Deep Learning and Multimodal Artificial Intelligence in Orthopaedic Surgery.

This review article focuses on the applications of deep learning with neural networks and multimodal neural networks in the orthopaedic domain. By providing practical examples of how artificial intelligence (AI) is being applied successfully in orthopaedic surgery, particularly in the realm of imaging data sets and the integration of clinical data, this study aims to provide orthopaedic surgeons with the necessary tools to not only evaluate existing literature but also to consider AI's potential in their own clinical or research pursuits. We first review standard deep neural networks which can analyze numerical clinical variables, then describe convolutional neural networks which can analyze image data, and then introduce multimodal AI models which analyze various types of different data. Then, we contrast these deep learning techniques with related but more limited techniques such as radiomics, describe how to interpret deep learning studies, and how to initiate such studies at your institution. Ultimately, by empowering orthopaedic surgeons with the knowledge and know-how of deep learning, this review aspires to facilitate the translation of research into clinical practice, thereby enhancing the efficacy and precision of real-world orthopaedic care for patients.

Phase II Study Investigating the Safety and Efficacy of Savolitinib and Durvalumab in Metastatic Papillary Renal Cancer (CALYPSO).

PURPOSE: Metastatic papillary renal cancer (PRC) has poor outcomes, and new treatments are required. There is a strong rationale for investigating mesenchymal epithelial transition receptor (MET) and programmed cell death ligand-1 (PD-L1) inhibition in this disease. In this study, the combination of savolitinib (MET inhibitor) and durvalumab (PD-L1 inhibitor) is investigated. METHODS: This single-arm phase II trial explored durvalumab (1,500 mg once every four weeks) and savolitinib (600 mg once daily; ClinicalTrials.gov identifier: NCT02819596). Treatment-naïve or previously treated patients with metastatic PRC were included. A confirmed response rate (cRR) of > 50% was the primary end point. Progression-free survival, tolerability, and overall survival were secondary end points. Biomarkers were explored from archived tissue (MET-driven status). RESULTS: Forty-one patients treated with advanced PRC were enrolled into this study and received at least one dose of study treatment. The majority of patients had Heng intermediate risk score (n = 26 [63%]). The cRR was 29% (n = 12; 95% CI, 16 to 46), and the trial therefore missed the primary end point. The cRR increased to 53% (95% CI, 28 to 77) in MET-driven patients (n/N = 9/27) and was 33% (95% CI, 17 to 54) in PD-L1-positive tumors (n/N = 9/27). The median progression-free survival was 4.9 months (95% CI, 2.5 to 10.0) in the treated population and 12.0 months (95% CI, 2.9 to 19.4) in MET-driven patients. The median overall survival was 14.1 months (95% CI, 7.3 to 30.7) in the treated population and 27.4 months (95% CI, 9.3 to not reached [NR]) in MET-driven patients. Grade 3 and above treatment related adverse events occurred in 17 (41%) patients. There was 1 grade 5 treatment-related adverse event (cerebral infarction). CONCLUSION: The combination of savolitinib and durvalumab was tolerable and associated with high cRRs in the exploratory MET-driven subset.

Major disparities in patient-reported adherence compared to objective assessment of adherence using mass spectrometry: A prospective study in a tertiary-referral hypertension clinic.

AIM: Many challenges exist in determining true rates of adherence to antihypertensive medications among individuals in a clinic setting. For the first time, we aimed to compare patient-reported antihypertensive adherence with objective evidence using mass spectrometry spot urinalysis in a tertiary referral clinic setting. METHODS: A prospective observational single-centre cohort study was performed in a tertiary referral hypertension clinic, encompassing antihypertensive initiation and persistence. Patients were referred with apparent treatment-resistant hypertension or for suspected secondary causes. Participants completed a self-reported assessment of antihypertensive adherence and provided a spot urine sample. The presence of antihypertensive medications and/or their respective metabolites was evaluated using high-performance liquid chromatography tandem mass spectrometry. Patients were determined to be adherent if they demonstrated both self-reported adherence and objective mass spectrometry evidence. RESULTS: Of all 105 eligible participants initially recruited, 73 (69.5%) met the eligibility criteria. Only 27.4% (95% confidence interval 0.2-0.4) of participants demonstrated true adherence to their self-reported antihypertensives, despite 75.3% (0.6-0.8) reporting adherence. Greatest medication adherence was achieved with angiotensin II receptor blockers (61%), with calcium-channel blockers and mineralocorticoid antagonists demonstrating least adherence (38%). CONCLUSION: In patients attending a tertiary hypertension clinic, the combined use of spot urine mass spectrometry and self-reporting identifies higher rates of nonadherence when compared to either modality alone. Both techniques should be combined for more accurate detection of medication adherence.

Real-world outcomes with ipilimumab and nivolumab in advanced melanoma: a multicentre retrospective study.

PURPOSE: To assess efficacy and toxicity of combination immunotherapy with ipilimumab plus nivolumab in routine practice in a retrospective multicentre cohort of patients with advanced melanoma. PATIENTS AND METHODS: This retrospective analysis included patients with advanced melanoma treated with ipilimumab and nivolumab between October 2015 and January 2020 at six centres in Australia, Europe and the United States of America. We describe efficacy outcomes (overall survival [OS], progression-free survival [PFS] and objective response rate [ORR]) in treatment-naïve and pre-treated patients, with and without brain metastases, plus treatment-related adverse events (trAEs) in all patients treated. RESULTS: A total of 697 patients were identified; 472 were treatment-naïve of which 138 (29.2%) had brain metastases, and 225 were previously treated of which 102 (45.3%) had brain metastases. At baseline, 32.3% had stage M1c and 34.4% stage M1d disease. Lactate dehydrogenase was high in 280 patients (40.2%). With a median follow-up of 25.9 months, median OS in the 334 treatment-naïve patients without brain metastases was 53.7 months (95% confidence interval [CI] 40.8-NR) and 38.7 months (95% CI 18.6-NR) for the 138 treatment-naïve patients with brain metastases. For the entire cohort the ORR was 48%, for treatment-naïve patients without brain metastases ORR was 56.6% with a median PFS of was 13.7 months (95% CI 9.6-26.5). Median PFS was 7.9 months (95% CI 5.8-10.4) and OS 38 months (95% CI 31-NR) for the entire cohort. Grade 3-4 trAE were reported in 44% of patients, and 4 (0.7%) treatment-related deaths (1 pneumonitis, 2 myocarditis and 1 colitis) were recorded. CONCLUSION: The outcome and toxicity of combination immunotherapy with ipilimumab and nivolumab in a real-world patient population are similar to those reported in pivotal trials.

Aspirin in the Modern Era of Cardiovascular Disease Prevention.

Aspirin's antithrombotic effects have a long-established place in the prevention of cardiovascular disease (CVD), and its traditional use as a core therapy for secondary prevention of CVD is well recognized. However, with the advent of newer antiplatelet agents and an increasing understanding of aspirin's bleeding risks, its role across the full spectrum of modern CVD prevention has become less certain. As a consequence, recent trials have begun investigating aspirin-free strategies in secondary prevention. For example, a contemporary metanalysis of trials that assessed P2Y12 inhibitor monotherapy versus prolonged (≥ 12 months) dual antiplatelet therapy (which includes aspirin) after percutaneous coronary intervention reported a lower risk of major bleeding and no increase in stent thrombosis, all-cause mortality, myocardial infarction (MI), or stroke in the P2Y12 monotherapy group. In contrast to secondary prevention, aspirin's role in primary prevention has always been more controversial. While historical trials reported a reduction in MI and stroke, more contemporary trials have suggested diminishing benefit for aspirin in this setting, with no reduction in hard outcomes, and some primary prevention trials have even indicated a potential for harm. In this review, we discuss how changing population demographics, enhanced control of lipids and blood pressure, changes in the definition of outcomes like MI, evolution of aspirin formulations, and updated clinical practice guidelines have all impacted the use of aspirin for primary and secondary CVD prevention.

Lifileucel, a Tumor-Infiltrating Lymphocyte Therapy, in Metastatic Melanoma.

PURPOSE: Effective treatment options are limited for patients with advanced (metastatic or unresectable) melanoma who progress after immune checkpoint inhibitors and targeted therapies. Adoptive cell therapy using tumor-infiltrating lymphocytes has demonstrated efficacy in advanced melanoma. Lifileucel is an autologous, centrally manufactured tumor-infiltrating lymphocyte product. METHODS: We conducted a phase II open-label, single-arm, multicenter study in patients with advanced melanoma who had been previously treated with checkpoint inhibitor(s) and BRAF ± MEK targeted agents. Lifileucel was produced from harvested tumor specimens in central Good Manufacturing Practice facilities using a streamlined 22-day process. Patients received a nonmyeloablative lymphodepletion regimen, a single infusion of lifileucel, and up to six doses of high-dose interleukin-2. The primary end point was investigator-assessed objective response rate (ORR) per RECIST, version 1.1. RESULTS: Sixty-six patients received a mean of 3.3 prior therapies (anti-programmed death 1 [PD-1] or programmed death ligand 1 [PD-L1]: 100%; anticytotoxic T-lymphocyte-associated protein-4: 80%; BRAF ± MEK inhibitor: 23%). The ORR was 36% (95% CI, 25 to 49), with two complete responses and 22 partial responses. Disease control rate was 80% (95% CI, 69 to 89). Median duration of response was not reached after 18.7-month median study follow-up (range, 0.2-34.1 months). In the primary refractory to anti-PD-1 or PD-L1 therapy subset, the ORR and disease control rate were 41% (95% CI, 26 to 57) and 81% (95% CI, 66 to 91), respectively. Safety profile was consistent with known adverse events associated with nonmyeloablative lymphodepletion and interleukin-2. CONCLUSION: Lifileucel demonstrated durable responses and addresses a major unmet need in patients with metastatic melanoma with limited treatment options after approved therapy, including the primary refractory to anti-PD-1 or PD-L1 therapy subset.

Open-Label, Single-Arm Phase II Study of Pembrolizumab Monotherapy as First-Line Therapy in Patients With Advanced Clear Cell Renal Cell Carcinoma.

PURPOSE: Pembrolizumab, a programmed death 1 inhibitor, demonstrated promising single-agent activity in untreated patients with various cancer types. The phase II KEYNOTE-427 study evaluated efficacy and safety of single-agent pembrolizumab in treatment-naive patients with advanced clear cell renal cell carcinoma (ccRCC; cohort A) and advanced non-ccRCC (cohort B). Results of cohort A are reported. METHODS: In this open-label, single-arm phase II study, patients with advanced ccRCC received pembrolizumab 200 mg every 3 weeks for ≤ 24 months. The primary end point was objective response rate by RECIST, version 1.1. RESULTS: In the total population (N = 110), median time from enrollment to data cutoff was 35.9 (range, 29.5-40.3) months. Objective response rate was 36.4% with four (3.6%) complete responses and 36 (32.7%) partial responses; disease control rate was 58.2% (95% CI, 48.4 to 67.5). Most patients (68.2%) had a decrease in target lesions, including 30.9% with a reduction ≥ 60%. Median duration of response was 18.9 (range, 2.3-37.6+) months; 64.1% of responders had a response ≥ 12 months (Kaplan-Meier). Median progression-free survival was 7.1 months (95% CI, 5.6 to 11.0). Median overall survival was not reached; 12-month and 24-month overall survival rates were 88.2% and 70.8%, respectively. Durable responses were observed across all International Metastatic RCC Database Consortium categories. Grade 3-5 treatment-related adverse events were reported in 30.0% of patients, of which colitis and diarrhea were most frequent. CONCLUSION: Single-agent pembrolizumab showed promising antitumor activity as a first-line treatment in patients with advanced ccRCC, with durable responses across International Metastatic RCC Database Consortium categories. Safety and tolerability profile of pembrolizumab monotherapy was comparable to what has been previously described in other tumor types.

Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study.

BACKGROUND: Pembrolizumab improved progression-free survival and overall survival versus ipilimumab in patients with advanced melanoma and is now a standard of care in the first-line setting. However, the optimal duration of anti-PD-1 administration is unknown. We present results from 5 years of follow-up of patients in KEYNOTE-006. METHODS: KEYNOTE-006 was an open-label, multicentre, randomised, controlled, phase 3 study done at 87 academic institutions, hospitals, and cancer centres in 16 countries. Patients aged at least 18 years with Eastern Cooperative Oncology Group performance status of 0 or 1, ipilimumab-naive histologically confirmed advanced melanoma with known BRAFV600 status and up to one previous systemic therapy were randomly assigned (1:1:1) to intravenous pembrolizumab 10 mg/kg every 2 weeks or every 3 weeks or four doses of intravenous ipilimumab 3 mg/kg every 3 weeks. Treatments were assigned using a centralised, computer-generated allocation schedule with blocked randomisation within strata. Exploratory combination of data from the two pembrolizumab dosing regimen groups was not protocol-specified. Pembrolizumab treatment continued for up to 24 months. Eligible patients who discontinued pembrolizumab with stable disease or better after receiving at least 24 months of pembrolizumab or discontinued with complete response after at least 6 months of pembrolizumab and then progressed could receive an additional 17 cycles of pembrolizumab. Co-primary endpoints were overall survival and progression-free survival. Efficacy was analysed in all randomly assigned patients, and safety was analysed in all randomly assigned patients who received at least one dose of study treatment. Exploratory assessment of efficacy and safety at 5 years' follow-up was not specified in the protocol. Data cutoff for this analysis was Dec 3, 2018. Recruitment is closed; the study is ongoing. This study is registered with ClinicalTrials.gov, number NCT01866319. FINDINGS: Between Sept 18, 2013, and March 3, 2014, 834 patients were enrolled and randomly assigned to receive pembrolizumab (every 2 weeks, n=279; every 3 weeks, n=277), or ipilimumab (n=278). After a median follow-up of 57·7 months (IQR 56·7-59·2) in surviving patients, median overall survival was 32·7 months (95% CI 24·5-41·6) in the combined pembrolizumab groups and 15·9 months (13·3-22·0) in the ipilimumab group (hazard ratio [HR] 0·73, 95% CI 0·61-0·88, p=0·00049). Median progression-free survival was 8·4 months (95% CI 6·6-11·3) in the combined pembrolizumab groups versus 3·4 months (2·9-4·2) in the ipilimumab group (HR 0·57, 95% CI 0·48-0·67, p<0·0001). Grade 3-4 treatment-related adverse events occurred in 96 (17%) of 555 patients in the combined pembrolizumab groups and in 50 (20%) of 256 patients in the ipilimumab group; the most common of these events were colitis (11 [2%] vs 16 [6%]), diarrhoea (ten [2%] vs seven [3%]), and fatigue (four [<1%] vs three [1%]). Any-grade serious treatment-related adverse events occurred in 75 (14%) patients in the combined pembrolizumab groups and in 45 (18%) patients in the ipilimumab group. One patient assigned to pembrolizumab died from treatment-related sepsis. INTERPRETATION: Pembrolizumab continued to show superiority over ipilimumab after almost 5 years of follow-up. These results provide further support for use of pembrolizumab in patients with advanced melanoma. FUNDING: Merck Sharp & Dohme.

Tumor Board Shadowing: A Unique Approach for Integrating Radiation Oncologists Into General Medical Student Education.

PURPOSE: Radiation oncology is often overlooked in US medical school curricula, with few opportunities for most students to learn about the specialty or the value of radiation therapy in cancer care. Tumor boards represent a potential avenue not only to increase students' exposure to radiation oncologists but also to provide a fundamental understanding of the multidisciplinary nature of cancer care and effective collaboration in clinical practice. METHODS AND MATERIALS: In this study, we evaluated a novel radiation oncologist-driven tumor board shadowing experience at 3 medical schools in the United States and Canada. A total of 323 first- and second-year medical students participated, of whom 77.4% completed a follow-up survey assessing the effectiveness of the program as a learning tool. RESULTS: Compared with traditional clinical shadowing, students were more likely to believe that tumor board shadowing provided a similar or better experience in terms of educational content (85%), exposure to a new field (96%), and overall experience (89%). Forty-eight percent of students perceived a greater amount of multidisciplinary collaboration in oncologic care than they thought existed prior to attending. Forty-eight percent of students also felt more competent interacting with oncologists after participating, whereas 21% felt more competent interacting with patients with cancer. Students' perception of increased competence was correlated with the amount of time their assigned physician mentor spent answering their questions after the tumor board (P < .01). Second-year medical students also had a more favorable overall experience than first-year medical students did (P = .04). CONCLUSIONS: Multidisciplinary tumor boards can be used effectively as a unique immersive learning opportunity that can be feasibly implemented to improve knowledge of clinical oncology and multidisciplinary care in medical schools and expose students to physicians in smaller fields such as radiation oncology.

Novel combination strategies for enhancing efficacy of immune checkpoint inhibitors in the treatment of metastatic solid malignancies.

INTRODUCTION: Immune-checkpoint inhibitor (ICPI) drugs, which include antibodies against CTLA-4, PD-1 and PD-L1, have been shown to induce durable complete responses in a proportion of patients with particular efficacy demonstrated in both the first line and refractory setting in advanced NSCLC and melanoma. However, these drugs remain effective only in a minority of unselected patients. Areas covered: This review will focus on mechanisms of resistance to ICPI and underline the importance of identification of novel predictive markers of responsiveness. The rationale for the combination of ICPI with specific chemotherapies, targeted therapies and other immuno-oncology drugs in order to improve efficacy will be provided. Expert opinion: There are near-endless permutations of combination strategies of these agents with ICPI that have become feasible treatment strategies. Development of an understanding of resistance mechanisms to ICPI by a shift towards translational approaches to comprehensive genomic profiling and interrogation of the tumor microenvironment will encourage recruitment of patients into biomarker-driven combination trials. More than ever, industry professionals, clinicians and scientists will need to collaborate to increase the investment in clinical trials of those therapeutic agents and combination strategies which are most likely to be transformative for patients.

Active surveillance in metastatic renal-cell carcinoma: a prospective, phase 2 trial.

BACKGROUND: A subset of patients with metastatic renal-cell carcinoma show indolent growth of metastases. Because of the toxicity and non-curative nature of systemic therapy, some of these patients could benefit from initial active surveillance. We aimed to characterise the time to initiation of systemic therapy in patients with metastatic renal-cell carcinoma under active surveillance. METHODS: In this prospective phase 2 trial, we enrolled patients with treatment-naive, asymptomatic, metastatic renal-cell carcinoma from five hospitals in the USA, Spain, and the UK. Patients were radiographically assessed at baseline, every 3 months for year 1, every 4 months for year 2, then every 6 months thereafter. Patients continued on observation until initiation of systemic therapy for metastatic renal-cell carcinoma; a decision that was made at the discretion of the treating physician and patient. The primary endpoint of the study was time to initiation of systemic therapy in the per-protocol population. The follow-up of patients is ongoing. FINDINGS: Between Aug 21, 2008, and June 7, 2013, we enrolled 52 patients. Median follow-up of patients in the study was 38·1 months (IQR 29·4-48·9). In the 48 patients included in analysis, median time on surveillance from registration on study until initiation of systemic therapy was 14·9 months (95% CI 10·6-25·0). Multivariate analysis showed that higher numbers of International Metastatic Database Consortium (IMDC) adverse risk factors (p=0·0403) and higher numbers of metastatic disease sites (p=0·0414) were associated with a shorter surveillance period. 22 (46%) patients died during the study period, all from metastatic renal-cell carcinoma. INTERPRETATION: A subset of patients with metastatic renal-cell carcinoma can safely undergo surveillance before starting systemic therapy. Additional investigation is required to further define the benefits and risks of this approach. FUNDING: None.

Management of poor-risk metastatic renal cell carcinoma: current approaches, the role of temsirolimus and future directions.

Targeted therapies have substantially improved outcomes in metastatic renal cell carcinoma (mRCC). As expected, poor-risk patients have the worst outcomes. Temsirolimus is currently the only agent licensed for treatment of poor-risk mRCC patients. It is associated with meaningful improvements in survival and quality of life, highlighting the importance of correctly stratifying risk in mRCC patients so they receive optimal treatment. Currently, data for other targeted therapies in poor-risk patients are relatively sparse. Optimizing outcomes in these patients is the subject of ongoing research, including studies of biomarkers and studies to elucidate the role of nephrectomy and neoadjuvant targeted therapy in poor-risk mRCC patients. The impacts of novel combinations including temsirolimus have also been explored to further improve outcomes.

Lactate dehydrogenase as a selection criterion for ipilimumab treatment in metastatic melanoma.

INTRODUCTION: Ipilimumab, a cytotoxic T lymphocyte-associated antigen-4 blocking antibody, has improved overall survival (OS) in metastatic melanoma in phase III trials. However, about 80 % of patients fail to respond, and no predictive markers for benefit from therapy have been identified. We analysed a 'real world' population of patients treated with ipilimumab to identify markers for treatment benefit. METHODS: Patients with advanced cutaneous melanoma were treated in the Netherlands (NL) and the United Kingdom (UK) with ipilimumab at 3 mg/kg. Baseline characteristics and peripheral blood parameters were assessed, and patients were monitored for the occurrence of adverse events and outcomes. RESULTS: A total of 166 patients were treated in the Netherlands. Best overall response and disease control rates were 17 and 35 %, respectively. Median follow-up was 17.9 months, with a median progression-free survival of 2.9 months. Median OS was 7.5 months, and OS at 1 year was 37.8 % and at 2 years was 22.9 %. In a multivariate model, baseline serum lactate dehydrogenase (LDH) was demonstrated to be the strongest predictive factor for OS. These findings were validated in an independent cohort of 64 patients from the UK. CONCLUSION: In both the NL and UK cohorts, long-term benefit of ipilimumab treatment was unlikely for patients with baseline serum LDH greater than twice the upper limit of normal. In the absence of prospective data, clinicians treating melanoma may wish to consider the data presented here to guide patient selection for ipilimumab therapy.

Improved survival with MEK inhibition in BRAF-mutated melanoma.

BACKGROUND: Activating mutations in serine-threonine protein kinase B-RAF (BRAF) are found in 50% of patients with advanced melanoma. Selective BRAF-inhibitor therapy improves survival, as compared with chemotherapy, but responses are often short-lived. In previous trials, MEK inhibition appeared to be promising in this population. METHODS: In this phase 3 open-label trial, we randomly assigned 322 patients who had metastatic melanoma with a V600E or V600K BRAF mutation to receive either trametinib, an oral selective MEK inhibitor, or chemotherapy in a 2:1 ratio. Patients received trametinib (2 mg orally) once daily or intravenous dacarbazine (1000 mg per square meter of body-surface area) or paclitaxel (175 mg per square meter) every 3 weeks. Patients in the chemotherapy group who had disease progression were permitted to cross over to receive trametinib. Progression-free survival was the primary end point, and overall survival was a secondary end point. RESULTS: Median progression-free survival was 4.8 months in the trametinib group and 1.5 months in the chemotherapy group (hazard ratio for disease progression or death in the trametinib group, 0.45; 95% confidence interval [CI], 0.33 to 0.63; P<0.001). At 6 months, the rate of overall survival was 81% in the trametinib group and 67% in the chemotherapy group despite crossover (hazard ratio for death, 0.54; 95% CI, 0.32 to 0.92; P=0.01). Rash, diarrhea, and peripheral edema were the most common toxic effects in the trametinib group and were managed with dose interruption and dose reduction; asymptomatic and reversible reduction in the cardiac ejection fraction and ocular toxic effects occurred infrequently. Secondary skin neoplasms were not observed. CONCLUSIONS: Trametinib, as compared with chemotherapy, improved rates of progression-free and overall survival among patients who had metastatic melanoma with a BRAF V600E or V600K mutation. (Funded by GlaxoSmithKline; METRIC ClinicalTrials.gov number, NCT01245062.).

Metastatic renal mucinous tubular and spindle cell carcinoma. Atypical behavior of a rare, morphologically bland tumor.

Mucinous tubular and spindle cell carcinoma (MTSCC) is a rare, distinctive renal neoplasm characterized by an admixture of cuboidal cells in tubules and sheets of spindle cells, typically with low-grade nuclei and a myxoid or mucinous background. It is characteristically of low malignant potential, and only rare metastatic cases have been reported. We describe a case in which the patient presented with extensive regional and distant metastases, but both primary and metastatic tumor showed the typical histomorphology of bland cuboidal or spindle cells lacking pleomorphism, mitoses, and necrosis. Almost all previous cases of metastatic MTSCCs have shown nuclear atypia or sarcomatoid morphology of the primary tumor; and metastatic renal MTSCC in which the primary neoplasm does not display atypical features is exceptional, serving to highlight that these rare tumors can behave aggressively even with "indolent" histological appearances.

Tyrosine kinase inhibitors in the treatment of advanced renal cell carcinoma: focus on pazopanib.

Advances in our understanding of renal cancer biology have led to a new treatment paradigm in renal cancer. Tyrosine kinase inhibitors (TKI), that target the intracellular kinase domain of the VEGF receptor, have become established as the most successful class of agent in this disease. Three TKIs are currently approved for use in patients with advanced disease. Newer, more potent inhibitors have reached phase III clinical testing, meaning others are likely to follow. In 2009, pazopanib became the most recent TKI to receive FDA approval. This review sets out to discuss the key opportunities and challenges associated with TKI use in RCC, focusing particularly on pazopanib. We also review the current place of pazopanib in the management of patients with advanced disease, in what is a rapidly evolving therapeutic landscape.

Sorafenib and dacarbazine as first-line therapy for advanced melanoma: phase I and open-label phase II studies.

METHOD: The safety of oral sorafenib up to a maximum protocol-specified dose combined with dacarbazine in patients with metastatic, histologically confirmed melanoma was investigated in a phase I dose-escalation study and the activity of the combination was explored in an open-label phase II study. RESULTS: In the phase I study, three patients were treated with sorafenib 200 mg twice daily (b.i.d.) plus 1000 mg m(-2) dacarbazine on day 1 of a 21-day cycle and 15 patients had the sorafenib dose escalated to 400 mg b.i.d. without reaching the maximum tolerated dose of the combination. In the phase II study (n=83), the overall response rate was 12% (95% CI: 6, 21): one complete and nine partial, with median response duration of 46.7 weeks. Stable disease was the best response in 37%; median duration was 13.3 weeks. Median overall survival (OS) was 37.0 weeks (95% CI: 33.9, 46.0). CONCLUSION: Oral sorafenib combined with dacarbazine had acceptable toxicity and some antineoplastic activity against metastatic melanoma.

Contrast sensitivity of MT receptive field centers and surrounds.

Neurons throughout the visual system have receptive fields with both excitatory and suppressive components. The latter are responsible for a phenomenon known as surround suppression, in which responses decrease as a stimulus is extended beyond a certain size. Previous work has shown that surround suppression in the primary visual cortex depends strongly on stimulus contrast. Such complex center-surround interactions are thought to relate to a variety of functions, although little is known about how they affect responses in the extrastriate visual cortex. We have therefore examined the interaction of center and surround in the middle temporal (MT) area of the macaque (Macaca mulatta) extrastriate cortex by recording neuronal responses to stimuli of different sizes and contrasts. Our findings indicate that surround suppression in MT is highly contrast dependent, with the strongest suppression emerging unexpectedly at intermediate stimulus contrasts. These results can be explained by a simple model that takes into account the nonlinear contrast sensitivity of the neurons that provide input to MT. The model also provides a qualitative link to previous reports of a topographic organization of area MT based on clusters of neurons with differing surround suppression strength. We show that this organization can be detected in the gamma-band local field potentials (LFPs) and that the model parameters can predict the contrast sensitivity of these LFP responses. Overall our results show that surround suppression in area MT is far more common than previously suspected, highlighting the potential functional importance of the accumulation of nonlinearities along the dorsal visual pathway.

Perceptual and neural consequences of rapid motion adaptation.

Nervous systems adapt to the prevailing sensory environment, and the consequences of this adaptation can be observed in the responses of single neurons and in perception. Given the variety of timescales underlying events in the natural world, determining the temporal characteristics of adaptation is important to understanding how perception adjusts to its sensory environment. Previous work has shown that neural adaptation can occur on a timescale of milliseconds, but perceptual adaptation has generally been studied over relatively long timescales, typically on the order of seconds. This disparity raises important questions. Can perceptual adaptation be observed at brief, functionally relevant timescales? And if so, how do its properties relate to the rapid adaptation seen in cortical neurons? We address these questions in the context of visual motion processing, a perceptual modality characterized by rapid temporal dynamics. We demonstrate objectively that 25 ms of motion adaptation is sufficient to generate a motion aftereffect, an illusory sensation of movement experienced when a moving stimulus is replaced by a stationary pattern. This rapid adaptation occurs regardless of whether the adapting motion is perceived. In neurophysiological recordings from the middle temporal area of primate visual cortex, we find that brief motion adaptation evokes direction-selective responses to subsequently presented stationary stimuli. A simple model shows that these neural responses can explain the consequences of rapid perceptual adaptation. Overall, we show that the motion aftereffect is not merely an intriguing perceptual illusion, but rather a reflection of rapid neural and perceptual processes that can occur essentially every time we experience motion.