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You’re a New York motorist, running horribly late, and there’s an empty space beckoning right outside your destination. Problem is, it’s in front of a fire hydrant. Should you risk getting a ticket? Take some advice from Chris Andrade, Jonathan Auerbach, Icaro Bacelar, Hane Lee, Angela Tan, Mariana Vazquez, and Owen Ward

Background: PSMA-based targeted radionuclide therapy is now a standard of care for mCRPC since approval of 177Lu-PSMA-617. Use of antibodies (e.g., J591) to target PSMA with higher potency radionuclides (e.g., 225Ac) impacts kinetics, biodistribution, clinical efficacy, and toxicities. In our first-in-human ph I dose-escalation study of single dose 225Ac-J591 in patients with mCRPC, no MTD was reached (max dose 93.3 KBq/kg). Following this, we developed ph I/II parallel dose-escalation studies of fractionated (D1, D15) single cycle and multiple (q6w) dose regimens. Here we present safety data from the initial fractionated study in predominantly 177Lu-naive. Methods: Eligible patients had adequate organ function, ECOG performance status 0-2, and progressive mCRPC following potent AR pathway inhibitor (ARPI) and chemo (or unfit/refusing). Prior 177Lu-PSMA was allowed until an amendment developed a separate study for post-177Lu-PSMA. Baseline 68Ga-PSMA PET scans were performed, but not used to determine eligibility. A 3+3 dose-escalation design was used. Phase I primary objective: determination of dose-limiting toxicity (DLT) and recommended phase II dose (RP2D). DLT was defined as within 8 weeks of first dose: neutropenia (Gr 4 or febrile neutropenia), thrombocytopenia (TCP) (Gr 4, or Gr 3 with clinically significant bleeding), any Gr >2 non-hematologic toxicity deemed to be at least possibly related to 225Ac-J591, or any attributable toxicity precluding or delaying the second dose by >2 weeks. Secondary/exploratory objectives: efficacy measures (e.g., PSA decline, radiographic RR, biochemical/radiographic PFS, OS, CTCs, patient reported outcomes), safety (CTCAE v5), and correlatives (plasma and tissue genomics, PSMA imaging). Results: 24 patients were enrolled in phase I. Median age 73.5 (57-91), PSA 25.78 (3.39-2133.41); 53% (n=13) >1 prior ARPI, 58% (n=14) taxane chemo, 8% (n=2) anti-PSMA therapy, 12.5% (n=3) prior 223Ra. CALGB prognostic groups: Good 4 (16%), Intermediate 8 (33%), Poor 12 (50%). No DLTs were observed in Cohort 1 (n=3) or 2 (n=6). In C3, 2/6 subjects experienced DLTs (Gr 3 weakness, Gr 2 TCP with >2 week delay in second fraction). 8 patients were enrolled in an intermediate dose cohort (2.5) with 1 DLT (Gr 4 TCP). Two patients withdrew before the second dose (intercurrent illness; interruption of 225Ac supply). Most common low gr non-hematologic treatment emergent AEs: fatigue (95%), xerostomia (69%), and nausea (57%). Among evaluable patients for PSA change (n=22), 21 (95%) experienced PSA decline with 14 (67%) with decline of 50% and 6 (37%) with decline of 90%. 13/21 patients had CTCs samples collected at baseline and 12 wks; 5 were unfavorable at baseline (≥5/7.5 mL); 10/13 (77%) remained favorable or converted from unfavorable to favorable; 6/12 (50%) had 50% decline in CTC count; and 5/13 (38%) converted from detectable to undetectable. Conclusions: A single fractionated cycle of 225Ac-J591 was delivered with few high grade AEs and with evidence of preliminary efficacy by PSA and CTC changes across all dose levels. Citation Format: Jones T. Nauseef, Michael Sun, Charlene Thomas, Mahelia Bissassar, Escarleth Fernandez, Zachary Davidson, Amie Patel, Angela Tan, Tessa A. Chamberlain, Kara Earle, Rebecca Wunder, Sabrina Guervil, Sandra H. Castellanos, Judith Stangl-Kremser, Peter S. Gregos, Joseph R. Osborne, Karla V. Ballman, Ana M. Molina, Cora N. Sternberg, David M. Nanus, Neil H. Bander, Scott T. Tagawa. Phase I dose-escalation study of fractionated dose 225Ac J591 for metastatic castration resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT014.

TPS288 Background: As prostate-specific membrane antigen targeted radiotherapy (PSMA-TRT) is now an active standard-of-care treatment in mCRPC, ongoing studies with alternative approaches to targeting PSMA will increasingly need to consider the consequences of sequential PSMA-TRT exposure. Our past and ongoing investigations into antibody-based targeting (e.g., J591) and potent alpha emitting payloads (e.g., 225Ac) impact drug kinetics, biodistribution, and resultant clinical toxicities. In a first-in-human phase I dose-escalation study of 225Ac-J591, patients with mCRPC were treated with a single dose of 225Ac-J591 on seven dose levels, up to 93.3 KBq/kg without achievement of maximal tolerated dose (MTD). One patient treated at 80 KBq/kg developed dose-limiting toxicity (DLT) of Gr 4 anemia and thrombocytopenia, but 0 of 6 at 93.3 KBq/Kg had Gr > 3 heme toxicity or Gr > 2 non-heme toxicity. Although not intentionally preselected for prior exposure, 55% (12/22) of patients had 177Lu-PSMA previously. With approval of 177Lu vipivotide tetraxetan, we amended an ongoing phase I dose-escalation study to include a post-177-Lu-PSMA cohort. Methods: Entry criteria include progressive mCRPC by PCWG3 criteria, ECOG PS 0-2, intact organ function, and prior receipt of AR pathway inhibitor and chemotherapy (or refused/ineligible). There is no limit to prior lines of therapy except alpha-emitting therapies (i.e., PSMA-TRT, 223Ra) and in this amended dose-escalation cohort, all patients must have had prior treatment with 177Lu-PSMA. Treatment will be given in a single fractionated cycle of 225Ac-J591 administered on D1 and D15. The phase I component is a 3+3 dose-escalation study design with up to 18 patients, with the goal of identifying MTD. The phase II component will include up to 16-19 patients in a Simon 2-stage design with 90% power to exclude the null hypothesis (35% or fewer patients with PSA50). Eligible men with negative PSMA PET scans will be offered treatment with informed consent in an exploratory subgroup but will not be counted towards phase II efficacy. Secondary outcomes include radiographic response by PCWG3-modified RECIST 1.1 criteria and PSMA PET, biochemical and radiographic progression-free survival, circulating tumor cell counts, and overall survival. Patient reported outcomes, genomic, and immune analyses are exploratory. Enrollment to the post-177Lu-PSMA cohort began in August 2022. Clinical trial information: NCT04506567 .

36 Background: At Weill Cornell Medicine (WCM), we have had a research program utilizing anti-PSMA mAb J591 since the year 2000. With the addition of PSMA ligand-based therapies in 2017, we have enrolled around 300 patients on investigational PSMA-TRT clinical trials. Since the approval of 177Lu-PSMA-617 (Pluvicto; Lu-177 vipivotide tetraxetan), we began standard-of-care (SOC) treatment, co-enrolling willing patients into a research registry. Recognizing the low numbers of AA patients enrolled on therapeutic clinical trials in the U.S., we made a concerted effort to increase the number of AA patients with prostate cancer (PC) enrolled on clinical trials at WCM. We retrospectively assessed the demographic data of patients enrolled on PSMA-TRT clinical trials to determine changing patterns of enrollment, and to determine if our efforts have improved access to these novel treatments for this under-represented, but high-risk population of patients. Methods: We collected demographic data (namely race and ethnicity) on patients with PC from WCM who were included on our PSMA-TRT investigational clinical trial databases or enrolled on our SOC 177Lu-PSMA-617 research registry. We used self-reported race and, when not available (due to patient death or loss of follow-up), demographic information documented in the medical record. Patients were grouped into 5-year cohorts based on either the date of consent for trial enrollment, or the start date of PSMA-TRT treatment (based on available information). Institutional tumor registry data was used as a comparator to assess the total percentage of AA patients with PC seen at WCM. Results: The percentages of patients included on PSMA-TRT clinical trials at WCM who were identified as AA were as follows: 2000-2004: 3.1% (2/65), 2005-2009: 5.1% (3/59), 2010-2014: 6.1% (2/33), and 2015-2019: 5.9% (5/85). The percentage of AA patients on PSMA-TRT studies from 2020 through July 2022 was 18.2% (16/88, inclusive of 8/72 investigational TRT subjects and 8/16 SOC registry participants). The total percentages of AA patients seen at Cornell based upon analysis of our tumor registry data were as follows: 2000-2004: 10.5% (182/1728), 2005-2009: 6.9% (250/3607), 2010-2014: 10% (326/3255), 2015-2019: 11.5% (278/2413), and 2020: 14.1%. Tumor registry data for 2021-present were not yet available. Conclusions: The percentage of AA patients on investigational PSMA-TRT trials at our institution notably increased from 2000-2019 (3.1%-6.1%) to 2020-2022 (11.1%). Moreover, 50% of those treated with 177Lu-PSMA-617 since its FDA approval and co-enrolled on our research registry identified as AA. These data suggest that outreach and increasing access to AA patients for novel PC treatment such as PSMA-TRT can result in increased numbers of underrepresented patients enrolling on clinical trials and receiving the most modern standards of care (i.e., PSMA-TRT).

PURPOSE: AccessHope is a program developed initially by City of Hope to provide remote subspecialist input on cancer care for patients as a supplemental benefit for specific payers or employers. The leading platform for this work has been an asynchronous model of review of medical records followed by a detailed assessment of past and current management along with discussion of potential future options in a report sent to the local oncologist. This summary describes an early period of development and growth of this service, focusing on cases of lung cancer, particularly during the COVID-19 pandemic. METHODS: Cases were primarily identified by a trigger list of cancer diagnoses that included non–small-cell lung cancer and small-cell lung cancer. After medical records were obtained, a summary narrative was provided to a thoracic oncology specialist who wrote a case review sent to the local physician, followed by a direct discussion with the recipient. We focused on feasibility as measured by case volumes, the rates of concordance between the subspecialist reviewer with the local team, and cost savings from recommended changes, using descriptive statistics. RESULTS: From April 2019 to November 2020, 110 cases were reviewed: 55% male, median age 62.5 years (range, 33-92 years); 82% non–small-cell lung cancer (12% stage I or II, 16% stage III, and 57% stage IV), and 17% small-cell lung cancer (4% limited and 14% extensive). Median turnaround time for report send-out was 5.0 days. The review agreed with local management in 79 (72%) cases and disagreed in 31 (28%) cases; notably, specific additional recommendations were associated with evidence-based anticipated improvements in efficacy in 76 cases (69%) and improvement in potential for cure in 14 cases (13%). Recommendations leading to cost savings were identified in 14 cases (13%), translating to a projected cost savings of $19,062 (USD) per patient for the entire cohort of patient cases reviewed. CONCLUSION: We demonstrate the feasibility of completing a rapid turnaround of cases of lung cancer either patient-initiated for review or prospectively triggered by diagnosis and stage. This program of asynchronous second opinions identified evidence-based management changes affecting current treatment in 28% and potential improvements to improve care in 92% of patients, along with cost savings realized by eliminating low-value interventions.

Aim Minimally invasive surfactant therapy (MIST) is used to deliver exogenous surfactant to preterm neonates with respiratory distress syndrome. The objective of this study was to review the use of MIST in moderate to late preterm neonates born in a non-tertiary unit. Methods A retrospective review was conducted of neonates receiving MIST in a non-tertiary unit. MIST was considered in neonates requiring continuous positive airway pressure ≥ 6 cm H2 O and fraction of inspired oxygen ≥ 0.35. The Hobart method was used to deliver exogenous surfactant. The primary outcome was improvement in respiratory function. Secondary outcomes include intubation and transfer to a tertiary unit. Results Between 2016 and 2020, 23 infants were treated with MIST. The median gestational age was 33+5 ± 2.7 weeks and mean age of surfactant administration was 6.6 ± 3.6 h. Surfactant administration resulted in a reduction in median fraction of inspired oxygen from 0.3 to 0.21 at 4 h post MIST (P value: 0.001), and a reduction in median positive end-expiratory pressure (PEEP) from 7 to 6 cm H2 O at 24 h post MIST (P value: 0.003). Continuous positive airway pressure support was required for a median period of 3.5 days following MIST. There was respiratory improvement in 52 and 65% of neonates at 4 and 24 h, respectively, following MIST. The incidence of intubation was 13% and transfer to a tertiary unit was 44%. Conclusions Use of MIST at this unit improved respiratory outcomes in moderate to late preterm neonates with respiratory distress syndrome. This procedure was well tolerated with few adverse events. Further research evaluating the efficacy of MIST in other non-tertiary units is warranted.

Background: PSMA is overexpressed by the majority of PC and may be targeted by both antibodies (mAb) and small molecule ligands (SML), each with differing PSMA binding sites, kinetics, and biodistributions. mAbs have long circulating times (exposing organs such a bone marrow) but are too large to target normal tissue luminal PSMA expression in salivary glands, small bowel, and kidney; SMLs rapidly diffuse to all PSMA+ sites and are excreted by the kidneys within hours. Alpha emitters have high potency over a short range whereas beta emitters have lower energy over a significantly longer range. We hypothesized that combining mAb and SML targeting plus combining alpha and beta emitters offered complementary benefits and would be safe and effective. Methods: A series of cell line and xenograft studies were performed to test mAb vs SML vs combo binding, uptake, and efficacy. A phase I/II clinical trial was initiated, enrolling patients with progressive, PSMA+ (by PSMA PET) mCRPC following potent AR pathway inhibition and chemotherapy (or chemo ineligible/refused)[NCT04886986]. The primary endpoint of phase I is assessment of dose-limiting toxicity (DLT) with secondary endpoints of response, progression-free and overall survival, genomic and imaging correlatives, and patient-reported outcomes. Results: Binding studies demonstrated that mAb plus SML binding was additive rather than competitive in LNCaP and CWR22Rv1 cell lines. Uptake of 177Lu-mAb plus -SML in LNCaP, CWR22rv1, and PC3/PSMA xenograft models demonstrated synergism, with 44-65% greater tumor radioactivity in combination than the sum of the individual agents. Intracellular tracking studies indicate that the mAb re-directs SML to lysosomes from recycling endosomes, maintains retention of SML in tumor cells, and, therefore, prolongs intra-tumoral radioactivity exposure. Survival was prolonged in animals receiving 225Ac-mAb plus 177Lu-SML vs either drug alone (or control). Nine men with median age 68 (range 55-87), PSA 140 (2.4-9614) have been enrolled in both of 2 planned dose-escalation cohorts. 89% with bone, 44% lymph node, 22% liver, 22% lung metastases; 88% with detectable CTC count (75% unfavorable). All had at least 1 metastatic lesion with PSMA PET SUVmax > liver SUVmean, with SUVmax of the single hottest lesion ranging from 11.6-69.9. For the primary endpoint, 0 of 3 with DLT in cohort 1, and with follow up ongoing, no DLT has occurred to date in 6 patients in cohort 2. Of evaluable patients, 5 of 6 with PSA decline (8-97% decline). Conclusions: Targeting PSMA with the combination of mAb and SML leads to synergistic radioactivity in preclinical studies. The combination on mAb and SML radiolabeled with alpha and beta emitters appears safe with short-term follow up with phase 2 enrollment planned. Citation Format: Scott T. Tagawa, Edward Fung, Muhammad O. Niaz, Mahelia Bissassar, Sharon Singh, Amie Patel, Angela Tan, Juana Martinez Zuloaga, Sandra Huicochea Castellanos, Jones T. Nauseef, Ana Molina, Cora Sternberg, David M. Nanus, Joseph Osborne, Neil H. Bander. Results of combined targeting of prostate-specific membrane antigen (PSMA) with alpha-radiolabeled antibody 225Ac-J591 and beta-radiolabeled ligand 177Lu-PSMA I&T: preclinical and initial phase 1 clinical data in patients with metastatic castration-resistant prostate cancer (mCRPC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT143.

TPS5100 Background: PSMA is overexpressed by most prostate cancers and can be successfully targeted by both antibodies (mAb) and small molecule ligands (SML), each with overlapping and distinct binding sites, kinetics, and biodistributions [Kratochwil Sem Nuc Med 2019]. mAbs are larger, with longer circulating times resulting in greater exposure to bone marrow, but lesser access to PSMA expression on luminal tissue ( e.g. salivary glands, small bowel, and kidney). In contrast, SMLs are rapidly excreted via kidneys and readily diffuse to all PSMA-expressing sites. Toxicities of 177Lu vary with these differences in biodistribution ( e.g. more hematologic toxicity with mAb, more xerostomia and nausea with SML, p < 0.001)[Niaz AUA 2020]. Alpha emitting isotopes have shorter ranges but high potency compared to beta emitters which have longer ranges, but lower linear energy transfer. In preclinical models, the combination of mAb plus SML has demonstrated additive binding in LNCaP, CWR22Rv1, and PC3/PSMA PC cell lines, and synergistic uptake of 177Lu-mAb plus 177Lu-SML in xenograft models. We developed a phase I/II study to test our hypothesis that concomitant mAb and SML targeting, plus the combination of alpha (225Ac) and beta emitters (177Lu), may offer complementary benefits in a safe and effective manner. Methods: Key eligibility criteria include progressive mCRPC (PCWG3), at least 1 prior AR pathway inhibitor and taxane chemotherapy (or ineligible/refused), and adequate organ function and performance status. PSMA PET/CT must have at least 1 lesion with SUVmax > liver SUV. Prior PSMA-based therapy with radioisotopes is not allowed. 177Lu-PSMA-I&T (PNT2002) will be administered as in the phase III SPLASH study (6.8 GBq q8w for up to 2 doses). The phase I includes up to two dose-escalation cohorts of concurrent 225Ac-J591 (30 & 40 KBq/Kg q8w x2) in a modified 3+3 schema. All subjects undergo 177Lu SPECT on Day 8 after each dose. The primary objective of the Phase I study is to determine the dose-limiting toxicity and recommended phase II dose (RP2D) for this combination. Primary objective of the Phase II study is to assess the proportion of patients with > 50% PSA decline after treatment. Secondary objectives include radiographic response rate (PCWG3-modified RECIST 1.1), biochemical and radiographic progression-free survival, overall survival, safety (CTCAE 5.0), CTC count changes and conversions, and patient-reported outcomes (FACT-P, BPI-SF, EQ-5D). Exploratory objectives include pre- and post-treatment PSMA-based imaging changes, effects of PSMA radionuclides on the microbiome, relationship between genomic alterations and response, and relationship between PSMA PET/CT results and outcome. The phase I was activated at Weill Cornell Medicine in May 2021. Following determination of the RP2D, a multicenter phase II is planned at Prostate Cancer Clinical Trials Consortium (PCCTC) in 2022. Clinical trial information: 04886986.

e17007 Background: Prostate-specific membrane antigen (PSMA) is overexpressed on most prostate cancers (PCs), a fact that has been exploited to perform both targeted imaging and treatment. PSMA-based PET imaging allows for more sensitive detection of PC and can be useful even in the context of negative CT and bone scans. Prior to 2021, research protocols using PSMA-PET (PET) were common at large academic centers, but will likely be more commonplace as standard of care (SOC) after recent FDA approval. With a change in SOC imaging, the impact of cost to patients must be examined. We hypothesize that socioeconomic and demographic-based care disparities may widen and access may narrow in the face of these changes. Methods: We collected demographic data on patients with PC from Weill Cornell Medicine (WCM), Brooklyn Methodist Hospital (BMH), and Columbia University Medical Center (CUMC) who received a PSMA PET scan between 1 January 2018 and 31 January 2022. Data collected included age, zip code, primary language, self-reported race and ethnicity, and type of insurance coverage. Zip codes were used to estimate income strata of patients using publicly-available 2018 IRS adjusted gross income (AGIs) as follows ($): < 25k, 25k-50k, 50k-75k, 75k-100k, 100k-200k, and > 200k. Any AGI strata comprising > 20% of population was counted. Patients were divided into four cohorts: those who had a scan (1) as part of therapeutic-based studies for mCRPC, (2) non-therapeutic imaging studies, (3) as a part of a cost-recovery study with an out-of-pocket cost of $1054, and (4) commercial use under post-approval standards of care (SOC) billed to insurance. Proportion of self-reported race in each cohort was compared against overall race distribution for prostate cancer registry from WCM and CUIMC (Table). Results: 896 patients underwent PSMA PET. Approximately half of all scans were in Cohort 4 (49%, n = 368) including all BMH scans. CUMC scans were 90% in Cohort 2 (122/136). In Cohort 1, 2, and 3, > 90% of subjects resided in zip codes with AGI > $100k. In Cohort 4, 84% resided in zip codes with AGI > $100k. Overall 70.4% of subjects identified as White, 8.3% Black or African American, 3.5% Asian, 4.4% Other, and 13.5% were unknown/or declined. African American/Black was most represented on Cohort 4 (11%), and least represented in Cohort 1 (5%). Conclusions: White patients comprise the largest proportion or PET scans whereas non-white groups are underrepresented across all cohorts. Access to PETs has appeared to improve for lower AGI, non-white patients following FDA approval and insurance coverage. It will be critical to assure equitable access across all demographic groups as deployment of PET scanning becomes the new standard of care.[Table: see text]

77 Background: Prostate Specific Membrane Antigen (PSMA) is a conserved cell surface protein in PC and is used for targeted imaging and therapeutics. Antibodies circulate longer than small molecules and are less likely to reach luminal PSMA on normal organs. Here we report PROs and longer-term AEs from the dose-escalation and expansion cohorts of a first-in-human study of combined monoclonal antibody and potent alpha emitter (225Ac-J591). Methods: Eligible subjects with mCPRC were administered 225Ac-J591. Initial to maximum doses were 13.3 to 93.3 KBq/kg). AEs are reporting using CTCAE v5 and PROs, including pain (BPI-SF) and quality of life (QOL, FACT-P), and associations with PSA response were also examined. Results: A total of 32 subjects (one enrolled in both dose-escalation and expansion) were treated with a single dose of 225Ac-J591 across 7 dose levels with expansion at the level (93.3 KBq/kg, n = 16). Median age 69.5 (52-89) and PSA 149.1 (4.8-7168.4). All subjects had at least 1 AE of any grade. Most common were fatigue (31/32, 1 Gr > 2), anorexia (25/32, all Gr 1-2), and thrombocytopenia (25/32, 3 Gr 3, 2 Gr 4). Xerostomia was observed in 14/32 subjects (all Gr 1), 7 of whom had prior 177Lu-PSMA. Pain flare was reported in 43% (17/32) subjects (11 Gr 1, 6 Gr 2). 19 had evaluable PROs at baseline and efficacy visit (week 12). Pain severity (p = 0.8) and interference from pain (p = 0.4) were unchanged from baseline to 12 weeks, yet better PSA response (by percent) was associated with reduced pain severity (r = 0.7, p = 0.0023). Despite at least one AE in each subject, total FACT-P was not significantly changed after treatment (p = 0.2), but emotional well-being declined over time (15 [10.0, 18.0] v 10.0 [7.5, 13.0], p = 0.011). Reduction in median emotional well-being reached clinically important score differences. When stratified by AE, subjects with xerostomia had lower FACT-P total scores, but no difference was observed between those with and without pain. PSA response was not associated with change in QOL or subscales. Conclusions: Pain and quality of life in subjects with mCRPC did not change, on average, from baseline to 12 weeks after treatment with 225Ac-J591. This is despite preliminary evidence of clinical efficacy being accompanied by frequent, treatment emergent AEs. A promising trend toward improved pain in those with PSA response warrants further analysis. Small numbers limited statistical power for testing other subgroup associations. Additional correlations with pretreatment sites of disease, performance status, and adverse event distribution are ongoing. Assessment of changes in PROs in the follow up studies [NCT04506567] are underway. Clinical trial information: NCT03276572.

37 Background: We have previously reported a dose-intense single-cycle of 177Lu-PSMA-617 was effective in pretreated patients with mCRPC without requiring PSMA-positive imaging for enrollment. Prior post-hoc analyses of these data using approximate quantification of exclusively the most PSMA-positive disease sites have demonstrated associations between PSA response and PFS with pre-treatment 68Ga-PSMA11-PET signal. Greater sophistication in pre- and post-treatment evaluation of PSMA-expression in tumor and normal organs may allow for better patient selection and prediction of toxicities. Methods: A total of 50 patients were treated on a phase I/II study of fractionated-dose (D1, 15) 177Lu-617-PSMA. Quantification using artificial intelligence (AI) were used to measure pre- and post-treatment PSMA signal intensity. Scoring cutoffs with confidence intervals around scan variation were empirically established from a subset of test/re-test of subjects within 24h without intervening therapy. A variety of measurements were performed including SUVmean across all detectable tumor lesions, volume of lesions, and SUVtotal (Total + Volume), as well as select normal organs and changes after treatment. Associations with survival were tested via Cox proportional hazard models in univariate analyses and associations with adverse events (AEs) and PSA responses were via assessed via Wilcoxon rank sum tests. Results: 13 subjects were selected to complete AI-based quantification and associated survival analyses. Among these, 10 (77%) experienced any PSA decline, with 8 (62%) with PSA50 and 3 (23%)with PSA90. Median overall survival (OS) was 17.0 mos (10, NA) via Kaplan-Meier estimates. In univariate analysis, pretreatment SUVmean was associated with improved PFS (HR 0.66, 95% CI 0.49-0.90, p = 0.009) and OS (HR 0.81, 95% CI 0.65-1.00, p = 0.048). The metrics most strongly associated with PSA50 were pretreatment SUVmean (median [IQR]: 7.66 [6.52, 10.54] v 3.50 [3.02, 3.56], p = 0.019) and SUV Total (14982 [11110, 20595] v 1303 [576, 1512], p = 0.019), and change in Volume (-27 [-44, -20] v 145 [38, 154], p = 0.006) and SUVtotal (-57 [-67, -35] v 132 [9, 269], p = 0.030). Subjects with xerostomia had higher salivary gland SUVmax (pretreatment and change in after treatment). Those with pain flare had lower pretreatment SUV scores (Mean, Max, Total) in unaffected portions of bony skeleton. Conclusions: Sophisticated AI-based quantification analysis of PSMA expression on pre- and post-treatment 68Ga-PSMA11-PETs demonstrate associations with treatment efficacy (PSA response, OS), and associations between patient experience (AEs) and PSMA expression in non-tumor tissues. Expansion of this algorithm to a larger patient cohort may improve our ability to anticipate toxicity by body-wide PSMA detection and predict treatment response. Clinical trial information: NCT03042468.

TPS216 Background: The role of immune checkpoint inhibition (ICI) in prostate cancer remains undefined outside of the subset with mismatch repair. Several studies have suggested that ICI combined with androgen receptor signaling inhibitors (ARSI) or kinase inhibitors may result in improved and/or more durable response in a proportion of men with mCRPC. While not yet proven, addition of external beam radiation to ICI may improve outcomes (for instance Kwon et al Lancet Oncol 2014, Fizazi K et al, Eur Urol 2020). PSMA targeted therapy with 177Lu-PSMA-617 improves survival in men with CRPC, has been combined with ICI in early phase studies, and we have previously demonstrated the benefit of PSMA targeted therapy using radiolabeled mAb J591. PSMA-targeted alpha-emitters have a very high potency and the potential to generate immune response. Based upon i) ARSI may increase PSMA expression, ii) ARSI may radiosensitize tumors, iii) ARSI resistance may lead to increased PD-L1 expression, and iv) alpha emitters may generate an immune response, we hypothesize that the addition of an alpha-emitting radionuclide (225Ac) targeting prostate cancer (i.e PSMA+ tumors targeted with J591) will lead to double-stranded DNA breaks, cell death, and subsequent release of neoantigens, and thus will increase the response proportion to pembrolizumab plus ARSI resulting in more durable response. Methods: Key eligibility criteria include progressive mCRPC by PCWG3 on at least 1 prior AR pathway inhibitor and no prior chemotherapy for mCRPC. A phase I dose-finding study will first test safety of the triplet combination of pembrolizumab, an ARSI of physician choice, and 2 different doses of 225Ac-J591 (one with minimal and one with moderate single-agent toxicity). Following determination of the optimal dose, a randomized phase II trial will treat subjects with a fixed dose of pembrolizumab 400 mg every 6 weeks (for up to 2 years) plus a standard ARSI (until progression or intolerance) with or without 225Ac-J591. The primary endpoint of the study will test the hypothesis that the addition of a PSMA-targeted alpha emitter increases the composite of RECIST measurable disease, PSA, and CTC count response to immuno-hormonal therapy with 90% power. Key secondary clinical endpoints include 1-year progression-free survival, duration of response, and overall survival. Exploratory objectives include assessment of immunogenic cell death, immune serologic and host microbiome changes, plasma ctDNA, serial PSMA PET, and patient reported outcomes (FACT-P, BPI, EQ-5D-5L). The phase I portion of this DOD-funded study was activated in summer 2021 with the randomized phase II portion expected to open at PCCTC sites in 2022. Clinical trial information: NCT04946370.

VicTrack in the State of Victoria in Australia began using fair value to value its assets in 2011. In doing this the company encountered the difficulties normally associated with valuing long-lived assets that are specific to their use. In this paper, a case study is presented centred on VicTrack in order to provide information on the basic difficulties of determining the fair value of assets that are long-lived, specific-to-use and in markets that are incomplete; and to better understand some of the implications of the switch from historical costs to fair value.

Background: While many preschoolers with asthma experience remission, it remains unclear what drives disease evolution. We assessed if asthma control in the 2 years after diagnosis was associated with remission. Methods: We conducted a retrospective cohort study of children born from 1990-2013 in 4 Canadian provinces, aged 1-5 years at asthma diagnosis, with sustained disease activity. Sustained activity was defined as ≥1 medical visit or treatment for asthma every 6 months for at least 2 years within the 3 years post-diagnosis (cohort entry). Remission was defined as 2 consecutive years of no asthma treatment, medical visits, or hospitalizations. Cox models served to assess if asthma control patterns in the 2 years post-diagnosis, ascertained over 4 consecutive 6-month periods with a validated Pediatric Asthma Control Index, were associated with time-to-remission, adjusting for covariates. A random effects model summarized Hazard Ratios across provinces. Results: Of the 94,805 children with asthma, 45,331 (47.8%) entered the cohort. Compared to those controlled throughout, children with improving, variable, worsening control, and out-of-control asthma had decreasing hazards of remission in a dose-response pattern, after adjusting for covariates (Figure). Conclusion: Poorer asthma control in the 2 years post-diagnosis is associated with a lower rate of remission, suggesting a potential window of opportunity to alter disease evolution in preschoolers.

Background: Irreversible lung function deficits have been observed by age 6 in children with preschool asthma, suggesting the possibility of long-term adverse outcomes. We examined the impact of asthma control shortly after diagnosis in preschool children on long-term control. Methods: We constructed Canadian birth cohorts from 4 provincial administrative databases. Preschool asthma was defined as 1 hospitalization or 2 physician visits for asthma within 2 years in children Results: Of the 118365 preschoolers with asthma, 50188 (42.4%) were included. Compared to children controlled throughout the 2 years post-diagnosis, suboptimal control was associated with a higher pooled RR for long-term poor control in a dose-response manner towards worse control patterns. Conclusions: Suboptimal control after diagnosis in preschool is a strong predictor of long-term poor control, suggesting a window of opportunity to improve future morbidity.

TPS5095 Background: Despite a variety of therapy classes extending survival in mCRPC – and excepting select population eligible for PARP inhibitors – no molecularly selected drugs are FDA approved in mCRPC. Previously, cabo, an inhibitor of multiple tyrosine kinases ( e.g. MET, VEGFRs 1-3, RET, KIT, TRKB, FLT-3, AXL, TIE-2), was evaluated in phase III trials (COMET-1, COMET-2) in mCRPC. Despite initial promising results, particularly in bone scan responses and rPFS benefit, further application of cabo in mCRPC was halted after improvement in OS was not observed. It is unclear why prolonged rPFS in COMET-1 (vs. prednisone) did not translate into improved OS. Previous failures may reflect inclusion of relatively cabo-insensitive tumors due to an unselected population with regard to presumed cabo activity. Given that mCRPC specimens from our precision medicine cohort have increased expression of target genes MET and KIT, and qualifying genomic alterations (amplifications, activating mutations) are reported in ̃15% of a publicly-available mCRPC cohort, we developed this rationally-designed study. We predict a molecularly-defined mCRPC cohort will identify the population that most benefits from cabo therapy, as reflected by prolonged rPFS and OS, and more frequent PSA declines and CTC conversions. Methods: We have activated a phase II non-randomized, open label trial designed to evaluate treatment response and survival of patients with mCRPC who harbor evidence of increased signaling of the targets of cabo. Study population will have progressed on an ARSI; prior taxane therapy in castration-sensitive PC or CRPC (beyond 12 mos) will be eligible. Molecular eligibility: DNA (tumor or cfDNA) evidence of amplification or activating mutation in selected targets of cabo. Alternatively, IHC confirming high expression (2 or 3+) via CLIA-approved assay is allowed. Overexpression via RNAseq, validated by CLIA-approved IHC, is permitted. All patients will receive 40 mg/d of cabo, with dose-reductions allowed (to 20 mg/d, then 20 mg EOD). Repeat biopsy after 3 weeks on treatment is mandated. Primary endpoint is rPFS. Using median of 5.6 mos (COMET-1) to guide our H0 (50% rPFS rate at 6 mo), the H1 is ≥75% rPFS at 6 mo. Sample size (30) provides 90% power with one-sided alpha of 0.05 via chi-square test. Secondary endpoints include PSA decline by PCWG3, objective radiographic response proportion, OS, and CTC response rate. Exploratory studies will include serial evaluation of cfDNA (via PCF-SELECT); immune tumor microenvironment response via on-treatment biopsy and collection of plasma for circulating immune markers; and exploration of baseline and on-treatment tumor genomic alterations. This trial is multicentered via the Prostate Cancer Clinical Trials Consortium (PCCTC c20-254). Clinical trial information: NCT04631744.

This paper traces the financial developments of the desalination plant in the State of Victoria in Australia. The desalination plant was built via a public–private partnership (PPP) vehicle, and commissioned at a time when water storage levels in the state were low. Subsequent rainfall has meant that no water has yet been ordered by the Victorian Government from the plant. In the paper an analysis is undertaken of the impact of the manner in which accounting treatment has been used in valuing this infrastructure asset. It is concluded that the applied accounting policy choices and treatments for this infrastructure asset are not consistent with conventional accounting theory, the Conceptual Framework for accounting or generally accepted accounting principles.

TPS188 Background: Prostate-specific membrane antigen (PSMA)-based targeted radionuclide therapy (TRT) is a promising treatment. PSMA-targeting via large antibodies vs small molecules has different kinetics, biodistribution, and resulting clinical toxicities. Using beta-TRT, 177Lu-J591 has more heme toxicity and 177Lu-PSMA-617 more non-heme toxicity (xerostomia and nausea) [Niaz AUA 2020]. Alpha-emitters are more potent than beta radionuclides, and alpha-PSMA-TRT has efficacy even after beta-PSMA-TRT. In a first-in-human phase I dose-escalation study of 225Ac-J591, patients with mCRPC were treated with a single dose of 225Ac-J591 on seven dose levels, up to 93.3 KBq/kg [Tagawa ASCO 2020]. No maximal tolerated dose (MTD) was achieved. One patient treated at 80 KBq/kg developed dose-limiting toxicity (DLT) of grade 4 anemia and thrombocytopenia, but 0 of 6 at 93.3 KBq/Kg had grade > 3 heme toxicity or grade > 2 non-heme toxicity. Preliminary results indicate 64% had any PSA decline and 41% had > 50% PSA decline (PSA50) across all doses, despite lack of selection for PSMA expression and the majority having been previously treated with 177Lu-PSMA. Methods: Entry criteria include progressive mCRPC by PCWG3 criteria, ECOG PS 0-2, intact organ function (including normal neutrophil and platelet counts), and prior receipt of AR pathway inhibitor and chemotherapy (or refuse/ineligible for chemotherapy). There is no limit to prior lines of therapy except alpha-PSMA-TRT. Phase I includes 2 separate parallel dose-escalation cohorts. In the fractionated-dose cohort, men will receive a single cycle of 225Ac-J591 administered on D1 and D15. In the multiple-dose cohort, 225Ac-J591 will be given every 6 weeks for up to 4 cycles. The phase I component is a 3+3 dose-escalation study design, with the goal of identifying MTD. Each phase II component will treat up to 27 men with PSMA+ PET scans in a Simon 2-stage design with 90% power to exclude the null hypothesis (35% or fewer patients with PSA50). Eligible men with negative PSMA PET scans will be offered treatment with informed consent in an exploratory subgroup, but will not be counted towards phase II efficacy. Secondary outcomes include radiographic response by PCWG modified RECIST 1.1 criteria and PSMA PET, biochemical and radiographic progression-free survival, circulating tumor cell counts, and overall survival. Patient reported outcomes, genomic, and immune analyses are exploratory. Enrollment began in August 2020 (NCT04506567). Clinical trial information: NCT04506567.

158 Background: CTC counts are an independent prognostic factor in men with mCRPC; certain changes following treatment (conversion from detectable to undetectable or unfavorable to favorable) are associated with improved overall survival. Most PSMA-TRT efficacy data have focused on PSA or imaging changes. Here, we describe baseline and post-treatment CTC counts from subjects receiving PSMA-TRT. Methods: Men with mCRPC treated on prospective clinical trials of PSMA-TRT and with available CTC counts (CellSearch) were included in our analysis. Depending upon the era of the trial, post-treatment counts were performed at 4-6 (initial era) or 12 weeks (recent era) after a single cycle of PSMA-TRT (individual trial data reported elsewhere). We describe CTC counts at baseline and compare pre-treatment counts to those after PSMA-TRT. Results: 116 men treated with PSMA-TRT had baseline CTC count (90 with both pre- and post-treatment CTC). Forty-four patients (37.9%) received 177Lu-J951, 46 (39.7%) received 177Lu-PSMA-617, and 26 (22.4%) received 225Ac-J591. Median age was 71.5. Fifty-eight patients (50%) had previously received taxane chemotherapy, median PSA was 82.98 ng/mL, and 66 (56.9%) were in the high-risk Halabi (CALGB) prognostic group. Eighty-nine out of one hundred sixteen (76.7%) had detectable baseline CTC and 58/116 (50%) had unfavorable baseline CTC count. Forty-nine out of seventy (70%) had post-treatment CTC count decline, 23/70 (32.9%) converted from detectable to undetectable, and 17/47 (36.2%) converted from unfavorable to favorable. CTC changes stratified by type of PSMA-TRT are reported in the table. Conclusions: This is the largest analysis of CTC changes in patients who have received PSMA-TRT. In addition to PSA changes and other previously reported outcomes, even when low doses of radionuclide therapy as part of dose-escalation studies are included, the majority with detectable CTC counts have post-treatment CTC count decline. A significant portion of patients experience favorable CTC changes. [Table: see text]

Background: PSMA may be targeted by antibodies or small molecule ligands labeled with potent alpha emitters. Certain sites of PSMA expression such as salivary/lacrimal glands, kidneys, and small bowel are not accessible to antibodies such as J591. Following binding, immunoreactivity, and xenograft studies, we performed a first in human study of 225Ac-J591. Methods: Men with progressive mCRPC following at least 1 potent AR-targeted agent (e.g. abiraterone/enzalutamide) and taxane chemotherapy (or unfit/refuse chemo) without limit of # prior therapies (including radium-223 or prior PSMA therapy) provided adequate organ function were eligible. Baseline 68Ga-PSMA11 PET was performed, but not used for eligibility. Initially single-subject cohorts were treated until transition to 3+3 with dose level 5 (the dose level predicted by historical J591 dosimetry to have moderate toxicity) with a single infusion of 225Ac-J591 (13.3 KBq/kg with planned escalation up to 93.3 KBq/kg). Dose-limiting toxicity (DLT) was defined as attributable grade 4 hematologic toxicity or grade 3/4 non-heme toxicity. Imaging, genomic, patient-reported outcomes, and immune correlates are included. Results: In the dose-escalation phase, 22 men were treated on 7 dose levels; median age 72.5 (range 58-89), PSA 146.5 (4.8-7168.4); 82% with at least 2 prior potent AR pathway inhibitors, 64% chemo, 23% radium-223, 55% prior 177Lu-PSMA. 1 (4.5%) CALGB (Halabi) good prognostic risk, 10 (20.7%) intermediate, and 11 (50%) poor prognostic risk category. One of 6 subjects in cohort 6 (80 KBq/kg) had DLT (grade 4 anemia and platelets); no other subjects had any attributable grade >2 non-hematologic or grade >3 heme AE (including 0 of 6 at the highest dose level 93.3 KBq/Kg). Low grade temporary AE's include: 17 (77%) with fatigue, 11 (50%) pain flare, 11 (50%) nausea, 6 (27%) with Gr 1 xerostomia (5 of 6 with prior 177Lu-PSMA), 4 (18%) AST elevation. Despite the heavily pre-treated population including the majority with prior PSMA-TRT and no selection for PSMA expression, 14 (63.6%) with any PSA decline, 9 (40.9%) with >50% PSA decline. Interestingly, 15 (68%) had initial PSA increase followed by subsequent decline from peak (delayed effect). With follow up ongoing 2 with response > 1 year despite prior 177Lu-PSMA with correlative assays in process. Of 15 with paired baseline and 12-week CTC counts (CellSearch), 8 declined (45-100% decline), 4 remained undetectable, 3 increased. Conclusions: PSMA-targeted alpha-emitter 225Ac utilizing intact antibody J591 is tolerable with early evidence of clinical activity including long-term responders in a pre-treated population. Correlative studies are in progress and enrollment into a Simon 2-stage expansion cohort has been initiated. Clinicaltrials.gov NCT03276572 Citation Format: Scott T. Tagawa, Joseph Osborne, Charlene Thomas, Escarleth Fernandez, Muhammad J. Niaz, Shankar Vallabhajosula, Panagiotis Vlachostergios, Ana M. Molina, Cora Sternberg, Sharon Singh, Amie Patel, Angela Tan, John Babich, David M. Nanus, Karla Ballman, Neil H. Bander. Phase I dose-escalation study of prostate-specific membrane antigen (PSMA)-targeted alpha emitter 225Ac-J591 for progressive metastatic castration resistant prostate cancer (mCRPC) [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 CT122.

Using cointegration and error correction modeling techniques, this paper examines the dynamics of carbon dioxide (CO2) emissions in relation to economic growth, energy consumption, trade openness, urbanization and foreign direct investments in the case of the Philippines. The study finds that 1) economic growth and CO2 emissions have a significant positive linear relationship, suggesting that income growth policies must be subject to reasonably stringent environmental constraints related to CO2 emissions; 2) CO2 emissions are inelastic with respect to energy use in the short run, but its response becomes elastic in the long-run; and 3) CO2 emissions have a positive elasticity with respect to FDI which conforms with the Pollution Haven hypothesis.

45 Background: We performed the 1st dose-escalation study of PSMA-targeted radionuclide therapy with 177Lu-PSMA-617. Using dose-fractionation, we intended to deliver a dose-intense regimen designed to minimize radioresistance due to repopulation. Radionuclide therapy may be able to treat symptoms due to tumor and therefore may be associated with improvement in PRO. Methods: Inclusion: progressive mCRPC following potent AR-pathway inhibitor (ARPI, e.g. abi/enza) and taxane (or unfit/refuse chemo) without limit of # prior therapies, adequate organ function, ECOG performance status 0-2, without preselection for PSMA expression. Treatment was a single cycle of fractionated dose 177Lu-PSMA-617 on D1 and D15 (7.4 to 22 GBq in phase 1; 22.2 GBq in phase 2). PRO tools included FACT-P and BPI-SF at baseline and follow up. Results: 44 men with median age 69 (range 55-91), median PSA 182.97 (range 0.89-5541) were treated. 93% with bone, 45% nodal, 18% lung, 9% liver, 9% other visceral metastases. 55% with at least 1 prior chemo regimen, 52% >2 prior ARPI, 27% with Ra223, 30% sip-T, 5% 177Lu-J591. 59.1% with >50% PSA decline (66.7% at 22.2 GBq, n=21), median overall survival 16 months (95% CI 11-NR). High grade (Gr) toxicity was rare with 6.8% Gr 3 anemia and 2.3% Gr 3 platelets. Gr 1/2 treatment-emergent AE’s include 81.8% with pain flare, 61.4% xerostomia, 29.5% fatigue, 25% platelets, 25% anemia, 25% pain, 15.5% nausea. FACT-P scores tended to improve in all categories by D22 (1 week later), with overall FACT-P scores improving by mean of 8.9 points (p=0.07) at D22 and remaining improved at 12 wks. All BPI scores also improved, with BPI overall severity score improving by mean of 3.0 at D22 (p=0.008) and remained better than baseline at 12 wks. There was no clear association with any AE and PRO changes, but those with PSA decline tended to have improved pain scores (p=0.1). Conclusions: A single cycle of up to 22.2 GBq of 177Lu-PSMA-617 is safe with fractionated (D1 & D15) dosing, with encouraging early efficacy signals in a population unselected for PSMA expression and improved quality of life and pain scores by validated PRO instruments. Clinical trial information: NCT03042468.

We devised a comfort care kit (CCK) consisting of nonoral and nonparenteral rescue medications for caregivers to use at home for symptom control in imminently dying patients who have lost their ability to swallow. The aim of this study was to evaluate the feasibility of the CCK from the perspective of bereaved caregivers.CCKs were handed out to caregivers for patients who were entered into the care for the dying pathway (CDP). Each CCK includes morphine and haloperidol ampoules, lorazepam tablets, atropine drops, and paracetamol suppositories given either through sublingual or rectal route. We conducted a telephone survey of bereaved caregivers to assess CCK's feasibility (proportion of use), pattern of use, perceived benefits and challenges, and need to transfer to emergency department at the end of life.Forty-nine caregivers completed the survey. Thirty-three (67%) reported that they used the CCK. A majority (76%) only used one medication from the kit. Atropine drops were the most commonly used, followed by morphine and paracetamol. All family members reported that the CCK was easy to use and 98% found it to be effective for symptom management. All except one patient died at home.The CCK was feasible and perceived to be effective for symptom control and easy to use. Further research is necessary to optimize the use of this kit and to document related outcomes.

Singapore English has been, and still is, an enigma for many scholars and researchers. In recent years, much attention has been given to the analysis of its particles. However, rather than focusing on the analysis of one particle or several particles and how they operate at the level of the sentence, this paper looks at a particular phenomenon in Singapore English at a discursive level. Specifically, it examines right and its use as a discourse marker in Singapore English interactions. In doing so, this paper demonstrates how it contributes to the alignment of two kinds of stances between speakers, namely, the epistemic stance and the interpersonal stance. This is done with supporting data from naturally occurring Singaporean conversations. Furthermore, this paper also briefly suggests that the familiar particles in Singapore English can be analysed not only as particles, but also as discourse markers at an interactional level.

Proactive monitoring involves, in part, the effective use of time-based information such as Trends. In the oil and chemical industries, the benefits of a proactive approach include less down-time, fewer alarm-flooding stresses, and maximized product output. This report aims to describe the effective use of trend displays by examining how expert Distributed Control System (DCS) operators monitored and visualized trends proactively. We found two preferences for trend display layouts, suggesting a lack of design guidelines and understanding towards optimum trend usage performance in the industry. The decision process in proactive monitoring is discussed, along with the attributes that define an expert trends user.

In melanoma, mutations in KIT are most frequent in acral and mucosal subtypes and rarely reported in cutaneous melanomas particularly those associated with intermittent UV exposure. Conversely melanomas arising within chronic sun damaged skin are considered to harbour KIT mutations at higher rates. To characterize the frequency of KIT mutations in a representative melanoma population, 261 patients from two Australian melanoma centres were prospectively screened for mutations in exons 11, 13 and 17 of the KIT gene. A total of 257 patients had cutaneous melanoma arising from non-acral sites and four were acral melanomas. No mucosal or ocular melanomas were analysed. KIT mutations were identified in five tumours (2% of the entire cohort) including two acral melanomas. Two of the three non-acral melanomas with KIT mutations were associated with markers of chronic sun damage as assessed by the degree of skin elastosis. In the remaining cohort, 43% had chronically sun damaged skin. This report confirms that within an Australian population, KIT mutations are infrequent in cutaneous melanomas associated with both intermittent and chronic sun exposed skin.

235 Background: Spiritual care (SC) is a vital part of palliative care (PC) but its provision is still not routine. We studied the effect of a SC training program for staff on patient quality of life (QOL) and spiritual wellbeing (SPS), as measured by the Functional Assessment of Chronic Illness Therapy – Spiritual Well-Being (FACIT-Sp). Methods: This study was conducted at two sites: a PC consultative service in an acute hospital and a home PC service. The program comprised a 30 min training session for nurses and doctors on using the FICA tool for spiritual assessment and subsequent referral to a medical social worker (MSW) if needed, and a 60min training session with the MSWs on how to manage spiritual problems. A prospective cluster-controlled trial was done across 7 clusters. FACIT-Sp comprises 27 items for QOL (FACT-G) in the 4 domains and 12 items for SPS. This was administered at T1: upon referral to the palliative care service and T2: after 3 clinical visits by the PC team (doctor, nurse or MSW visits). Results: QOL data from 142 participants (69 intervention and 73 control) were analyzed. There appeared to be some benefit of the program on all domains of QOL as well as SPS, although only the FACT-G score achieved statistical significance. After further statistical adjustment for scores at T1 (to account for any regression to the mean), FACT-G score remained practically significant (p value 0.076). Conclusions: A brief SC training program for staff (30 min for nurses and doctors, 60 min for MSWs) appeared to result in some improved QOL and SPS for patients. However, a larger sample size will be needed to estimate the degree of benefit more accurately. [Table: see text]

Background: The 2447 A>T pathogenic variation at codon 816 of exon 17 (D816V) in the KIT gene, occurring in systemic mastocytosis (SM), leads to constitutive activation of tyrosine kinase activity and confers resistance to the tyrosine kinase inhibitor imatinib mesylate. Thus detection of this variation in SM patients is important for determining treatment strategy, but because the population of malignant cells carrying this variation is often small relative to the normal cell population, standard molecular detection methods can be unsuccessful. Methods: We developed 2 methods for detection of KIT D816V in SM patients. The first uses enriched sequencing of mutant alleles (ESMA) after BsmAI restriction enzyme digestion, and the second uses an allele-specific competitive blocker PCR (ACB-PCR) assay. We used these methods to assess 26 patients undergoing evaluation for SM, 13 of whom had SM meeting WHO classification criteria (before variation testing), and we compared the results with those obtained by direct sequencing. Results: The sensitivities of the ESMA and the ACB-PCR assays were 1% and 0.1%, respectively. According to the ACB-PCR assay results, 65% (17/26) of patients were positive for D816V. Of the 17 positive cases, only 23.5% (4/17) were detected by direct sequencing. ESMA detected 2 additional exon 17 pathogenic variations, D816Y and D816N, but detected only 12 (70.5%) of the 17 D816V-positive cases. Overall, 100% (15/15) of the WHO-classified SM cases were codon 816 pathogenic variation positive. Conclusion: These findings demonstrate that the ACB-PCR assay combined with ESMA is a rapid and highly sensitive approach for detection of KIT D816V in SM patients.

Patients suspected on clinical grounds to have hereditary non-polyposis colorectal cancer (HNPCC) may be offered laboratory testing in order to confirm the diagnosis and to facilitate screening of pre-symptomatic family members. Tumours from an affected family member are usually pre-screened for microsatellite instability (MSI) and/or loss of immunohistochemical expression of mismatch repair (MMR) genes prior to germline MMR gene mutation testing. The efficiency of this triage process is compromised by the more frequent occurrence of sporadic colorectal cancer (CRC) showing high levels of MSI (MSI-H) due to epigenetic loss of MLH1 expression. Somatic BRAF mutations, most frequently V600E, have been described in a significant proportion of sporadic MSI-H CRC but not in HNPCC-associated cancers. BRAF mutation testing has therefore been proposed as a means to more definitively identify and exclude sporadic MSI-H CRC cases from germline MMR gene testing. However, the clinical validity and utility of this approach have not been previously evaluated in a familial cancer clinic setting. Testing for the V600E mutation was performed on MSI-H CRC samples from 68 individuals referred for laboratory investigation of suspected HNPCC. The V600E mutation was identified in 17 of 40 (42%) tumours showing loss of MLH1 protein expression by immunohistochemistry but in none of the 28 tumours that exhibited loss of MSH2 expression (P < 0.001). The assay was negative in all patients with an identified germline MMR gene mutation. Although biased by the fact that germline testing was not pursued beyond direct sequencing in many cases lacking a high clinical index of suspicion of HNPCC, BRAF V600E detection was therefore considered to be 100% specific and 48% sensitive in detecting sporadic MSI-H CRC amongst those cases showing loss of MLH1 protein expression, in a population of patients with MSI-H CRC and clinical features suggestive of HNPCC. Accordingly, we recommend the incorporation of BRAF V600E mutation testing into the laboratory algorithm for pre-screening patients with suspected HNPCC, whose CRCs show loss of expression of MLH1. In such tumours, the presence of a BRAF V600E mutation indicates the tumour is not related to HNPCC and that germline testing of MLH1 in that individual is not warranted. We also recommend that in families where the clinical suspicion of HNPCC is high, germline testing should not be performed on an individual whose CRC harbours a somatic BRAF mutation, as this may compromise identification of the familial mutation.

Mast cells from over 80% of adult systemic mastocytosis (SM) patients carry an activating mutation at codon 816 of the KIT gene. In fact, a KIT mutation constitutes one of the minor WHO 2008 classification criteria for SM. The most common is the c.2447A>T: p.Arg816Val (D816V) mutation. The KIT gene encodes a type III transmembrane receptor tyrosine kinase whose ligand is stem cell factor. Activation of KIT mediates proliferation and maturation signalling. D816 V causes constitutive activation of the KIT tyrosine kinase activity, which also results in resistance to the tyrosine kinase inhibitor imatinib mesylate. Therefore knowing the mutational status of KIT codon 816 is important for diagnosis and treatment strategy. The population of mutant mast cells is often low in relation to normal cells and so a sensitive molecular detection technique is required. Several have been reported in the literature, the most sensitive include RT-PCR + RFLP, PNA-mediated PCR and allele-specific PCR. Within the diagnostic setting the Peter MacCallum uses the rapid and highly sensitive allele-specific competitive blocker PCR (ACB-PCR) assay with a sensitivity level of between 1 and 0.1%. Between Jan 2008 and Oct 2010, 338 samples were tested, of which 58% were positive.