivosidenib (IVO), a small molecule oral mIDH1 inhibitor, is FDA-approved for mIDH1 newly diagnosed and relapsed/refractory acute myeloid leukemia. Moreover, IVO has efficacy in clinical trials for recurrent mIDH1 gliomas. Given the lack of targeted treatments for gliomas, we initiated off-label IVO for mIDH glioma patients in October 2020. Methods Retrospectively, we sought to assess early outcomes in our patients and describe their experience on IVO from October 2020 through February 2022. Our objective was to report on the following variables of off-label use of IVO: radiographic response, seizure control, tolerability, and access to the medication. All patients initially received single-agent IVO dosed at 500 mg orally once daily. Results The cohort age range was 21–74 years. Tumor types included astrocytoma (n = 14) and oligodendroglioma (n = 16), with most being grade 2 (n = 21). The best radiographic response in nonenhancing disease (n = 22) was 12 stable diseases, 5 minor responses, 3 partial responses, and 2 progressive diseases. Seizure frequency was stable to improved for most patients (70%, n = 21). IVO was well-tolerated, with the most common toxicities being diarrhea, elevated creatine kinase, and QTc interval prolongation. Most patients (66.7%, n = 20) received drugs via the patient assistance program, with insurance initially covering a third of patients and with ongoing use, later covering 60%. Conclusions Targeted therapies like IVO are options for mIDH glioma patients and can provide positive oncologic and neurological outcomes. [ABSTRACT FROM AUTHOR]

Background: Collaborative relationships between academic oncology and industry (pharmaceutical, biotechnology, "omic," and medical device companies) are essential for therapeutic development in oncology; however, limited research on engagement in and perceptions of these relationships has been done. Methods: Survey questions were developed to evaluate relationships between academic oncology and industry. An electronic survey was delivered to 1000 randomly selected members of the American Society of Clinical Oncology, a professional organization for oncologists, eliciting respondents' views around oncology‐industry collaborations. The responses were analyzed according to prespecified plans. Results: There were 225 survey respondents. Most were from the United States (70.0%), worked at an academic institution (60.1%), worked in medical oncology (81.2%), and had an active relationship with industry (85.8%). One quarter (26.7%) of respondents reported difficulty establishing a relationship with industry collaborators, and most respondents (75%) did not report having had mentorship in developing these relationships. The majority (85.3%) of respondents considered these collaborations important to their careers. Respondents generally thought that scientific integrity was preserved (92%), and most respondents (95%) had little concern over the quality of the collaborative product. Many (60%) shared concerns over potential conflict of interest if an individual with a compensated relationship promoted an industry product for clinical care/research, yet most respondents (67%) stated these relationships did not shape their interactions with patients. Conclusions: This study provides novel data characterizing the nature of collaborative relationships between clinicians, researchers, and industry in oncology. Although respondents considered these collaborations an important part of clinical and academic oncology, formal education or mentorship around these relationships was rare. Conflicting findings around conflict of interest highlight the importance of more dedicated research in this area. Plain Language Summary: Business enterprises in health care play a central role in cancer research and care, driving the development of new medical testing, drugs, and devices. Effective working relationships among clinicians, researchers, and these industry partners can promote innovative research and enhance patient care. Study of these collaborations has been limited to date. Through distribution of a questionnaire to cancer clinicians and researchers, we found that most participants consider these relationships valuable, though they find establishing such relationships challenging partly because of gaps in educational programs in this area. Our findings also highlight the need for further policy around the potential bias these relationships can introduce. Oncology‐industry collaborations can be mutually beneficial relationships that contribute to both scientific and clinical innovation. Despite their value, a deficit of education and policy around these collaborations is recognized by cancer clinicians and researchers. [ABSTRACT FROM AUTHOR]

The article discusses a comparative study of the neurocognitive function in patients who had received radiotherapy for low-grade gliomas (LGG) against those who had not. In particular, the radiological and cognitive complications following radiotherapy in long-term LGG survivors were assessed by L. Douw and colleagues. It notes that careful consideration is needed with regard to the use of radiotherapy for LGG patients. Such a study is said to highlight the importance of long-term follow-up when forming conclusions related to late sequelae of treatment.

The article focuses on cases that indicate the importance of monitoring the left ventricular ejection fraction (LVEF) when using the tyrosine kinase inhibitor sunitinib to prevent morbidity and mortality resulting from cardiotoxicity. A 70-year-old man was admitted to the hospital with dyspnea, pallor, lethargy and dehydration after 2 months of receiving sunitinib for metastatic renal cell carcinoma (RCC). A 78-year-old man reported symptoms of occasional chest tightness and worsening tiredness after a year of receiving the drug for clear cell RCC.

Glioblastoma is highly aggressive and remains difficult to treat despite being the most common malignant primary brain tumor in adults. Current standard-of-care treatment calls for maximum resection of the tumor mass followed by concurrent chemotherapy and radiotherapy and further adjuvant chemotherapy if necessary. Despite this regimen, prognosis remains grim. Immunotherapy has shown promising success in a variety of solid tumor types, but efficacy in glioblastoma is yet to be demonstrated. Barriers to the success of immunotherapy in glioblastoma include: a heterogeneous tumor cell population, a highly immunosuppressive microenvironment, and the blood–brain barrier, to name a few. Several immunotherapeutic approaches are actively being investigated and developed to overcome these limitations. In this review, we present different classes of immunotherapy targeting glioblastoma, their most recent results, and potential future directions. [ABSTRACT FROM AUTHOR]

Simple Summary: Gliomas are the most common primary brain tumors. These cancers are universally fatal with limited treatment options. Glioma cells co-opt non-cancerous cells present in normal brain tissue. This manipulation results in a complex network of cell interactions. This interplay is further complicated by variations depending on specific mutations in glioma cells. In order to identify future treatments for gliomas, a better understanding of these interactions is needed. To address this, we review the literature to highlight these interactions and how they relate to different glioma mutations. Gliomas are the most common primary brain malignancy and are universally fatal. Despite significant breakthrough in understanding tumor biology, treatment breakthroughs have been limited. There is a growing appreciation that major limitations on effective treatment are related to the unique and highly complex glioma tumor microenvironment (TME). The TME consists of multiple different cell types, broadly categorized into tumoral, immune and non-tumoral, non-immune cells. Each group provides significant influence on the others, generating a pro-tumor dynamic with significant immunosuppression. In addition, glioma cells are highly heterogenous with various molecular distinctions on the cellular level. These variations, in turn, lead to their own unique influence on the TME. To develop future treatments, an understanding of this complex TME interplay is needed. To this end, we describe the TME in adult gliomas through interactions between its various components and through various glioma molecular phenotypes. [ABSTRACT FROM AUTHOR]

Successful drug development for people with cancers of the CNS has been challenging. There are multiple barriers to successful drug development including biological factors, rarity of the disease, and ineffective use of clinical trials. Based upon a series of presentations at the First Central Nervous System Clinical Trials Conference hosted by the American Society of Clinical Oncology and the Society for Neuro-Oncology, we provide an overview on drug development and novel trial designs in neuro-oncology. This Review discusses the challenges of therapeutic development in neuro-oncology and proposes strategies to improve the drug discovery process by enriching the pipeline of promising therapies, optimising trial design, incorporating biomarkers, using external data, and maximising efficacy and reproducibility of clinical trials. [ABSTRACT FROM AUTHOR]

Neurocognitive impairment is being increasingly recognized as an important issue in patients with cancer who develop cognitive difficulties either as part of direct or indirect involvement of the nervous system or as a consequence of either chemotherapy-related or radiotherapy-related complications. Brain radiotherapy in particular can lead to significant cognitive defects. Neurocognitive decline adversely affects quality of life, meaningful employment, and even simple daily activities. Neuroprotection may be a viable and realistic goal in preventing neurocognitive sequelae in these patients, especially in the setting of cranial irradiation. Lithium is an agent that has been in use for psychiatric disorders for decades, but recently there has been emerging evidence that it can have a neuroprotective effect.This review discusses neurocognitive impairment in patients with cancer and the potential for investigating the use of lithium as a neuroprotectant in such patients. [ABSTRACT FROM AUTHOR]

Aim: Palbociclib was approved in the United States in 2015 to treat estrogen receptor–positive/human epidermal growth factor receptor 2–negative (HER2–) advanced breast cancer (ABC). This study evaluated outcomes and safety in patients treated with palbociclib in Australia and India with hormone receptor–positive (HR+)/HER2– ABC before palbociclib became commercially available. Methods: Postmenopausal women (≥18 years) with HR+/HER2– ABC who were appropriate candidates for letrozole therapy received palbociclib 125 mg once daily for 21 days followed by 7 days off, and letrozole 2.5 mg once daily (continuous). Safety, tumor response, and patient‐reported outcomes (Australian cohort) were evaluated. Results: In total, 252 patients received palbociclib plus letrozole (Australia, n = 152; India, n = 100). More patients in the Australian versus Indian cohort had received prior chemotherapy (advanced/metastatic setting: 45.9% vs. 32.0%), endocrine therapy (advanced/metastatic setting: 63.2% vs. 54.3%), and advanced/metastatic therapies (61.8% vs. 31.0%). The most frequently reported all‐grade palbociclib‐related treatment‐emergent adverse events were neutropenia (66.7%), fatigue (35.3%), and stomatitis (26.6%); grade 3/4 neutropenia was reported as palbociclib‐related in 62.7% of patients. Febrile neutropenia was reported in six patients (2.4%). Eight patients (3.2%) discontinued because of an adverse event. The objective response rate was 19.4% (95% CI, 14.7%–24.9%) overall and 2.3% in Australian patients with ≥2 lines of prior therapy for metastatic disease. Patient‐reported quality of life scores were maintained throughout the study. Conclusions: In an expanded access setting in Australia and India, palbociclib plus letrozole was well tolerated in patients with HR+/HER2– ABC, with a safety profile consistent with previous reports. [ABSTRACT FROM AUTHOR]

Purpose: Data on the use of targeted therapies at the end of life are scarce. This study reviews the pattern of use of targeted and potentially futile, toxic, or costly therapies at an Australian cancer centre.Methods: This retrospective single-centre review of data from patients who died within 3 months of having targeted therapy examined demographic characteristics, types of cancers, types of therapy, age, and lines of prior therapy.Results: Over 24 months, two groups were analysed. Firstly, 889 patients died with 107 patients who were prescribed targeted therapy. Secondly, 457 patients were treated with targeted therapies with 52 patients, (11 %) dying within 3 months. To focus on the 52 patients: median age was 69 years, 65 % were men and 35 % were women, 50 % had haematologic cancers and 50 % had solid tumours. Ten therapeutic agents were represented: a higher total number of deaths among those prescribed erlotinib, bevacizumab, and rituximab. There were no deaths within 3 months of treatment with trastuzumab, ipilimumab, or vemurafenib. The targeted therapy was the first-line treatment in 54 %, second in 15 %, and third and beyond in 15 %. The patient's sex and type of cancer had no statistically significant influence on death within 3 months of targeted treatment.Conclusions: The use of targeted therapy at the end of life in this single-centre descriptive study was lower than documented in other studies. There is a need to prospectively document the factors leading to this prescribing behaviour to guide future protocols. [ABSTRACT FROM AUTHOR]

Aim: The neuro‐oncology community in Australia is well positioned to collaborate internationally, with a motivated trials group, strong regulatory bodies and an attractive fiscal environment. We sought to identify gaps in the Australian neuro‐oncology clinical trials landscape and describe strategies to increase international trial access in Australia. Methods: We searched clinical trial registries to identify active adult primary brain cancer trials. We compared the participation rate and phase of these trials between tumour types and countries. A survey was distributed to the Cooperative Trials Group for Neuro‐Oncology membership to identify barriers and solutions to effective international collaboration. Results: Globally, 307 trials for adult primary brain cancers were identified. These included 50% pharmaceutical agents, 18% cellular therapies and 9% radiation therapy. Twelve adult primary brain cancer trials were actively recruiting in Australia at the time the survey was sent out. There were more early phase brain cancer trials (34%) compared with colorectal and breast cancer (21% and 24%, respectively). In Australia, 92% of brain cancer trials were involving pharmaceutical agents. The most commonly cited barrier was lack of funding for international trials (86%) and insufficient research time (75%). High ranking solutions included increasing the availability of funding for international trials and creating opportunities to develop personal relationships with collaborators. Accreditation of clinical research key performance indicators into practice (88%) and hospital accreditation (73%) also ranked highly. Conclusions: Participation in international research in Australia could be improved by embedding clinical research targets into institutional funding, provision of funding for early phase studies and streamlining mutual ethics schemes. [ABSTRACT FROM AUTHOR]

Simple Summary: There is a pressing need for new effective treatments against glioma. A promising option is a class of drugs called poly(ADP-Ribose) polymerase (PARP) inhibitors. PARP inhibitors block the repair of DNA damage. They may work synergistically with radiotherapy, chemotherapy and immunotherapy. They may work particularly well in settings where other DNA damage repair pathways are impaired. This article reviews the clinical trials investigating PARP inhibitors in glioma. Gliomas are the most common malignant primary brain tumor in adults. Despite advances in multimodality therapy, incorporating surgery, radiotherapy, systemic therapy, tumor treating fields and supportive care, patient outcomes remain poor, especially in glioblastoma where median survival has remained static at around 15 months, for decades. Low-grade gliomas typically harbor isocitrate dehydrogenase (IDH) mutations, grow more slowly and confer a better prognosis than glioblastoma. However, nearly all gliomas eventually recur and progress in a way similar to glioblastoma. One of the novel therapies being developed in this area are poly(ADP-Ribose) polymerase (PARP) inhibitors. PARP inhibitors belong to a class of drugs that target DNA damage repair pathways. This leads to synthetic lethality of cancer cells with coexisting homologous recombination deficiency. PARP inhibitors may also potentiate the cytotoxic effects of radiotherapy and chemotherapy, and prime the tumor microenvironment for immunotherapy. In this review, we examine the rationale and clinical evidence for PARP inhibitors in glioma and suggest therapeutic opportunities. [ABSTRACT FROM AUTHOR]

As many as 30% of patients with non–small cell lung cancer (NSCLC) will develop brain metastases (BMs) over the course of their illness. Here, we quantitatively compare the efficacy of the various emerging regimens for NSCLC BMs without a definitive targetable epidermal growth factor receptor mutation/ALK rearrangement. We searched MEDLINE, EMBASE, Web of Science, ClinicalTrials.gov , CENTRAL, and references of key studies for randomized controlled trials (RCTs) published from inception until June 2020. Comparative RCTs that included ≥10 patients were included. We used a frequentist fixed or random-effects model for network meta-analysis. The outcomes of interest included intracranial progression-free survival (iPFS), overall survival (OS), and overall progression-free survival. In total, 18 studies representing 17 trials (n = 2726 patients) were identified. Immune checkpoint inhibitor regimens showed significant improvement in OS compared with chemotherapy alone, including pembrolizumab and chemotherapy (6 studies, hazard ratio [HR] 0.36, 95% confidence interval [CI] 0.21–0.62), atezolizumab alone (HR 0.54, 95% CI 0.33–0.89), and nivolumab and ipilimumab (HR 0.64, 95% CI 0.42–0.97). An improvement in overall PFS was seen with use of pembrolizumab and chemotherapy compared with chemotherapy alone (3 studies, HR 0.42, 95% CI 0.26–0.68). Studies evaluating checkpoint inhibitors did not report iPFS data, and we did not find improvement in iPFS or OS with the addition of any chemotherapy regimen to whole-brain radiation therapy. In this network meta-analysis, we demonstrate the promising survival benefit with use of checkpoint inhibitor-based regimens in NSCLC BMs without a targetable epidermal growth factor receptor mutation/ALK rearrangement. Moving forward, large-scale BM-focused RCTs are necessary to establish the iPFS benefit of immune checkpoint inhibitor-based immunotherapy in this patient population. [ABSTRACT FROM AUTHOR]

The SARS-CoV-2 pandemic has resulted in considerable consequences for many cancer patients, exacerbating pre-existing systemic health system limitations as well as creating new challenges. From socially distanced clinics and the widespread introduction of telehealth, to the halting of clinical trials and the reassessment of what constitutes "essential" treatment, care in oncology has abruptly changed. There is currently limited analysis of cancer patients' experiences of the pandemic and its impacts on illness, wellness, and everyday life. Through semi-structured interviews with 54 people living with cancer during the 2020 phase of the SARS-CoV-2 pandemic in Australia, we explore how patients experience illness and care in reflecting upon a range of pandemic challenges, including delay, distance, and vulnerability. We find that in some cases, these pandemic conditions redefined the meaning of essential cancer care, reconfigured expectations around clinical trials, constructed new affective distances, and amplified dread and fear for people living with cancer. [ABSTRACT FROM AUTHOR]

The idea of 'precision medicine', which has gained increasing traction since the early 2000s, is now ubiquitous in health and medicine. Though varied in its implementation across fields, precision medicine has raised hopes of revolutionary treatments and has spurred the proliferation of novel therapeutics, the alteration of professional trajectories and various reconfigurations of health/care. Nowhere is the promise of precision medicine more apparent, nor further institutionalised, than in the field of oncology. While the transformative potential of precision medicine is widely taken for granted, there remains scant attention to how it is being experienced at the coalface of care. Here, drawing on the perspectives of 54 cancer care professionals gleaned through eight focus group discussions in two hospitals in Australia, we explore clinicians' experiences of the day‐to‐day dynamics of precision‐in‐practice. We illustrate some of the affective and temporal complexities, analysed here under the rubrics of enchantment, acceleration and distraction that are emerging alongside the uptake of precision medicine in the field of oncology. We argue that these complexities, and their dis/continuities with earlier iterations of cancer care, demonstrate the need for sociological analyses of precision medicine as it is being implemented in practice and its varied effects on 'routine' care. [ABSTRACT FROM AUTHOR]

Integration of external control data, with patient-level information, in clinical trials has the potential to accelerate the development of new treatments in neuro-oncology by contextualising single-arm studies and improving decision making (eg, early stopping decisions). Based on a series of presentations at the 2020 Clinical Trials Think Tank hosted by the Society of Neuro-Oncology, we provide an overview on the use of external control data representative of the standard of care in the design and analysis of clinical trials. High-quality patient-level records, rigorous methods, and validation analyses are necessary to effectively leverage external data. We review study designs, statistical methods, risks, and potential distortions in using external data from completed trials and real-world data, as well as data sources, data sharing models, ongoing work, and applications in glioblastoma. [ABSTRACT FROM AUTHOR]

Background: Neuroendocrine neoplasms (NENs) are a complex group of tumours that occur in many organs. Routinely used IHC markers for NEN diagnosis include CgA, synaptophysin, Ki67 and CD56. These have limitations including lack of correlation to clinical outcomes and their presence in non-tumour tissue. Identification of additional markers and more quantitative analyses of tumour tissue has the potential to contribute to improved clinical outcomes. We used qRT-PCR to profile the expression levels of a panel of markers in tumour and matched non-tumour tissue from a patient with a G1 pancreatic neuroendocrine tumour. Differences in mRNA levels between tumour and non-tumour tissue were compared with IHC analyses of the same sample.Case Presentation: An elderly man presented with lower abdominal pain for 6 months. Histological analysis identified a low grade, well differentiated pancreatic endocrine neoplasm. Twenty-seven tumour markers for neuroendocrine status, proliferation, stem cell phenotype, angiogenesis, epithelial to mesenchymal transition, cell adhesion, differentiation and tumour suppression were selected from previous studies and mRNA levels of these markers were measured in tumour and adjacent non-tumour tissue sample using qRT-PCR. IHC was carried out on the same tissue to detect the corresponding marker proteins. Of the markers analysed, seven showed higher mRNA levels in tumour relative to non-tumour tissue while thirteen had lower expression in tumour relative to non-tumour tissue. Substantial differences in mRNA levels were a gain of CgA, CD56, β-catenin, CK20, PDX1 and p53 and loss of Ki67, PCAD, CK7, CD31, MENA, ECAD, EPCAM, CDX2 and CK6. Comparison of qRT-PCR data with IHC showed correlation between fifteen markers.Conclusion: Our study is unique as it included matched controls that provided a comparative assessment for tumour tissue analysis, whereas many previous studies report tumour data only. Additionally, we utilised qRT-PCR, a relatively quantitative diagnostic tool for differential marker profiling, having the advantage of being reproducible, fast, cheap and accurate. qRT-PCR has the potential to improve the defining of tumour phenotypes and, in combination with IHC may have clinical utility towards improving tumour stratification or distinguishing tumour grades. The results need to be validated with different grades of NENs and related to clinical outcomes. [ABSTRACT FROM AUTHOR]

The management of non-small cell lung cancer (NSCLC) has transformed with the discovery of therapeutically tractable oncogenic drivers. In addition to activating driver mutations, gene fusions or rearrangements form a unique sub-class, with anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) targeted agents approved as the standard of care in the first-line setting for advanced disease. There are a number of emerging fusion drivers, however, including neurotrophin kinase (NTRK), rearrangement during transfection (RET), and neuregulin 1 (NRG1) for which there are evolving high-impact systemic treatment options. Brain metastases are highly prevalent in NSCLC patients, with molecularly selected populations such as epidermal growth factor receptor (EGFR) mutant and ALK-rearranged tumors particularly brain tropic. Accordingly, there exists a substantial body of research pertaining to the understanding of brain metastases in such populations. Little is known, however, on the molecular mechanisms of brain metastases in those with other targetable fusion drivers in NSCLC. This review encompasses key areas including the biological underpinnings of brain metastases in fusion-driven lung cancers, the intracranial efficacy of novel systemic therapies, and future directions required to optimize the control and prevention of brain metastases. [ABSTRACT FROM AUTHOR]

Spinal ependymal tumors form a histologically and molecularly heterogeneous group of tumors with generally good prognosis. However, their treatment can be challenging if infiltration of the spinal cord or dissemination throughout the central nervous system (CNS) occurs and, in these cases, clinical outcome remains poor. Here, we describe a new and relatively rare subgroup of spinal ependymal tumors identified using DNA methylation profiling that is distinct from other molecular subgroups of ependymoma. Copy number variation plots derived from DNA methylation arrays showed MYCN amplification as a characteristic genetic alteration in all cases of our cohort (n = 13), which was subsequently validated using fluorescence in situ hybridization. The histological diagnosis was anaplastic ependymoma (WHO Grade III) in ten cases and classic ependymoma (WHO Grade II) in three cases. Histological re-evaluation in five primary tumors and seven relapses showed characteristic histological features of ependymoma, namely pseudorosettes, GFAP- and EMA positivity. Electron microscopy revealed cilia, complex intercellular junctions and intermediate filaments in a representative sample. Taking these findings into account, we suggest to designate this molecular subgroup spinal ependymoma with MYCN amplification, SP-EPN-MYCN. SP-EPN-MYCN tumors showed distinct growth patterns with intradural, extramedullary localization mostly within the thoracic and cervical spine, diffuse leptomeningeal spread throughout the whole CNS and infiltrative invasion of the spinal cord. Dissemination was observed in 100% of cases. Despite high-intensity treatment, SP-EPN-MYCN showed significantly worse median progression free survival (PFS) (17 months) and median overall survival (OS) (87 months) than all other previously described molecular spinal ependymoma subgroups. OS and PFS were similar to supratentorial ependymoma with RELA-fusion (ST-EPN-RELA) and posterior fossa ependymoma A (PF-EPN-A), further highlighting the aggressiveness of this distinct new subgroup. We, therefore, propose to establish SP-EPN-MYCN as a new molecular subgroup in ependymoma and advocate for testing newly diagnosed spinal ependymal tumors for MYCN amplification. [ABSTRACT FROM AUTHOR]

Background: Patients with anaplastic glioma (AG) harboring an isocitrate dehydrogenase mutation have potential durable survival after intensity-modulated radiotherapy (IMRT) and chemotherapy. Understanding long-term functioning, and the factors that have an impact on later effects, is important for decision making.Methods: Consecutive patients with AG who received IMRT were reviewed with regard to 6 survivorship domains, including Eastern Cooperative Oncology Group (ECOG) performance status, Medical Research Council (MRC) neurological status, late toxicity, comorbidity, functional status (employment/driving), and psychosocial events. Assessments were performed at baseline before RT; at month +6; and at years +1, +3, and +5 after RT. The primary endpoints were ECOG at year +3 and employment at year +3.Results: A total of 146 patients were included, with a median follow-up of 5.1 years. The 6-year overall survival rate was 78.7% (95% CI, 71.1%-87.0%). Baseline ECOG performance status was 0 to 1 in 82.2% of patients but improved at year +1 (95.7%) and year +3 (97.2%). Employment rates at year +3 and year +5 were 70.1% and 76.5%, respectively, compared with 61.6% at baseline. Worse ECOG performance status at year +3 was related to the anaplastic astrocytoma subtype (P = .001), delayed RT (P = .081), multiple craniotomies performed before RT (P = .002), worse ECOG performance status before RT (P < .001), worse MRC neurological status before RT (P < .001), seizures (P = .038), neurocognitive disturbance (P < .001), and the presence of recurrent disease (P = .004). Absent or impaired employment at year +3 was found to be related to older age (P = .007), delayed timing of RT (P = .023), multiple craniotomies prior to RT (P = .005), worse ECOG performance status before RT (P < .001), worse MRC neurological status before RT (P < .001), and neurocognitive disturbance (P < .001).Conclusions: Patients with AG with an isocitrate dehydrogenase mutation have the potential for prolonged survival. Functional status appears to be good in patients who are free of disease progression at 3 to 5 years after IMRT, with >95% of patients having high ECOG performance status and >75% being employed. [ABSTRACT FROM AUTHOR]

PURPOSE: Travel for patients with cancer has become more achievable because of gains in quality of life and overall survival. The risk assessment of these patients is complex, and there is a paucity of data to which clinicians can refer. We present the challenges of traveling with cancer and a review of the literature. METHODS: A review using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was performed. A search using the terms "cancer," "advanced cancer," "metastases," "brain edema," "lymphoedema," "pneumothorax," "pleural effusion," "pericardial effusion," pneumonitis," "hypoxia," "end-of-life," and "shunt," combined with "flying" and "air travel," was conducted. The PubMed and Cochrane databases were searched for English-language studies up to December 2018. Studies, case reports, or guidelines referring to travel in the context of adult patients with malignancies were included. A total of 745 published articles were identified; 16 studies were included. An inclusive approach to data extraction was used. RESULTS: There were no specific criteria to deem a patient with cancer fit to travel. Neurologic, respiratory, and cardiac implications, and time from recent surgery or procedure need to be considered There was a lack of high-quality studies to inform decisions, but the British Thoracic Society and Aerospace Medical Association Medical Guidelines included recommendations for fitness to fly for patients with cancer. CONCLUSION: In the absence of large prospective studies, individual fitness to travel should be assessed on a case-by-case basis, bearing in mind that maximizing a patient's ability to safely travel is an important goal for many individuals with cancer. [ABSTRACT FROM AUTHOR]

Background: Residents of rural and regional areas, compared to those in urban regions, are more likely to experience geographical difficulties in accessing healthcare, particularly specialist services. We investigated associations between region of residence, socioeconomic status (SES) and utilisation of all-cause revision hip replacement or revision knee replacement surgeries.Methods: Conducted in western Victoria, Australia, as part of the Ageing, Chronic Disease and Injury study, data from the Australian Orthopaedic Association National Joint Replacement Registry (2011-2013) for adults who underwent a revision hip replacement (n = 542; 54% female) or revision knee replacement (n = 353; 54% female) were extracted. We cross-matched residential addresses with 2011 census data from the Australian Bureau of Statistics (ABS), and using an ABS-derived composite index, classified region of residence according to local government areas (LGAs), and area-level SES into quintiles. For analyses, the control population (n = 591,265; 51% female) was ABS-determined and excluded adults already identified as cases. Mixed-effects logistic regression was performed.Results: We observed that 77% of revision hip surgeries and 83% of revision knee surgeries were performed for residents in the three most socially disadvantaged quintiles. In adjusted multilevel models, total variances contributed by the variance in LGAs for revisions of the hip or knee joint were only 1% (SD random effects ±0.01) and 3% (SD ± 0.02), respectively. No differences across SES or sex were observed.Conclusions: No differences in utilisation were identified between SES groups in the provision of revision surgeries of the hip or knee, independent of small between-LGA differences. [ABSTRACT FROM AUTHOR]

Introduction: Assess survival of patients with anaplastic glioma (AG) and the relationship to molecular subtype.Methods: Patients with AG managed with IMRT between 2008 and 2014 were entered into a prospective database assessing relapse-free survival (RFS) and overall survival (OS). Isocitrate dehydrogenase (IDH) mutations were assessed prospectively from 2011, and subsequent testing of historical patients allowing categorisation under WHO 2016 classification as anaplastic astrocytoma IDH wild type (AAwt), anaplastic astrocytoma IDH mutated (AAmut), anaplastic oligodendroglioma (AOD) or other glial tumour (OTH). Kaplan-Meier estimates of survival distribution were calculated for the primary endpoint of overall survival and Log-rank test used to determine associated factors.Results: One hundred and fifty-six patients were included with median follow-up for survivors of 4.7 years. Fifty-six per cent were managed after initial diagnosis, whilst 18% received IMRT at second or later relapse. Seventy-three per cent had temozolomide as part of initial therapy. A total of 118 or 75% of patients had IDH mutated glioma, of which 61 were AOD and 57 AAmut. There were 68 relapses and 52 deaths for a 6yrRFS of 51.2% and 6yrOS of 62.5%. AAwt was associated with worse survival (P < 0.001); and delay of RT until second or later relapse (P = 0.03). Within the 118 patients with IDH mutated tumours, 6yrOS for AOD and AAmut were 90.0% and 62.5%, respectively (P = 0.003). Also two or more craniotomies (P < 0.001), delayed RT (P = 0.006) and age <40 years (P = 0.022) were associated with worse survival on univariate analysis but only AAmut subtype and number of craniotomies on multivariate analysis.Conclusion: Within AG, molecular classification predicts for survival, and should influence current decision-making. [ABSTRACT FROM AUTHOR]

Background: This study evaluated the feasibility of achieving high response rates in stage II or III breast cancer by tailoring neoadjuvant therapy using clinical and histopathological features and the Oncotype DX Breast Recurrence Score. Genomic determinants of response and resistance were also explored. Patients and outcome measures: Fifty-one patients were enrolled. The primary cohort comprised 40 patients: 15 human epidermal growth factor receptor type 2 (HER2)-amplified; 15 triple-negative (TNBC); and ten hormone receptor (HR)-positive, HER2-non-amplified tumours; with recurrence scores ≥25. Patients were treated with epirubicin and cyclophosphamide, followed by nab-paclitaxel, with the addition of trastuzumab if HER2-amplified. The primary endpoint was pathological complete response (pCR) in the breast. Pre- and post-treatment tumour samples underwent variant burden, gene and gene pathway, mutational signature profile and clonal evolution analyses. Results: The pCR rates were: overall 55% (n = 22), HER2-amplified 80% (n = 12), triple-negative 46% (n = 7) and HR-positive, HER2-non-amplified 30% (n = 3). Grade 3 or 4 adverse events included febrile neutropenia (8%), neutropenia (18%), sensory neuropathy (5%), deranged transaminases (5%), fatigue (2%), diarrhoea (2%), and pneumothorax (2%). Molecular analyses demonstrated strong similarities between residual disease and matched primary tumour. ATM signalling pathway alterations and the presence of a COSMIC Signature 3 implied the majority of tumours contained some form of homologous repair deficiency. ATM pathway alterations were identified in the subset of TNBC patients who did not achieve pCR; Signature 3 was present in both pCR and non-pCR subgroups. Clonal evolution analyses demonstrated both persistence and emergence of chemoresistant clones. Conclusions: This treatment regime resulted in a high rate of pCR, demonstrating that tailored neoadjuvant therapy using a genomic recurrence score is feasible and warrants further investigation. Molecular analysis revealed few commonalities between patients. For TNBC future clinical gains will require precision medicine, potentially using DNA sequencing to identify specific targets for individuals with resistant disease. Trial registration: Clinicaltrials.gov [ABSTRACT FROM AUTHOR]

Background: In a phase III study, sunitinib led to a significant increase in progression-free survival (PFS) versus placebo in patients with pancreatic neuroendocrine tumours (panNETs). This study was a post-marketing commitment to support the phase III data. Methods: In this ongoing, open-label, phase IV trial (NCT01525550), patients with progressive, advanced unresectable/metastatic, well-differentiated panNETs received continuous sunitinib 37.5 mg once daily. Eligibility criteria were similar to those of the phase III study. The primary endpoint was investigator-assessed PFS per Response Evaluation Criteria in Solid Tumours v1.0 (RECIST). Other endpoints included PFS per Choi criteria, overall survival (OS), objective response rate (ORR), and adverse events (AEs). Results: Sixty-one treatment-naive and 45 previously treated patients received sunitinib. By March 19, 2016, 82 (77%) patients had discontinued treatment, mainly due to disease progression. Median treatment duration was 11.7 months. Investigator-assessed median PFS per RECIST (95% confidence interval [CI]) was 13.2 months (10.9–16.7): 13.2 (7.4–16.8) and 13.0 (9.2–20.4) in treatment-naive and previously treated patients, respectively. ORR (95% CI) per RECIST was 24.5% (16.7–33.8) in the total population: 21.3% (11.9–33.7) in treatment-naive and 28.9% (16.4–44.3) in previously treated patients. Median OS, although not yet mature, was 37.8 months (95% CI, 33.0–not estimable). The most common treatment-related AEs were neutropenia (53.8%), diarrhoea (46.2%), and leukopenia (43.4%). Conclusions: This phase IV trial confirms sunitinib as an efficacious and safe treatment option in patients with advanced/metastatic, well-differentiated, unresectable panNETs, and supports the phase III study outcomes. AEs were consistent with the known safety profile of sunitinib. [ABSTRACT FROM AUTHOR]

Abstract: Background: Magnetic resonance imaging (MRI) accuracy after neoadjuvant systemic therapy (NST) for breast cancer varies according to hormone receptor (HR), human epidermal growth factor receptor type‐2 (HER2) subtype and Ki‐67 proliferation index. Whether MRI accuracy varies by genomic signatures is unknown. We examined the accuracy of MRI in the NEONAB trial ( Clinicaltrials.gov #: NCT01830244). Aim: To examine the accuracy of MRI to predict pathological response to neoadjuvant therapy for breast cancer in the NEONAB trial. Methods: Patients with stages II–III breast cancer received sequential epirubicin, cyclophosphamide and nab‐paclitaxel and trastuzumab if they were HER2+. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated to assess the utility of preoperative MRI to predict pathological complete response (pCR). Bland‐Altman plots were used to assess agreement between MRI and pathological assessment of residual disease. Results: MRI correctly predicted pCR in 64.1% of the cohort. Sensitivity and specificity were 52% and 78%, respectively; PPV 73% and NPV 58%. MRI predicted pCR most accurately in HER2‐positive patients; sensitivity 58%, specificity 100%, PPV 100% and NPV 38%. MRI had higher PPV and NPV in tumours with Ki‐67 ≥ 15% than tumours with Ki‐67 < 15%, 75% versus 50% and 57.5% versus 50%, respectively. In this study, MRI underestimated residual tumour size by 1.65 mm (limits of agreement: 43.07–39.77 mm). Conclusions: MRI appears more accurate for predicting pCR in HER2+ disease than other subtypes and in cancers with Ki‐67 ≥ 15% compared to those with Ki‐67 < 15%. Accuracy of MRI in our HR+, RS ≥ 25 cohort is comparable to previous reports of unselected HR+ disease. MRI post‐NST should be interpreted in conjunction with HER2 status and Ki‐67 index of the primary. [ABSTRACT FROM AUTHOR]

Aim: Despite the considerable impact of neuroendocrine tumors (NETs) on patients' lives, the patient journey is not well documented. The aim of this survey was to identify the impact and burden of NETs from the patient perspective. Methods: This was a self-reported global survey regarding NET knowledge/awareness, disease impact/management, interaction with medical teams, and desired improvements. One hundred thirty-eight patients (7% of the global study) in the Oceania region answered closed-ended questions using graded descriptors on their experience of living with NETs. Results: The personal lives of patients were negatively impacted by NETs, including overall energy levels (72%, 99/138), emotional health (66%, 91/138), and finances (56%, 77/138). Eighty-one percent (22/27) of patients not currently working stated that their NET was the reason they were not employed. Of those still working, taking days off work (64%, 39/61), working reduced hours (44%, 27/61) and stopping work for a period of time (31%, 19/61) were the most frequently reported outcomes of having a NET. Although most patients felt supported by their medical team (53% [73/138] reported being extremely or very supported by healthcare professionals in general), patients also identified areas for improvement in patient care. Better access to NET-specific treatments (58%, 80/138), more awareness about NETs (58%, 80/138) and materials to help patients better explain their condition (52%, 72/138) were indicated by patients as ways to help them live better with their disease. Conclusion: The survey demonstrated a considerable burden of NETs on patients' lives and identified areas for improvements in long-term management. [ABSTRACT FROM AUTHOR]

Background Hip fractures are associated with considerable morbidity and mortality. Hip fracture incidence varies across different levels of accessibility/remoteness and socioeconomic status (SES). As part of the Ageing, Chronic Disease and Injury Study, we aimed to map the pattern of hip fractures across the western region of the Australian state of Victoria, which contains a range of remoteness levels and SES. Methods Data on hip fractures resulting in hospital admission were extracted from the Victorian Admitted Episodes Dataset (VAED) for men and women aged 40 + years during 2010–2013 inclusive. An age-adjusted incidence rate (per 10,000 population/year) was calculated for the entire region. Crude incidence rates and length of acute care hospital stay (excluding rehabilitation) were calculated for each Local Government Area (LGA). The impact of aggregated age, accessibility/remoteness index of Australia (ARIA) and SES on hip fracture rates aggregated across LGAs was determined using Poisson regression. Results For men, the age-standardised rate of hospitalisations for hip fracture across the whole region was 19.2 per 10,000 population/year (95%CI 18.0–20.4) and for women, 40.0 (95%CI 38.3–41.7). The highest incidence rates for both sexes occurred in the less accessible LGAs of Yarriambiack and Hindmarsh, as well as the LGA with the lowest SES, Central Goldfields. In both sexes, approximately two thirds of individuals were discharged from acute hospital care within 14 days. Increasing age, higher remoteness and lower SES were all associated with higher hip fracture rates. Conclusion Crude incidence rates varied by location. Given that a high proportion of patients had acute hospital care of ≤ 14 days, and accessibility and SES were associated with hip fracture rates, these results can inform policy and provide a model for other groups to conduct similar research in their local environment. [ABSTRACT FROM AUTHOR]

Purpose: To assess the outcomes of the most elderly cohort of patients with a diagnosis of glioblastoma multiforme (GBM) after intensity modulated radiation therapy (IMRT).Methods and Materials: The data of patients with GBM who had underwent IMRT from May 2007 to December 2015 were entered into a prospective database. Analysis was performed on the data from patients diagnosed during or after 75 years of age. The primary endpoint was the median survival. Univariate and multivariate analyses were performed with respect to survival for patients aged 74 to 80 versus >80 years, Eastern Cooperative Oncology Group performance status of 0 to 1 versus 2 to 3, extent of resection, a high radiation dose (60 Gy) versus any hypofractionated schedule, MGMT methylation status, planning target volume, and the use of temozolomide (TMZ) versus no TMZ.Results: Of the 108 patients, 35 received best supportive care, 1 received TMZ alone, 40 received RT alone, and 32 received combined RT and TMZ. IMRT was delivered with a hypofractionated technique (40 Gy) in 58 patients or long-course RT (60 Gy) in 11 patients. The median age was 79 years, with 61.6% of patients aged 74 to 80 years and 38.4% aged >80 years. Of the 108 patients, 64 died during the follow-up period, with a median survival of 10 months (95% confidence interval 7.1-11.9), projected 12-month survival rate of 35.6%, and 24-month survival rate of 7.9%. On univariate analysis, the independent predictors of survival included younger age (P=.02), better performance status (P=.014), greater resection extent (P=.002), and TMZ use (P<.001). MGMT methylation status, RT dose, and planning target volume showed no significant differences between the groups. Only chemotherapy use remained statistically significant (P=.035) on multivariate analysis.Conclusion: The current data underrepresent elderly patients aged >75 years with GBM. Despite elderly patients having a worse prognosis, the results of the present study suggest the presence of survival benefits with IMRT for selected patients that can be further extended with addition of TMZ. Further study of this cohort and an understanding of the appropriate selection criteria are warranted. [ABSTRACT FROM AUTHOR]

Background: The O 6 -methylguanine methyltransferase (MGMT) gene is frequently unmethylated in patients with glioblastoma (GBM), rendering them non-responsive to the standard treatment regime of surgery followed by concurrent radiotherapy (RT) and temozolomide. Here, we investigate the efficacy of adding a PARP inhibitor, veliparib, to radiotherapy to treat MGMT unmethylated GBM.Methods: The inhibition of PARP with veliparib (ABT-888), a potent and orally bioavailable inhibitor in combination with RT was tested on a panel of patient derived cell lines (PDCLs) and patient-derived xenografts (PDX) models generated from GBM patients with MGMT unmethylated tumors.Results: The combination of veliparib and RT inhibited colony formation in the majority of PDCLs tested. The PDCL, RN1 showed significantly reduced levels of the homologous repair protein, Mre11 and a heightened response to PARP inhibition measured by increased apoptosis and decreased colony formation. The oral administration of veliparib (12.5 mg/kg, twice daily for 5 days in a 28-day treatment cycle) in combination with whole brain RT (4 Gy) induced apoptosis (Tunel staining) and decreased cell proliferation (Ki67 staining) in a PDX of MGMT unmethylated GBM. Significantly longer survival times of the PDX treated with the combination treatment were recorded compared to RT only or veliparib only.Conclusions: Our results demonstrate preclinical efficacy of targeting PARP at multiple levels and provide a new approach for the treatment of MGMT unmethylated GBM. [ABSTRACT FROM AUTHOR]

Objectives The role of anti-angiogenic tyrosine kinase inhibitors (AATKI) for patients with non-small-cell lung cancers (NSCLC) is uncertain. We conducted a comprehensive meta-analysis to assess the overall utility of adding AATKI to chemotherapy. Materials and Methods We included 15 randomized controlled trials (RCTs) of AATKI plus chemotherapy versus chemotherapy involving 7997 patients with advanced NSCLC. Meta-analysis was performed to obtain pooled hazard ratios (HR) for OS and PFS, and pooled odds ratios (OR) for objective response rate (ORR) and grade 3 or greater toxicity. Pre-specified subgroup analyses were performed according to line of chemotherapy, chemotherapeutic regimen and histology. Results The addition of AATKI to chemotherapy significantly increased progression-free survival (PFS) (HR 0.83, 95% CI 0.79, 0.87; P < 0.00001) and ORR [OR 1.63, 95% CI 1.45, 1.84; P < 0.00001], but not overall survival (OS) (HR 0.96, 95% CI 0.91, 1.01; P = 0.14). OS benefit was seen in the subset of patients with adenocarcinomas (HR 0.86; 95% CI 0.79, 0.95; P = 0.002), especially in the second line setting (HR 0.85; 95% CI 0.76, 0.96; P = 0.008). However, both grade ≥3 toxicity (HR 2.08, 95% CI 1.59, 2.73; P < 0.00001) and treatment-related deaths (OR 2.37, 95% CI 1.58, 3.56; P<0.0001) were significantly higher with the addition of AATKI. Conclusion The addition of AATKI to chemotherapy in patients with advanced NSCLC significantly increased PFS and ORR but not OS, and did so at the expense of increased toxicity and treatment-related deaths. Preclinical and translational research in predictive biomarkers are essential for the clinical development of this class of drugs. [ABSTRACT FROM AUTHOR]

Background: Patients with metastatic colorectal cancer whose disease has progressed on oxaliplatin- and irinotecan-containing regimens may benefit from EGFR-inhibiting monoclonal antibodies if they do not contain mutations in the KRAS gene (are "wild type"). It is unknown whether these antibodies, such as cetuximab, are more efficacious in refractory metastatic colorectal cancer as monotherapy, or in combination with irinotecan. Lack of mutation in KRAS, BRAF and PIK3CA predicts response to EFGR-inhibitors. The ICECREAM trial examines the question of monotherapy versus combination with chemotherapy in two groups of patients: those with a "quadruple wild type" tumour genotype (no mutations in KRAS, NRAS, PI3KCA or BRAF genes) and those with the specific KRAS mutation in codon G13D, for whom possibly EGFR-inhibitor efficacy may be equivalent.Methods and Design: ICECREAM is a randomised, phase II, open-label, controlled trial comparing the efficacy of cetuximab alone or with irinotecan in patients with "quadruple wild type" or G13D-mutated metastatic colorectal cancer, whose disease has progressed on, or who are intolerant of oxaliplatin- and fluoropyrimidine-based chemotherapy. The primary endpoint is the 6-month progression-free survival benefit of the treatment regimen. Secondary endpoints are response rate, overall survival, and quality of life. The tertiary endpoint is prediction of outcome with further biological markers. International collaboration has facilitated recruitment in this prospective trial of treatment in these infrequently found molecular subsets of colorectal cancer.Discussion: This unique trial will yield prospective information on the efficacy of cetuximab and whether this is further enhanced with chemotherapy in two distinct populations of patients with metastatic colorectal cancer: the "quadruple wild type", which may 'superselect' for tumours sensitive to EGFR-inhibition, and the rare KRAS G13D mutated tumours, which are also postulated to be sensitive to the drug. The focus on establishing both positive and negative predictive factors for the response to targeted therapy is an attempt to improve outcomes, reduce toxicity and contain treatment costs. Tissue and blood will yield a resource for molecular studies. Recruitment, particularly of patients with the rare G13D mutation, will demonstrate the ability for international collaboration to run prospective trials in small colorectal cancer molecular subgroups.Trial Registration: Australian and New Zealand Clinical Trials Registry: ACTRN12612000901808 , registered 16 August 2012. [ABSTRACT FROM AUTHOR]

Objective This paper aims to describe cancer survival and examine association between survival and socio-demographic characteristics across Barwon South- Western region ( BSWR) in Victoria, Australia. Design This study is based on the retrospective cohort database of patients accessing oncology services across BSWR. Setting Six rural and three urban hospital settings across the BSWR. Participants The participants were patients who were diagnosed with cancer in 2009. Main outcome measures Overall survival (OS) of participants was the main outcome measure. Results Total of 1778 eligible patients had four-year OS for all cancers combined of 59.7% (95% CI, 57.4-62.0). Improved OS was observed for patients in the upper socio-economic tertile (64.2%; 95% CI, 60.9-67.5) compared to the middle (59.3%; 95% CI, 55.5-63.1) and lowest tertiles (49.6%; 95% CI, 44.2-54.9) ( P < 0.01). On multivariate analyses, higher socio-economic status remained a significant predictor of OS adjusting for gender, remoteness and age ( HR [hazard ratio] 0.81; 95% CI 0.74-0.89; P < 0.01). Remoteness was significantly associated with improved OS after adjusting for age, gender and socio-economic status ( HR 0.86; 95% CI, 0.77-0.97; P = 0.01). Older age ≥70 years compared to <70 years conferred inferior OS ( HR 3.08; 95% CI, 2.64-3.59; P < 0.01). Conclusions Our study confirmed improved survival outcomes for patients of higher socio-economic status and younger age. Future research to explain the unexpected survival benefit in patients who lived in more remote areas should examine factors including the correlation between geographical residence and eventual treatment facility as well as compare the BSWR care model to other regions' approaches. [ABSTRACT FROM AUTHOR]

Background: An increasing burden of chronic disease and associated health service delivery is expected due to the ageing Australian population. Injuries also affect health and wellbeing and have a long-term impact on health service utilisation. There is a lack of comprehensive data on disease and injury in rural and regional areas of Australia. The aim of the Ageing, Chronic Disease and Injury study is to compile data from various sources to better describe the patterns of chronic disease and injury across western Victoria. Design: Ecological study. Methods: Information on demographics, socioeconomic indicators and lifestyle factors are obtained from health surveys and government departments. Data concerning chronic diseases and injuries will be sourced from various registers, health and emergency services, local community health centres and administrative databases and compiled to generate profiles for the study region and for sub-populations within the region. Expected impact for public health: This information is vital to establish current and projected population needs to inform policy and improve targeted health services delivery, care transition needs and infrastructure development. This study provides a model that can be replicated in other geographical settings. [ABSTRACT FROM AUTHOR]

Aim Tyrosine kinase inhibitors ( TKIs) targeting the epidermal growth factor receptor ( EGFR) are well established in treating metastatic pulmonary adenocarcinoma, especially patients with activating EGFR mutations. EGFR mutations are rare in pulmonary squamous cell carcinomas ( SCCs). There are conflicting data supporting the efficacy of EGFR- TKIs in advanced lung SCC. We analyzed the impact of EGFR- TKIs on progression-free survival ( PFS) and overall survival ( OS) in unselected patients with lung SCC. Methods We searched for randomized controlled trials ( RCTs) comparing EGFR- TKIs alone with placebo in patients with metastatic non-small cell lung cancer. RCTs in all settings (front line/maintenance/subsequent) were included. The primary outcome was OS in the SCC population. We used published hazard ratios ( HRs), and when unavailable, unpublished data were sought. Pooled estimates of treatment effect on OS and PFS were calculated using the fixed-effects inverse variance weighted method. Results Eight eligible RCTs were included: 2 first-line, 6 second-line or beyond, evaluating 1781 patients. Data were available for OS in four studies (second-line; N = 1420) and for PFS in four studies (3 second-line, 1 first-line; N = 788). EGFR- TKIs significantly prolonged OS with a HR of 0.88 (95% confidence interval [ CI] 0.78-1.00, P = 0.04), and significantly prolonged PFS with a HR of 0.77 (95% CI 0.65-0.92, P = 0.004). Conclusion EGFR mutations are rare in lung SCC. However, EGFR- TKIs have a modest therapeutic effect compared to placebo in unselected patients with advanced pulmonary SCC, and can be considered in these patients. EGFR-mutation-independent mechanisms may explain efficacy of EGFR inhibitors in this setting. [ABSTRACT FROM AUTHOR]

Advances in the diagnosis and multi-modality treatment of cancer have increased survival rates for many cancer types leading to an increasing load of long-term sequelae of therapy, including that of cognitive dysfunction. The cytotoxic nature of chemotherapeutic agents may also reduce neurogenesis, a key component of the physiology of memory and cognition, with ramifications for the patient's mood and other cognition disorders. Similarly radiotherapy employed as a therapeutic or prophylactic tool in the treatment of primary or metastatic disease may significantly affect cognition. A number of emerging pharmacotherapies are under investigation for the treatment of cognitive dysfunction experienced by cancer patients. Recent data from clinical trials is reviewed involving the stimulants modafinil and methylphenidate, mood stabiliser lithium, anti-Alzheimer's drugs memantine and donepezil, as well as other agents which are currently being explored within dementia, animal, and cell culture models to evaluate their use in treating cognitive dysfunction in cancer patients. [ABSTRACT FROM AUTHOR]

BACKGROUND: This study sought to estimate the risk of breast cancer (BC) after a diagnosis of ovarian cancer (OC) associated with mutation of the BRCA1/2 (breast cancer, early onset) genes ( BRCA-OC). METHODS: The Memorial Sloan-Kettering Cancer Center and the University of Pennsylvania, clinical genetics databases were searched to identify women with BRCA-OC who participated in genetic testing and follow-up studies from 1995 to 2009. The primary objective was to determine the risk of developing BC after BRCA-OC. Overall survival (OS) and BC-free survival (BCFS) were determined by the Kaplan-Meier method; patients were censored at the time of last follow-up. RESULTS: A total of 164 patients had BRCA-OC (115 with BRCA1; 49 with BRCA2). Of these 164 patients, 152 developed OC prior to BRCA testing (median time to testing, 2.4 years [0.01-55 years]). Median follow-up from OC for those not developing BC was 5.8 years (0.25-55.6 years). There were 46 deaths, but none were due to BC. The 5- and 10-year OS were 85% (95% confidence interval [CI] = 0.78, 0.90) and 68% (95% CI = 0.59, 0.76), respectively. There were 18 metachronous BC diagnoses. The 5- and 10-year BCFS were 97% (95% CI = 0.92, 0.99) and 91% (95% CI = 0.82, 0.95), respectively. A subset of 64 women were tested either before or within 12 months of BRCA-OC. In this pseudo-incident subset, 5- and 10- year OS was 71% (95% CI = 0.53, 0.83) and 62% (95% CI = 0.44, 0.75), respectively, and 5- and 10-year BCFS were 100% and 87% (95% CI = 0.56, 0.96), respectively. CONCLUSIONS: OS was dominated by OC deaths. Metachronous BC risk was lower than reported for unaffected BRCA mutation carriers. These results support nonsurgical management of BC risk in women with BRCA-OC. Cancer 2013. © 2012 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: Cancer is a leading burden of disease in Australia and worldwide, with incidence rates varying with age, sex and geographic location. As part of the Ageing, Chronic Disease and Injury study, we aimed to map the incidence rates of primary cancer diagnoses across western Victoria and investigate the association of age, accessibility/remoteness index of Australia (ARIA) and area-level socioeconomic status (SES) with cancer incidence.Methods: Data on cancer incidence in the study region were extracted from the Victorian Cancer Registry (VCR) for men and women aged 40+ years during 2010-2013, inclusive. The age-adjusted incidence rates (per 10,000 population/year), as well as specific incidence for breast, prostate, lung, bowel and melanoma cancers, were calculated for the entire region and for the 21 Local Government Areas (LGA) that make up the whole region. The association of aggregated age, ARIA and SES with cancer incidence rates across LGAs was determined using Poisson regression.Results: Overall, 15,120 cancer cases were identified; 8218 (54%) men and 6902 women. For men, the age-standardised rate of cancer incidence for the whole region was 182.1 per 10,000 population/year (95% CI 177.7-186.5) and for women, 162.2 (95% CI: 157.9-166.5). The incidence of cancer (overall) increased with increasing age for men and women. Geographical variations in cancer incidence were also observed across the LGAs, with differences identified between men and women. Residents of socioeconomically disadvantaged and less accessible areas had higher cancer incidence (p < 0.001).Conclusion: Cancer incidence rates varied by age, sex, across LGAs and with ARIA. These findings not only provide an evidence base for identifying gaps and assessing the need for services and resource allocation across this region, but also informs policy and assists health service planning and implementation of preventative intervention strategies to reduce the incidence of cancer across western Victoria. This study also provides a model for further research across other geographical locations with policy and clinical practice implications, both nationally and internationally. [ABSTRACT FROM AUTHOR]

Delivery of highly sophisticated, and subspecialised, management protocols for glioblastoma in low volume rural and regional areas creates potential issues for equivalent quality of care. This study aims to demonstrate the impact on clinical quality indicators through the development of a novel model of care delivering an outsourced subspecialised neuro-oncology service in a regional centre compared with the large volume metropolitan centre. Three hundred and fifty-two patients with glioblastoma were managed under the European Organisation for Research and Treatment of Cancer and National Cancer Institute of Canada Clinical Trials Group (EORTC-NCIC) Protocol, and survival outcome was assessed in relation to potential prognostic factors and the geographical site of treatment, before and after opening of a regional cancer centre. The median overall survival was 17 months (95% CI: 15.5–18.5), with more favourable outcome with age less than 50 years (p < 0.001), near-total resection (p < 0.001), Eastern Cooperative Oncology Group (ECOG) Performance status 0, 1 (p < 0.001), and presence of O-6 methylguanine DNA methyltransferase (MGMT) methylation (p = 0.001). There was no difference in survival outcome for patients managed at the regional centre, compared with metropolitan centre (p = 0.35). Similarly, no difference was seen with clinical quality process indicators of clinical trial involvement, rates of repeat craniotomy, use of bevacizumab and re-irradiation. This model of neuro-oncology subspecialisation allowed equivalent outcomes to be achieved within a regional cancer centre compared to large volume metropolitan centre. [ABSTRACT FROM AUTHOR]

The article focuses on a survey conducted to analyze the prevalence of cancer in Iraq among young patients. It informs that data related with 100 patients presented with colorectal cancer (CRC) between January 2008 and December 2009 is presented. It reports several incidences of CRC in economically transitioning countries.