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Adenosine mediates immunosuppression within the tumor microenvironment through triggering adenosine 2A receptors (A2AR) on immune cells. To determine whether this pathway could be targeted as an immunotherapy, we performed a phase I clinical trial with a small-molecule A2AR antagonist. We find that this molecule can safely block adenosine signaling in vivo. In a cohort of 68 patients with renal cell cancer (RCC), we also observe clinical responses alone and in combination with an anti-PD-L1 antibody, including subjects who had progressed on PD-1/PD-L1 inhibitors. Durable clinical benefit is associated with increased recruitment of CD8 + T cells into the tumor. Treatment can also broaden the circulating T-cell repertoire. Clinical responses are associated with an adenosine-regulated gene-expression signature in pretreatment tumor biopsies. A2AR signaling, therefore, represents a targetable immune checkpoint distinct from PD-1/PD-L1 that restricts antitumor immunity. SIGNIFICANCE: This first-in-human study of an A2AR antagonist for cancer treatment establishes the safety and feasibility of targeting this pathway by demonstrating antitumor activity with single-agent and anti-PD-L1 combination therapy in patients with refractory RCC. Responding patients possess an adenosine-regulated gene-expression signature in pretreatment tumor biopsies.Copyright © 2019 American Association for Cancer Research.

Adenosine mediates immunosuppression within the tumor microenvironment through triggering adenosine 2A receptors (A2AR) on immune cells. To determine whether this pathway could be targeted as an immunotherapy, we performed a phase I clinical trial with a small-molecule A2AR antagonist. We find that this molecule can safely block adenosine signaling in vivo. In a cohort of 68 patients with renal cell cancer (RCC), we also observe clinical responses alone and in combination with an anti-PD-L1 antibody, including subjects who had progressed on PD-1/PD-L1 inhibitors. Durable clinical benefit is associated with increased recruitment of CD8 + T cells into the tumor. Treatment can also broaden the circulating T-cell repertoire. Clinical responses are associated with an adenosine-regulated gene-expression signature in pretreatment tumor biopsies. A2AR signaling, therefore, represents a targetable immune checkpoint distinct from PD-1/PD-L1 that restricts antitumor immunity. SIGNIFICANCE: This first-in-human study of an A2AR antagonist for cancer treatment establishes the safety and feasibility of targeting this pathway by demonstrating antitumor activity with single-agent and anti-PD-L1 combination therapy in patients with refractory RCC. Responding patients possess an adenosine-regulated gene-expression signature in pretreatment tumor biopsies.Copyright © 2019 American Association for Cancer Research.

A series of 1-(2,3-dihydro-1H-indan-1-yl)-3-aryl urea/thiourea derivatives (4a-j) have been synthesized from the reaction of 2,3-dihydro-1H-inden-1-amine (2) with various aryl isocyanates/isothiocyanates (3a-j) by using N,N-DIPEA base (Hunig's base) catalyst in THF at reflux conditions. All of them are structurally confirmed by spectral (IR, 1H & 13C NMR and MASS) and elemental analysis and screened for their in-vitro antioxidant activity against DPPH and NO free radicals and found that compounds 4b, 4i, 4h & 4g are potential antioxidants. The obtained in vitro results were compared with the molecular docking, ADMET, QSAR and bioactivity study results performed for them and identified that the recorded in silico binding affinities were observed in good correlation with the in vitro antioxidant results. The Molecular docking analysis had unveiled the strong hydrogen bonding interactions of synthesized ligands with ARG 160 residue of protein tyrosine kinase (2HCK) enzyme and plays an effective role in its inhibition. Toxicology studies have assessed the potential risks of 4a-j and inferred that all of them were in the limits of potential drugs. The conformational analysis of 4a-j inferred that the urea/thiourea spacer linking 2,3-dihydro-1H-inden-1-amino and substituted aryl units has facilitated all these molecules to effectively bind with ARG 160 amino acid residue present on the α-helix of the protein tyrosine kinase (2HCK) enzyme specifically on chain A of hemopoetic cell kinase. Collectively this study has established a relationship between the antioxidant potentiality and ligands binding with ARG 160 amino acid residue of chain A of 2HCK enzyme to inhibit its growth as well as proliferation of reactive oxygen species in vivo. © 2019 Elsevier Inc.

Introduction and Objectives: To evaluate long-term outcomes in patients undergoing radical nephrectomy and tumour thrombectomy at Monash Health over the last 10 years. Method(s): We performed a retrospective analysis of 27 patients undergoing surgery between 2005 and 2015. Follow-up data were available for 24 patients. Data on clinical presentation, laboratory and imaging investigations, tumour characteristics, staging, operative details, complications, and long-term follow-up were evaluated. Result(s): Twenty-seven patients were included in the study (19 males, 8 females). Patients aged between 37- 80 years with a mean age of 61 years. Eighteen patients (67%) had nodal or distant metastasis at the time of diagnosis. According to AJCC tumour thrombus classifications - level I in 13 patients (48%), level II in 5 patients (19%) and level III in 2 patients (7%). Post-operative complications of Clavien-Dindo grade III or above occurred in 4 patients (15%). Four patients (15%) received adjuvant chemotherapy and 10 patients (37%) received tyrosine-kinase inhibitor (TKI) therapy post-operatively. Mean follow-up period in this cohort was 62 months. At the time of follow-up 21 patients (78%) were still alive. Of the 6 deaths, 4 patients died of metastatic RCC, 1 patient died during re-operation and the cause of death was not recorded for the last patient. Conclusion(s): Radical nephrectomy and tumour thrombectomy offer reasonable long-term survival in patients with locally advanced RCC. The complication rates at our centre are comparable with that of the literature.

Introduction and Objectives: To evaluate long-term outcomes in patients undergoing radical nephrectomy and tumour thrombectomy at Monash Health over the last 10 years. Method(s): We performed a retrospective analysis of 27 patients undergoing surgery between 2005 and 2015. Follow-up data were available for 24 patients. Data on clinical presentation, laboratory and imaging investigations, tumour characteristics, staging, operative details, complications, and long-term follow-up were evaluated. Result(s): Twenty-seven patients were included in the study (19 males, 8 females). Patients aged between 37- 80 years with a mean age of 61 years. Eighteen patients (67%) had nodal or distant metastasis at the time of diagnosis. According to AJCC tumour thrombus classifications - level I in 13 patients (48%), level II in 5 patients (19%) and level III in 2 patients (7%). Post-operative complications of Clavien-Dindo grade III or above occurred in 4 patients (15%). Four patients (15%) received adjuvant chemotherapy and 10 patients (37%) received tyrosine-kinase inhibitor (TKI) therapy post-operatively. Mean follow-up period in this cohort was 62 months. At the time of follow-up 21 patients (78%) were still alive. Of the 6 deaths, 4 patients died of metastatic RCC, 1 patient died during re-operation and the cause of death was not recorded for the last patient. Conclusion(s): Radical nephrectomy and tumour thrombectomy offer reasonable long-term survival in patients with locally advanced RCC. The complication rates at our centre are comparable with that of the literature.

There is a strong argument for the use of antifungal prophylaxis in high-risk patients given the significant mortality associated with invasive fungal disease, the late identification of these infections, and the availability of safe and well-tolerated prophylactic medications. Clinical decisions about which patients should receive prophylaxis and choice of antifungal agent should be guided by risk stratification, knowledge of local fungal epidemiology, the efficacy and tolerability profile of available agents, and estimates such as number needed to treat and number needed to harm. There have been substantial changes in practice since the 2008 guidelines were published. These include the availability of new medications and/or formulations, and a focus on refining and simplifying patient risk stratification. Used in context, these guidelines aim to assist clinicians in providing optimal preventive care to this vulnerable patient demographic.Copyright © 2014 The Authors; Internal Medicine Journal © 2014 Royal Australasian College of Physicians.

Aims: Thyroid cancer represents less than 1% of all human cancers. Metastatic thyroid cancer forms an even rarer entity. There have been a number of recent advances in treatment, namely in molecular profiling and targeted therapy. Method(s): We reviewed the latest literature as well as all cases of metastatic thyroid cancer managed at our institution over the past five years. We selected three cases that best highlight key management principles. Result(s): The first case is of a 27 year old Vietnamese male with metastatic follicular cancer on a background of thyroid lobectomy 7 years prior for follicular adenoma. He presented with symptomatic pulmonary and vertebral metastases. Retrospective review of the original lobectomy revealed a missed minimally invasive follicular carcinoma. He was commenced on systemic therapy with the tyrosine kinase inhibitor sorafenib, then changed to lenvatinib on progression. He was briefly transitioned to MEK inhibitor trametinib to facilitate tumour re-differentiation and sensitisation to radioactive iodine. The second case is of a BRAF mutation positive metastatic papillary thyroid cancer in a 57 year old East Timorese female. Her condition was complicated by DIC and SVC obstruction. Commencement of BRAF inhibitor vemurafenib resulted in clinical and haematological improvement allowing for discharge home. The third case is of a 28 year old Caucasian male with a new diagnosis of sporadic MEN2A syndrome. Diagnosis was made during an inpatient admission for back pain. Investigations revealed metastatic medullary thyroid cancer complicated by extensive bone metastases. Screening detected phaeochromocytoma and primary hyperparathyroidism. Radiotherapy for bone metastases was commenced and access for vandetanib was arranged, after considering cabozantinib through clinical trial. Unfortunately, he developed tumour-induced DIC and significant functional decline. He was discharged home with palliative care. Conclusion(s): All three cases high

There is a strong argument for the use of antifungal prophylaxis in high-risk patients given the significant mortality associated with invasive fungal disease, the late identification of these infections, and the availability of safe and well-tolerated prophylactic medications. Clinical decisions about which patients should receive prophylaxis and choice of antifungal agent should be guided by risk stratification, knowledge of local fungal epidemiology, the efficacy and tolerability profile of available agents, and estimates such as number needed to treat and number needed to harm. There have been substantial changes in practice since the 2008 guidelines were published. These include the availability of new medications and/or formulations, and a focus on refining and simplifying patient risk stratification. Used in context, these guidelines aim to assist clinicians in providing optimal preventive care to this vulnerable patient demographic.Copyright © 2014 The Authors; Internal Medicine Journal © 2014 Royal Australasian College of Physicians.

Introduction: Renal cell carcinoma is known to extend into the IVC in 4-10% of cases.1-3 Despite the technical difficulty, cytoreductive nephrectomy has a role in palliation and may increase survival. We present a retrospective, multi-institution case series of patients undergoing radical nephrectomy and IVC thrombectomy. Material(s) and Method(s): We conducted a retrospective review of the medical records of patients undergoing a radical nephrectomy with caval thrombectomy performed by three uro-oncology units from June 1997 to June 2011. Patient demographics, thrombus extension, tumour size, length of stay, blood loss and complications were recorded. Outcome measures were based on disease progression and patient status at time of follow-up. Result(s): 29 patients were identified with 18 males and 11 females. The male mean age was 54, the female mean age was 63, and the overall mean age was 58 years. The patients were classified according to Neves score. 14 patients had Neves classification of I, 8 Neves II, 2 Neves III, and 5 Neves IV. Mean tumour size was 103.9mm (range 25-180). Mean blood loss was 1580mL (range 90-8500). Mean operative time (n=22) was 180 minutes (range 70-390). Mean LOS (n=18) was 8.8 days (range 5-22). 31% of patients had a positive surgical margin. Complication and follow-up data was limited. Complication data was available for 9 patients. There was one grade V complication, one IVb, one IIIa, six II, and one grade I complication. Followup data was available for 15 patients. Of these the mean survival time post operatively was 17.7 months (range 3-90) Conclusion(s): Despite the invasive nature of radical nephrectomy with caval thrombectomy, blood loss, LOS and complication rates are acceptable. Mean survival post surgery of 17.7 months will likely increase in the Tyrosine Kinase Inhibitor era. However, one must consider the physiological status of the patient prior to embarking on surgical intervention.

Introduction: Renal cell carcinoma is known to extend into the IVC in 4-10% of cases.1-3 Despite the technical difficulty, cytoreductive nephrectomy has a role in palliation and may increase survival. We present a retrospective, multi-institution case series of patients undergoing radical nephrectomy and IVC thrombectomy. Material(s) and Method(s): We conducted a retrospective review of the medical records of patients undergoing a radical nephrectomy with caval thrombectomy performed by three uro-oncology units from June 1997 to June 2011. Patient demographics, thrombus extension, tumour size, length of stay, blood loss and complications were recorded. Outcome measures were based on disease progression and patient status at time of follow-up. Result(s): 29 patients were identified with 18 males and 11 females. The male mean age was 54, the female mean age was 63, and the overall mean age was 58 years. The patients were classified according to Neves score. 14 patients had Neves classification of I, 8 Neves II, 2 Neves III, and 5 Neves IV. Mean tumour size was 103.9mm (range 25-180). Mean blood loss was 1580mL (range 90-8500). Mean operative time (n=22) was 180 minutes (range 70-390). Mean LOS (n=18) was 8.8 days (range 5-22). 31% of patients had a positive surgical margin. Complication and follow-up data was limited. Complication data was available for 9 patients. There was one grade V complication, one IVb, one IIIa, six II, and one grade I complication. Followup data was available for 15 patients. Of these the mean survival time post operatively was 17.7 months (range 3-90) Conclusion(s): Despite the invasive nature of radical nephrectomy with caval thrombectomy, blood loss, LOS and complication rates are acceptable. Mean survival post surgery of 17.7 months will likely increase in the Tyrosine Kinase Inhibitor era. However, one must consider the physiological status of the patient prior to embarking on surgical intervention.

Free to read The majority of patients with non-small-cell lung cancer (NSCLC) present with advanced disease, with targeted therapies providing some improvement in clinical outcomes. The epidermal growth factor receptor (EGFR) tyrosine kinase (TK) plays an important role in the pathogenesis of NSCLC. Tyrosine kinase inhibitors (TKIs), which target the EGFR TK domain, have proven to be an effective treatment strategy; however, patient responses to treatment vary considerably. Therefore, the identification of patients most likely to respond to treatment is essential to optimise the benefit of TKIs. Tumour-associated activating mutations in EGFR can identify patients with NSCLC who are likely to have a good response to TKIs. Nonetheless, the majority of patients relapse within a year of starting treatment. Studies of tumours at relapse have demonstrated expression of a T790M mutation in exon 20 of the EGFR TK domain in approximately 50% of cases. Although conferring resistance to reversible TKIs, these patients may remain sensitive to new-generation irreversible/panerb inhibitors. A number of techniques have been employed for genotypic assessment of tumourassociated DNA to identify EGFR mutations, each of which has advantages and disadvantages. This review presents an overview of the current methodologies used to identify such molecular markers. Recent developments in technology may make the monitoring of changes in patients' tumour genotypes easier in clinical practice, which may enable patients' treatment regimens to be tailored during the course of their disease, potentially leading to improved patient outcomes.

Free to read Receptor tyrosine kinases (RTKs) and their downstream signalling pathways have long been hypothesized to play key roles in melanoma development. A decade ago, evidence was derived largely from animal models, RTK expression studies and detection of activated RAS isoforms in a small fraction of melanomas. Predictions that overexpression of specific RTKs implied increased kinase activity and that some RTKs would show activating mutations in melanoma were largely untested. However, technological advances including rapid gene sequencing, siRNA methods and phospho-RTK arrays now give a more complete picture. Mutated forms of RTK genes including KIT, ERBB4, the EPH and FGFR families and others are known in melanoma. Additional over- or underexpressed RTKs and also protein tyrosine phosphatases (PTPs) have been reported, and activities measured. Complex interactions between RTKs and PTPs are implicated in the abnormal signalling driving aberrant growth and survival in malignant melanocytes, and indeed in normal melanocytic signalling including the response to ultraviolet radiation. Kinases are considered druggable targets, so characterization of global RTK activity in melanoma should assist the rational development of tyrosine kinase inhibitors for clinical use. © 2011 John Wiley & Sons A/S.