A targeted review of worldwide indirect treatment comparison (ITC) guidelines and best practices.

OBJECTIVES: Controls and governance over the methodology and reporting of indirect treatment comparisons (ITCs) have been introduced to minimize bias and ensure scientific credibility and transparency in healthcare decision-making. The objective of this study was to highlight ITC techniques that are key to conducting objective and analytically-sound analyses, and to ascertain circumstantial suitability of ITCs as a source of comparative evidence for healthcare interventions. METHODS: Ovid MEDLINE® was searched from January 2010 through August 2023 to identify publicly available ITC-related documents (i.e., guidelines and best practices) in the English language. This was supplemented with hand-searches of websites of various international organizations, regulatory agencies, and reimbursement agencies of Europe, North America, and Asia-Pacific. The jurisdiction-specific ITC methodology and reporting recommendations were reviewed. RESULTS: Sixty-eight guidelines from 10 authorities worldwide were included for synthesis. Many of the included guidelines were updated within the last five years and commonly cited the absence of direct comparative studies as primary justification for employing ITCs. Most jurisdictions favored population-adjusted or anchored ITC techniques opposed to naïve comparisons. Recommendations on the reporting and presentation of these ITCs varied across authorities; however, there was some overlap among the key elements. CONCLUSIONS: Given the challenges of conducting head-to-head randomized controlled trials, comparative data from ITCs offer valuable insights into clinical effectiveness. As such, multiple ITC guidelines have emerged worldwide. According to the most recent versions of the guidelines, the suitability and subsequent acceptability of the ITC technique employed depends on the data sources, available evidence, and magnitude of benefit/uncertainty.

Donor blood cultures and outcomes after lung transplantation: a single-center report.

BACKGROUND: Transplanting lungs from donors with positive blood cultures has not been shown to adversely affect survival. There is limited evidence for potential effects on other outcomes, such as hospital course, graft function, and transmission of infection. METHODS: This retrospective cohort study included adult patients who underwent lung-only transplantation for the first time between March 2010 and December 2022. Outcomes of patients whose donors had positive blood cultures within 72 h of transplant were compared to patients whose donors had negative blood cultures. RESULTS: Twenty-five (10.8%) of 232 donors had positive blood cultures, including a single, unexpected case with candidemia. The most commonly isolated bacteria were Enterobacter cloacae (n = 5), Klebsiella pneumoniae (n = 5), Acinetobacter baumannii (n = 3), Pseudomonas aeruginosa (n = 3), and Staphylococcus aureus (n = 3). Eleven donors had identical bacteria in their respiratory cultures. All patients who were transplanted from donors with positive blood cultures survived beyond 90 days. Positive donor blood cultures were not associated with longer hospital stay, in-hospital complications, acute cellular rejection, or the achievement of 80% predicted forced expiratory volume in the first second. Probable transmission of donor bacteremia occurred in only two cases (both with S. aureus). These two donors had positive respiratory cultures with the same organism. CONCLUSION: The study did not find an increased risk of adverse events when transplanting lungs from donors with positive blood cultures. Allograft cultures may be more predictive of the risk of transmitting infections.

A SYSTEMATIC LITERATURE REVIEW OF DISEASE PROGRESSION REPORTED IN RPGR -ASSOCIATED X-LINKED RETINITIS PIGMENTOSA.

PURPOSE: Retinitis pigmentosa GTPase regulator-associated X-linked retinitis pigmentosa ( RPGR -associated XLRP) is a rare and severe form of retinitis pigmentosa, resulting in progressive visual impairment; however, disease progression data are limited. A systematic literature review was conducted to assess available data on disease progression in RPGR -associated XLRP. METHODS: PubMed, Embase, and select congress abstracts were evaluated through June 2022. Eligible studies included results specific to RPGR -associated XLRP or populations with ≥80% of patients with retinitis pigmentosa carrying disease-causing RPGR variants. End points of interest included visual acuity, visual field, ellipsoid zone width, progression to blindness, and patient-reported outcomes. RESULTS: Fourteen studies met ≥1 end point of interest. Progressive declines in visual acuity, visual field, and ellipsoid zone width were reported across studies. Nearly all publications reported annual declines in visual acuity (3.5%-8.2%). Annual visual field declines ranged from 4.2% to 13.3%. Changes in retinal structure were also observed (ellipsoid zone width changes: -177 to -830 µ m/year). Most studies measured blindness using visual acuity; visual field-based definitions resulted in blindness by age ∼25 years. Patient-reported outcome data were limited. CONCLUSION: Published evidence shows that patients with RPGR -associated XLRP experience progressive decline in visual acuity, visual field, and ellipsoid zone width, eventually resulting in blindness. Additional longitudinal data with standardized end points and expanded collection of patient-reported outcomes are needed to assess visual decline in RPGR -associated XLRP.

Impact of Treatment Sequencing on Overall Survival in Patients with Transplant-Ineligible Newly Diagnosed Myeloma.

BACKGROUND: Because patients with newly diagnosed multiple myeloma (NDMM) do not always receive any treatment beyond first-line (1L) therapy, it is imperative that patients receive the best treatment in the 1L setting. However, the optimal initial treatment remains to be identified. We performed a clinical simulation to assess potential outcomes with different treatment sequences. PATIENTS AND METHODS: We used a partitioned survival model to compare overall survival (OS) with (1) daratumumab, lenalidomide, and dexamethasone (D-Rd) in 1L followed by a pomalidomide- or carfilzomib-based regimen in second line (2L) versus (2) bortezomib, lenalidomide, and dexamethasone (VRd) in 1L followed by a daratumumab-based regimen in 2L versus (3) lenalidomide and dexamethasone (Rd) in 1L followed by a daratumumab-based regimen in 2L. Probabilities of transition between health states (1L, 2L+, and death) were based on published clinical data and real-world data from the Flatiron Health database. The proportion of patients discontinuing treatment after 1L (attrition rates) in the base case was estimated with a binomial logistic model using data from the MAIA trial. RESULTS: Using D-Rd in 1L conferred a longer median OS compared with delaying daratumumab-based regimens until 2L after VRd or Rd, respectively (8.9 [95% CrI 7.58-10.42] vs. 6.92 [5.92-8.33] or 5.75 [4.50-7.25] years). Results of scenario analyses were consistent with the base case. CONCLUSION: Our simulation, which incorporates clinically representative treatments and attrition rates, supports the use of D-Rd as initial therapy, rather than delaying the use of daratumumab until later lines of therapy, in patients with transplant-ineligible NDMM.

Hepatitis B virus core-related antigen (HBcrAg) as a prognostic marker for the development of hepatocellular carcinoma: A mini systematic review of the literature.

Chronic hepatitis B (CHB) infection is a risk factor for hepatocellular carcinoma (HCC). Previous studies showed that elevated levels of Hepatitis B Virus (HBV) DNA and HBsAg are associated with increased HCC risk in patients with chronic HBV infection. Multiple studies showed that high levels of HBV DNA and Hepatitis B Surface Antigen (HBsAg) are associated with higher HCC risk in CHB patients. Patients treated with antiviral therapy may have undetectable or low levels of HBV DNA and HBsAg loss. However, HCC may develop in some patients with low-level HBV DNA and HBsAg seroconversion. In this study, we evaluated the role of HBcrAg in predicting HBV related HCC development. We searched PubMed, Scopus, and Web of Science databases using keywords (hepatitis B core-related antigen, hepatocellular carcinoma, liver neoplasm, hepatocellular and hepatic cancer, to identify studies assessing serum level of HBcrAg in patients with CHB and HCC. The search resulted in 184 studies. Seven studies were included: Four of which were retrospective cohort studies, and the rest were prospective cohort, case controls. Six of them reported a higher HBcrAg positivity rate in the HCC group when compared with the HBV DNA assay, yet with similar hazard ratio (HR) in predicting the incidence of HCC. However, four studies found that HBcrAg positivity was an independent risk factor for HCC development with a HR ranging from 3.27 to 7.05. HBV-related HCC has many proposed biomarkers in its prediction, yet our findings revealed HBcrAg to may have superiority over other biomarkers. High quality studies with bigger sample size research is needed to understand the potential role of HBcrAg in CHB induced HCC.

International multicenter validation of GES score for HCC risk stratification in chronic hepatitis C patients.

We have recently demonstrated the ability of a simple predictive model (GES) score to determine the risk of hepatocellular carcinoma (HCC) after using direct-acting antivirals. However, our results were restricted to Egyptian patients with hepatitis C virus (HCV) genotype 4. Therefore, we studied a large, independent cohort of multiethnic populations through our international collaborative activity. Depending on their GES scores, patients are stratified into low risk (≤ 6/12.5), intermediate risk (> 6-7.5/12.5), and high risk (> 7.5/12.5) for HCC. A total of 12,038 patients with chronic HCV were analyzed in this study, of whom 11,202 were recruited from 54 centers in France, Japan, India, the U.S., and Spain, and the remaining 836 were selected from the Gilead-sponsored randomized controlled trial conducted across the U.S., Europe, Canada, and Australia. Descriptive statistics and log-rank tests. The performance of the GES score was evaluated using Harrell's C-index (HCI). The GES score proved successful at stratifying all patients into 3 risk groups, namely low-risk, intermediate-risk, and high-risk. It also displayed significant predictive value for HCC development in all participants (p < .0001), with HCI ranging from 0.55 to 0.76 among all cohorts after adjusting for HCV genotypes and patient ethnicities. The GES score can be used to stratify HCV patients into 3 categories of risk for HCC, namely low-risk, intermediate-risk, and high-risk, irrespective of their ethnicities or HCV genotypes. This international multicenter validation may allow the use of GES score in individualized HCC risk-based surveillance programs.

Comparison of efficacy from two different dosing regimens of bortezomib: an exposure-response analysis.

Bortezomib is a first-in-class proteasome inhibitor, approved for the treatment of multiple myeloma. The originally approved dosing schedule of bortezomib results in significant toxicities that require dose interruptions and discontinuations. Consequentially, less frequent dosing has been explored to optimise bortezomib's benefit-risk profile. Here, we performed exposure-response analysis to compare the efficacy of the original bortezomib dosing regimen with less frequent dosing of bortezomib over nine 6-week treatment cycles using data from the VISTA clinical trial and the control arm of the ALCYONE clinical trial. The relationship between cumulative bortezomib dose and clinical response was evaluated with a univariate logit model. The median cumulative bortezomib dose was higher in ALCYONE versus VISTA (42·2 vs. 38·5 mg/m2 ) and ALCYONE patients stayed on treatment longer (mean: 7·2 vs. 5·8 cycles). For all endpoints and regimens, probability of clinical response correlated with cumulative bortezomib dose. Similar to results observed for VISTA, overall survival was longer in ALCYONE patients with ≥ 39·0 versus < 39·0 mg/m2 cumulative dose (hazard ratio, 0·119; P < 0·0001). Less frequent bortezomib dosing results in comparable efficacy, and a higher cumulative dose than the originally approved bortezomib dosing schedule, which may be in part be due to reduced toxicity and fewer dose reductions/interruptions.

Extrapolating Survival Data Using Historical Trial-Based a Priori Distributions.

OBJECTIVES: To show how clinical trial data can be extrapolated using historical trial data-based a priori distributions. METHODS: Extrapolations based on 30-month pivotal multiple myeloma trial data were compared with 75-month data from the same trial. The 30-month data represent a typical decision-making scenario where early results from a clinical trial are extrapolated. Mature historical trial data with the same comparator as in the pivotal trial were incorporated in 2 stages. First, the parametric distribution selection was based on the historical trial data. Second, the shape parameter estimate of the historical trial was used to define an informative a priori distribution for the shape of the 30-month pivotal trial data. The method was compared with standard approaches, fitting parametric distributions to the 30-month data with noninformative prior. The predicted survival of each method was compared with the observed survival (ΔAUC) in the 75-month trial data. RESULTS: The Weibull had the best fit to the historical trial and the log-normal to the 30-month pivotal trial data. The ΔAUC of the Weibull with informative priors was considerably smaller compared with the standard Weibull. Also, the predicted median survival based on the Weibull with informative priors was more accurate (melphalan and prednisone [MP] 40 months, and bortezomib [V] combined with MP [VMP] 62 months) than based on the standard Weibull (MP 45 months and VMP 72 months) when compared with the observed median (MP 41.3 months and VMP 56.4 months). CONCLUSIONS: Extrapolation of clinical trial data is improved by using historical trial data-based informative a priori distributions.

Do Surrogate Endpoints Better Correlate with Overall Survival in Studies That Did Not Allow for Crossover or Reported Balanced Postprogression Treatments? An Application in Advanced Non-Small Cell Lung Cancer.

BACKGROUND: In previous studies, correlation between overall survival (OS) and surrogate endpoints like objective response rate (ORR) or progression-free survival (PFS) in advanced non-small cell lung cancer (NSCLC) was poor. This can be biased by crossover and postprogression treatments. OBJECTIVES: To evaluate the relationship between these two surrogate endpoints and OS in advanced NSCLC studies that did not allow for crossover or reported balanced post-progression treatments. METHODS: A systematic review in patients with advanced NSCLC receiving second- and further-line therapy was performed. The relationship between the absolute difference in ORR or median PFS (mPFS) and the absolute difference in median OS (mOS) was assessed using the correlation coefficient (R) and weighted regression models. The analysis was repeated in predefined data cuts based on crossover and balance of postprogression treatments. When the upper limit of R's 95% confidence interval (CI) was more than 0.7, the surrogate threshold effect (STE) was estimated. RESULTS: In total, 146 randomized clinical trials (43,061 patients) were included. The mean ORR, mPFS, and mOS were 12.2% ± 11.2%, 3.2 ± 1.3 months, and 9.6 ± 4.1 months, respectively. The correlation coefficients of ORR and mPFS were 0.181 (95% CI 0.016-0.337) and 0.254 (95% CI 0.074-0.418), respectively, with mOS. Nevertheless, in trials that did not allow crossover and reported balanced postprogression treatments, the correlation coefficients of ORR and mPFS were 0.528 (95% CI 0.081-0.798) and 0.778 (95% CI 0.475-0.916), respectively, with mOS. On the basis of STE estimation, in trials showing significant treatment effect size of 41.0% or more ORR or 4.15 or more mPFS months, OS benefit can be expected with sufficient certainty. CONCLUSIONS: Crossover and postprogression treatments may bias the relationship between surrogate endpoints and OS. Presented STE calculation can be used to interpret treatment effect on either ORR or PFS when used as primary endpoints.

Pitfalls in Urinary Tract Cytopathology.

Urine cytopathology is a cost-effective method to diagnose and follow patients with high grade urothelial carcinoma (HGUC). However, some benign, reactive and metaplastic changes may mimic HGUC and pose a diagnostic challenge for cytopathologists. Summary: Our comprehensive review focuses on summarizing common pitfalls encountered in urine cytopathology, based largely on the experience of the senior author (AC) utilising the diagnostic criteria described in the 2nd edition of The Paris system (TPS) for reporting urinary tract cytopathology and in recent published literature. These include urothelial tissue fragments, instrumented samples, degenerative changes, treatment effects, viral cytopathic changes, iatrogenic and metaplastic changes. Our aim is to provide a clear understanding of these challenges to assist cytopathologists in making accurate diagnoses. Key Message: It's crucial for cytopathologists to recognize benign, reactive and metaplastic lesions that could resemble HGUC. Awareness of these cytological features is essential to minimise diagnostic errors.

A matching-adjusted indirect comparison of results from REDUCE and RESPECT-two randomized trials on patent foramen ovale closure devices to prevent recurrent cryptogenic stroke.

AIMS: Two randomized clinical trials, REDUCE and RESPECT, demonstrated that patent foramen ovale (PFO) closure in combination with antithrombotic therapy was more effective for the prevention of recurrent ischemic stroke compared with antithrombotic therapy alone. The aim of this study was to determine the relative efficacy and safety of the PFO closure devices used in REDUCE (HELEX and CARDIOFORM Septal Occluders) compared with the device used in RESPECT (Amplatzer PFO Occluder). METHODS: An unanchored matching-adjusted indirect comparison (MAIC) of the PFO closure arms of the REDUCE and RESPECT trials was performed using patient-level data from REDUCE weighted to match baseline characteristics from RESPECT. Comparisons of the following outcomes were made between the devices assessed in the trials: risk of recurrent ischemic stroke; recurrent ischemic stroke one year after randomization; any serious adverse event (SAE) related to the procedure or device; and atrial fibrillation or atrial flutter as an SAE related to the procedure or device. RESULTS: After conducting the MAIC, baseline characteristics were well-matched between the two trials. Compared to RESPECT, PFO closure using the devices from REDUCE resulted in a hazard ratio of 0.46 (95% confidence interval [CI] 0.15-1.43; p = 0.17) for the risk of recurrent stroke. For the recurrence of stroke after one year, SAE related to the procedure or device, and atrial fibrillation or atrial flutter as SAE related to the procedure or device, the MAIC resulted in a rate difference of -0.68 (95%CI -2.06 to 0.70; p = .34), -1.29 (95%CI -3.82 to 1.25; p = .32), and -0.19 (95%CI -1.16 to 0.78; p = .71), respectively. These findings were consistent across scenario analyses. CONCLUSIONS: This MAIC analysis found no statistically significant differences in efficacy and safety outcomes between PFO closure with the HELEX and CARDIOFORM Septal Occluders versus the Amplatzer PFO Occluder, as used in the REDUCE and RESPECT trials.

The individual efficacy and safety of medical devices used for patent foramen ovale (PFO) closure in patients with stroke of unknown origin has been demonstrated in two independent trials: REDUCE (using the HELEX Septal Occluder and the CARDIOFORM Septal Occluder) and RESPECT (using the Amplatzer PFO Occluder). In the absence of a direct head-to-head trial for these devices, indirect treatment comparisons offer an alternative to assess their relative efficacy and safety. This study used a matching-adjusted indirect comparison to demonstrate that there were no significant differences between the devices used for PFO closure in the REDUCE and RESPECT trials in terms of safety outcomes.

Feasibility of Indirect Treatment Comparisons Between Niraparib Plus Abiraterone Acetate and Other First-Line Poly ADP-Ribose Polymerase Inhibitor Treatment Regimens for Patients with BRCA1/2 Mutation-Positive Metastatic Castration-Resistant Prostate Cancer.

INTRODUCTION: Poly(ADP-ribose) polymerase inhibitors (PARPi) are a novel option to treat patients with metastatic castration-resistant prostate cancer (mCRPC). Niraparib plus abiraterone acetate and prednisone (AAP) is indicated for BRCA1/2 mutation-positive mCRPC. Niraparib plus AAP demonstrated safety and efficacy in the phase 3 MAGNITUDE trial (NCT03748641). In the absence of head-to-head studies comparing PARPi regimens, the feasibility of conducting indirect treatment comparisons (ITC) to inform decisions for patients with first-line BRCA1/2 mutation-positive mCRPC has been explored. METHODS: A systematic literature review was conducted to identify evidence from randomized controlled trials on relevant comparators to inform the feasibility of conducting ITCs via network meta-analysis (NMA) or population-adjusted indirect comparisons (PAIC). Feasibility was assessed based on network connectivity, data availability in the BRCA1/2 mutation-positive population, and degree of within- and between-study heterogeneity or bias. RESULTS: NMAs between niraparib plus AAP and other PARPi regimens (olaparib monotherapy, olaparib plus AAP, and talazoparib plus enzalutamide) were inappropriate due to the disconnected network, differences in trial populations related to effect modifiers, or imbalances within BRCA1/2 mutation-positive subgroups. The latter issue, coupled with the lack of a common comparator (except for olaparib plus AAP), also rendered anchored PAICs infeasible. Unanchored PAICs were either inappropriate due to lack of population overlap (vs. olaparib monotherapy) or were restricted by unmeasured confounders and small sample size (vs. olaparib plus AAP). PAIC versus talazoparib plus enzalutamide was not possible due to lack of published arm-level baseline characteristics and sufficient efficacy outcome data in the relevant population. CONCLUSION: The current randomized controlled trial evidence network does not permit robust comparisons between niraparib plus AAP and other PARPi regimens for patients with 1L BRCA-positive mCRPC. Decision-makers should scrutinize any ITC results in light of their limitations. Real-world evidence combined with clinical experience should inform treatment recommendations in this indication.

Donor respiratory multidrug-resistant bacteria and lung transplantation outcomes.

RATIONALE: Respiratory culture screening is mandatory for all potential lung transplant donors. There is limited evidence on the significance of donor multidrug-resistant (MDR) bacteria on transplant outcomes. Establishing the safety of allografts colonized with MDR bacteria has implications for widening an already limited donor pool. OBJECTIVES: We aimed to describe the prevalence of respiratory MDR bacteria among our donor population and to test for associations with posttransplant outcomes. METHODS: This retrospective observational study included all adult patients who underwent lung-only transplantation for the first time at King Faisal Specialist Hospital & Research Centre in Riyadh from January 2015 through May 2022. The study evaluated donor bronchoalveolar lavage and bronchial swab cultures. MAIN RESULTS: Sixty-seven of 181 donors (37%) had respiratory MDR bacteria, most commonly MDR Acinetobacter baumannii (n = 24), methicillin-resistant Staphylococcus aureus (n = 18), MDR Klebsiella pneumoniae (n = 8), MDR Pseudomonas aeruginosa (n = 7), and Stenotrophomonas maltophilia (n = 6). Donor respiratory MDR bacteria were not significantly associated with allograft survival or chronic lung allograft dysfunction (CLAD) in adjusted hazard models. Sensitivity analyses revealed an increased risk for 90-day mortality among recipients of allografts with MDR Klebsiella pneumoniae (n = 6 with strains resistant to a carbapenem and n = 2 resistant to a third-generation cephalosporin only) compared to those receiving culture-negative allografts (25.0% versus 11.1%, p = 0.04). MDR Klebsiella pneumoniae (aHR 3.31, 95%CI 0.95-11.56) and Stenotrophomonas maltophilia (aHR 5.35, 95%CI 1.26-22.77) were associated with an increased risk for CLAD compared to negative cultures. CONCLUSION: Our data suggest the potential safety of using lung allografts with MDR bacteria in the setting of appropriate prophylaxis; however, caution should be exercised in the case of MDR Klebsiella pneumoniae.

Lung transplantation outcomes in underweight recipients: A single center experience.

Background: Current guidelines recommend a body mass index (BMI) of 16 kg/m2 as the minimum threshold for lung transplantation, despite mixed evidence on outcomes in underweight patients. The current study aimed to describe survival outcomes of underweight patients who underwent lung transplantation at a single center. Methods: This retrospective observational study included adult lung transplant recipients who underwent transplantation for the first time between March 2010 and March 2022 at King Faisal Specialist Hospital and Research Center and excluded patients with obesity. We defined an underweight status as a BMI <17 kg/m2. Results: Forty-eight of the 202 lung transplant recipients were underweight at the time of surgery. The underweight patients had similar lengths of hospital (p = 0.53) and intensive care unit (p = 0.81) stays compared to other patients. Thirty-three percent of underweight patients had died within 5-year follow-up, compared to 34% of patients who were not underweight. There was no significant difference in mortality risk between underweight patients and patients with normal BMIs in our multivariable Cox regression model (adjusted HR 1.57, 95%CI: 0.77-3.20, p = 0.21). Exploratory analyses revealed that a pre-transplant BMI <13 kg/m2 was associated with a trend towards increased 5-year mortality (adjusted HR 4.00, 95%CI: 0.87-18.35, p = 0.07). Conclusions: Our findings suggest that patients with BMIs of 13-17 kg/m2 may be candidates for lung transplantation. Large multi-center cohort studies are needed to confirm the lower BMI limit for safely transplanting patients.

How are Companion Diagnostics Considered in Economic Evaluations of Oncology Treatments? A Review of Health Technology Assessments.

BACKGROUND: Companion diagnostic (CDx) testing is increasingly used to identify eligible patients for targeted treatments. Guidance on how CDx testing should be incorporated into cost-effectiveness models (CEM) is limited. This review evaluated how health technology assessment bodies and research organizations considered CDx in CEMs of targeted therapies in oncology and whether this ultimately impacted their decisions or time from regulatory approval to recommendations. METHODS: An exhaustive list of approved CDx tests in oncology was compiled. For corresponding indications and treatments, NICE appraisals published between 2016 and 2019 were identified. Then, assessments for the same treatments issued from 11 other agencies were reviewed. Data extracted included background and CDx information, CDx's role in the CEM, and recommendations. RESULTS: Twenty-seven NICE appraisals were identified; 15 considered CDx testing in the CEM, while 12 did not, mainly because testing had already been established for the comparators within the same class or in clinical practice from a prior treatment line. Both testing costs and mutation prevalence drove CDx testing costs per patient. The cross-comparison of assessments showed that CDx test characteristics were inconsistently reported. Time from regulatory approval to recommendations was not impacted by CDx cost inclusion in CEMs. CONCLUSION: CDx testing was included in cost-effectiveness models whenever mutation testing was required solely for patients receiving targeted treatment; cost per patient was based on test costs and mutation prevalence. It is unclear if expanded reliance on CDx testing will impact future assessments of targeted therapies. A future update is warranted to track trends over time.

Estimating the Gender Distribution of Patients with Wild-Type Transthyretin Amyloid Cardiomyopathy: A Systematic Review and Meta-Analysis.

INTRODUCTION: This study investigates the gender distribution in patients diagnosed with wild-type transthyretin amyloidosis cardiomyopathy (ATTRwt). METHODS: A systematic review and meta-analysis of the male proportion in diagnosed ATTRwt patients were conducted. To avoid overlapping population, pooled estimates in the primary analysis were based on all unique studies. In secondary analyses, we considered predefined subsets of studies based on study sample size, recruitment years, geography, study design, age at diagnosis, and method of diagnosis. Additional meta-regression analyses were tested for potential determinants of gender distribution. RESULTS: Twenty-eight unique studies (2542 patients) were included in the meta-analysis. Male proportion in patients with ATTRwt was 86.9% (95% confidence interval 81.5-91.6%). Studies, including patients older than 80 years at diagnosis, had a 29.1% (p value < 0.001) lower male proportion compared to studies, including younger patients. After adjusting for age, studies using autopsy as a method of diagnosis had a 21.1% (p value 0.002) lower male proportion compared to other studies. CONCLUSIONS: Studies conducted to date suggest ATTRwt disproportionally affects males. The proportion of males was significantly impacted by the age at diagnosis and method diagnosis, which may suggest important gender-based differences in the clinical manifestation and diagnostic challenges of ATTRwt in females that warrant future research.

First record of the nematode, Huffmanela sp. infecting the broomtail wrasse (Cheilinus lunulatus) from Egypt.

A total of 385 Red Sea coral reef fish representing three species; Broom tail wrasse (Cheilinus lunulatus), Blacktip grouper (Epinephelus fasciatus) and Rabbit fish (Siganus sp.). were examined for the presence of nematode Huffmanela species. The eggs of Huffmanela species were isolated and identified only from the C. lunulatus. The total prevalence of Huffmanela sp. infestation were 69.5%. The highest prevalence was observed in winter and the lowest in spring and summer. The prevalence was increased in correlation with fish body weight. Fully developed eggs of Huffmanela species were dark brown embryonated, elongated, with slightly protruding plugs. A high density of Huffmanela sp. eggs with different developmental stages packed the epithelial layer of the gas bladder. The surrounding tissue of gas bladder was hemorrhagic and sometimes necrotic associated with chronic inflammatory cell infiltration. This is the first record of Huffmanela species infestation in Broom tail wrasse C. lunulatus, Red Sea coral reef fishes.

A systematic review of noninferiority margins in oncology clinical trials.

Aim: A systematic literature review was conducted to identify and characterize noninferiority margins for relevant end points in oncology clinical trials. Materials & methods: Randomized, controlled, noninferiority trials of patients with cancer were identified in PubMed and Embase. Results: Of 2284 publications identified, 285 oncology noninferiority clinical trials were analyzed. The median noninferiority margin was a hazard ratio of 1.29 (mean: 1.32; range: 1.05-2.05) for studies that reported time-to-event end points (n = 192). The median noninferiority margin was 13.0% (mean: 12.7%; range: 5.0-20.0%) for studies that reported response end points as absolute rate differences (n = 31). Conclusion: Although there was consistency in the noninferiority margins' scale, variability was evident in noninferiority margins across trials. Increased transparency may improve consistency in noninferiority margin application in oncology clinical trials.

Comparative efficacy and safety of bortezomib, thalidomide, and dexamethasone (VTd) without and with daratumumab (D-VTd) in CASSIOPEIA versus VTd in PETHEMA/GEM in transplant-eligible patients with newly diagnosed multiple myeloma, using propensity score matching.

Background: Traditional bortezomib, thalidomide, and dexamethasone (VTd) regimens for patients with newly diagnosed multiple myeloma (NDMM) include doses of thalidomide up to 200 mg/day (VTd-label). Clinical practice has evolved to use a lower dose (100 mg/day) to reduce toxicity (VTd-mod), which was evaluated in the phase III CASSIOPEIA study, without or with daratumumab (D-VTd; an anti-CD38 monoclonal antibody). We used propensity score matching to compare efficacy and safety for VTd-mod and D-VTd with VTd-label. Methods: Patient-level data for VTd-mod and D-VTd from CASSIOPEIA (NCT02541383) and data for VTd-label from the PETHEMA/GEM study (NCT00461747) were analyzed. Propensity scores were estimated using logistic regression, and nearest-neighbor matching procedure was used. Outcomes included overall survival (OS), progression-free survival (PFS), time to progression (TTP), postinduction and posttransplant responses, as well as rate of treatment discontinuation and grade 3/4 peripheral neuropathy. Results: VTd-mod was noninferior to VTd-label for OS, PFS, TTP, postinduction very good partial response or better (≥VGPR) and overall response rate (ORR). VTd-mod was significantly better for posttransplant ≥VGPR and ORR versus VTd-label. VTd-mod safety was not superior to VTd-label despite the lower thalidomide dose. D-VTd was significantly better than VTd-label for OS, PFS, TTP, postinduction and posttransplant ≥VGPR and ORR, and was noninferior to VTd-label for safety outcomes. Conclusions: In transplant-eligible patients with NDMM, D-VTd had superior efficacy compared with VTd-label. Despite a lower dose of thalidomide, VTd-mod was noninferior to VTd-label for safety and was significantly better for posttransplant ≥VGPR/ORR. These data further support the first-line use of daratumumab plus VTd.

Front-line daratumumab-VTd versus standard-of-care in ASCT-eligible multiple myeloma: matching-adjusted indirect comparison.

Aim: To compare daratumumab plus standard-of-care (SoC; bortezomib/thalidomide/dexamethasone [VTd]) and VTd alone with other SoC for transplant-eligible newly diagnosed multiple myeloma. Patients & methods: We conducted an unanchored matching-adjusted indirect comparison of progression-free and overall survival (PFS/OS) with D-VTd/VTd versus bortezomib/lenalidomide/dexamethasone (VRd), bortezomib/cyclophosphamide/dexamethasone (VCd) and bortezomib/dexamethasone (Vd). Results: After matching adjustment, significant improvements in PFS were estimated for D-VTd versus VRd (hazard ratio [HR]: 0.47 [95% CI: 0.33-0.69]), VCd (HR: 0.35 [95% CI: 0.21-0.58]) and Vd (HR: 0.42 [95% CI: 0.28-0.63]). OS was significantly longer with D-VTd versus VRd (HR: 0.31 [95% CI: 0.16-0.57]), VCd (HR: 0.35 [95% CI: 0.14-0.86]) and Vd (HR: 0.38 [95% CI: 0.18-0.77]). No significant PFS/OS differences were seen for VTd versus other SoC. Conclusion: This analysis supports front-line daratumumab for transplant-eligible newly diagnosed multiple myeloma.