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207 Background: Docetaxel with androgen deprivation therapy (ADT) has been shown to improve survival in metastatic castration-sensitive prostate cancer (mCSPC). There is limited data on the immunologic effects of docetaxel in mCSPC. Greater knowledge of the immune impact of docetaxel could inform future trials in prostate cancer. Methods: A clinical trial in mCSPC evaluated sequencing docetaxel and ADT with Prostvac, a poxviral vaccine targeting prostate-specific antigen (PSA). Eligibility criteria included mCSPC within 4 months of ADT and ECOG performance status 0-2. Patients given 6 cycles of docetaxel 75mg/m2 with ADT alone for mCSPC were included in this analysis. Peripheral blood mononuclear cells (PBMCs) were sampled at baseline and at 3 weeks after commencing docetaxel. Immune cell subsets analyzed included CD4+ and CD8+ T-cells, T regulatory cells (Tregs), natural killer (NK) cells, dendritic cells (DCs) and myeloid-derived suppressor cells (MDSCs). Analyses were performed to determine if the baseline immune status or immune changes induced by therapy associate with PSA at 2 years. Results: Fifteen patients were evaluated for peripheral immune responses in this study. Median age was 63 years (range 50-73). Fourteen were white and 1 was black. ECOG performance status was 0 in 11 patients, 1 in 4 patients. Disease volume was high in 7 and low in 8 patients. Among 158 immune cell subsets assessed, only changes in Tregs and activated NK cells with a lytic and cytokine producing phenotype (CD16+ CD56br) were noted after initiation of docetaxel in addition to ADT. Patients with PSA ≤0.2 at 2 years had higher baseline frequencies of total CD4+ T cells, several activated CD4+ T-cell subsets, plasmacytoid DCs, and CD49d- Tregs. They also had lower baseline frequencies of total CD8+ T cells, naïve CD8+ T cells, and CD73+CD8+ T-cells. Patients with PSA ≤0.2 at 2 years also had greater percent increases in CD8+ effector memory (EM) PD-1+ T-cells after treatment. Conclusions: This is the first study to demonstrate increases in activated NK cells with lytic and cytokine producing potential after treatment with docetaxel. Given that NK cells are associated with clinical outcomes in prostate cancer (Zhao SG, JNCI, 2019) and that increased NK cells were seen after treatment with enzalutamide as well (Madan, JITC, 2021), developing immunotherapy combinations to capitalize on NK cell activity may be a path forward for developing immunotherapy in prostate cancer. Clinical trial information: NCT02649855 . [Table: see text]

Background Anaplastic prostate cancer has a poor prognosis with limited treatment options. Seven clinical features of anaplastic prostate cancer have been prospectively identified. In this phase II clinical trial, we identified mutations, including DNA-damage repair (DDR) mutations, in patients with metastatic castration-resistant prostate cancer (mCRPC), who were treated with durvalumab and olaparib, and determined how many of these patients can be described as anaplastic and the overlap between anaplastic features and DDR mutations. Methods Eligible patients with mCRPC received prior enzalutamide and/or abiraterone. Patients were treated with durvalumab 1500 mg i.v. every 28 days and olaparib 300 mg p.o. every 12 hours until disease progression or unacceptable toxicity. Patients underwent mandatory baseline biopsies of metastatic lesions. Results Baseline characteristics were similar between anaplastic and non-anaplastic patients. Eleven patients (20%) displayed clear anaplastic features and 43 (78.2%) lacked anaplastic features. In the anaplastic group, 2/11 (18.2%) had germline DRR mutations and 4/11 (36.3%) had somatic DDR mutations. In the non-anaplastic group, 7/43 (16.3%) had germline mutations and 13/43 (30.2%) had somatic mutations. Median PFS in patients with anaplastic features (6.5 months) and without anaplastic features (5.1 months) were similar (hazard ratio [HR], 0.998, p=0.996). Conclusions Patients with and without anaplastic features appear to have similar total rates of DDR mutations and also have similar rates of somatic and germline DDR mutations. Patients with anaplastic features have a trend toward improved PFS when treated with olaparib and durvalumab compared to non-anaplastic patients. Micro-Abstract Relationships between DNA-damage repair (DDR) mutations and anaplastic features, which confers poor prognosis, are unknown. Fifty-five patients with mCRPC treated with olaparib and durvalumab were classified into anaplastic and non-anaplastic groups and had similar rates of DDR mutations. Anaplastic patients had a trend toward improved progression-free survival when treated with olaparib and durvalumab compared to non-anaplastic patients.

e17033 Background: M9241 is an immunocytokine that targets single- and double-stranded DNA which allows the treatment to localize IL-12 to necrotic tumor (Xu, CCR 2017). M9241 was well-tolerated as a monotherapy in a Phase I study with solid tumors (Strauss J, CCR 2019). Additional preclinical data has demonstrated synergy of M9241 with cytotoxic therapy. This is the first study to examine the safety of a novel combination of chemotherapy and immunocytokines in metastatic prostate cancer. Methods: This safety analysis included patients with mCSPC or mCRPC. Patients were enrolled in a 2-dose level (DL) escalation cohort of M9241 (DL 1: 12mcg/kg, DL 2: 16.8mcg/kg) combined with docetaxel (75mg/m2) with 6 patients planned per DL. A third DL of 8mcg/kg will enroll 6 more patients after the 16.8mcg/kg DL has fully enrolled. All patients were treated with ADT. Patients were initiated on treatment with docetaxel with a plan for mCSPC patients to receive six 3-week cycles of combined treatment and mCRPC patients to continue until progression or unacceptable toxicity. M9241 was given starting with the second cycle of treatment for each patient. Dose-limiting toxicity (DLT) was evaluated in the first 6 weeks after start of docetaxel (from cycle 1 day 1 through the end of the first cycle with M9241). Results: The study has enrolled 10 patients out of a planned 18 for the safety portion. Age range is 58-82 with a median of 69 years. Race distribution is 80% White and 20% Black. Gleason scores for patients were 8 (40%), 9 (40%), and 10 (20%). No DLTs were seen with either dose-level. Only 1 patient had a Grade 4 AE, neutropenia. Grade 3 toxicities included anemia, diarrhea, leukopenia, and hypotension (each occurring in 10% of the patients). The most frequent adverse events (AEs) of any grade were anemia (40%) and lymphopenia (40%), followed by fatigue (30%), diarrhea (20%), and fever (20%). Conclusions: We established a safe dose-level of M9241 at ≥ 12mcg/kg. Updated clinical data from the safety cohort (n = 18) will be presented. This demonstrates that an immunocytokine and chemotherapy can be safely combined for treatment in metastatic prostate cancer. Two planned expansion cohorts will evaluate docetaxel and M9241 in mCSPC and mCRPC, respectively. Clinical trial information: NCT04633252.

e17046 Background: Multiple treatment options combined with androgen deprivation therapy (ADT) provide a survival advantage in mCSPC. In this prospective study, mCSPC patients were treated with docetaxel and Prostvac, a therapeutic cancer vaccine. Since initiation of the study, a phase 3 trial of Prostvac did not show independent clinical activity in metastatic castration-resistant prostate cancer. Still, this study offers a chance to evaluate responses to docetaxel-based therapy in mCSPC. More specifically, with FDA approval of prostate-specific membrane antigen (PSMA) PET imaging in just the last year, there is a paucity of data regarding the use of this scan in long-term responders to therapies for mCSPC. Methods: Eligible patients included those with mCSPC and ECOG PS of ≤ 2. As per the CHAARTED regimen, patients started docetaxel within 4 months of initiating ADT with a plan to receive 75mg/m2 for 6 cycles. Patients were randomized to receive Prostvac prior to, concurrent with, or after docetaxel. Restaging was done annually with CT and Tc99 bone scan. The study was powered to evaluate immune responses, which is being reported separately. For this analysis, patients were evaluated as one group. Ten patients are in follow up with continued PSA values of ≤ 0.2 ng/mL and 7/10 were evaluated with 18F-DCFPyL PSMA PET. Results: Seventy-three patients enrolled. Median age was 63 years with a range of 41-86 years. Race distribution was 71.6% White, 20.3% Black, 4.1% other, and 4.1% unknown. Gleason 6, 7, and 8 to 10 was 4.1%, 21.6%, and 68.9% of patients, respectively, with 5.4% being unknown. Median pre-ADT PSA was 34.75 ng/mL. Low-volume disease represented 41.1% of patients and high-volume was 58.9%. After 2 years from the start of ADT, 22% of patients had PSA values of ≤ 0.2 ng/mL. This included 37% of the low-volume group and 12% of the high-volume group. Three years from starting ADT, 14% of patients had PSA values ≤ 0.2 ng/mL (20% of the low-volume group, 9% of the high-volume group). Of the 7 patients who remain in follow-up with PSA values ≤ 0.2 ng/mL and who were evaluated with PSMA PET, median time from start of ADT was 4 years with a range of 3.5-6 years. These patients either had no evidence of disease or minimal residual findings on CT/Tc99 bone scan. Four of the 7 patients still had residual areas of uptake on PSMA PET. Conclusions: Patients treated with docetaxel for mCSPC have the potential for long-term clinical responses. In these long-term responders, despite prolonged PSA response and minimal findings on conventional CT and Tc99 scans, more than half of patients still had findings on PSMA PET imaging. Further studies are required to better understand the clinical implications of these findings and the role of PSMA PET in mCSPC. Clinical trial information: NCT02649855.

Background Checkpoint inhibitors have not been effective for prostate cancer as single agents. Durvalumab is a human IgG1-K monoclonal antibody that targets programmed death ligand 1 and is approved by the U.S. Food and Drug Administration for locally advanced or metastatic urothelial cancer and locally advanced, unresectable stage 3 non-small cell lung cancer. Olaparib, a poly (ADP-ribose) polymerase inhibitor, has demonstrated an improvement in median progression-free survival (PFS) in select patients with metastatic castration-resistant prostate cancer (mCRPC). Data from other trials suggest there may be improved activity in men with DNA damage repair (DDR) mutations treated with checkpoint inhibitors. This trial evaluated durvalumab and olaparib in patients with mCRPC with and without somatic or germline DDR mutations. Methods Eligible patients had received prior enzalutamide and/or abiraterone. Patients received durvalumab 1500 mg i.v. every 28 days and olaparib 300 mg tablets p.o. every 12 h until disease progression or unacceptable toxicity. All patients had biopsies of metastatic lesions with an evaluation for both germline and somatic mutations. Results Seventeen patients received durvalumab and olaparib. Nausea was the only nonhematologic grade 3 or 4 toxicity occurring in > 1 patient (2/17). No patients were taken off trial for toxicity. Median radiographic progression-free survival (rPFS) for all patients is 16.1 months (95% CI: 4.5–16.1 months) with a 12-month rPFS of 51.5% (95% CI: 25.7–72.3%). Activity is seen in patients with alterations in DDR genes, with a median rPFS of 16.1 months (95% CI: 7.8–18.1 months). Nine of 17 (53%) patients had a radiographic and/or PSA response. Patients with fewer peripheral myeloid-derived suppressor cells and with alterations in DDR genes were more likely to respond. Early changes in circulating tumor cell counts and in both innate and adaptive immune characteristics were associated with response. Conclusions Durvalumab plus olaparib has acceptable toxicity, and the combination demonstrates efficacy, particularly in men with DDR abnormalities. Trial registration ClinicalTrials.gov identifier: NCT02484404. Electronic supplementary material The online version of this article (10.1186/s40425-018-0463-2) contains supplementary material, which is available to authorized users.

130 Background: Docetaxel is a standard of care for metastatic castration-sensitive prostate cancer (mCSPC). PROSTVAC is a pox viral-based therapeutic cancer vaccine encoding for PSA and three T-cell co-stimulatory molecules. Pox viral-based vaccines had previously demonstrated potential immune synergy with docetaxel. This clinical trial evaluated the optimal sequence of immunotherapy and chemotherapy in mCSPC. Methods: Key eligibility criteria were mCSPC within 4 months of ADT and ECOG performance status 0-2. Patients were randomized between Arms A (6 cycles of docetaxel 75mg/m2 followed by 6 doses of PROSTVAC) and B (docetaxel concurrent with PROSTVAC). After rapid accrual to the first 2 arms, Arm C was added by protocol amendment (6 doses of PROSTVAC prior to 6 cycles of docetaxel). ADT was continued throughout the treatment period. The primary endpoint was to evaluate antigen-specific responses to the tumor antigens, PSA and MUC1, and brachyury, a transcription factor implicated in the metastatic process, after patients completed their respective sequence of docetaxel and PROSTVAC. This was done using intracellular cytokine staining of 4 established markers in both CD4+ and CD8+ T-cells, for a total of 8 measures of activation per antigen. Results: The study enrolled 73 patients with a median age of 63 years (range 41-86). Gleason scores for patients were 6 (4.1%), 7 (21.6%) and 8-10 (68.9%), with 5.4% being unknown. Median pre-ADT PSA was 34.75 ng/mL. Per CHAARTED criteria, disease volume was low in 41.1% and high in 58.9% of patients. Numbers of patients evaluable for immune responses in arms A, B, and C were 16, 12 and 18, respectively. Clinical responses have previously been presented (Atiq, MO et al., ASCO 2021), with 22% of all patients having PSA

93 Background: M9241 is an immunocytokine that targets single- and double-stranded DNA which allows the treatment to localize IL-12 to necrotic tumor (Xu, CCR 2017). M9241 was well-tolerated as a monotherapy in a Phase I study with solid tumors (Strauss J, CCR 2019). Additional preclinical data has demonstrated synergy of M9241 with cytotoxic therapy. This is the first study to examine the safety of a novel combination of chemotherapy and immunocytokines in metastatic prostate cancer. Methods: This safety analysis included patients with mCSPC or mCRPC. Patients were enrolled in a 2-dose level (DL) escalation cohort of M9241 (DL 1: 12mcg/kg, DL 2: 16.8mcg/kg) combined with docetaxel (75mg/m2) with 6 patients planned per DL. A third DL of 8mcg/kg will enroll 6 more patients after the 16.8mcg/kg DL has fully enrolled. All patients were treated with ADT. Patients were initiated on treatment with docetaxel with a plan for mCSPC patients to receive six 3-week cycles of combined treatment and mCRPC patients to continue until progression or unacceptable toxicity. M9241 was given starting with the second cycle of treatment for each patient. Dose-limiting toxicity (DLT) was evaluated in the first 6 weeks after start of docetaxel (from cycle 1 day 1 through the end of the first cycle with M9241). Results: The study has enrolled 10 patients out of a planned 18 for the safety portion. Age range is 58-82 with a median of 69 years. Race distribution is 80% White and 20% Black. Gleason scores for patients were 8 (40%), 9 (40%), and 10 (20%). No DLTs were seen with either dose-level. Only 1 patient had a Grade 4 AE, neutropenia. Grade 3 toxicities included anemia, diarrhea, leukopenia, and hypotension (each occurring in 10% of the patients). The most frequent adverse events (AEs) of any grade were anemia (40%) and lymphopenia (40%), followed by fatigue (30%), diarrhea (20%), and fever (20%). Conclusions: We established a safe dose-level of M9241 at ≥ 12mcg/kg. Updated clinical data from the safety cohort (n = 18) will be presented. This demonstrates that an immunocytokine and chemotherapy can be safely combined for treatment in metastatic prostate cancer. A planned expansion cohort will evaluate docetaxel and M9241 in mCRPC. Clinical trial information: NCT04633252.

Objective To evaluate the safety and efficacy of cabozantinib combined with docetaxel. Patients and methods This was a phase 1/2 multicentre study in patients with metastatic castration-resistant prostate cancer (mCRPC). Docetaxel (75 mg/m2 every 3 weeks with daily prednisone 10 mg) was combined with escalating doses of daily cabozantinib (20, 40 and 60 mg). Based on the results of the phase 1 study, the investigation was expanded into a randomized study of docetaxel with prednisone (hereafter 'docetaxel/prednisone') plus the maximum tolerated dose (MTD) of cabozantinib compared with docetaxel/prednisone alone. Results A total of 44 men with mCRPC were enrolled in this phase 1/2 trial. An MTD of 40 mg cabozantinib plus docetaxel/prednisone was determined. Dose-limiting toxicities were neutropenic fever and palmar-plantar erythrodysesthesia, and there was one death attributable to a thromboembolic event. In addition, grade 3 or 4 myelosuppression, hypophosphataemia and neuropathy were seen in three or more patients. In the phase 1 study, the median time to progression (TTP) and overall survival (OS) time were 13.6 and 16.3 months, respectively. In the phase 2 study, which was terminated early because of poor accrual, the median TTP and OS favoured the combination (n = 13) compared to docetaxel/prednisone alone (n = 12; 21.0 vs 6.6 months; P = 0.035 and 23.8 vs 15.6 months; P = 0.072, respectively). Conclusion Despite the limited number of patients in this study, preliminary data suggest that cabozantinib can be safely added to docetaxel/prednisone with possible enhanced efficacy.

e17044 Background: Patients with mCPSC have multiple treatment options to combine with androgen deprivation therapy (ADT) including docetaxel, abiraterone, enzalutamide and apalutamide, all of which have demonstrated a survival advantage. While oral anti-androgens are administered daily until progression but are less toxic, docetaxel has more upfront side effects. One of the advantages of using docetaxel is that the 6-cycle regimen (over approximately 4 months) potentially affords patients a respite from daily therapies thereafter. Furthermore, docetaxel may be more cost-effective. In this prospective study, mCSPC patients were treated with docetaxel and Prostvac, a therapeutic cancer vaccine. Since this study was initiated, Prostvac did not demonstrate independent clinical activity in a phase 3 trial in metastatic castration resistant prostate cancer. Nonetheless, this study provides an opportunity to evaluate responses to docetaxel-based therapy in mCSPC. Methods: Eligible patients included those with mCSPC and ECOG of ≤ 2. All patients were treated with docetaxel and were planned to receive 75mg/m2 for 6 cycles within 4 months of starting ADT, as per the CHAARTED regimen. Patients were randomized to receive Prostvac prior to, concurrent with or after docetaxel. Patients were restaged annually with CT and Tc99 bone scan. The study was powered to evaluate immunologic responses, which is ongoing. For the purposes of this analysis, all patients were analyzed as one group and long-term PSA responses were evaluated. Results: The study enrolled 73 patients. Age range was 41-86 with a median of 63 years. Race distribution was 71.6% White, 20.3% Black, 4.1% other, and 4.1% unknown. Gleason scores were 6 (4.1%), 7 (21.6%), and 8-10 (68.9%), with 5.4% being unknown. Median pre-ADT PSA was 34.75 ng/mL. Low-volume disease represented 41.1% of patients and high-volume was 58.9%. After 2 years from the start of ADT, 22% of all patients had PSA values of ≤ 0.2 ng/mL. This included 37% of the low-volume group and 12% of the high-volume group. Three years from the start of ADT, 14% of all patients had PSA values ≤ 0.2 ng/mL (20% of the low-volume group, 9% of the high-volume group). Conclusions: These data highlight long-term outcomes of 6 cycles of docetaxel for men with mCSPC. Although there are concerns about the short-term toxicity of docetaxel, there is potential for prolonged stable disease after ̃4 months of chemotherapy that allows these patients to defer additional oral anti-androgen therapy for years in some patients. The proportions of patients presented here are an underestimate of those who could continue to be monitored for slowly rising, but low PSAs, before starting the next line of therapy. Additional research is required to determine the optimal therapeutic sequence for men diagnosed with mCSPC and long-term implications for quality of life and cost-effectiveness. Clinical trial information: NCT02649855.

Background Seviteronel was being developed by Innocrin Pharmaceuticals as a selective cytochrome P450c17a (CYP17) 17,20-lyase (lyase) inhibitor and androgen receptor antagonist with activity against prostate cancer cells in vitro and in vivo. This open-label phase 2 clinical study evaluated the tolerability and efficacy of seviteronel in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with enzalutamide. Patients and Methods Patients with mCRPC whose disease previously progressed while receiving enzalutamide therapy were divided into 2 cohorts on the basis of prior exposure to docetaxel. Seviteronel was administered without routine oral steroids either twice daily with dose titration (450 mg) or once daily without dose titration (600 or 750 mg). The primary objective was to determine the rate of significant prostate-specific antigen response (ie, decline of ≥ 50%) after 12 weeks of seviteronel therapy. Results Seventeen patients, with a median (range) age of 71 (60-92) years, were enrolled, with 8 patients having received prior docetaxel. Patients received a median of 2 cycles of treatment, with most patients discontinuing treatment because of toxicity related to the study drug. The most common adverse events included concentration impairment, fatigue, tremor, and nausea. Despite changes in dosing, the study was closed prematurely because of the high magnitude of toxicity. One (6%) of 17 patients experienced a significant decline in prostate-specific antigen. Conclusion Seviteronel was not generally well tolerated nor associated with significant clinical responses in patients with mCRPC who had previously received enzalutamide. Further investigation of single-agent seviteronel in this patient population is not warranted; however, studies investigating seviteronel with low-dose dexamethasone are ongoing in patients with androgen receptor–positive tumors.

BackgroundThe standard treatment for non-metastatic castration sensitive prostate cancer (nmCSPC) is androgen deprivation therapy (ADT) or surveillance. This study evaluated the potential synergy of immunotherapy and enzalutamide (without ADT) in nmCSPC. In addition, the immunologic impact of enzalutamide was also evaluated in men with normal testosterone.MethodsPatients with rising prostate-specific antigen (PSA) after definitive therapy, normal testosterone and no radiographic metastasis were randomized to enzalutamide for 3 months with/without PROSTVAC for 6 months. Thereafter, patients could be retreated with another 3 month course of enzalutamide when PSA returned to baseline. Immune profiles were evaluated in these patients.ResultsThirty-eight patients were randomized with a median PSA=4.38 ng/dL and PSA doubling time=4.1 months. No difference was observed between the two groups for PSA growth kinetics, but PSA responses to enzalutamide were noteworthy regardless of PROSTVAC. The median PSA decline after short-course enzalutamide without ADT/testosterone lowering therapy was 99% in both courses. The median time to PSA recovery to baseline after each 84-day course of enzalutamide was also noteworthy because of the duration of response after enzalutamide was discontinued. After the first and second 3 month cycle of enzalutamide, PSA recovery to baseline took a median 224 (range 84–1246) and 189 days (78–400), respectively. The most common adverse events related to the enzalutamide were grade 1 fatigue (71%) and grade 1 breast pain/nipple tenderness (81%). The only grade 3 toxicity was aspartate aminotransferase (AST)/alanine aminotransferase (ALT) elevation in two patients. Enzalutamide was independently associated with immune changes, increasing natural killer cells, naïve-T cells, and decreasing myeloid-derived suppressor cells.ConclusionsThree months of enzalutamide without ADT induced substantial PSA control beyond the treatment period and was repeatable, perhaps representing an alternative to intermittent ADT in nmCSPC. In addition, enzalutamide was associated with immune changes that could be relevant as future immune combinations are developed.Trail registration numberclinicaltrials.gov (NCT01875250).

92 Background: Anaplastic prostate cancer displays features of small-cell carcinoma, a type of neuroendocrine tumor. Treatments for anaplastic prostate cancer are based on small cell lung cancer regimens. Both AnaF and mutations in DDR pathways, including BRCA2 confer an aggressive phenotype. For patients (pts) with certain DDR mutations, olaparib (O) was recently FDA approved, and an ongoing study is evaluating whether the addition of durvalumab (D) confers additional benefit in mCRPC (NCT02484404). We evaluate a potential preliminary relationship between DDR mutations, treatment with D and O, and AnaF. Methods: This is a phase II study of O plus D in pts with mCRPC with disease that is amenable to biopsy. On-study core biopsies undergo mutational analysis. Prior treatment with enzalutamide (enza) and/or abiraterone (abi) is required. D is given at 1500 mg iv q28 days + O 300 mg tablets po q12 hours. The primary endpoint is PFS. Pts were categorized into those with and without AnaF as defined by Aparicio et al. (2013). AnaF include small-cell histology; exclusively visceral metastases; predominantly lytic bone metastases; bulky lymphadenopathy (≥5 cm) or high-grade (Gleason ≥8) mass in prostate/pelvis; low PSA (≤10 ng/mL) at initial presentation with high volume (≥20) bone metastases; neuroendocrine markers in histology or serum plus elevated LDH, malignant hypercalcemia, or elevated serum CEA; or short interval (≤6 months) to androgen-independent progression. Results: Of 55 pts accrued, 24 had prior abi and enza; 19 pts had prior taxane. Common adverse events include anemia, fatigue, and nausea. Also, 11 pts (20.0%) displayed clear AnaF (Table) and 43 pts lacked AnaF, including 8 (14.5%) with partial AnaF that did not meet the full criteria, 4 (7.3%) who likely did not have AnaF due to difficulty in quantifying disease burden, 29 (52.7%) who did not have AnaF, and 2 (3.6%) had unknown status. Four pts (36.4%) with clear AnaF had DDR aberrations, including 3 (27.3%) with BRCA2, 1 (9.1%) with both BRCA2 and CHEK2, and 1 (9.1%) with ATM. Conclusions: Pts with mCRPC with DDR mutations can also have AnaF. This preliminary data demonstrates that pts with anaplastic prostate cancer and pts with DDR mutations are two distinct populations with some degree of overlap. O+D is well-tolerated, and future studies should focus on finding optimal treatments for pts with AnaF without and without DDR mutations. Clinical trial information: NCT02484404. [Table: see text]

e16536 Background: Docetaxel has become a standard of care for mCSPC. Enzalutamide and abiraterone have been proven to improve survival in metastatic castration-resistant prostate cancer (mCRPC) patients. Little is known about patients who have been treated with docetaxel for mCSPC and subsequent therapeutic responses. This retrospective analysis is to evaluate the response duration of abiraterone and enzalutamide in patients who previously received docetaxel for mCSPC but developed mCRPC within 12 months. Methods: Clinical Trial NCT02649855 enrolled patients with newly diagnosed mCSPC who were treated with standard androgen deprivation therapy (ADT) and docetaxel (75 mg/m2 every 3 weeks for 6 cycles) sequenced with immunotherapy (PROSTVAC) from February 2016 to present. Patients who had progression (based on consecutive PSA rises or imaging) within 1 year of completing docetaxel and went on to subsequent abiraterone/enzalutamide were evaluated. (Note these are different PSA progression criteria than used in CHAARTED, Sweeney, NEJM, 2015). A PCR-based NGS panel (OncoMine Comprehensive Assay v3) will evaluate available tissue from these patients. Results: Of the 46 patients evaluated regardless of immunotherapy sequence, 15 (33%) went on subsequent therapy after progression on docetaxel for mCSPC, with 12 patients starting abiraterone/enzalutamide (7 with high volume disease and 5 with low volume disease). The median age was 62 (41-83) years. 6/12 patients (50%) initiated enzalutamide and 6/12 patients (50%) initiated abiraterone. The median duration of treatment for both was 7.43 (1.53 – 16.0) months, the median time to prostate-specific antigen (PSA) progression was 2 (0 – 11) months; the median duration of PSA decline was 2 months in patients with both high and low volume disease. Of note, 3/12 (25%) of patients did not have PSA response, all of them had high volume disease. Conclusions: These data from a small cohort suggest that patients who have progression within 12 months of completing docetaxel for mCSPC have limited subsequent benefit from enzalutamide or abiraterone. Additional studies are required to determine optimal timing and treatment sequence for patients with mCSPC who rapidly develop mCRPC. Clinical trial information: NCT02649855.

173 Background: A phase I study of Cabozantinib (C) in combination with docetaxel (D) and prednisone (P) in patients (pts) with mCRPC determined that 40 mg daily was the maximum tolerated dose of C in combination with D and P (C+DP). We report a pooled analysis of the phase I and randomized phase II study comparing C+DP to DP alone. Methods: Eligible pts had mCRPC without prior chemotherapy in the castrate setting. All pts received a fixed dose of D (75 mg/m2IV day one of each 21 day cycle) and P (5 mg PO twice daily), and in the C+DP group, C at three escalating dose levels: 20 mg, 40 mg, or 60 mg in the phase I cohort (all PO daily) and 40 mg daily in the phase II cohort. Results: A total of 32 pts received C+DP (19 pts in phase I and 13 pts in the phase II cohort). 12 pts received DP alone. Baseline characteristics for C+DP vs DP included median age 69 (45 – 84) vs 69 (50-83) and median PSA 74.8 ng/ml (0.01-4093.7) vs 309.5 ng/ml (94.6 – 2649) respectively. Clinical trial information: NCT01683994. 18/32 C+DP pts had previous enzalutamide or abiraterone, with a median PFS of 13.6 months (95% CI: 5.2 – 21.0). 23/32 pts (72%) treated with C+DP required dose reduction or discontinuation of C, and 10/32 (31%) required C discontinuation. 2/32 patients (6%) in the C+DP group died on protocol, possibly related to study drug (sudden death NOS/venous thromboembolism). Grade 4 adverse events (AEs) in the C+DP group included: neutropenia (28%), leukopenia (6%), pulmonary embolism (3%), and mucositis (3%) and in DP: hyperglycemia (8%). Grade 3 AEs (>10%) in C+DP included: neutropenia (31%), febrile neutropenia (16%), leukopenia (13%), hypophosphatemia (13%) and in DP: anemia (17%). Conclusions: In pts with mCRPC, C+DP is associated with a greater PFS and PSA responses compared to DP alone. Toxicities with the combination were manageable. Further study is required to better define the potential benefits of C+DP in mCRPC.[Table: see text]

241 Background: Docetaxel is a standard of care for mCSPC. Enzalutamide and abiraterone have been proven to improve survival in metastatic castration-resistant prostate cancer (mCRPC) patients. Little is known about patients who have been treated with docetaxel for mCSPC and subsequent therapeutic responses. This retrospective analysis is to evaluate the response duration of abiraterone and enzalutamide in patients who previously received docetaxel for mCSPC but developed mCRPC within 12 months. Methods: Clinical Trial NCT02649855 enrolled patients with newly diagnosed mCSPC who were treated with standard androgen deprivation therapy (ADT) and docetaxel (75 mg/m2 every 3 weeks for 6 cycles) sequenced with immunotherapy (PROSTVAC) from February 2016 to present. Patients who had progression (based on consecutive PSA rises or imaging) within 1 year of completing docetaxel and went on to subsequent abiraterone/enzalutamide were evaluated. (Note these are different PSA progression criteria than used in CHAARTED, Sweeney, NEJM, 2015). Results: Of the 46 patients evaluated regardless of immunotherapy sequence, 15 (33%) went on subsequent therapy after progression on docetaxel for mCSPC, with 12 patients starting abiraterone/enzalutamide (6 each with high and low volume disease). The median age was 62 (41-83) years. 7/12 patients (58.3%) initiated enzalutamide and 5/12 patients (41.7%) initiated abiraterone. The median duration of treatment for both was 7.12 (1.53–16.0) months, the median time to prostate-specific antigen (PSA) progression was 5.54 (0–15.83) months; 5/12 (41.7%) of patients did not have PSA response. Of note, patients with low volume disease had a median treatment duration of 5.88 months, 3 of them did not have PSA response. Conclusions: These data from a small cohort suggest that patients who have progression within 12 months of completing docetaxel for mCSPC have limited subsequent benefit from enzalutamide or abiraterone. Additional studies are required to determine optimal timing and treatment sequence for patients with mCSPC who rapidly develop mCRPC. Clinical trial information: NCT02649855.

TPS5096Background: Prostate cancer is the most commonly diagnosed cancer among men in the United States. While prostate cancer is initially responsive to androgen deprivation therapy (ADT), most pa...

163 Background: Data suggests 25-30% of sporadic mCRPC has defects in DNA repair pathways which may confer sensitivity to PARP inhibition (PARPi). Immune checkpoint blockade may increase the proportion of patients that respond to PARPi. We hypothesize that increased DNA damage by olaparib (O) will complement anti-tumor activity of immune checkpoint blocking antibody, durvalumab (D), in mCRPC (NCT02484404). Methods: Single arm pilot study with accrual of 25 patients (pts) with mCRPC and disease that is amenable to biopsy. Prior treatment with enzalutamide and/or abiraterone is required. D is given at 1500 mg iv q28 days + O 300 mg tablets po q12 hours. The primary endpoint is PFS. Core biopsies undergo mutational analysis. Results: In the first 17 pts, median age is 66 (range 45-79 years), median baseline PSA is 79.67 ng/mL [3.93-2356 ng/mL]). Median Gleason score is 8. 6 patients have bone only disease and 11 patients have bone and soft tissue/visceral disease. Median number of cycles is 7 (2-17). Grade 3/4 adverse events include anemia 4/17 (24%), lymphopenia 2/17 (12%), infection 2/17 (12%), thrombocytopenia, leukopenia, neutropenia, nausea, vomiting, UTI, hypertension, hearing impairment, fatigue, syncope, oral mucositis, muscle weakness, and muscle cramps [1/17 each, (6%)]. 8/17 pts (47%) had PSA responses >50%. 6 of these pts had mutations in the DNA damage repair pathways (DNAdr). 2/17 pts (11%) had PSA responses >30% with no known mutations in DNAdr. 4 pts had a PR. The 12 month PFS is 51.5% (95% CI: 25.7-72.3%). Conclusions: Preliminary data shows D+O is well tolerated with activity in an unselected population. Accrual is ongoing with biomarker analysis. Clinical trial information: NCT02484404.

Corneal fragility was measured with the Cochet-Bonnet aesthesiometer on 171 eyes of various ages. It was found to remain the same until about age 40. It increased significantly and progressively afterwards. It was compared to corneal sensitivity which diminishes significantly after about the same age.

38 persons with various degrees of keratoconus were examined. Using the photokeratoscope an index of the severity of the cone was established and compared to a group of normal eyes. Sensitivity was measured in the centre and periphery of the cornea. It was found to be significantly lower than in normal eyes and those eyes wearing contact lenses exhibited the lowest sensitivity. There was no correlation between peripheral CTT (Corneal Touch Threshold) and the severity of keratoconus, but there was a significant correlation between central CTT and severity, though only for the group of eyes not wearing contact lenses. Corneal fragility was also found to be greater in keratoconus than in normal eyes and more so in those eyes wearing contact lenses. There was a significant correlation between the severity and the fragility.

PURPOSE: To screen a population of teenagers for emerging topographic signs of keratoconus (KC), with particular reference to ethnicity. METHODS: Corneal topography, visual acuity, and an environmental risk factor analysis were included in a screening program designed to identify early indications of potential KC in teenagers. Two schools from central North Island, New Zealand, were invited to participate: one with predominantly Maori/Polynesian students and the other with students of mainly European descent. RESULTS: A total of 198 Maori/Polynesian, 16.8 ± 1.05 years of age, and 243 European students, 16.2 ± 1.3 years of age, participated in the study. Corneal topography suggestive strongly of KC was evident in 3 Maori/Polynesian [1.2%; 95% confidence interval (CI): 0.3-4.3] and no European students (0%; 95% CI, 0%-1.5%). Anomalous corneal topography reminiscent of emerging KC in at least 1 eye were found in 19% (95% CI, 15.6%-22.9%). A significant difference (P = 0.0014) in the percentage of suspected KC was found between European students (12.9%; 95% CI, 9.2%-17.9%) and Maori/Polynesian students (26.9%; 95% CI, 21.0%-33.7%). In multivariate analyses, the significant independent predictors of probable or suspected KC included being Maori/Polynesian [odds ratio (OR) = 2.1; 95% CI, 1.25-3.54; P = 0.0052], increasing age (OR = 1.4; 95% CI, 1.10-1.80; P = 0.0067), and a history of hayfever (OR = 2.0; 95% CI, 1.16-3.59; P = 0.013). Topographical indicators that were associated significantly with suspected KC included central keratometry (P < 0.0001), astigmatism (P = 0.014), and inferior-superior asymmetry (P < 0.0001). CONCLUSIONS: Although only a longitudinal study will determine the proportion of true KC candidates, these data provide evidence of ethnicity-related differences in corneal topography in teenage New Zealanders. © 2007 Lippincott Williams & Wilkins, Inc.

Background The insulin/IGF1 signalling (IIS) pathways are involved in longevity regulation and are dysregulated in neurons in Alzheimer’s disease (AD). We previously showed downregulation in IIS gene expression in astrocytes with AD-neuropathology progression, but IIS in astrocytes remains poorly understood. We therefore examined the IIS pathway in human astrocytes and developed models to reduce IIS at the level of the insulin or the IGF1 receptor (IGF1R). Results We determined IIS was present and functional in human astrocytes by immunoblotting and showed astrocytes express the insulin receptor (IR)-B isoform of Ir. Immunocytochemistry and cell fractionation followed by western blotting revealed the phosphorylation status of insulin receptor substrate (IRS1) affects its subcellular localisation. To validate IRS1 expression patterns observed in culture, expression of key pathway components was assessed on post-mortem AD and control tissue using immunohistochemistry. Insulin signalling was impaired in cultured astrocytes by treatment with insulin + fructose and resulted in decreased IR and Akt phosphorylation (pAkt S473). A monoclonal antibody against IGF1R (MAB391) induced degradation of IGF1R receptor with an associated decrease in downstream pAkt S473. Neither treatment affected cell growth or viability as measured by MTT and Cyquant® assays or GFAP immunoreactivity. Discussion IIS is functional in astrocytes. IR-B is expressed in astrocytes which differs from the pattern in neurons, and may be important in differential susceptibility of astrocytes and neurons to insulin resistance. The variable presence of IRS1 in the nucleus, dependent on phosphorylation pattern, suggests the function of signalling molecules is not confined to cytoplasmic cascades. Down-regulation of IR and IGF1R, achieved by insulin + fructose and monoclonal antibody treatments, results in decreased downstream signalling, though the lack of effect on viability suggests that astrocytes can compensate for changes in single pathways. Changes in signalling in astrocytes, as well as in neurons, may be important in ageing and neurodegeneration. Electronic supplementary material The online version of this article (doi:10.1186/s13041-015-0138-6) contains supplementary material, which is available to authorized users.

Purpose. To investigate changes in corneal thickness and the radius of curvature of the posterior corneal surface after orthokeratology (OK) rigid lens wear. Methods. Nineteen young myopic subjects wore reverse-geometry OK lenses (BE/ABE, Ultravision Contact Lenses, Brisbane, Australia) every night for 1 month. Central and midperipheral corneal thickness (Allergan Humphrey ultrasound, Carl Zeiss Meditec, Dublin, CA), topography (EyeSys v.3.1, Houston, TX), subjective refraction, and posterior corneal radii (video photography of Purkinje images) were evaluated withi n2ho f waking, prelens wear, and on four occasions postlens wear during a 1-month period. A mixed-models approach was used to analyze the data. We modeled the changes in posterior corneal radius of curvature and corneal thickness in terms of the sagittal height of the anterior and posterior cornea using an ellipsoidal model for the corneal surfaces. Results. Refractive error reduced from 2.28 to 0.01 DS within 1 month. A significant thinning of the cornea was evident between 1 (p 0.03) and 2 weeks (p 0.0048) postlens wear. A significant increase in the anterior corneal radius of curvature was present at all time periods beyond 1 night (p < 0.001), and a significant posterior corneal flattening occurred centrally and midperipherally after 1 week (p 0.04 and p 0.013, respectively). Conclusions. These findings suggest that in addition to the significant topographic flattening of the anterior corneal surfaces, there is also a significant flattening of the posterior surface during the early adaptive stages of OK lens wear. (Optom Vis Sci 2004;81:421-426)

Purpose: To establish the accuracy of Orbscan II (Orbtek Inc.) slit-scanning elevation topography in analyzing the anterior surface of complex test objects. Setting: Discipline of Ophthalmology, University of Auckland, Faculty of Medical and Health Sciences, Auckland, New Zealand. Methods: Six test objects were created from 2 materials: standard calibration poly(methyl methacrylate) (PMMA) (Orbtek Inc.) and a research PMMA material. The test objects were produced with spherical (radii of curvature 6.00 mm, 7.67 mm, and 8.88 mm), aspherical (apical radius 7.67, eccentricity 0.5, Q -0.25), and toroidal (7.67/7.92 mm radii of curvature) surfaces. The accuracy of the test surfaces was established by Form Talysurf Analysis. A single calibrated Orbscan II device was used to obtain 20 separate anterior elevation maps of each test object. The data obtained from Orbscan II, at 0.2 mm intervals along the chosen meridian, were directly compared with the Talysurf values for each test surface. Results: Orbscan II measurements of all test objects were statistically significantly different from the Talysurf values (P < .001). The test objects produced from standard calibration material were more accurately measured by Orbscan II than the objects produced from the research material. Data obtained by Orbscan II from the central 3.5 mm of all test objects were more accurate than peripheral data when compared with the Talysurf values (P = .001). Conclusions: Orbscan II anterior surface elevation measurements differed significantly from Form Talysurf Analysis of complex test surfaces. However, the magnitude of the errors in the measurement of standard test objects was small, less than 0.20 μm centrally and 0.70 μm peripherally. Clinically, if similar accuracy of measurement is confirmed in the human eye, anterior surface elevation maps can be considered accurate representations of corneal shape. © 2002 ASCRS and ESCRS.

5026 Background: About 30% of sporadic mCRPC has defects in DNA repair pathways which may confer sensitivity to PARP inhibition. There is limited data about PDL1 inhibition in mCRPC. We hypothesize increased DNA damage by olaparib (O) will complement anti-tumor activity of immune checkpoint blocking antibody, durvalumab (D), in mCRPC:NCT02484404. Methods: Single arm pilot study with accrual of 25 patients (pts) with mCRPC and biopsiable disease. Prior treatment with enzalutamide and/or abiraterone is required. D is given at 1500 mg iv q28 days + O 300 mg po q12 h. Primary endpoint is PFS. Pretreatment and on-study core biopsies undergo mutational analysis. Results: 10 pts have enrolled (median age 65 yr [range 51-79], median baseline PSA: 85.78 [22.17-809.9 ng/mL]). 7 pts have GS ≥ 8. Grade 3/4 adverse events include anemia 2/7 (29%), thrombocytopenia, lymphopenia, neutropenia, nausea, fatigue, UTI, and lung infection [1/7 each, (14%)]. 5/7 pts (71%) on-study >2 months (mos) have PSA declines > 50%. Median PFS is 7.8 mos (95% CI: 1.8 mos-undefined). Conclusions: Preliminary data shows D+O is well tolerated with activity in an unselected population. Accrual is ongoing with biomarker analysis. Clinical trial information: NCT02484404. [Table: see text]

162 Background: Recent data suggests 25-30% of sporadic mCRPC has defects in DNA repair pathways which may confer sensitivity to PARP inhibition. Immune checkpoint blockade is a promising avenue in mCRPC treatment. We hypothesize that increased DNA damage by O will complement anti-tumor activity of immune checkpoint inhibitor, D, in mCRPC (NCT02484404). Methods: Eligible pts have mCRPC with adequate end organ function and biopsiable disease (bone or soft tissue). Prior treatment with enzalutamide and/or abiraterone is required. D is administered at 1500 mg iv q28 days with O at 300 mg po q12 h. Primary endpoint is PFS. Secondary endpoints include PSA responses, safety and ORR. Single arm pilot study with a total accrual of 25 pts. On-study core biopsies undergo mutational analysis. Results: 6 pts have enrolled (median age 67 yr [range 60-79], median ECOG PS 1 [1-2]). Median baseline PSA: 258.1 (54.1-809.9 ng/mL). 4 pts have Gleason score (GS) > 8 and 2 pts have GS of 7. Grade 3/4 adverse events include anemia 2/6 (33%), thrombocytopenia, lymphopenia, nausea, febrile neutropenia, aspiration pneumonia [1 each, (17%)]. Conclusions: Exploiting synergy of D+O is a treatment option for heavily pre-treated pts. Preliminary data shows D+O is tolerable and active in mCRPC pts without germline BRCA mutation. Paired tumor biopsies and blood samples including ctDNA are being collected. Accrual is ongoing. Clinical trial information: NCT02484404. [Table: see text]

To quantify the tear spreading velocity and stabilization time after blinks in healthy patients.Video recordings (magnification, x130) were made of the movements of naturally occurring particles in the tear film while patients blinked naturally. After each blink, tear spreading velocity was computed every 40 milliseconds from particle displacements determined from a frame-by-frame analysis of the records.After a blink, tears moved rapidly upward over the cornea. Forty milliseconds after passage of the lid, the velocity was 7.34 +/- 2.73 mm/s (mean +/- standard deviation, n = 20). The time to tear stabilization (i.e., zero velocity) was 1.05 +/- 0.30 seconds. The decay of spreading velocity with time was well described by a logarithmic function for all individual patient data (R2 range, 0.88-0.99; n = 20). We have shown that initial velocity and stabilization time are independent descriptors of tear spreading. Meibomian gland expression markedly reduced initial velocity leaving a normal stabilization time, whereas inhalation of an irritant reduced stabilization time leaving a normal initial velocity. In a patient with Sjögren syndrome, punctal plugs rapidly restored initial velocity and stabilization time from near zero values to normal values.We provide normal values for two descriptors of tear spreading, namely initial velocity and time to stabilization. These values can be modified by manipulations that alter tear constituents. Consequently, these descriptors may provide a basis for quantitative, noninvasive tear assessment.

Background. Tibetan and Sherpa children living in Nepal share a common ancestry in Tibet and areas to the north of Nepal, but it is evident that these people experience widely contrasting educational and environmental conditions. The purpose of this study was to compare the prevalence of myopia in children with similar genetic backgrounds but who are exposed to contrasting environments. Methods. Unaided vision and refractive error was measured in 555 Tibetan children in Kathmandu and 270 Sherpa children in the Solu Khumbu region of Nepal. Results. There were marked differences in vision and the prevalence of myopia in the two groups. Ninety-two percent of the Sherpa children had Snellen vision of 20/22 (0.89) or better compared with 70% of the Tibetan children. The range of refractive errors was -6.50 to +7.00 D for the Tibetan children and -1.00 to +3.50 D for the Sherpa children. The Sherpa children had a prevalence of myopia of 2.9% compared with 21.7% for the Tibetan children. Conclusions. The prevalence of myopia in Sherpa children is low and their rural lifestyle appears to be relatively unstressed. Tibetan children have a higher prevalence of myopia and more rigorous schooling. We did not establish a causal relationship between myopia and the type of schooling, or the environment in general, but we did demonstrate that a simple, rural lifestyle is at least compatible with a virtual absence of myopia.

We report on a case of keratoconus in identical twins who were brought up in Christchurch, New Zealand. Videokeratoscopy using an EyeSysa (EyeSys Laboratories, Houston, Texas, USA) revealed not only marked differences in severity of keratoconus between the sisters, but also non-equivalent cone types. Both twin sisters reported an exacerbation of their keratoconus during pregnancy and during breast feeding. Various factors affecting the development and progression of keratoconus are discussed. (Clin Exp Optom 1995; 78: 4: 125–129)

Four key issues arising from the Johnson paper relating to ongoing reform of Australia's health sector are discussed.

We review the research which has attempted to determine whether the characteristics of autonomic innervation of ciliary smooth muscle are relevant to the process of accommodative adaptation. The effect of various topical autonomic drugs on the three phases of adaptation were analyzed: pre-task tonic accommodation (open-loop); within-task accommodative response (closed-loop); and post-task regression of accommodation to pre-task tonic levels. Although it is clear that parasympathetic innervation predominates, there is evidence that some individuals utilize supplementary inhibitory sympathetic innervation. When sympathetic innervation is augmented by substantial levels of concurrent parasympathetic accommodative activity, it may serve to attenuate the magnitude and duration of post-task shifts in tonic accommodation. It is proposed that individuals with a deficit in sympathetic inhibition may therefore be predisposed to anomalies of accommodative adaptation. However, the mechanism by which the oculomotor system responds to such predisposition is at present obscure.

PURPOSE. To identify differences in potential biometric markers for predicting refractive error in school children. METHODS. Biometric data on 895 Tibetan children, aged 6 to 18 years, residing in Katmandu, Nepal, were collected biennially from 1992 to 2000. Measurements included cycloplegic autorefraction, A-scan ultrasonography, and video phacometry. Only those children who had been studied at least once at age 12 years or more were included in the analysis. Subjects were divided into two groups: a myopia group if the refractive error was myopic by more than -0.50 D and a nonmyopia group if the refractive error was maximally myopic by -0.50 D, expressed as a spherical equivalent error in the left eye. RESULTS. Biometric measures that differed significantly with increasing age between the two refractive groups included: anterior chamber depth + 0.012 mm/year (p = 0.014), anterior lens radius of curvature + 0.073 mm/year (p = 0.001), lens power -0.059 D/year (p = 0.082), lens thickness -0.005 mm/year (p = 0.02), and vitreous chamber depth + 0.084 mm/year (p < 0.001). Corneal radii of curvature of the myopic group were steeper at all ages by 0.09 mm (p < 0.001), but the rate of change with age was equivalent across the refractive groups. CONCLUSIONS. Compared with those who remained nonmyopic, children who developed myopia had a crystalline lens that was initially thicker and steeper, and a vitreous chamber that was initially shorter. With age, children who became myopic developed greater lens thinning, greater flattening of the anterior lens surface radius, and a greater increase in vitreous chamber depth than their nonmyopic counterparts. Copyright © 2006 American Academy of Optometry.

The radius of curvature of the posterior surface of the cornea was measured in the vertical meridian for 120 children aged 6 to 17 years, using a Purkinje image method. The mean radius of curvature (+/-SD) was 6.42 +/- 0.31 mm, with a range from 5.62 to 7.22 mm. The ratio of anterior to posterior corneal radius was 1.210 +/- 0.045 or 0.827 +/- 0.029 when expressed as a reciprocal. There was a significant correlation between the anterior and posterior corneal radius (y = 0.798x + 0.228, r2 = 0.45). The study provides data that may be applied to a four-surface schematic eye.

Changes in the sagitta of the anterior corneal surface associated with a change in the corneal radius of curvature have been used to calculate the change in refractive error of the eye in two areas: the ablation depth for laser surgery, and the change in corneal thickness associated with orthokeratology lens wear. An approximate formula known as Munnerlyn's formula is commonly used to calculate the refractive error change from sagittal data. This article compares the change in refraction calculated using the approximate formulae with the change calculated from a formula based on an elliptical corneal section. The approximate formula underestimates the ablation depth for a given refractive change and overestimates the refractive change for a given change in corneal thickness, assuming a constant asphericity. When the corneal asphericity increases together with an increase in radius of curvature, a suggested mechanism in orthokeratology, the approximate formula underestimates the change in ocular refraction.

The tear film plays a crucial role in the areas of contact lens wear and dry eye. However, despite its accessibility, there is no “gold-standard” test for assessing its functional quality. Current clinical tests are often poorly correlated with each other and may be subjective and/or invasive in nature. While much effort has been expended in assessing tear volume and stability, significantly less attention has been paid to the mechanism of tear film formation. Early work using motion-photography of naturally occurring lipid particles within the tear film noted that, immediately following a blink, the tears spread upwards over the cornea with a velocity of about 10 mm/sec. More recent work analysing tear spreading in relation to the thickness of the tear film proposed that the key factors influencing spreading were eyelid velocity, tear meniscus, tear viscosity, and surface tension.

Amongst other things, this report: --provides a statistical overview of the structure of the industry and the activities of the 500 acute care, psychiatric and day hospitals that operate within it; --looks at some indicators of the industry's financial performance, efficiency and quality of service (though it does not attempt to benchmark private hospitals against the public hospital system); --discusses some of the key factors affecting performance, including the relationships between private hospitals, doctors and the health insurance funds; and --draws attention to a number of policy issues germane to the industry's future performance, including licensing arrangements for private hospitals and competitive neutrality, both within the industry and between private and public hospitals.

Background The absolute accuracy of videokeratoscope (VKS) mapping of keratoconus is still in question, with contact lens-induced corneal warpage and chalazion having been shown to resemble this condition closely. Corneal thinning is investigated as a further aid to the diagnosis and description of keratoconus. Methods The diagnosis of keratoconus in 41 individuals was verified by measuring the corneal thickness difference (I-S difference) between two disparate corneal locations, one inferior to (I) and one superior to (S) the corneal apex, using a Humphrey model 870 Ultrasound pachometer. Corresponding measures of I-S radii were made using radius values obtained from the EyeSys VKS. Results A comparison between I-S pachometry and I-S radius demonstrated a marginally increased sensitivity for the latter measurement. Using 95% confidence levels from normative pachometric data, classification of severity of keratoconus is proposed as follows: (1) keratoconus suspect/early keratoconus: I-S pachometry 75 to 100 microns; (2) moderate keratoconus: 100 to 125 microns; and (3) advanced keratoconus: > 125 microns. Conclusion I-S pachometry can be used as a descriptor of keratoconus.

Background: Cyclopentolate continues to be the cycloplegic of choice for refracting young children, although many studies of ocular biometry promote the use of tropicamide. Methods: To clarify the role of drug type in biometric measurements, cycloplegia was induced in two disparate age groups using cyclopentolate and tropicamide on two separate occasions. Refraction, phakometry and A-scan ultrasonography measurements were made on two groups of Tibetan children resident in Nepal. Results: Cyclopentolate produced significantly more cycloplegia in the younger group, which was supported by phakometry measurements. However, in clinical terms, the difference between the measurements was not significant. Conclusion: We conclude that although cyclopentolate is more effective than tropicamide in relaxing accommodation in young children, the use of a local anaesthetic prior to instillation of tropicamide produces refractive data virtually equivalent to that of cyclopentolate, regardless of the age group measured. However, biometric measurements may be susceptible to greater error when near fixation targets are used during phakometry procedures.

The aim of this study was to examine whether folic acid supplements had been taken and dietary folate intake increased in 662 pregnant women attending the antenatal clinic at St Mary's Hospital, Portsmouth. An assessment was also made of the factors that influenced correct compliance with the recommendations of the Expert Advisory Group on folic acid. Thirty-seven percent (245/662) women had taken folic acid supplements and 26.4% (175/ 662) increased their dietary folate before or during early pregnancy. The majority of women who commenced folic acid supplements after conception did so after the neural tube had closed (220/247). Women were more likely to have adhered to the Expert Advisory Group's recommendations if the pregnancy was planned, the woman was primiparous, there was no past or family history of neural tube defect and the patient had the correct existing knowledge of folic acid prophylaxis. The relevance of these findings to the current Health Education Authority's folic awareness campaign is discussed.