Met Progression Criteria Research Articles

Using 68Ga-PSMA-11 PET/CT for Therapy Response Assessment in Patients with Metastatic Castration-Resistant Prostate Cancer: Application of EAU/EANM Recommendations in Clinical Practice.

For patients with metastatic castration-resistant prostate cancer (mCRPC), no reliable biomarkers for predicting therapeutic response or assisting in treatment selection and sequencing are currently available. Using the recent European Association of Urology and European Association of Nuclear Medicine recommendations, we aimed to compare response assessment between prostate-specific membrane antigen (PSMA) PET/CT and conventional imaging in mCRPC patients starting first-line treatment with a novel hormonal agent (NHA) and to perform a sequential comparative analysis of PSMA PET/CT-derived parameters after 4 and 12 wk of therapy. Methods: Data from 18 mCRPC patients who started NHA treatment and underwent 68Ga-PSMA-11 PET/CT before therapy initiation (baseline), at week 4 (W4), and at week 12 (W12) in addition to conventional imaging (bone scintigraphy, CT) at baseline and W12 were retrospectively included. PET/CT images were quantitatively analyzed for maximum and mean SUV and total PSMA ligand-positive lesions. Comparative analysis of PET/CT-derived parameters was performed, and patients were classified as having nonprogressive disease or progressive disease (PD) according to 68Ga-PSMA-11 PET/CT, prostate-specific antigen, and conventional imaging criteria. Results: Treatment response was evaluable by 68Ga-PSMA-11 PET/CT in 16 of 18 patients (89%) and by conventional imaging in 11 of 18 patients (61%). Five of 16 patients classified as having PD by 68Ga-PSMA-11 PET/CT at W12 had already met progression criteria at W4, and substantial agreement was observed between W4 and W12 (κ, 0.74) 68Ga-PSMA-11 PET/CT results. Nonetheless, 2 of 16 patients (13%) were incorrectly classified as having PD because of a flare phenomenon on PSMA PET/CT that disappeared at W12. Conclusion: Volumetric assessments of 68Ga-PSMA-11 PET/CT imaging can improve response evaluation in NHA-treated patients with mCRPC. Although early response assessments at W4 need to be approached with caution because of flare, 68Ga-PSMA-11 PET/CT imaging at W4 and W12 revealed substantial agreement in therapy response assessments; these findings warrant further investigation to distinguish PD from flare at W4 and help improve the understanding of resistance to therapy.

The Positive Choices trial: update to study protocol for a phase-III RCT trial of a whole-school social-marketing intervention to promote sexual health and reduce health inequalities

BackgroundPositive Choices is a whole-school social-marketing intervention to promote sexual health among secondary school students. Intervention comprises the following: school health promotion council involving staff and students coordinating delivery, student survey to inform local tailoring, teacher-delivered classroom curriculum, student-run campaigns, parent information and review of sexual/reproductive health services to inform improvements. This trial builds on an optimisation/pilot-RCT study which met progression criteria, plus findings from another pilot RCT of the Project Respect school-based intervention to prevent dating and relationship violence which concluded such work should be integrated within Positive Choices. Young people carry a disproportionate burden of adverse sexual health; most do not report competence at first sex. Relationships and sex education in schools can contribute to promoting sexual health but effects are small, inconsistent and not sustained. Such work needs to be supplemented by ‘whole-school’ (e.g. student campaigns, sexual health services) and ‘social marketing’ (harnessing commercial marketing to social ends) approaches for which there is good review-level evidence but not from the UK.MethodsWe will conduct a cluster RCT across 50 schools (minimum 6440, maximum 8500 students) allocated 1:1 to intervention/control assessing outcomes at 33 months. Our primary outcome is non-competent first sex. Secondary outcomes are non-competent last sex, age at sexual debut, non-use of contraception at first and last sex among those reporting heterosexual intercourse, number of sexual partners, dating and relationship violence, sexually transmitted infections and pregnancy and unintended pregnancy for girls and initiation of pregnancy for boys. We will recruit 50 school and undertake baseline surveys by March 2022, implement the intervention over the 2022–2024 school years and conduct the economic and process evaluations by July 2024; undertake follow-up surveys by December 2024; complete analyses, all patient and policy involvement and draft the study report by March 2025 and engage in knowledge exchange from December 2024.DiscussionThis trial is one of a growing number focused on whole-school approaches to public health in schools. The key scientific output will be evidence about the effectiveness, costs and potential scalability and transferability of Positive Choices.Trial registrationISRCTN No: ISRCTN16723909. Registered on 3 September 2021.

The Positive Choices trial: study protocol for a Phase-III RCT trial of a whole-school social marketing intervention to promote sexual health and reduce health inequalities

BackgroundPositive Choices is a whole-school social marketing intervention to promote sexual health among secondary school students. Intervention comprises school health promotion council involving staff and students coordinating delivery; student survey to inform local tailoring; teacher-delivered classroom curriculum; student-run campaigns; parent information; and review of sexual/reproductive health services to inform improvements. This trial builds on an optimisation/pilot RCT study which met progression criteria, plus findings from another pilot RCT of the Project Respect school-based intervention to prevent dating and relationship violence which concluded such work should be integrated within Positive Choices. Young people carry a disproportionate burden of adverse sexual health; most do not report competence at first sex. Relationships and sex education in schools can contribute to promoting sexual health but effects are small, inconsistent and not sustained. Such work needs to be supplemented by ‘whole-school’ (e.g. student campaigns, sexual health services) and ‘social marketing’ (harnessing commercial marketing to social ends) approaches for which there is good review-level evidence but not from the UK.MethodsWe will conduct a cluster RCT across 50 schools (minimum 6440, maximum 8500 students) allocated 1:1 to intervention/control assessing outcomes at 33 months. Our primary outcome is non-competent first sex. Secondary outcomes are non-competent last sex, age at sexual debut, non-use of contraception at first and last sex among those reporting heterosexual intercourse, number of sexual partners, dating and relationship violence, sexually transmitted infections, and pregnancy and unintended pregnancy for girls and initiation of pregnancy for boys. We will recruit 50 school and undertake baseline surveys by March 2022; implement the intervention over the 2022–2024 school years and conduct the economic and process evaluations by July 2024; undertake follow-up surveys by December 2024; complete analyses, all patient and policy involvement and draft the study report by March 2025; and engage in knowledge exchange from December 2024.DiscussionThis trial is one of a growing number focused on whole-school approaches to public health in schools. The key scientific output will be evidence about the effectiveness, costs and potential scalability and transferability of Positive Choices.Trial registrationISRCTN No: ISRCTN16723909. Trial registration summary: Date:. Funded by: National Institute for Health Research Public Health Research Programme (NIHR131487). Sponsor: LSHTM. Public/scientific contact: Chris Bonell. Public title: Positive Choices trial. Scientific title: Phase-III RCT of Positive Choices: a whole-school social marketing intervention to promote sexual health and reduce health inequalities. Countries of recruitment: UK. Intervention: Positive Choices. Inclusion criteria: Students in year 8 (age 12–13 years) at baseline deemed competent by schools to participate in secondary schools excluding pupil referral units, schools for those with special educational needs and disabilities, and schools with ‘inadequate’ Ofsted inspections. Study type: interventional study with superiority phase III cluster RCT design. Enrollment: 1/9/21-31/3/22. Sample size: 50 schools and 6440–8500 students. Recruitment status: pending. Primary outcome: binary measure of non-competent first sex. Secondary outcomes: non-competent last sex; age at sexual debut; non-use of contraception at first and last sex; number of sexual partners; dating and relationship violence (DRV) victimisation; sexually transmitted infections; pregnancy and unintended pregnancy for girls and initiation of pregnancy for boys using adapted versions of the RIPPLE measures. Ethics review: LSHTM research ethics committee (reference 26411). Completion data: 1/3/25. Sharing statement: Data will be made available after the main trial analyses have been completed on reasonable request from researchers with ethics approval and a clear protocol. Amendments to the protocol will be communicated to the investigators, sponsor, funder, research ethics committee, trial registration and the journal publishing the protocol. Amendments affecting participants’ experience of the intervention or important amendments affecting the overall design and conduct of the trial will be communicated to participants.

Ibrutinib Is Highly Active As First Line Therapy in Symptomatic Waldenstrom's Macroglobulinemia

Activating mutations in MYD88 and CXCR4 mutations are present in 95-97% and 40-45% of previously untreated patients with Waldenström's macroglobulinemia, respectively. MYD88 mutations trigger malignant cell growth through Bruton's Tyrosine Kinase and Hematopoietic Cell Kinase, both targets of ibrutinib (Yang et al, Blood 2013; Blood 2016). CXCR4 mutations confer in vitro as well as clinical evidence of resistance in previously treated WM patients to ibrutinib (Cao et al, Leukemia 2014, Treon et al NEJM 2015). Ibrutinib produces overall and major [partial response (PR) or better] responses in 90% and 70-75% of previously treated WM patients (Treon et al, NEJM 2015; Dimopoulos et al, Lancet Oncol. 2017). The activity of ibrutinib in untreated, symptomatic WM patients is not known. We therefore investigated the activity and safety of ibrutinib in this patient population. Thirty patients were enrolled in this study. Key baseline characteristics were as follows: median age 67 (range 43-83 yrs); 23 (77%) were male, IPSSWM scores were low (n=5; 17%), intermediate (n=11; 37%), and high (n=14; 47%); median serum IgM was 4,369 (range 844-10,321); median hemoglobin level was 10.3 (range 7.5-14.5 g/dL); median serum B2M level was 3.8 (2.0-7.6 mg/L); adenopathy >1.5 cm (n=10; 33%); splenomegaly >15 cm (n=5; 17%), and median bone marrow disease involvement was 65% (range 5-95%). All patients expressed the MYD88L265P mutation, and 14 (47%) had a CXCR4 mutation. Patients received 420 mg a day of ibrutinib, and dose de-escalation for toxicity was permitted. The median time on therapy was 8.1 (range 2.0-16.4 months), and was similar for CXCR4 wild-type (CXCR4WT) and CXCR4 mutated (CXCR4Mut) patients (9.4 vs. 8.0 months, respectively p=0.98). The overall and major (>PR) response rates were 96.7% and 80%. Five (17%) patients achieved a VGPR. No complete responses were observed. At best response, median serum IgM level declined from 4,380 to 1,786 (p=0.0001). At baseline 18/30 (60%) patients had a serum IgM >3,000 mg/dL versus 2/30 (7%) patients at best response (p<0.0001). At best response, median bone marrow involvement declined from 65% to 20% (p<0.0001), with decreased or resolved adenopathy (n=7; 70%) and splenomegaly (n=4; 80%) observed in most patients with baseline extramedullary disease. The median hemoglobin level increased from 10.3 to 13.6 g/dL (p<0.0001). The impact of CXCR4 mutation status on responses and time to at least a minor (overall) and PR or better (major) response are shown in Table 1.With a median follow-up of 8.1 months, two patients met progression criteria while on therapy, both of whom were CXCR4 mutated, and one of whom self-held protocol therapy >2 weeks due to travel. The latter patient continues treatment for clinical benefit per protocol. Overall, treatment was well tolerated. Grade 2 AEs: arthralgia (n=1); bruising (n=1); procedure related bleeding (n=1); hypertension (n=2); muscle cramps (n=1); neutropenia (n=3); vasculitic rash (n=1); URI (n=1); UTI (n=2). Grade 3 AEs: reversible AST/ALT elevation (n=1); foot pain (n=1); thrombocytopenia (n=1); and hypertension (n=1). Three patients (10%) had treatment-related atrial arrhythmia [Grade 1 (n=1); Grade 2 (n=2)] and continued ibrutinib with medical management for their atrial arrhythmia. Four study patients are off protocol therapy due to progression (n=1); reversible drug-induced hepatitis (n=1); unrelated ventricular arrhythmia (n=1); and withdrawal of consent due to travel (n=1). One patient required dose reduction for vasculitic rash/foot pain (to 140 mg/day). Our findings provide the first report of activity and safety of ibrutinib in previously untreated and symptomatic patients with Waldenström's macroglobulinemia, and show that ibrutinib is highly active and well-tolerated as a single agent, with no unexpected toxicities. Delays in ibrutinib response are associated with expression of mutated CXCR4. (ClinicalTrials.gov number, NCT02604511). [Display omitted] DisclosuresTreon:Pharmacyclics: Consultancy, Research Funding. Castillo:Millennium: Research Funding; Abbvie: Research Funding; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy, Research Funding.

PD45-11 UPDATED OUTCOMES FOR UNIVERSAL ACTIVE SURVEILLANCE OF SMALL RENAL MASS PATIENTS

You have accessJournal of UrologyKidney Cancer: Epidemiology & Evaluation/Staging/Surveillance II (PD45)1 Apr 2020PD45-11 UPDATED OUTCOMES FOR UNIVERSAL ACTIVE SURVEILLANCE OF SMALL RENAL MASS PATIENTS Arun Menon*, Ahmed Abouelenin, Tashionna White, Gaybrielle James, Kristopher Attwood, and Eric Kauffman Arun Menon*Arun Menon* More articles by this author , Ahmed AboueleninAhmed Abouelenin More articles by this author , Tashionna WhiteTashionna White More articles by this author , Gaybrielle JamesGaybrielle James More articles by this author , Kristopher AttwoodKristopher Attwood More articles by this author , and Eric KauffmanEric Kauffman More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000932.011AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Metastatic risk for small renal mass (SRM) patients on active surveillance (AS) is low and often outweighed by treatment morbidity. Rates of treatment conversion in unselected SRM patients based on specific radiographic/histologic progression criteria are unknown. We report our updated experience with “universal AS” management, which uses defined clinical progression criteria for triggering treatment, and recommends AS to all SRM patients who lack these criteria METHODS: All non-end stage renal disease patients with SRM tumors presenting from January 2013 to September 2017 to a single urologic oncologist at a National Comprehensive Cancer Network institute were recommended AS if specific radiographic/histologic progression criteria for triggering treatment were absent at presentation. Progression criteria included any of the following in the absence of benign tumor biopsy histology: longest tumor diameter (LTD) >4 cm, growth rate >5 mm/year, LTD >3 cm + growth rate ≥3 mm/year, high risk biopsy histology, >cT3a stage, or symptoms. Biopsy was performed for LTD >2 cm. Outcome measures included progression-free survival (PFS) and metastasis-free survival (MFS). RESULTS: Of 127 SRM patients (143 tumors) with no prior RCC history and >3 months follow up, 4 met progression criteria at presentation and were recommended treatment. All remaining 123 SRM patients (median LTD 2.2, range 0.9-3.9 cm) were managed with AS. Over a median follow up was 31 (range 6-68) months, 36 (29%) AS patients met >/=1 progression criterion, leading to treatment conversion in most cases (28 resection, 1 ablation). 3-year PFS and MFS rates were 70% and 100%, respectively; lower PFS rates were associated with initial LTD (84% for <2 cm, 75% for 2.1-3 cm, 49% for >3cm) and clear cell RCC biopsy histology (43%) (Figure). Resected tumors were enriched for adverse pathology (64% high grade and/or pT3a) and malignant histology (100% RCC). Only 1 (1%) non-progressing patient converted to treatment (anxiety). CONCLUSIONS: Universal AS using specific clinical progression criteria allows treatment avoidance for many SRM patients (particularly if LTD <3 cm), and improves identification of more aggressive tumors for treatment selection. Longer follow up is needed to assess the durability and oncologic safety of universal AS for SRM patients. Source of Funding: None © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e917-e918 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Arun Menon* More articles by this author Ahmed Abouelenin More articles by this author Tashionna White More articles by this author Gaybrielle James More articles by this author Kristopher Attwood More articles by this author Eric Kauffman More articles by this author Expand All Advertisement PDF downloadLoading ...

Feasibility of procedures for a randomised pilot study of reduced exertion, high-intensity interval training (REHIT) with non-diabetic hyperglycaemia patients

BackgroundPhysical activity and exercise interventions to improve health frequently bring about intended effects under ideal circumstances but often fail to demonstrate benefits in real-world contexts. The aim of this study was to describe the feasibility of an exercise intervention (reduced-exertion, high-intensity interval training) in non-diabetic hyperglycaemia patients delivered in a National Health Service setting to assess whether it would be appropriate to progress to a future large-scale study.MethodsThe intention was to recruit 40 participants from a single centre (specialist diabesity centre). Patients were eligible to take part if they were diagnostically defined as non-diabetic hyperglycaemic based on a glycated haemoglobin (HbA1c) value of 42–46 mmol mol. Study procedures including recruitment, occurrence of adverse events, intervention acceptability, and intervention adherence were used to assess feasibility.ResultsKey criteria for progression to a larger study were not met. The study revealed several issues including patient eligibility, challenges to recruitment, patient consent, and poor clinician engagement. Furthermore, despite the simplicity and convenience of using HbA1c to screen for diabetes risk, the process of accurately screening and case finding eligible patients was problematic. The small sample recruited for this trial (n = 6) also limits the interpretation of data, thus it is not possible to estimate the variability of intended outcomes to use in a formal sample size calculation for a full-scale trial. Some aspects of the intervention worked well. The acceptability of the exercise intervention and outcome measures met progression criteria thresholds and adherence was very high, with 97% of exercise sessions completed for participants that finished the study.ConclusionsGiven the issues, the trial is not feasible in its current form. Yet, this preparatory stage of trial design pre-empted problems with the intervention that could be changed to optimise the design and conduct of future studies. Solutions to the issues identified in this study revolve around using a dedicated local recruiter with a strong relationship among the healthcare team and patients, using participant incentives to take part, and allowing for a longer recruitment period.Trial registrationClinicalTrials.gov, NCT04011397. Registered 07 July 2019—retrospectively registered.

Severity profiles in patients diagnosed of benign prostatic hyperplasia in Spain

ObjectivesTo analyze the severity profiles and progression criteria in patients diagnosed of benign prostatic hyperplasia (BPH) in urology clinics in Spain. Material and methodsA multicentre observational epidemiological study conducted in Spain between May and November 2008. A representative sample of 392 urologist gathered socio-demographic, clinical and patient-centered data from three consecutive patients with new diagnosis of BPH in urology clinics. ResultsA total of 1.115 patients were evaluated. Mean age was 65.7 years. Mean time from the onset of symptoms to diagnostic was 18.8 months. Mean IPSS score was 17.2. 63 patients (5.7%) had mild symptoms; 670 (60.1%) had moderate symptoms with a mean IPSS score of 14.6 and 382 (34.3%) had severe symptoms with a mean IPSS score of 23.7. Mean PSA was 2.6ng/ml and ultrasound measured prostatic volume was 49.2cc. A total of 713 (63.9%) patients met progression criteria (PSA>1.5ng/ml and volume>30cc). Symptoms severity was directly correlated with age, prostatic volume, PSA, presence of progression criteria and time from the onset of symptoms and inversely correlated with urine flow rate (p<0.001). Progression criteria were directly correlated with age, symptoms severity and inversely with urine flow rate (p<0.01). ConclusionsMore than 90% of patients diagnosed of BPH in urology clinics in Spain had moderate to severe symptoms. Two-thirds met progression criteria that correlate with age and severity of symptoms.

Perfiles de severidad en pacientes diagnosticados de hiperplasia benigna prostática en España

ObjectivesTo analyse the severity profiles and progression criteria in patients diagnosed of benign prostatic hyperplasia (BPH) in urology clinics in Spain. Material and methodsA multicentre observational epidemiological study conducted in Spain between May-November 2008. A representative sample of 392 urologist gathered socio-demographic, clinical and patient-centered data from three consecutive patients with new diagnostic of BPH in urology clinics. ResultsA total of 1.115 patients were evaluated. Mean age was 65.7 years old. Mean time from the onset of symptoms to diagnostic was18,8 months. Mean IPSS score was 17.2. 63 patients (5,7%) had mild symptoms; 670 (60,1%) had moderate symptoms with a mean IPSS score of 14.6 and 382 (34.3%) had severe symptoms with a mean IPSS score of 23.7. Mean PSA was 2.6ng/ml and ultrasound measured prostatic volume was 49.2cc. A total of 713 (63,9%) patients met progression criteria (PSA >1.5ng/ml and volume>30cc). Symptoms severity was directly correlated with age, prostatic volume, PSA, presence of progression criteria and time from the onset of symptoms and inversely correlated with urine flow rate (P<.001). Progression criteria was directly correlated with age, symptoms severity and inversely with urine flow rate (P<.01). ConclusionsMore than 90% of patients diagnosed of BPH in urology clinics in Spain had moderate to severe symptoms. Two thirds met progression criteria that correlate with age and severity of symptoms.

Correlation of 18F-fluoride PET response to dasatinib in castration-resistant prostate cancer bone metastases with progression-free survival: Preliminary results from ACRIN 6687.

5003 Background: Dasatinib is a SRC kinase inhibitor that decreases bone turnover in men with metastatic castration-resistant prostate cancer (mCRPC). 18F-fluoride PET was used to evaluate differential response between normal and tumor bone to dasatinib. Methods: Patients with bone mCRPC underwent dynamic 18F-flouride PET imaging prior to and 12 weeks after dasatinib treatment. Up to 5 bone metastases with matching normal bone regions were selected for analysis by SUVmax, Ki, K1and Patlak flux. Their pre-treatment values and change from pre-treatment to post-treatment values were evaluated via generalized estimating equations to predict skeletal-related events (SRE) and via Cox proportional hazards modeling to predict progression-free survival (PFS) with Prostate Cancer Working Group 2 criteria, overall survival and time to SRE. Results: Eighteen patients treated with dasatinib underwent baseline 18F-flouride PET imaging; 12 had follow-up scans allowing assessment of changes due to therapy. Median age for all patients was 69 (range 48-86) years. Significant decrease in SUVmax (p=0.0002) occurred in bone metastases with dasatinib while significant increases in Patlak flux (p=0.0033) occurred in normal bone. Significant differences in changes from tumor bone compared to normal bone in response to dasatinib were noted for SUVmax (p&lt;0.0001). Of 18 patients, 17 have either met progression criteria or death by the time of this analysis. Decrease in tumor bone SUVmax (p=0.019), Ki(p=0.022), and Patlak flux (p=0.034) from pre-treatment to post-treatment correlates with longer PFS. Conclusions: 18F-fluoride PET indicates differential effect of dasatinib on tumor compared to normal bone in men with mCRPC. In patients undergoing pre- and post-dasatinib 18F-fluoride PET imaging a decrease in bone mCRPC fluoride uptake in response to treatment correlates with PFS. Clinical trial information: NCT00936975.

ONCOLOGICAL OUTCOMES FOLLOWING ROBOT ASSISTED RADICAL PROSTATECTOMY IN PATIENTS WHO ARE CANDIDATES FOR ACTIVE SURVEILLANCE

INTRODUCTION AND OBJECTIVE: To assess the association between PSA velocity (PSAV) and PSA doubling time (PSADT) with progression among patients with lowrisk prostate cancer enrolled in an active surveillance program. METHODS: We evaluated 290 men who met criteria for active surveillance (PSA density 7 or more, or > 2 cores with cancer, or > 50% involvement of any core with cancer). PSAV and PSADT were calculated using each participant’s complete PSA history after diagnosis. PSAV was calculated as PSA multiplied by the slope of a linear regression of log(PSA) (instantaneous velocity of PSA). PSADT was calculated as the ratio of ln(2) to the slope of a linear regression of log(PSA). RESULTS: Of 290 men, 188 (65%) with a median followup 3.5 years (range 0.5 to 12) remained on active surveillance and 102 (35%) with median followup 2.4 years (range 0.6 to 12.2) met progression criteria (p=0.01). Higher PSA at diagnosis (p=0.01) and higher PSA density at diagnosis (p=0.02) were significantly associated with progression. Overall, PSAV (p=0.06) and PSADT (p=0.83) were not significantly associated with progression and no PSAV or PSADT cut point had both high sensitivity and specificity (Table). PSAV was however associated with progression (p=0.01) in the subset of men (n=117) with a PSA<4ng/ml at diagnosis. CONCLUSIONS: PSA velocity was associated with progression in our expectant management population. However, there was considerable overlap between the groups and we were unable to identify a cutpoint which could reliably distinguish progressors from non-progressors. We did not find an association between PSADT and progression in our cohort. These results likely suggest that, PSA kinetics alone are not sufficient as a trigger for intervention, and without surveillance biopsies men could miss the window of opportunity for cure.