Management of patients with advanced prostate cancer: recommendations of the St Gallen Advanced Prostate Cancer Consensus Conference (APCCC) 2015.

The first St Gallen Advanced Prostate Cancer Consensus Conference (APCCC) Expert Panel identified and reviewed the available evidence for the ten most important areas of controversy in advanced prostate cancer (APC) management. The successful registration of several drugs for castration-resistant prostate cancer and the recent studies of chemo-hormonal therapy in men with castration-naïve prostate cancer have led to considerable uncertainty as to the best treatment choices, sequence of treatment options and appropriate patient selection. Management recommendations based on expert opinion, and not based on a critical review of the available evidence, are presented. The various recommendations carried differing degrees of support, as reflected in the wording of the article text and in the detailed voting results recorded in supplementary Material, available at Annals of Oncology online. Detailed decisions on treatment as always will involve consideration of disease extent and location, prior treatments, host factors, patient preferences as well as logistical and economic constraints. Inclusion of men with APC in clinical trials should be encouraged.

Combination immunotherapy approaches.

Combination immunotherapy approaches involving radiation, chemotherapy, androgen manipulation and T-cell modulation have been studied extensively in animal models, setting the stage for clinical trials. Radiation therapy, in particular, is an interesting modality in this regard, leading to synergistic efficacy when used in combination with immunotherapies in several models. Chemotherapy, the foundation of treatment of metastatic disease, may also augment the immune response to cancer; however, the potential immunosuppressive effects of chemotherapy render issues of dosing and timing critical. Perhaps, the most exciting combinatorial approach may be the co-administration of multiple immunological treatments. For example, in preclinical investigations, combined blockade of programmed death-1 (PD1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), which have key roles in the negative regulation of T-cell activation, has been shown to enhance antitumour immune responses compared with either agent alone. Taken together, the available data provide a strong rationale for initiating combination clinical trials, but lend a note of caution in that issues of dosing and timing likely require careful exploration in a phase II setting.

Assessing oncologic benefit in clinical trials of immunotherapy agents.

BACKGROUND: USA Food and Drug Administration approval for cancer therapy requires demonstration of patient benefit as a marker of clinical efficacy. Prolonged survival is the gold standard for demonstration of efficacy, but other end points such as antitumor response, progression-free survival, quality of life, or surrogate end points may be used. DESIGN: This study was developed based on discussion during a roundtable meeting of experts in the field of immunotherapy. RESULTS: In most clinical trials involving cytotoxic agents, response end points use RECIST based on the premise that 'effective' therapy causes tumor destruction, target lesion shrinkage, and prevention of new lesions. However, RECIST may not be appropriate in trials of immunotherapy. Like other targeted agents, immunotherapies may mediate cytostatic rather than direct cytotoxic effects, and these may be difficult to quantify with RECIST. Furthermore, significant time may elapse before clinical effects are quantifiable because of complex response pathways. Effective immunotherapy may even mediate transient lesion growth secondary to immune cell infiltration. CONCLUSIONS: RECIST may not be an optimal indicator of clinical benefit in immunotherapy trials. This article discusses alternative clinical trial designs and end points that may be more relevant for immunotherapy trials and may offer more effective prediction of survival in pivotal phase III studies.

Molecular imaging for cancer immunotherapy.

Immunotherapy has changed the treatment landscape for many cancers; however, not all patients treated have a favorable response and others can develop immune-related adverse events. A method to predict the treatment response to immunotherapeutic agents could allow for improved selection of patients more likely to benefit from treatment while sparing those who would suffer serious complications. While this has been an active area of research and has resulted in significant insights, current proposed mechanisms do not fully explain responses to therapy. One problem is that our understanding relies mostly on tumor biopsy samples that do not account for the complex spatiotemporal heterogeneity of cancers and their microenvironment. Radiolabeled probes targeting immune biomarkers and imaged using positron emission tomography with computed tomography could provide in vivo, real-time and non-invasive imaging of these biomarkers. Here we review the current field of functional nuclear imaging agents in immuno-oncology including antibodies and small molecule tracers to image PD-1, PD-L1, CTLA-4, T-cell markers and other targets being studied for potential therapies.

Genetic linkage of IgG autoantibody production in relation to lupus nephritis in New Zealand hybrid mice.

F1 hybrids of New Zealand black (NZB) and New Zealand white (NZW) mice are a model of human systemic lupus erythematosus. These mice develop a severe immune com-plex-mediated nephritis, in which antinuclear autoantibodies are believed to play the major role. We used a genetic analysis of (NZB x NZW)F1 x NZW backcross mice to provide insight into whether different autoantibodies are subject to separate genetic influences and to determine which autoantibodies are most important in the development of lupus-like nephritis. The results showed one set of loci that coordinately regulated serum levels of IgG antibodies to double-stranded DNA, single-stranded DNA, total histones, and chromatin, which overlapped with loci that were linked to the production of autoantibodies to the viral glycoprotein, gp70. Loci linked with anti-gp70 compared with antinuclear antibodies demonstrated the strongest linkage with renal disease, suggesting that autoantibodies to gp70 are the major pathogenic antibodies in this model of lupus nephritis. Interestingly, a distal chromosome 4 locus, Nba1, was linked with nephritis but not with any of the autoantibodies measured, suggesting that it contributes to renal disease at a checkpoint distal to autoantibody production.

Genetic and immunological mechanisms in the pathogenesis of systemic lupus erythematosus.

Recent research in systemic lupus erythematosus and animal models of lupus has provided new insight into the pathogenesis of this complex autoimmune disease. Progress has been made towards understanding the genetic contributions to disease susceptibility and induction, as well as towards elucidation of the lymphocyte abnormalities involved in pathogenic autoantibody production.

Transforming the Perioperative Treatment Paradigm in Non-Metastatic RCC-A Possible Path Forward.

In 2017, there is no adjuvant systemic therapy proven to increase overall survival in non-metastatic renal cell carcinoma (RCC). The anti-PD-1 antibody nivolumab improves overall survival in metastatic treatment refractory RCC and is generally tolerable. Mouse solid tumor models have revealed a benefit with a short course of neoadjuvant PD-1 blockade compared to adjuvant therapy. Two ongoing phase 2 studies of perioperative nivolumab in RCC patients have shown preliminary feasibility and safety with no surgical delays or complications. The recently opened PROSPER RCC trial (A Phase 3 RandOmized Study Comparing PERioperative Nivolumab vs. Observation in Patients with Localized Renal Cell Carcinoma Undergoing Nephrectomy; EA8143) will examine if the addition of perioperative nivolumab to radical or partial nephrectomy can improve clinical outcomes in patients with high risk localized and locally advanced RCC. With the goal of increasing cure and recurrence-free survival (RFS) rates in non-metastatic RCC, we are executing a three-pronged, multidisciplinary approach of presurgical priming with nivolumab followed by resection and adjuvant PD-1 blockade. We plan to enroll 766 patients with clinical stage ≥T2 or node positive M0 RCC of any histology in this global, randomized, unblinded, phase 3 National Clinical Trials Network study. The investigational arm will receive two doses of nivolumab 240 mg IV prior to surgery followed by adjuvant nivolumab for 9 months. The control arm will undergo the current standard of care: surgical resection followed by observation. Patients are stratified by clinical T stage, node positivity, and histology. The trial is powered to detect a 14.4% absolute benefit in the primary endpoint of RFS from the ASSURE historical control of 55.8% to 70.2% at 5 years (HR = 0.70). The study is also powered to detect a significant overall survival benefit (HR 0.67). Key safety, feasibility, and quality of life endpoints are incorporated. PROSPER RCC exemplifies team science with a host of planned correlative work to investigate the impact of the baseline immune milieu and changes after neoadjuvant priming on clinical outcomes.

Correlation of B7-H3 with androgen receptor, immune pathways and poor outcome in prostate cancer: an expression-based analysis.

BACKGROUND: B7-H3 (CD276), part of the B7 superfamily of immune checkpoint molecules, has been shown to have an immunomodulatory role. Its regulation, receptor and mechanism of action remain unclear. B7-H3 protein expression correlates with prostate cancer outcomes, and humanized monoclonal antibodies (that is, enoblituzumab) are currently being investigated for therapeutic use. Here we used genomic expression data to examine the relationship between B7-H3 mRNA expression and prostate cancer. METHODS: Prostatectomy tissue from 2781 patients were profiled using the Affymetrix HuEx 1.0 ST microarray. Pairwise comparisons were used to identify significant associations between B7-H3 expression and clinicopathologic variables, and survival analyses were used to evaluate the prognostic significance of B7-H3. Pearson's correlation analyses were performed to assess the relationship of B7-H3 expression with molecular subtypes and individual transcripts. Androgen receptor (AR) occupancy at the B7-H3 locus was determined using chromatin immunoprecipitation (ChIP), and androgen-dependent expression changes in B7-H3 was evaluated by quantitative reverse transcription PCR in LNCaP cell lines. Oncomine was queried to evaluate B7-H3 expression in metastatic disease. RESULTS: B7-H3 mRNA expression was positively associated with higher Gleason score (P<0.001), tumor stage (P<0.001), and castrate resistant metastatic disease (P<0.0001). High B7-H3 expression correlated with the development of metastasis and prostate cancer specific mortality, but this was not significant on multi-variable analysis. B7-H3 expression correlated with ERG-positive disease (r=0.99) and AR expression (r=0.36). ChIP revealed an AR-binding site upstream of B7-H3, and the presence of androgens decreased B7-H3 expression in LNCaP suggesting potential direct AR regulation. Gene set enrichment analysis demonstrated an association of B7-H3 with androgen signaling as well as immune regulatory pathways. CONCLUSIONS: Higher B7-H3 expression correlates with Gleason grade, prostate cancer stage and poor oncologic outcomes in prostatectomy cohorts. B7-H3 expression appears to be related to androgen signaling as well as the immune reactome.

Paucity of PD-L1 expression in prostate cancer: innate and adaptive immune resistance.

BACKGROUND: Primary prostate cancers are infiltrated with programmed death-1 (PD-1) expressing CD8+ T-cells. However, in early clinical trials, men with metastatic castrate-resistant prostate cancer did not respond to PD-1 blockade as a monotherapy. One explanation for this unresponsiveness could be that prostate tumors generally do not express programmed death ligand-1 (PD-L1), the primary ligand for PD-1. However, lack of PD-L1 expression in prostate cancer would be surprising, given that phosphatase and tensin homolog (PTEN) loss is relatively common in prostate cancer and several studies have shown that PTEN loss correlates with PD-L1 upregulation--constituting a mechanism of innate immune resistance. This study tested whether prostate cancer cells were capable of expressing PD-L1, and whether the rare PD-L1 expression that occurs in human specimens correlates with PTEN loss. METHODS: Human prostate cancer cell lines were evaluated for PD-L1 expression and loss of PTEN by flow cytometry and western blotting, respectively. Immunohistochemical (IHC) staining for PTEN was correlated with PD-L1 IHC using a series of resected human prostate cancer samples. RESULTS: In vitro, many prostate cancer cell lines upregulated PD-L1 expression in response to inflammatory cytokines, consistent with adaptive immune resistance. In these cell lines, no association between PTEN loss and PD-L1 expression was apparent. In primary prostate tumors, PD-L1 expression was rare, and was not associated with PTEN loss. CONCLUSIONS: These studies show that some prostate cancer cell lines are capable of expressing PD-L1. However, in human prostate cancer, PTEN loss is not associated with PD-L1 expression, arguing against innate immune resistance as a mechanism that mitigates antitumor immune responses in this disease.

Intraprostatic inflammation is positively associated with serum PSA in men with PSA <4 ng ml(-1), normal DRE and negative for prostate cancer.

BACKGROUND: Biopsies performed for elevated serum PSA often show inflammatory infiltrates. However, the influence of intraprostatic inflammation on serum PSA in men without biopsy indication and negative for prostate cancer has not been described in detail. METHODS: We studied 224 men in the placebo arm of the Prostate Cancer Prevention Trial (PCPT) who underwent end-of-study biopsy per trial protocol, had PSA <4 ng ml(-1), normal digital rectal examination and a biopsy negative for cancer. We analyzed data from hematoxylin and eosin-stained slides containing a mean of three biopsy cores. Inflammation measures included the extent (percentage of tissue area with inflammation) and intensity (product of scores for extent and grade) of total, acute and chronic inflammation in the entire tissue area examined, and by tissue compartment. We calculated median measures of inflammation by prebiopsy serum PSA tertile (>0 to ≤0.8, >0.8 to ≤1.5 and >1.5 to <4.0 ng ml(-1)). We estimated the association between percentage of tissue area with inflammation and natural logarithm of PSA using linear regression adjusting for age at biopsy. RESULTS: Median percentage of tissue area with inflammation increased from 2 to 5 to 9.5% across PSA tertiles (P-trend <0.0001). For every 5% increase in tissue area with inflammation, log PSA increased by 0.061 ng ml(-1) (P=0.0002). Median extent and intensity scores increased across PSA tertiles in luminal and intraepithelial compartments for acute inflammation and in stromal and intraepithelial compartments for chronic inflammation (all P-trend ≤0.05). CONCLUSIONS: In men without clinical suspicion of prostate cancer, greater overall inflammation, luminal and intraepithelial acute inflammation and stromal and intraepithelial chronic inflammation were associated with higher serum PSA.

'Foreign' particles in encephalic vascular malformations.

Among 84 surgically resected arteriovenous malformations (AVMs), four were found to have refractile foreign particles lined by endothelium in the vessel walls. In three cases, this was associated with granuloma formation. The particles were probably introduced during cerebral angiography. They represent a not unusual pathologic finding, are relatively more common in AVMs than in other neurosurgically excised lesions, and may have clinical significance, especially if abundant.

Subarachnoid hemorrhage secondary to ruptured cerebral aneurysm in pregnancy.

Eight patients suffering ruptured cerebral aneurysms during pregnancy were managed at the University of Western Ontario hospitals between 1967 and 1977. Seven aneurysms were managed surgically. All of these patients survived, 1 with permanent neurologic deficit. Seven living infants were delivered, 6 by vaginal delivery and 1 by cesarean section. One pregnancy was terminated surgically. One maternal death occurred in a patient whose aneurysm was inoperable. Fetal heart rates (FHR) were monitored by Doptone monitor during the aneurysm surgery. Clipping of the aneurysms was performed under induced hypotension. The prognosis for ruptured cerebral aneurysms during pregnancy is good for both mother and fetus. A short course of conservative therapy followed by surgical management of the aneurysm is advocated. Delivery may be managed according to obstetrical indications following surgical correction of the aneurysm.

Rolandic arteriovenous malformations: improvement in limb function by IBC embolization.

Three patients with arteriovenous malformations in the rolandic region and significant limb deficit showed virtually complete functional recovery after awake operative embolization of most of the malformations using isobutyl-2 cyanoacrylate. Two of these patients, with functionally useless hands, had sustained the deficits months earlier as the result of a specific brain-damaging event: one as a result of surgery and the other as a result of a hemorrhage. Both of these showed significant return of function during the awake operative embolization procedure. The other patient had had progressive leg weakness over a 2 year period. The theory of steal phenomenon as an explanation for progressive neurologic deficits in association with large arteriovenous malformations must be extended to explain apparently stable deficits after some brain trauma (surgery or hemorrhage). These results suggest that some patients with arteriovenous malformations and without clinical deficits who are near a critical level of "near ischemia" may be thrown out of balance by an acute interceding event.

Progressive thrombosis of brain arteriovenous malformations after embolization with isobutyl 2-cyanoacrylate.

Embolization of brain arteriovenous malformations (AVMs) with isobutyl 2-cyanoacrylate (IBCA) is an alternative to surgical treatment when dealing with large AVMs with multiple arterial feeders. The deposition of IBCA in the nidus of the AVM may produce an active and progressive thrombosis that may lead to complete occlusion of the nidus and/or to progressive thrombosis of the draining veins. Four clinical examples of progressive thrombosis after IBCA embolization are demonstrated, including two cases in which late follow-up angiography showed complete obliteration of a partly embolized AVM.

Saccular aneurysms in basilar artery fenestration.

Of 59 cases of vertebrobasilar junction aneurysms diagnosed and treated from January 1977 to April 1986, 21 (35.5%) saccular aneurysms arose in a fenestration of the proximal basilar artery. Defects of the media at the junctures of the fenestrated segments, as well as the possible presence of turbulent flow at the vertebrobasilar junction, may explain the high incidence of vertebrobasilar aneurysms associated with proximal basilar artery fenestration.

Treatment of ischemic deficits from cerebral vasospasm with high dose barbiturate therapy.

In 12 patients with life-threatening neurological deficits from vasospasm refractory to other measures, high dose barbiturate therapy was used in an attempt to prevent permanent changes in the brain. In each case angiography was performed and intracranial pressure was measured. Dexamethasone, a low molecular weight dextran, and mannitol were administered. If intracranial pressure (ICP) was elevated, drainage of cerebrospinal fluid and hyperventilation were used. Arterial pressure was maintained at not less than 140/90 preoperatively and 180/100 postoperatively. Barbiturate therapy was continued until vasospasm decreased angiographically and ICP was normal. Eleven of the 12 patients perished. One had a fatal rebleed. One died of an iatrogenic hemothorax. Four died from uncontrollable intracranial hypertension. One improved slightly and then died from a cardiac arrhythmia. One died of increased ICP when her ventriculostomy malfunctioned. One improved and was responding purposefully to pain, only to die suddenly with a low ICP. Two patients became awake and responsive to verbal commands; 1 of these died from Klebsiella meningitis and the other died from an intracerebral hematoma. In the 3 patients in whom hypothermia was also used, profound alterations in acid-base and fluid electrolyte balance occurred. These discouraging results are most likely a reflection of the severity of the patients' condition at the beginning of therapy. There may be some benefit of barbiturates in the management of vasospasm, and the potential effectiveness of barbiturates may be more obvious if therapy is started at an earlier stage. However, until further evidence of the usefulness of this modality becomes manifest, it should be limited to patients with life-threatening impairments unresponsive to all other measures.

How old people tolerate intracranial surgery for aneurysm.

The purpose of this paper is to examine how well (or poorly) patients past the age of 60 tolerate intracranial surgery for aneurysms in all locations. The records of 93 consecutive good risk patients (Botterell Grades 1 and 2) have been reviewed. Co-existing chronic medical conditions, e.g., hypertension, were ignored in patient grading. The results indicate that, for treatment of aneurysms on the anterior circulation, older patients tolerate intracranial procedures as well as younger patients. This is not true for operations upon posterior circulation aneurysms. Some possible reasons for this discrepancy are suggested.

Treatment of ischemic deficits from vasospasm with intravascular volume expansion and induced arterial hypertension.

In 58 patients with progressive neurological deterioration from angiographically confirmed cerebral vasospasm after spontaneous subarachnoid hemorrhage, arterial hypertension was induced in an attempt to improve their deficits. The most effective regimen consisted of intravascular volume expansion, blockade of the vagal depressor response, and the administration of antidiuretics and vasopressor agents. With this protocol, arterial blood pressure could be sustained at high levels for prolonged periods. Neurological deterioration was reversed in 47 patients, transiently in 4; permanent improvement occurred in 43. Complications experienced during therapy included pulmonary edema, dilutional hyponatremia, aneurysmal rebleeding, coagulopathy, hemothorax, and myocardial infarction. Elevating systemic arterial pressure in states of cerebrovascular insufficiency resulting from vasospasm is safe if meticulous attention is paid to physiological, biochemical, and hematological parameters, with the exception that it may be hazardous in the presence of an untreated ruptured or intact aneurysm. Intravascular volume expansion and induced hypertension are effective in reversing ischemic deficits from vasospasm provided that treatment commences before cerebral infarction and that adequate pressures are maintained for a sufficient period. The production of a hypervolemic state by the use of colloid and crystalloid infusion accompanied by atropine blockade of the vagal depressor response and blunting of the diuresis with vasopressin enables arterial pressure to be elevated for longer than 1 week.