Biochemical Responders Research Articles

Correlation of [68Ga]Ga-PSMA PET/CT response and PSA decline in first-line enzalutamide for metastatic castration-resistant prostate cancer patients.

to assess the utility of response monitoring to enzalutamide by using [68Ga]Ga-PSMA PET in mCRPC patients treated with enzalutamide as first-line therapy. patients underwent [68Ga]Ga-PSMA PET less than 8 weeks before and 3 months after starting enzalutamide. On the basis of EAU/EANM criteria, patients were categorized as PSMA responders (PET-R) or PSMA non-responders (PET-NR), whilst, based on PSA, they were classified as biochemical responders (PSA-R) or non-responders (PSA-NR). Survival analysis was performed using the Cox regression hazard model and the Kaplan-Meier method. 69 patients were considered fully evaluable. We observed 47.8% of concordance between [68Ga]Ga-PSMA PET and PSA monitoring at 3 months after starting enzalutamide. For discordant cases, the PSA reduction has a weak impact on PFS and a significant impact on OS in PET-NR patients, whilst this change has no impact either for PFS and OS in PET-R ones. [68Ga]Ga-PSMA PET could be a useful imaging tool for monitoring response to enzalutamide in mCRPC patients, being more informative than PSA in this setting, and possibly better guiding clinicians in therapeutic decisions.

Utilization of genetic and genomic data and correlation to outcomes of treatment with PARP inhibitors in advanced or metastatic castrate-resistant prostate cancer.

e17034 Background: Prostate cancer is the second-leading cause of cancer death in men in the United States, with aggressive forms associated with mutations in homologous recombination repair (HRRm) genes. PARP inhibitors (PARPi) (olaparib, rucaparib, niraparib, and talazoparib) are FDA approved for treatment of HRRm metastatic castration-resistant prostate cancer (mCRPC). Previous data have shown PARPi has the greatest benefit in patients with HRRm, but the responses in HRR genes other than BRCA1/2 and ATM are less robust based on available data. Methods: This retrospective study utilized the electronic health record to identify adult patients diagnosed with prostate cancer and treated at Avera Cancer Institute from 1/1/2018 to 12/31/2022 who received somatic (tumor and/or ctDNA) and/or germline genetic testing. Testing results were reviewed for pathogenic HRRm (BRCA1, BRCA2, ATM, ATR, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, or RAD51C) and treatment histories were reviewed to identify PARPi use. Data about PARPi received, duration, and biochemical response (decline in PSA during therapy) were collected. Results: 191 patients were included in the final analysis. Of these, 88 (46%) patients had germline only testing, 31 (16%) had somatic only testing, and 72 (38%) had both germline and somatic testing completed. 45 patients had HRRm of which 22 were somatic and 33 were germline. The average patient age at time of testing was 70 years. Thirteen of the patients in this cohort received treatment with a PARPi . Twelve of these patients received treatment with olaparib monotherapy, and one patient received olaparib in combination with abiraterone. Average progression free survival was 26 months (range 5-92 months) and the median PFS was 11 months. Four patients were biochemical non-responders, with an average PFS of 8 months, compared to 33 months for the 9 biochemical responders (p=0.04). Gene alterations present in non-responders included germline BRCA1 (n=1), germline CHEK2 (n=2), and somatic ATM (n=1). Germline alterations present in responders included BRCA2 (n=7) and PALB2 (n=2). In patients who received PARPi therapy, the average age of testing was 73 years. Conclusions: The patients found to have HRRm that were treated with a PARPi showed similar responses to previously described data in that the BRCA2 mutated group showed best response, followed by PALB2 mutated tumors. The overall proportion of patients with HRRm that were ultimately treated with PARPi was smaller than expected warranting further investigation. New FDA approvals of PARPi combined with next generation hormonal agents in the first line mCRPC setting are expected to increase utilization of PARPi. Additional outcomes data for individual HRR genes are needed to improve patient selection, outcomes, and reduce unnecessary toxicity due to PARPi therapy.

In Neoadjuvant FOLFIRINOX Chemotherapy for Pancreatic Ductal Adenocarcinoma, Which Response is the More Reliable Indicator for Prognosis, Radiologic or Biochemical?

In this era of increasing neoadjuvant chemotherapy, methods for evaluating responses to neoadjuvant chemotherapy are still diverse among institutions. Additionally, the efficacy of adjuvant chemotherapy for patients undergoing neoadjuvant chemotherapy remains unclear. Therefore, this retrospective study was performed to evaluate the effectiveness of methods for assessing response to neoadjuvant chemotherapy and the need for adjuvant chemotherapy in treating patients with non-metastatic pancreatic ductal adenocarcinoma. The study identified 150 patients who underwent neoadjuvant FOLFIRINOX chemotherapy followed by curative-intent pancreatectomy. The patients were stratified by biochemical response based on the normalization of carbohydrate antigen 19-9 and by radiologic response based on size change at imaging. The patients were classified into the following three groups based on their response to neoadjuvant chemotherapy and prognosis: biochemical responders (BR+), radiology-only responders (BR-/RR+), and non-responders (BR-/RR-). The 3-year overall survival rate was higher for BR+ (71.0%) than for BR-/RR+ (53.6%) or BR-/RR- (33.1%) (P < 0.001). Response to neoadjuvant chemotherapy also was identified as a significant risk factor for recurrence in a comparison between BR-/RR+ and BR+ (hazard ratio [HR], 2.15; 95% confidence interval [CI] 1.19-3.88; P = 0.011) and BR-/RR- (HR, 3.82; 95% CI 2.41-6.08; P < 0.001). Additionally, regardless of the response to neoadjuvant chemotherapy, patients who completed adjuvant chemotherapy had a significantly higher 3-year overall survival rate than those who did not. This response evaluation criterion for neoadjuvant chemotherapy is feasible and can significantly predict prognosis. Additionally, completion of adjuvant chemotherapy could be helpful to patients who undergo neoadjuvant chemotherapy regardless of their response to neoadjuvant chemotherapy.

PSMA PET/CT for Response Assessment and Overall Survival Prediction in Patients with Metastatic Castration-Resistant Prostate Cancer Treated with Androgen Receptor Pathway Inhibitors.

We aimed to evaluate the role of prostate-specific membrane antigen (PSMA) PET/CT for response assessment and outcome prediction in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with androgen receptor pathway inhibitors (ARPIs), including abiraterone acetate or enzalutamide. Methods: We retrospectively analyzed 30 ARPI-treated mCRPC patients who underwent 68Ga-PSMA-11 PET/CT within 8 wk before (baseline) and 12 ± 4 wk after treatment initiation. Total PSMA tumor volume was calculated using the fixed threshold method (SUV ≥ 3). Patients were categorized as PSMA responders (PSMA-Rs) or PSMA nonresponders (PSMA-NRs) on the basis of both European Association of Urology/European Association of Nuclear Medicine (EAU/EANM) criteria and Response Evaluation Criteria in PSMA PET/CT (RECIP) 1.0. PSMA-R included patients with a complete response, a partial response, or stable disease, and PSMA-NR included those with progressive disease. On the basis of prostate-specific antigen (PSA), patients were classified as biochemical responders if PSA decreased by at least 50% and as nonresponders if it did not. The Φ-coefficient was used to evaluate the correlation of PSMA- and PSA-based responses. Survival analysis was performed using the Cox regression hazard model and the Kaplan-Meier method. Predictive accuracy was tested for both response criteria. Results: On the basis of PSMA PET/CT, 13 (43%) patients were PSMA-NR according to the EAU/EANM criteria and 11 (37%) patients were PSMA-NR according to RECIP 1.0. Significant correlations were observed between PSMA- and PSA-based responses for both criteria (Φ = 0.79 and 0.66, respectively). After a median follow-up of 25 mo (interquartile range, 21-43 mo), the median overall survival was significantly longer for PSMA-R than PSMA-NR (54 vs. 22 mo) for both the EAU/EANM criteria and RECIP 1.0, with hazard ratios of 6.9 (95% CI, 1.9-26; P = 0.004) and 5.6 (95% CI, 1.69-18.26, P = 0.005), respectively. No significant difference in predictive accuracy was found between the 2 criteria (C-index, 0.79 vs. 0.76, respectively, P = 0.54). Flare phenomena at the second PSMA PET study were not observed in our cohort. Conclusion: Our results demonstrate that PSMA PET/CT is a valuable imaging biomarker for response assessment and overall survival prediction when performed at 3 mo after ARPI treatment initiation in mCRPC patients. Both proposed PSMA response criteria (EAU/EANM and RECIP 1.0) seem to perform equally well. No PSMA flare was observed. Prospective validation of these findings is strongly needed.

Early biochemical and radiographic response after one cycle of [177Lu]Lu-PSMA I&T radioligand therapy in metastatic castration-resistant prostate cancer patients

PurposeThe aim of this study was to investigate very early radiographic PSMA PET response after one cycle of [177Lu]Lu-PSMA I&T radioligand therapy (RLT) of metastatic castration-resistant prostate cancer (mCRPC) and to assess its role in predicting overall response and survival.MethodsThis retrospective study enrolled 40 mCRPC patients who were treated with a median of 3 (2–9) [177Lu]Lu-PSMA I&T RLT cycles. Biochemical response was based on the relative change of serum PSA according to PCWG3 criteria, while radiographic response referred to the relative change of PSMA-derived total viable tumor volumes expressed as total lesion PSMA (TLP).ResultsAfter one cycle of RLT, biochemical partial response (PR) was seen in 8/40 (20.0%), stable disease (SD) in 22/40 (55.0%), and progressive disease (PD) in 10/40 (25%) patients. In PSMA PET, very early molecular PR was observed in 12 (30.0%), SD in 19 (47.5%), and PD in 9 (22.5%) subjects. The PSA and TLP nadir were achieved after a median of 1 (1–5) and 2 (1–6) cycles, respectively. Nineteen (47.5%) patients showed overall biochemical PR, 11 (27.5%) had SD, and 10 (25%) experienced PD. In PSMA-directed PET, 4 patients experienced molecular complete response (CR), 24 (60.0%) had PR, 4 (10.0%) SD, and 8 (20.0%) PD. Early biochemical or radiographic response was not associated with longer overall survival (OS). Overall biochemical responders had a nearly significantly longer median OS (22.7 months) than non-responders (14.4 months, p = 0.08). Early PSA progression was associated with shorter OS (12.2 months), compared to biochemical SD/PR (18.7 months, p = 0.09).ConclusionIn this retrospective cohort, there was no association between early PSMA PET radiographic response and overall survival; hence, treatment should not be prematurely discontinued. In contrast, early PSA progression after one cycle of [177Lu]Lu-PSMA I&T RLT was an indicator of overall progression and poor clinical outcome.

Predicting Treatment Response in Primary Aldosteronism Using 11C-Metomidate Positron Emission Tomography

Appropriate treatment of primary aldosteronism (PA) depends on accurate lateralization. 11 C-metomidate (MTO) is a tracer used in PET that provides functional information about the adrenal cortex. We aimed to perform MTO PET for patients with PA who are managed according to the guideline and to verify its correlation with other lateralization modalities and usefulness in outcome prediction. Seventeen patients with PA who underwent MTO PET and had ≥1 lateralization modality (adrenal venous sampling and/or NP-59 adrenal scintigraphy) were included. SUV max of each adrenal gland (higher uptake side, HSUV max ; lower uptake side, LSUV max ) and the ratio of HSUV max to LSUV max (contrast) were compared with lateralization modalities, postsurgical outcomes, and medical treatment outcomes. Cutoff values were used as outcome predictors. HSUV max and LSUV max increased in the order of bilateral, unilateral, and negative findings of CT, with opposite order of contrast. High discordant rate between MTO PET and other lateralization modalities was noted. Biochemical responders (n = 8) had significantly lower HSUV max and LSUV max than nonresponders, and clinical responders (n = 6) had borderline lower HSUV max than nonresponders. By optimal cutoff values of HSUV max and LSUV max , MTO PET was able to predict biochemical and clinical outcomes in patients with medical treatment. According to adrenal CT findings, MTO PET presented different uptake patterns. Patients with PA under medical treatment showed significantly lower tracer uptake in responders. Thus, MTO PET may be a useful imaging biomarker to predict medical treatment outcome. Multicenter prospective study with a larger number of patients is needed for further validation.

Bone marrow impairment during early [177Lu]PSMA-617 radioligand therapy: Haematotoxicity or tumour progression?

BackgroundThe recent phase III VISION-trial confirms the treatment efficacy of radioligand therapy with [177Lu]PSMA-617 (PSMA-RLT) in metastatic castration-resistant prostate cancer (mCRPC). In PSMA-RLT, the relatively low absorbed bone marrow dose allows for multiple therapy cycles with relatively low risk of haematological adverse events (hAE). However, as disease progression itself may be a cause of bone marrow impairment, the aim of this study was to assess potential relations between impairment of haematological status and response to PSMA-RLT.MethodsIn this retrospective analysis, haematological parameters (HP) of 64 patients with mCRPC were systematically acquired over two cycles (12–16 weeks) of PSMA-RLT from baseline to restaging. Changes in HP were analysed qualitatively (CTCAE 5.0) and quantitatively. The HP changes from baseline were compared to quantitative and qualitative biochemical and imaging response, using PCWG3 and PROMISE criteria.ResultsAll grade 3/4 hAE observed were associated with disseminated or diffuse bone involvement as well as biochemical non-response at restaging. Quantitatively, at baseline, HP inversely correlated with biochemical and volumetric (on PET) tumour burden as well as bone involvement pattern (p ≤ 0.043). Among patients with disseminated or diffuse bone involvement, percentage changes in HP (%HP) at restaging inversely correlated with serological and imaging tumour burden (p ≤ 0.017). Biochemical non-responders showed a significant decrease in %HP (p ≤ 0.001) while HP in biochemical responders remained stable (p ≥ 0.079).ConclusionDuring early cycles of PSMA-RLT, qualitative and quantitative bone marrow impairment appears to be closely associated with osseous tumour burden as only patients with advanced bone involvement and non-response to therapy exhibited high-grade haematological adverse events, showing a significant decline of haematological parameters. This implies that in patients with advanced mCRPC, non-response to PSMA-RLT may be a major cause of bone marrow impairment during early treatment cycles.German Clinical Trial Register DRKS00013665. Registered 28 December 2017, retrospectively registered (www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00013665)

From the Editor’s Desk...

From the Editor’s Desk...

Combined 177 Lu-PSMA-617 PRLT and abiraterone acetate versus 177 Lu-PSMA-617 PRLT monotherapy in metastatic castration-resistant prostate cancer: An observational study comparing the response and durability.

The aim of present study was to determine and compare the overall response rates, progression-free survival (PFS), overall survival (OS), and clinical toxicity of the combination of 177Lu-PSMA-617 radioligand therapy (PRLT) and abiraterone acetate (AA) versus 177Lu-PSMA-617 PRLT as monotherapy in metastatic castration-resistant prostate cancer (mCRPC) patients. The mCRPC patients who received at least one cycle of 177 Lu-PSMA-617 PRLT with or without AA therapy, were included and analyzed in the present study. The patients were divided into two major groups. Group 1 received only 177 Lu-PSMA PRLT and Group 2 received combined 177 Lu-PSMA PRLT + AA therapy. Therapeutic dose of 177 Lu-PSMA-617 PRLT was 4.4-5.55 GBq per patient per cycle administered at intervals of 10-12 weeks in both groups. The Group 2 patients additionally received a dose of 1000 mg of AA once daily and 5 mg of prednisone twice daily. Treatment response in two groups was evaluated under four broad categories (a) symptomatic, (b) biochemical (serum prostate-specific antigen level), (c) objective molecular imaging (68 Ga-PSMA-11 and 18 F-FDG PET/CT), and (d) objective anatomical imaging (computed tomography). For assessing treatment response, patients in two groups were categorized into responders (complete response [CR], partial response [PR], and stable disease [SD]) and nonresponders (progressive disease [PD]). The Kaplan-Meier product-limit method was used to calculate PFS and OS following first 177 Lu-PSMA PRLT in the two groups. Univariate analysis was used to compare the patients' characteristics in two groups using a χ2 or Fisher exact test. The Kaplan-Meier curves of PFS and OS between two groups were compared by using the log-rank test (p < 0.05 significant). A total of 58 mCRPC patients (Group 1, 38 patients and Group 2, 20 patients) were included in this study analysis. The clinical and demographic characteristics of these patients (age, Gleason score, FDG avid disease, metastatic disease burden, and average number of 177 Lu-PSMA PRLT cycles) in two groups were compared and found to be similar (p > 0.05). Post-treatment, symptomatic, biochemical, molecular, and anatomic imaging responders were found in 22 patients (58%) and 17 patients (85%), 22 patients (58%) and 16 patients (80%), 19 patients (54%) and 14 patients (78%), and 19 patients (54%) and 14 patients (78%) in Group 1 and Group 2, respectively. The median PFS of 7 months and median OS of 8 months were documented in Group 1, whereas median PFS was not reached and median OS of 16 months registered in Group 2. Transient hematological toxicity of Grades 1 and 2 was found in total seven patients (five patients in Group 1 and two patients in Group 2). On comparison of the treatment outcome between two groups, significant p value was found for symptomatic responders (58% in Group 1 vs. 85% in Group 2), median PFS (7 months in Group 1 vs. not reached in Group 2), and median OS (8 months in Group 1 vs. 16 months in Group 2), with better outcome in Group 2 patients for these variables. In the present study, the combination of 177 Lu-PSMA-617 PRLT and AA therapy showed significant improvement in mCRPC patients' symptomatic response, PFS, and OS as compared to 177 Lu-PSMA-617 PRLT monotherapy.

Oral octreotide capsules for the treatment of acromegaly: comparison of 2 phase 3 trial results

PurposeResults are presented from 2 to 3 trials investigating oral octreotide capsules (OOC) as an alternative to injectable somatostatin receptor ligands (iSRLs) in the treatment of acromegaly.MethodsCH-ACM-01 was an open-label trial (N = 155) and CHIASMA OPTIMAL was a double-blind placebo-controlled (DPC) trial (N = 56), both investigating OOC as maintenance therapy for patients with acromegaly who were biochemical responders receiving iSRLs.ResultsBaseline characteristics in both trials reflected those expected of patients with acromegaly responding to treatment and were similar between trials, despite differences in inclusion criteria. OOC demonstrated a consistent degree of biochemical response across trials, with 65% of patients in CH-ACM-01 maintaining response during the core period and 64% of patients in CHIASMA OPTIMAL at the end of the DPC. Mean insulin-like growth factor I (IGF-I) levels remained within inclusion criteria at the end of treatment in both trials. Of 110 patients entering the fixed-dose phase in CH-ACM-01, 80% maintained or improved acromegaly symptoms from baseline to the end of treatment. Over 85% of patients in both trials elected to continue into the extension phases. OOC were found to be well tolerated across both trials, and no dose-related adverse events were observed.ConclusionsOOC demonstrated remarkably consistent results for biochemical response, durability of response, and preference to continue with oral treatment across these 2 complementary landmark phase 3 trials, despite differences in the design of each.Trial registration NCT03252353 (August 2017), NCT01412424 (August 2011).

Efficacy and predictors of short-term first-generation somatostatin analog presurgical treatment in acromegaly: A hospital-based study of 237 cases

ObjectiveTo investigate the effectiveness and predictors of short-term somatostatin analog (SSA) presurgical therapy in a large cohort and to assess the correlation between clinical and pathological variables. Design237 newly diagnosed patients with acromegaly received presurgical SSA treatment for three months were recruited. Clinical characteristics were collected, and response to SSA in hormone and tumor size was evaluated. The correlation between clinical information and pathological variables were analyzed. ResultsAfter 3 months presurgical SSA therapy, 51 (21.5%) patients were biochemically responsive with ≥50% decrease in IGF-1 while 126 (53.2%) patients showed at least 20% tumor size decrease. Biochemical responders were associated with a smaller maximum tumor diameter (MTD) and an older age (OR, 0.448; P = 0.003; OR, 1.050; P = 0.001). Tumor size responders were associated with a smaller MTD (OR, 0.435; P < 0.001). A combination of MTD < 2 cm and age ≥49 years predicted biochemical responders (PPV, 54.5%; NPV, 86.0%; P < 0.001), while MTD ≤2.2 cm (PPV, 67.1%; NPV, 67.0%; P < 0.001) predicted tumor size responders. Compared to patients with MTD < 2 cm, patients with MTD ≥ 2 cm showed higher percentage of sparsely granulated (SG) adenoma (62.1% vs. 31.3%, P = 0.005). In addition, the percentage of SG adenoma tended to be higher in patients < 49 years than ≥49 years (48.1% and 31.0% P = 0.089). ConclusionsThe baseline MTD and age correlate with granulation patterns and may be used as easily acquired predictors of presurgical SSA treatment in acromegaly. Patients over their 50s with a tumor less than 2 cm in diameter are more likely to have a response to the short-term presurgical SSA therapy.

Elevated Pretreatment Plasma Oncostatin M Is Associated With Poor Biochemical Response to Infliximab.

BackgroundWe hypothesized that elevations of plasma Oncostatin M (OSM) would be associated with infliximab nonresponse.MethodsPlasma OSM was measured in Crohn disease patients pre-infliximab with biochemical response (>50% reduction in fecal calprotectin) as the primary outcome.ResultsThe median OSM in biochemical responders was 86 (69–148) pg/mL compared with 166 (74–1766) pg/mL in nonresponders (P = 0.03). Plasma OSM > 143.5 pg/mL was 71% sensitive and 78% specific for biochemical nonresponse (area under the curve 0.71). Early biochemical nonremission was also associated with an elevated neutrophil CD64 expression (odds ratio 8.9, P = 0.011).ConclusionsElevated preinfliximab plasma OSM and nCD64 surface expression were both associated with poor biochemical outcomes.

Ursodeoxycholic acid therapy and liver transplant-free survival in patients with primary biliary cholangitis

The clinical efficacy of ursodeoxycholic acid (UDCA) in primary biliary cholangitis (PBC) remains subject to debate as definitive randomized controlled trials are lacking. We aimed to determine whether UDCA prolongs liver transplant (LT)-free survival in patients with PBC. This international cohort study included patients from the Global PBC Study Group database, originating from 8 countries in Europe and North America. Both UDCA-treated and untreated patients were included. LT and death were assessed as a combined endpoint through Cox regression analyses, with inverse probability treatment weighting (IPTW). In the 3,902 patients included, the mean (SD) age was 54.3 (11.9) years, 3,552 patients (94.0%) were female, 3,529 patients (90.4%) were treated with UDCA and 373 patients (9.6%) were not treated. The median (interquartile range) follow-up was 7.8 (4.1-12.1) years. In total, 721 UDCA-treated patients and 145 untreated patients died or underwent LT. After IPTW, the 10-year cumulative LT-free survival was 79.7% (95% CI 78.1-81.2) among UDCA-treated patients and 60.7% (95% CI 58.2-63.4) among untreated patients (p <0.001). UDCA was associated with a statistically significant reduced risk of LT or death (hazard ratio 0.46, 95% CI 0.40-0.52; p <0.001). The hazard ratio remained statistically significant in all stages of disease. Patients classified as inadequate biochemical responders after 1 year of UDCA had a lower risk of LT or death than patients who were not treated (adjusted hazard ratio 0.56; 95% CI 0.45-0.69; p <0.001). The use of UDCA improves LT-free survival among patients with PBC, regardless of the disease stage and the observed biochemical response. These findings support UDCA as the current universal standard of care in PBC. In this international multicenter study of 3,902 patients with primary biliary cholangitis, we found that treatment with ursodeoxycholic acid is associated with prolonged liver transplant-free survival. This association was significant, irrespective of sex, age, or disease stage. The survival benefit remained statistically significant in patients with an incomplete biochemical response to ursodeoxycholic acid therapy.

30 ELEVATION OF PLASMA ONCOSTATIN M IS ASSOCIATED WITH PRIMARY BIOCHEMICAL NONRESPONSE AND SECONDARY CLINICAL NONRESPONSE TO INFLIXIMAB IN PEDIATRIC CROHN’S DISEASE PATIENTS

Oncostatin M (OSM) and OSM receptor (OSMR) were found to be highly expressed in inflamed intestinal tissue in patients with Crohn’s disease (CD) and ulcerative colitis (UC).1 West et al. also found elevations of mucosal OSM was strongly associated with treatment nonresponse to tumor necrosis factor-α inhibitors (anti-TNF).1 We hypothesized that increased abundance of plasma OSM would also be associated with anti-TNF nonresponse with our primary aim to identify an OSM cut-point for early anti-TNF nonresponse. We enrolled anti-TNF naïve children with CD starting infliximab into this prospective, observational study. The primary outcome was biochemical response and defined by a fecal calprotectin <400 µg/ml prior to the first maintenance dose (infusion 4). This outcome was restricted to patients with both a pre-infliximab fecal calprotectin >400 µg/ml and a stool sample collected at infusion 4. Clinical remission at 12 months was defined as a weighted pediatric CD activity index <12.5, off steroids, and on infliximab without surgery in the first year. The ideal OSM cut-point was identified using the Youden index from the receiver operating characteristic curve analysis of biochemical responders and nonresponders. OSM was measured using ELISA (ThermoFisher, Frederick, MD) with an intra-assay CV<10%. Fecal calprotectin was measured with ELISA (Buhlmann, Switzerland). Infliximab concentrations were measured with ELISA (Immundiagnostik, Germany). We measured pre-infliximab OSM in 40 consecutive CD patients. The cohort was 35% female, 90% white race with a mean age of 13 (SD 4) years at the start of infliximab. One patient remained on methotrexate during induction and 50% of the cohort received prednisone prior to the first induction dose. 33/40 met criteria for evaluation for the primary aim with 16/33 (49%) in biochemical remission at infusion 4. The median (IQR) OSM in biochemical nonresponders was 96 (69-198) pg/ml compared to 166 (84-1766) pg/ml in nonresponders (p=0.035, Figure1). Using the Youden index, we identified plasma OSM >143 pg/ml was 71% sensitive and 75% specific for biochemical nonresponse (Figure 2). The median infusion 4 fecal calprotectin in the OSMhigh (>143 pg/ml) group was 985 (382-2501) µg/g compared to 317 (141-676) µg/g in OSMlow group (p=0.04). We found only 25% of the OSMhigh patients achieved biochemical response compared to 71% with OSMlow (p=0.015). Thirty-five percent of OSMhigh patients achieved steroid-free clinical remission at month 12 (odd’s ratio of 0.21, 95% CI 0.05-0.77, p=0.023). We found no differences in infliximab concentration at infusions 2, 3 and 4 between OSMhigh and OSMlow patients. In a small pediatric CD cohort, we identified a pre-infliximab cut-point of >143 pg/ml was predictive of early biochemical nonresponse and secondary clinical nonresponse at year 1. Figure 1. Oncostatin M (OSM) was measured with ELISA prior to the first infliximab infusion. Fecal calprotectin was measured prior to infusion 1 and 4. Groups compared by Mann-Whitney test. Figure 2. Oncostatin M (OSM) was measured prior to the first infliximab infusion. Area under the curve (AUC) was determined by the receiver operating characteristic curve for biochemical nonresponse at infusion 4 (defined by a fecal calprotectin ≥400 µg/g). The ideal cut-point for OSM was determined by the Youden index.

Tophus resolution in patients with chronic refractory gout who have persistent urate-lowering responses to pegloticase

BackgroundPegloticase is a recombinant mammalian uricase conjugated to polyethylene glycol approved in the United States for treatment of chronic refractory gout. It can profoundly decrease serum urate to < 1 mg/dl. In patients receiving pegloticase who did not generate high-titer antidrug antibodies (responders), the serum urate remained low for the duration of therapy, 6 months in the phase III clinical trials plus the open-label extension. The objective of this study was to assess the velocity of tophus resolution in subjects treated with pegloticase.MethodsData from two randomized controlled trials of pegloticase in chronic refractory gout were analyzed. Tophi were assessed by computer-assisted measurements of standardized digital photographs. Subjects were designated as responders and nonresponders based on maintenance of serum urate < 6 mg/dl at months 3 and 6 of treatment. The projected time of complete resolution of all tophi was determined by linear regression analysis.ResultsThe mean total tophus area at baseline was 585.8 mm2 for responders, 661.5 mm2 for nonresponders, and 674.4 mm2 for placebo-treated patients. Complete resolution at 6 months of at least one tophus was achieved by 69.6% of 23 responders, 27.9% of 43 nonresponders, and 14.3% of 21 patients who received placebo. Complete resolution of all photographed tophi was achieved by 34.8% of biochemical responders, 11.6% of nonresponders, and 0% of placebo-treated patients. The mean velocity of resolution of all tophi was 60.1 mm2/month in responders with a mean projected time of complete resolution of 9.9 months (4.6–32.6 months). There was a significant inverse correlation between serum urate AUC and tophus resolution velocity (r = − 0.40, P = 0.0002), although considerable heterogeneity in the velocity of resolution was noted. The only patient characteristic that correlated with the velocity of tophus resolution was the baseline tophus area.ConclusionsPegloticase treatment caused a rapid resolution of tophi in responders that correlated with the serum urate lowering associated with this therapy.

Patterns of Progression After 68Ga-PSMA-Ligand PET/CT-Guided Radiation Therapy for Recurrent Prostate Cancer

To determine the patterns of progression after 68Ga prostate-specific membrane antigen (PSMA)-ligand positron emission tomography (PET)/computed tomography (CT)-guided radiation therapy (RT) for recurrent oligometastatic prostate cancer (PCa). One hundred and eight patients with increased prostate-specific antigen levels, who received 68Ga-PSMA-ligand PET/CT-guided RT for recurrent oligometastatic disease after primary therapy for PCa were included. The biochemical progression-free survival and distant disease-free survival after PSMA-ligand PET/CT-guided RT were determined. The patterns of progression were determined using renewed 68Ga-PSMA-ligand PET/CT in patients with biochemical progression and compared with the clinical target volume of the 68Ga-PSMA-ligand PET/CT-guided RT. The frequency of infield and outfield relapses was recorded. A total of 97.2% (105 of 108) of patients showed a decrease in prostate-specific antigen levels after RT and were classified as biochemical responders. After the median follow-up of 18months, 43.5% (47 of 108) of the patients experienced biochemical progression, resulting in an estimated biochemical progression-free survival of 16months. Renewed 68Ga-PSMA-ligand PET/CT allowed localization of recurrent disease in 91.7% (33 of 36) of patients. Analysis of the patterns of progression resulted in a cumulative infield relapse rate of 12.1% (4 of 33) and a cumulative outfield relapse rate of 87.9% (29 of 33). The resultant median disease-free survival was 11months. In terms of the pattern of progression, we observed a shift in the pattern of metastases toward skeletal involvement and distant lymph node metastases. Of these patients, 45.5% (15 of 33) were treated with further RT to delay initiation or escalation of systemic therapies. PSMA-ligand PET/CT-guided RT for relapsed PCa with limited tumor burden allowed individualization of treatment approaches, provided effective local control, and resulted in considerably prolonged biochemical progression-free survival. As indicated by the PSMA-ligand PET/CT-based patterns of progression, repeated PET/CT-guided RT may represent a treatment option in well-selected patients with relapse after RT for oligometastatic disease.

Major Hepatic Complications in Ursodeoxycholic Acid-Treated Patients With Primary Biliary Cholangitis: Risk Factors and Time Trends in Incidence and Outcome.

In this era of near universal ursodeoxycholic acid (UDCA) treatment for primary biliary cholangitis (PBC), progression to cirrhosis still occurs in an important proportion of patients. The aim of this study was to describe the incidence of cirrhosis-associated complications in patients with PBC and assess risk factors and impact on survival. Cohorts of UDCA-treated patients from 16 European and North-American liver centers were included. We used Cox proportional hazards assumptions and Kaplan-Meier estimates. During 8.1 years' median follow-up, 278 of 3,224 patients developed ascites, variceal bleeding, and/or encephalopathy (incidence rate of 9.7 cases/1,000 patient years). The overall cumulative incidence was 9.1% after 10 years of follow-up, but decreased over time to 5.8% after the year 2000. Earlier calendar year of diagnosis (P<0.001), high aspartate aminotransferase to platelets ratio index (APRI; P<0.001) and biochemical non-response (P<0.001) were independently associated with future complications. Patients with both biochemical non-response and an APRI >0.54 after 12 months of UDCA had a 10-year complication rate of 37.4%, as compared to 3.2% in biochemical responders with an APRI ≤0.54. The 10-year transplantation-free survival after a complication was 9% (time-dependent hazard ratio 21.5; 20.1-22.8). Prognosis after variceal bleeding has improved over time. In this large international cohort, up to 15% of UDCA-treated PBC patients developed major non-neoplastic, cirrhosis-associated hepatic complications within 15 years, but cumulative incidence has decreased over time. Biochemical non-response to UDCA and APRI were independent risk factors for these complications. Subsequent long-term outcome after complications is generally poor, but has improved over the past decades.

Impact of treatment against hepatitis C virus on overall survival of naive patients with advanced liver disease.

The beneficial effect of achieving a sustained virological response (SVR) after antiviral treatment against hepatitis C virus is well established. However, it remains unclear whether unsuccessful treatment (non-SVR) also improves patient survival, especially in patients with advanced liver fibrosis. We retrospectively evaluated the incidence of death or liver transplantation in the 427 naive patients with a Child-Pugh score of A and advanced fibrosis newly admitted to the Hospital Beaujon between 2000 and 2010. Patients were followed for a median time of 5.5 years. The baseline characteristics of untreated (n=102) and treated (n=325) patients were largely similar, and there was no evidence of a bias of indication. Treated patients received a combination of interferon and ribavirin and had an SVR rate of 32%. The incidence of death or liver transplantation per 100 person-years was 1.00, 3.20, and 5.44 in SVR, non-SVR, and untreated patients, respectively. After adjusting for baseline characteristics, the risk of death or liver transplantation was significantly lower in SVR than in non-SVR patients and in non-SVR than in untreated patients (hazard ratios, 0.35 and 0.51, respectively; P=0.019 and 0.038, respectively). The effect of treatment in non-SVR patients was higher in patients who had a virological or a biochemical response than in those who did not have a virological or a biochemical response. The risk of death or liver transplantation was significantly lower in treated than in untreated patients. Moreover, there was a gradient of mortality between patients with SVRs, virological or biochemical responders, and untreated patients, suggesting that treatment, even in the absence of viral eradication, has a beneficial effect on survival.

Editorial for ‘Randomized controlled trial assessing the effect of simvastatin in primary biliary cirrhosis’

Editorial for ‘Randomized controlled trial assessing the effect of simvastatin in primary biliary cirrhosis’

Long-term evaluation of partial splenic embolization followed by interferon therapy in patients with hepatitis C virus (HCV) cirrhosis and thrombocytopenia.

Patients with hepatitis C virus (HCV) cirrhosis and thrombocytopenia are often excluded from receiving interferon therapy because the treatment results in severe platelet depletion. Surgical splenectomy or partial splenic embolization (PSE) is a promising procedure for increasing the platelet count before interferon therapy. We performed PSE and evaluated the long-term clinical course in HCV cirrhotic patients. Patients with HCV cirrhosis and thrombocytopenia were included (n=108) in this study. The straight-coiled PSE procedure (Takatsuka method) was performed. The platelet count, hemodynamic changes, rate of a sustained virological response (SVR) and prevalence of hepatocellular carcinoma (HCC) were evaluated. PSE resulted in a significant increase in the platelet count (before PSE: 7.9±2.3×10(4)/μL, two weeks after PSE: 16.7±6.6×10(4)/μL (p<0.001). Therefore, all participants were started on regular-dose interferon therapy. The SVR rate was 24% for serotype 1 and 62% for serotype 2. In the biochemical responders (BR) with SVR, the overall survival rate was 94.6% over five years and 89.3% over 10 years. In the non-responders (NR), the overall survival rate was 78.7% over five years and 62.2% over 10 years. The overall survival rate of the patients with SVR+BR was significantly higher than that observed in the patients with NR (p=0.0082). There were no differences in the prevalence of HCC between the patients with SVR+BR and NR. PSE enabled the induction of regular-dose interferon therapy in patients with HCV cirrhosis and thrombocytopenia. Although the prevalence of HCC did not differ between the SVR+BR and NR patients, there was a significant survival benefit in the patients with SVR+BR.