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Therapies based on immune checkpoint inhibitors (ICIs) are transforming the treatment landscape of urologic oncology. Nevertheless, an exhaustive overview of the toxicity spectrum of these novel therapies has yet to be provided.To comprehensively investigate the incidence and profile of ICI therapy-related adverse events (AEs) across urologic cancers.We searched for all clinical trials investigating the role of ICI therapy published between January 2010 and September 2021. Studies involving urologic cancers with reported overall incidence or tabulated data of treatment-related AEs (trAEs) or immune-related AEs (irAEs) were included. A systematic review and meta-analysis was performed after protocol registration in PROSPERO (CRD42021276435).We identified 2638 records, of which 92 studies (including 22942 participants) met the inclusion criteria. The pooled overall incidence was 81.6% (95% confidence interval [CI] 78.0-84.7) for any-grade trAEs and 29.3% (95% CI 24.9-34.1) for grade ≥3 trAEs. The pooled overall incidence was 34.3% (95% CI 28.5-40.7) for any-grade irAEs and 10.2% (95%CI 8.2-12.7) for grade ≥3 irAEs. On a multivariable analysis, cancer type, therapy combination, clinical settings (perioperative vs advanced/metastatic), and drug exposure were independently associated with the occurrence of trAEs or irAEs. The overall rate of treatment-related mortality was 0.94% (140 of 14 899 participants), with pneumonitis (9.3%), pneumonia (7.9%), and respiratory failure (7.1%) being the most common causes. Immune-related mortality occurred in 0.26% (28 of 10 723) patients, with pneumonitis (35.7%), hepatic failure (10.7%), and hepatitis (7.1%) being most common.Our study provides a comprehensive overview of ICI-associated AEs in urologic cancer patients. The spectrum and incidence of AEs vary across cancer types, ICI types, clinical settings, and therapy combinations. These findings provide important guidance to clinicians in counseling and management of patients with urologic cancers.A high proportion of patients experience immune checkpoint inhibitor-associated toxicity. Physician and patient education is critical for early recognition and proper management.

PURPOSE Cediranib, a pan-vascular endothelial growth factor receptor inhibitor, suppresses expression of homologous recombination repair (HRR) genes and increases sensitivity to poly-(ADP-ribose) polymerase inhibition in preclinical models. We investigated whether cediranib combined with olaparib improves the clinical outcomes of patients with prostate cancer. METHODS Patients with progressive metastatic castration-resistant prostate cancer (mCRPC) were randomly assigned 1:1 to arm A: cediranib 30 mg once daily plus olaparib 200 mg twice daily or arm B: olaparib 300 mg twice daily alone. The primary end point was radiographic progression-free survival (rPFS) in the intention-to-treat patients. The secondary end points were rPFS in patients with HRR-deficient and HRR-proficient mCRPC. RESULTS In the intention-to-treat set of 90 patients, median rPFS was 8.5 (95% CI, 5.4 to 12.0) and 4.0 (95% CI, 3.2 to 8.5) months in arms A and B, respectively. Cediranib/olaparib significantly improved rPFS versus olaparib alone (hazard ratio [HR], 0.617; 95% CI, 0.392 to 0.969; P = .0359). Descriptive analyses showed a median rPFS of 10.6 (95% CI, 5.9 to not assessed [NA]) and 3.8 (95% CI, 2.33 to NA) months (HR, 0.64; 95% CI, 0.272 to 1.504) among patients with HRR-deficient mCRPC, and 13.8 (95% CI, 3.3 to NA) and 11.3 (95% CI, 3.8 to NA) months (HR, 0.98; 95% CI, 0.321 to 2.988) among patients with BRCA2-mutated mCRPC in arms A and B, respectively. The incidence of grades 3-4 adverse events was 61% and 18% in arms A and B, respectively. CONCLUSION Cediranib combined with olaparib improved rPFS compared with olaparib alone in men with mCRPC. This combination was associated with an increased incidence of grades 3-4 adverse events. BRCA2-mutated subgroups treated with olaparib with or without cediranib were associated with a numerically longer median rPFS.

ObjectivesUniversal screening of upper tract urothelial carcinoma (UTUC) for Lynch syndrome by mismatch repair (MMR) protein immunohistochemistry (IHC) has been recommended by some investigators. Herein, we assess this recommendation retrospectively by simulating its performance on a retrospective, unselected cohort of UTUCs, with comparison to the established setting of colorectal and endometrial adenocarcinoma.MethodsWe assessed for complete loss of MMR protein (MLH1, MSH2, MSH6, and PMS2) IHC in 74 consecutive cases of UTUC and then tabulated clinical and pathologic factors. MMR findings from same-institution colorectal and endometrial adenocarcinomas were tabulated for comparison.ResultsWe observed loss of at least one MMR protein in 12% in our UTUC cohort (three MSH2/MSH6, three MSH6 only, one MLH1/PMS2, and two PMS2 only). Of these nine cases (seven males, two females, median age 67 years, five associated with colorectal adenocarcinoma), at least three (4% of the overall cohort) proved to be Lynch syndrome. Overall, MMR loss in UTUC was comparable to colorectal (11%; 50 of 471 cases) and endometrial (12%; 12 of 101 cases) adenocarcinomas.ConclusionsThe rate of MMR loss observed in UTUC was comparable to that in the established setting of colorectal and endometrial adenocarcinomas, supporting universal UTUC screening at our institution and others.

TPS4618 Background: ABACUS and PURE-01 trials demonstrated the activity of single agent atezolizumab and pembrolizumab respectively as neoadjuvant therapy for muscle invasive bladder carcinoma (MIBC). However, downstaging to non-muscle invasive disease was noted in only 50 percent of patients. Resistance to programmed death (PD)- 1/L1 antibodies is likely to include factors such as impaired dendritic cell maturation/function, infiltration of T-Regs and myeloid derived suppressor cells, impaired T-cell priming and T-cell trafficking in tumors. Cabozantinib is a tyrosine kinase inhibitor which targets MET, AXL, MER, Tyro3 and VEGFR2. Cabozantinib has a unique immunomodulatory profile and has demonstrated clinical activity as monotherapy and in combination with PD-1/L1 antibodies in various solid tumors including urothelial cancer (UC), renal cell, castrate- resistant prostate and non-small cell lung cancer. We hypothesize that the combination of cabozantinib and atezolizumab as neoadjuvant therapy for MIBC would improve rates of pathologic downstaging compared to single-agent checkpoint inhibitors. Methods: ABATE is an open-label, single arm, multi-center study to assess the efficacy and safety of cabozantinib with atezolizumab as neoadjuvant therapy for cT2-T4aN0/xM0 MIBC. An estimated 42 patients will be enrolled to obtain 38 evaluable patients, and the study will have over 80% power to declare the investigational combination to be successful using a Bayesian evaluation at 90% posterior probability cutoff, if the response probability is 59%, i.e., 20% higher than the 39% response rate with the single agent atezolizumab. Eligible patients will receive cabozantinib 40 mg PO daily with atezolizumab 1200mg every 3 weeks for a total duration of 9 weeks (3 cycles) followed by radical cystectomy. Adults (≥18 years) with resectable MIBC who are either cisplatin-ineligible or decline cisplatin-based chemotherapy are eligible. Patients are required to have an ECOG PS of 0-2 and provide tumor tissue for PD-L1 expression analysis. UC should be predominant component (≥ 50%). Previous systemic anticancer therapies for MIBC are not permitted. CT/MRI will be performed before investigational therapy and cystectomy. Primary endpoint is pathologic response rate defined as the absence of residual muscle-invasive cancer in the surgical specimen (< pT2). Secondary endpoints are safety and toxicity, pathologic complete response rate and event-free survival. Exploratory end points include patient-reported outcomes and outcome associations with biomarkers. Accrual began May 2020. Clinical trial information: NCT04289779.

INTRODUCTION Radical cystectomy (RC) is the current mainstay for muscle-invasive bladder cancer (MIBC). Concerns regarding morbidity, mortality and quality of life have favored the introduction of bladder sparing strategies. Trimodal therapy, combining transurethral resection, chemotherapy and radiotherapy is the current standard of care for bladder preservation strategies in selected patients with MIBC. EVIDENCE ACQUISITION A comprehensive search of the Medline and Embase databases was performed. A total of 19 studies were included in a systematic review of bladder sparing strategies in MIBC management was carried out following the preferred reporting items for systematic reviews and meta-analysis (PRISMA). EVIDENCE SYNTHESIS The overall median complete response rate after trimodal therapy (TMT) was 77% (55-93). Salvage cystectomy rate with TMT was 17% on average (8-30). For TMT, the 5-year cancer-specific survival and overall survival rates range from 42-82% and 32-74%, respectively. Currently data supporting neoadjuvant or adjuvant chemotherapy in bladder sparing approaches are emerging, but robust definitive conclusions are still lacking. Gastrointestinal toxicity rates are low around 4% (0.5-16), whereas genitourinary toxicity rates reached 8% (1-24). Quality of life outcomes are still underreported. CONCLUSIONS Published data and clinical experience strongly support trimodal therapy as an acceptable bladder sparing strategy in terms of oncological outcomes and quality of life in selected patients with MIBC. A strong need exists for specialized centers, to increase awareness among urologists, to discuss these options with patients and to stress the increased participation of patients and their families in treatment path decision-making.

Ongoing trials are evaluating immune checkpoint inhibitors—used alone, in combination with cytotoxic, targeted, radiation therapies, or with other such inhibitors—for therapy in patients with advanced bladder cancer.

Docetaxel represent the standard of care in patients with metastatic, hormone sensitive prostate cancer. However, androgen receptor axis targeted therapies have also been shown to be effective. We aimed to analyze findings in randomized controlled trials investigating first-line treatment for hormone sensitive prostate cancer.We systematically reviewed the literature according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) criteria and the PICO (Population, Intervention, Comparator, Outcomes) methodology. Outcomes of interest were overall and progression-free survival, and the rate of high grade adverse events.No treatment was superior to docetaxel in terms of overall survival. However, abiraterone (HR 0.89, 95% CI 0.76-1.05), enzalutamide (HR 0.90, 95% CI 0.69-1.19) and apalutamide (HR 0.90, 95% CI 0.67-1.22) showed nonstatistically significant lower overall mortality rates than docetaxel. Abiraterone (HR 0.71, 95% CI 0.59-0.86), enzalutamide (HR 0.61, 95% CI 0.49-0.75) and apalutamide (HR 0.74, 95% CI 0.57-0.95) also showed statistically significant lower disease progression rates than docetaxel. Furthermore, abiraterone (OR 0.83, 95% CI 0.56-1.21) showed no statistically significant lower rate of high grade adverse events compared to docetaxel. Finally, enzalutamide (OR 0.56, 95% CI 0.35-0.92) and apalutamide (OR 0.44, 95% CI 0.24-0.79) showed statistically significant lower rates of high grade adverse events compared to docetaxel.Treatment with androgen receptor axis targeted therapies combined with androgen deprivation therapy in patients with hormone sensitive prostate cancer did not offer a statistically significant advantage in overall survival compared to the standard, docetaxel. However, it was associated with a lower disease progression rate. Moreover, apalutamide and enzalutamide offer a better safety profile.

Introduction In the last years, there have been significant developments in the therapeutic armamentarium of metastatic castration-resistant prostate cancer (mCRPC). New evidence shows that the addition of bone-targeted agents (BTA) to "life-prolonging agents" result in improved clinical benefit. This review aims to give an overview of data for the use of BTAs in a new era of mCRPC where new agents are used in daily practice. Evidence acquisition A non-systematic review of the literature was performed combining the keywords: "castration-resistant prostate cancer" and "bone-targeted therapy". The primary objective was to provide a critical assessment of data for the use of BTAs in mCRPC, and the secondary objective was to assess novel targeted therapy. Evidence synthesis Zoledronic acid and denosumab have shown to be effective in reducing the risk of SREs in patients with mCRPC. The point at which treatment with bisphosphonates or denosumab should be initiated during PCa evolution has yet to be determined. The EMA has restricted the usage of Ra-223 to patients who have had two previous treatments for mCRPC to the bone or who cannot receive other treatments. Ra-223 should only be used as monotherapy or in combination with ADT for the treatment of mCRPC, symptomatic bone metastases and without visceral metastases. With recent developments in PSMA-targeted radiopharmaceuticals, PSMA RLT agents are now under investigation for the treatment of mCRPC. Conclusions Reducing skeletal-related morbidity remains a crucial goal of palliative life-extending therapy in mCRPC. New data about dosing schedules and combinations of different treatments will continue to refine the optimal strategy for incorporating BTAs into the new treatment paradigms for PCa. Novel molecules such as PSMA-targeted small molecules promise theranostic agents in the management of PCa patients.

7 Background: We previously reported that cediranib, a vascular endothelial growth factor receptor tyrosine kinase inhibitor, combined with olaparib, a poly (ADP-ribose) polymerase inhibitor, prolonged radiographic progression-free survival (rPFS) compared with olaparib alone in patients with mCRPC. Herein, we present updated clinical data in the overall population and in subgroups by homologous recombination (HR) gene status. Methods: Men with a minimum of one prior line of systemic therapy for mCRPC were randomized 1:1 to receive olaparib 200 mg by mouth twice daily with cediranib 30 mg by mouth daily (C+O) or olaparib 300 mg by mouth twice daily (O). Patients were required to undergo a baseline metastasis biopsy. Next generation sequencing of HR genes was performed on available samples using BROCA-HR assay. HR deficiency (HRD) was defined by presence of homozygous deletions or deleterious mutations in HR genes including BRCA1, BRCA2, ATM, and others. The primary endpoint was rPFS and secondary endpoint was overall survival (OS). Results: Eighty-four patients were included in the analysis of whom 26 patients (31.0%) had HRD mCRPC. The most common HR gene alterations included BRCA2 (n=17, 20%), CDK12 (n=9, 11%), and ATM (n=7, 8%). Consistent with our prior report, in the overall cohort, C+O compared to O resulted in a significant improvement in rPFS (Table). The benefit in rPFS was most pronounced in patients with HRD mCRPC; however, there was no difference between arms in HR proficient (HRP) cancers. Independent of arm allocation, rPFS and OS were numerically longer in patients with HRD mCRPC compared to HRP mCRPC (rPFS: 8.8 versus 4.3 months, p=0.14; OS: 18.6 vs. 12.3 months, p=0.24). Conclusions: C+O improved rPFS in patients with mCPRC compared with O alone. The biomarker analyses revealed that the rPFS benefit of C+O over O is likely driven by patients with HRD mCRPC. Our data warrant validation and support further investigation of the combination of C+O in patients with HRD mCRPC. Clinical trial information: NCT02893917. [Table: see text]

Background: Paraneoplastic glomerulonephropathies (PGN) are paraneoplastic syndromes associated with solid tumors and hematologic malignancies. PGN is difficult to differentiate from other forms of glomerulonephropathies and standard management of glomerulonephropathies is often ineffective. A delay in diagnosis may lead to significant morbidity and mortality. To date, no retrospective or prospective data on PGN have been published. We reviewed clinical variables, treatment, and outcome in published case reports of PGN associated with solid tumors over the past three decades. Methods: We conducted a search to identify published case reports on solid tumors associated with PGN in English PubMed-indexed journals. Keywords used included: “solid tumor”, “lung cancer”, “gastrointestinal cancer”, “gynecological cancer”, “genitourinary cancer”, “paraneoplastic nephropathy,” “paraneoplastic glomerulopathy,” “minimal change disease,” “IgA nephropathy,” “membranoproliferative,” “membranous,” “nephropathy” and “glomerulonephropathy”. Published articles from January 1st, 1987 to November 30,2019 were screened. Included were the patients who had laboratory and/or biopsy proven nephrotic syndrome in association with a solid tumor diagnosis. Results: We identified 95 patients who fulfilled the inclusion criteria. The median age of the patients were 58 years. The majority of the patients were male (65%). Among them, 37 (39%) were diagnosed with PGN prior to the diagnosis of cancer. Membranous nephropathy (41%) was the most common subtype, followed by minimal change disease (17%), focal segmental glomerulonephritis (14%) and IgA nephropathy (11%). Genitourinary cancers (36%) followed by lung cancers (30%), gastrointestinal cancers (15%) and gynecological cancers (13%) are the common cancers associated with PGN. Among the patients, 44 (46%) had non-metastatic tumors, 39 (41%) had metastatic tumors and 12 (13%) were unspecified. Treatment information were available for 79 of 95 (83%) patients. Overall, PGN improved in 76% of patients who received definitive or systemic therapy with or without steroid compared to 57% of patients who were treated with steroid alone. Definitive and systemic treatment alone led to improvement of PGN in 24 of 29 (83%) patients without metastasis and 13 of 17 (76%) patients with metastasis. Conclusions: PGNs associated with solid tumors are rare and can happen in both non-metastatic and metastatic cancers. Diagnosis of PGN might precede the diagnosis of cancer. Definitive or systemic anticancer therapies improved PGN in most cases and were more effective than steroid alone. Citation Format: Xiaojie Zhang, Asit K. Paul. Paraneoplastic glomerulonephropathies associated with solid tumor: A review of published literature [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3527.

111 Background: Cediranib, a vascular endothelial growth factor receptor tyrosine kinase inhibitor, suppresses expression of BRCA1, BRCA2, and RAD51 and increases sensitivity of tumors to poly (ADP-ribose) polymerase (PARP) inhibitors in vitro. Olaparib, a PARP inhibitor, demonstrates clinical efficacy in men with DNA repair deficient, mCRPC. We therefore performed a randomized phase 2 trial comparing olaparib with or without cediranib in men with mCRPC. Methods: Men with a minimum of one prior line of systemic therapy for mCRPC were randomized 1:1 to receive cediranib 30mg po daily plus olaparib 200mg po BID (Arm A) or olaparib 300mg BID alone (Arm B). At radiographic progression, patients (pts) in Arm B could crossover to Arm A. The primary endpoint was radiographic progression-free survival (rPFS). Secondary endpoints were objective response rate (ORR) and PSA50 decline rate (PSA50). Tumor biopsy specimens were obtained for biomarker analyses pre- and on-treatment. Results: Baseline characteristics of the 90 pts enrolled are summarized below. The median rPFS was 11.1 versus 4.0 months in Arm A and Arm B, respectively (Hazard Ratio 0.54, 95% CI 0.317, 0.928, p=0.026). Trends toward a higher ORR (19% and 12%), Disease Control Rate (Stable Disease + Partial Response) (77% and 64%,) and PSA50 (29% and 17%) were observed in Arm A compared to Arm B, respectively. Thirteen pts in Arm B crossed over to Arm A. One pt had a PR after crossover. Grade 3/4 adverse events (G3/4 AEs), irrespective of attribution, occurred in 77% and 58% of Arm A and Arm B pts, respectively. G3/4 AEs occurring in >10% of pts were hypertension (32%), fatigue (23%) and diarrhea (11%) in Arm A, and anemia (16%) and lymphopenia (11%) in Arm B. Conclusions: The cediranib/olaparib combination significantly improves rPFS in unselected, mCRPC pts. AEs were manageable. Analyses of mutation status in homologous recombination DNA repair genes are pending and will be key in interpreting the data. Clinical trial information: NCT02893917. [Table: see text]

In patients with breast cancer, a number of biomarkers, such as estrogen receptor, progesterone receptor and HER2, are part of routine work-up and used to guide endocrine, cytotoxic and HER2-targeted treatment. Interaction among these markers may also impact on treatment response and is being investigated. Multigene assays have reached varying levels of validation and clinical use as predictive biomarkers of cytotoxic therapy in specific clinical situations. A number of pharmacogenomic biomarkers based on germline polymorphisms have reached some degree of validation for predicting variation in treatment response and treatment-associated adverse effects. The challenge of validating biomarkers will be exacerbated as the cost of nucleic acid sequencing rapidly declines and more potential biomarkers emerge. New, carefully designed approaches will be needed to address this issue and realize the potential of biomarkers in breast cancer.

Objective This study examined the economic burden of renal cell carcinoma (RCC) among older adults. The study also examined healthcare costs by types of resources used and stage at which RCC was diagnosed. Methods The study analyzed the Surveillance Epidemiology and End Result—Medicare linked data. We included a prevalent cohort of RCC patients from 2013, diagnosed and continuously enrolled in Medicare from 2005 to 2013. RCC patients were matched to controls selected from a 5% sample of noncancer beneficiaries using propensity score matching to calculate incremental costs. Total healthcare costs (THC) were calculated using a phase-based approach, which classified patients into early, continuing, and late phases of care. Costs were also examined by types of resources used and stage at which RCC was diagnosed. Generalized linear models estimated annual incremental costs per patient. The number of older RCC patients was calculated using SEER-Stat and ProjPrev software. The average incremental THC was multiplied by the estimated number of RCC patients to calculate the total economic burden of RCC among older adults. Results The study included 10,392 each of RCC and control patients. The average annual THC associated with RCC was $7,419 for all phases, $22,752 for the initial phase, $4,860 for the continuing phase, and $13,232 for the late phase of care. The average THC was $4,584 for patients diagnosed at stage I, $4,727 for stage II, $9,331 for stage III, and $31,637 for stage IV. For patients diagnosed at stages I to III, hospital cost (approximately $1,500–$3,400) was the largest component of THC. For stage IV patients, prescription drug cost ($11,747) was the largest component of THC. The projected number of older RCC patients in 2015 was 204,256. The annual economic burden of RCC after weighting for proportion of patients diagnosed at various stages was estimated to be $2.1 billion. Conclusions RCC was associated with a significant economic burden on Medicare. Healthcare costs associated with RCC varied substantially between early stage and metastatic patients. This research provided a baseline that can be used to assess the economic value of emerging therapies among older RCC patients.

Human melanoma proteoglycan (HMP), a melanoma-associated antigen, is expressed in both human melanomas and gliomas. We used HMP-specific monoclonal antibody (mAb) VT68.2 to investigate whether murine GL261 cerebral gliomas express the HMP homologue AN2 and to determine whether AN2 could be targeted for selective delivery of radiation in vivo. HMP-specific mAb VT68.2 stained murine GL261 glioma cells grown in culture and intracerebrally in syngeneic C57BL/6 mice. Positron emission tomography with radiolabeled mAb VT68.2 showed high-contrast, positive images of gliomas against a negative background. At 96 h after injection, glioma uptake of radiolabeled mAb VT68.2 was 10 times greater than that of the isotype control mAb and 20 times greater than that detected in normal cerebral tissue. Our results show murine GL261 cerebral gliomas express AN2 and HMP-specific mAb VT68.2 accumulates selectively and specifically at high concentration and is retained within murine cerebral gliomas. Thus, HMP is a potential target for antibody-mediated selective delivery of radiation to cerebral gliomas in vivo.

Although much is known about the perceptual characteristics of tinnitus, its neural origins remain poorly understood. We investigated the pattern of neural activation in central auditory structures using positron emission tomography (PET) imaging in a rat model of salicylate-induced tinnitus. Awake rats were injected with the metabolic tracer, fluorine-18 fluorodeoxyglucose (FDG), once in a quiet state (baseline) and once during salicylate-induced tinnitus. Tinnitus was verified using a behavioral technique. Brain imaging was performed using a high-resolution microPET scanner. Rats underwent magnetic resonance imaging (MRI) and reconstructed MRI and microPET images were fused to identify brain structures. FDG activity in brain regions of interest were quantified and compared. MicroPET imaging showed that FDG activity in the frontal pole was stable between baseline and tinnitus conditions, suggesting it was metabolically inert during tinnitus. Inferior colliculi (p=0.03) and temporal cortices (p=0.003) showed significantly increased FDG activity during tinnitus relative to baseline; activity in the colliculi and temporal cortices increased by 17%+/-21% and 29%+/-20%, respectively. FDG activity in the thalami also increased during tinnitus, but the increase did not reach statistical significance (p=0.07). Our results show increased metabolic activity consistent with neuronal activation in inferior colliculi and auditory cortices of rats during salicylate-induced tinnitus. These results are the first to show that microPET imaging can be used to identify central auditory structures involved in tinnitus and suggest that microPET imaging might be used to evaluate the therapeutic potential of drugs to treat tinnitus.

Electrocardiographically gated myocardial perfusion SPECT (GSPECT) is a state-of-the-art technique for the combined evaluation of myocardial perfusion and left ventricular function within a single study. It is currently one of the most commonly performed cardiology procedures in a nuclear medicine department. Automation of the image processing and quantification has made this technique highly reproducible, practical, and user friendly in the clinical setting. In patients with coronary artery disease, gating enhances the diagnostic and prognostic capability of myocardial perfusion imaging, provides incremental information over the perfusion data, and has shown potentials for myocardial viability assessment and sequential follow-up after therapy. After reading this article, the readers will understand (a) the general principles of GSPECT and quantitation, (b) the methods of the image acquisition and analysis, (c) validation of GSPECT with other cardiac imaging modalities, and (d) application of the GSPECT-derived functional parameters in the clinical practice.

Heparin-induced thrombocytopenia (HIT) is an IgG mediated adverse reaction of heparin use associated with increased thrombosis. Heparin-platelet factor 4 (HPF4) enzyme immunoassay (EIA) detects all classes of antibody against HPF4 resulting in potential over-diagnosis of HIT. The objective of the current study was to determine an optimal threshold for diagnosis of HIT by EIA that would improve the diagnostic specificity and predict thrombosis. We retrospectively analyzed data of 101 consecutive patients who were tested positive based on conventional cut-off value of optical density (OD) obtained from EIA. Study patients were grouped as low (n=22), intermediate (n=26) and high (n=53) clinical probability group of HIT based on the 4T clinical probability scoring. An OD ratio (ODR) by EIA was calculated for each patient by dividing patient’s OD by the cut-off OD. Using low and high clinical probability as negative and positive diagnosis of HIT, a receiver operating characteristic curve was generated for the range of ODRs. An ODR of >2.5 provided the best trade-off between sensitivity and specificity. When a combination of clinical probability and ODR>2.5 were used to diagnose HIT, 20/26 patients with intermediate probability were reclassified as not having HIT. This reduced the overall diagnosis of HIT by 42% compared to that by EIA alone. Using this diagnostic criterion, the rate (58% vs. 10%, P Disclosures: No relevant conflicts of interest to declare.

Background and objectives: RRx-001, is the first member of a new class of anticancer compounds that binds to hemoglobin and drives heme and iron-catalyzed redox reactions under hypoxic conditions thereby enhancing oxidative and nitrosative stress in cancer cells through glutathione depletion and the generation of high local concentrations of nitric oxide. The objectives of this Phase 1 dose-escalation trial were to investigate safety, dose-limiting toxicities (DLTs), pharmacodynamics and pharmacokinetics (PK) of RRx-001. Methodology: Eligible patients had advanced solid tumor malignancies; ECOG PS 0-2; adequate bone marrow function. In a 3+3 escalation design, RRx-001 was administered intravenously (IV) for up to 6 hours weekly for 8 weeks to patients with advanced cancer in successive dose-escalating cohorts. PK samples were collected. Tumor response (CT, PET-CT, biopsy) was determined every 4 or 8 weeks. Preliminary Data: 19 pts have been dosed over 5 successive cohorts (10, 16.7, 24.6, 33 and 55 mg/m2). Tumor types included pancreas (3), colorectal (9), head and neck (2), melanoma (1), cholangiocarcinoma (1), uterine (1), lung (1) and HCC (1). RRx-001 has been extremely well tolerated with no DLTs or treatment-associated SAEs observed. The only drug-related adverse event (AEs) across all cohorts was acute and transient injection-site vasodilation and pain on infusion, moderate in severity and generally managed with lengthening of the infusion time, using peripheral venous access and prior administration of corticosteroids. No RRx-001-induced systemic toxicities have been observed to date. 14 patients were evaluable for response, 1 with partial response (parotid tumor). Eight patients had stable disease (3 pancreas, 3 with colorectal cancer, 1 uterine, 1 HCC). Two of these pts (salivary and CRC) have remained stable for 6 and 10 months, respectively, and another 2 pts (uterine and HCC) are continuing stably on trial for >3 months. The pt. with CRC who progressed after 10 months on trial responded to previously failed chemotherapy as evidenced by marked decrease in CEA (511 to 311) and re-stabilization of disease for >3 months. Two patients with pancreatic and CRC had an increase in tumor size with extensive central necrosis suggestive of pseudoprogression. Conclusions: In the ongoing nearly completed Phase 1 trial, RRx-001, an anticancer agent with a novel structure and mechanism of action, is well tolerated with infusion-site pain the only observed AE. Toxicities normally associated with anticancer agents were absent. Single agent activity with a high response rate (64-79%) among patients with advanced, refractory cancer was observed including a renewed response to a previously failed chemotherapy regimen. Phase 2 planning in colorectal cancer and HCC is underway. Citation Format: Tony Reid, Jeffrey R. Infante, Asit Paul, Howard A. Burris, Bryan Oronsky, Curtis Scribner, Susan Knox, Janet Stephens, John Santini, Jan Scicinski. Preliminary results from an ongoing phase I trial of RRx-001, a tumor selective cytotoxic agent. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-86. doi:10.1158/1538-7445.AM2013-LB-86

An 84-year-old woman presented with a one-year history of intermittent chest pain and progressive difficulty swallowing while eating solid food. She had no history of gastrointestinal problems. She had been taking alendronate sodium (a 70-mg tablet, once a week) for the past year for the treatment