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A 75-year-old Caucasian woman presented with sudden-onset multifocal scotomas in her right eye's central vision for 1 day. There were subtle white intraretinal foveal lesions that correlated with patchy inner retinal hyperreflectivity on optical coherence tomography, suggestive of paracentral acute middle maculopathy. Initial cerebrovascular work-up was negative. Review of systems was positive for lethargy and jaw claudication. The sedimentation rate and c-reactive protein were elevated, but platelet count was normal. The patient was started on 60 mg oral prednisone daily and underwent bilateral temporal artery that confirmed the diagnosis of giant cell arteritis.

Contemporary chronic total occlusion (CTO) percutaneous coronary intervention (PCI) incorporates wire escalation and dissection/re-entry recanalisation strategies.The purpose of the study was to investigate changes in collateral function after CTO PCI and to identify whether the mode of successful recanalisation influences collateral function regression.Patients scheduled for elective CTO PCI with evidence of viability in the CTO territory by noninvasive imaging were included in this study. After successful CTO PCI, the aortic pressure (Pa) and distal coronary artery wedge pressure (Pw) during balloon occlusion were measured, both in a resting state and during infusion of intravenous adenosine, allowing the calculation of the pressure-derived collateral pressure index at rest and hyperaemia (CPIEighty-one patients had physiological measurements at baseline and follow-up. In the final cohort the mean age was 64 years and 82% were male. The mean maximal stent diameter and total stent length were 3.2±0.5 mm and 68±31 mm, respectively. Successful strategies were antegrade wiring (64.2%), antegrade dissection re-entry (8.6%), and retrograde dissection re-entry (27.1%). Between the index procedure and follow-up, wedge pressure decreased from 34±11 mmHg to 21±8.5 mmHg (p0.01), respectively. FFRThere was a significant reduction in collateral flow over time, independent of the recanalisation technique.

In sub-Saharan Africa, sexually active adolescent girls and young women (AGYW) experience high rates of intimate partner violence (IPV) and low levels of contraceptive use, but the effect of IPV on contraceptive use is not well understood.In the Girl Power-Malawi study, AGYW aged 15-24 were recruited from 4 health centers in Lilongwe, Malawi, and followed for 1 year. At baseline, AGYW were assessed for IPV using the modified Conflict Tactics Scale. AGYW reported contraceptive method use at 6 and 12 months, characterized as barrier, non-barrier, or any modern method. Modified Poisson regression was implemented to estimate risk ratios (RRs) and 95% confidence intervals (CIs) to examine the effect of IPV on contraceptive use.One thousand AGYW were enrolled, and 954 non-pregnant participants were included. Baseline prevalence of IPV with the most recent partner was 35.5% (physical), 46.2% (sexual), and 76.9% (emotional). Baseline IPV did not affect contraceptive use at 6 months (aRR [95% CI]: physical 0.98 [0.91-1.05]; sexual 1.00 [0.94-1.07]; emotional 1.03 [0.94-1.12]) or 12 months (physical 0.95 [0.89-1.02]; sexual 0.96 [0.90-1.02]; emotional 0.98 [0.91-1.05]). None of the 3 IPV categories affected contraceptive use when the outcome was restricted to either barrier or non-barrier methods.In this cohort, IPV was not a key driver of contraceptive use in longitudinal analyses. Interventions are needed to address the alarming rates of IPV in this population, but addressing IPV alone might be insufficient to address low contraceptive use, and multifaceted youth-friendly health services might be necessary.

Objective-\ud \ud The impact of adjunctive manual thrombus aspiration (TA) in patients with stent thrombosis (ST) treated with percutaneous intervention has not been evaluated in the current era of potent P2Y12 agents and new-generation drug-eluting stents. We sought to assess the effect of TA using data from a large contemporary registry.\ud \ud Methods-\ud \ud The study population was derived from the Essex ST Investigation Registry (ESTHIR), which contains all consecutive cases of angiographically determined definite ST undergoing interventional treatment in a tertiary cardiac centre between November 2015 and June 2018. Propensity score matching was performed to match patients who underwent TA (TA group) to those who did not (n-TA group). The study endpoints were final TIMI flow and survival free of cardiovascular death (CD) or target lesion revascularisation (TLR).\ud \ud Results-\ud \ud A total of 128 ST patients were included in the present analysis. The mean age was 65 ± 11 years, and 84% were male. About 90% of the patients presented with STEMI, and 85% had very late ST. Seventy-two patients (56%) underwent TA. After propensity score matching, 30 patients were included in each study group. A higher rate of final TIMI III flow was observed in the TA group (TA vs n-TA group, 100% vs 83%), but this difference did not reach statistical significance (p = 0.052). At 1000 days of follow-up, survival free of CD or TLR was not different between the two groups (p = 0.8).\ud \ud Conclusion-\ud \ud In a propensity-matched population of ST patients undergoing PCI in a contemporary setting, TA was not associated with improved final TIMI flow or long-term cardiovascular outcomes.

Nootropics (smart drugs) are used by students to enhance cognitive performance which have been reported times in recent years. However, some of the nootropics are central nervous system stimulants which are very likely to lead to addiction or complications such as vomiting and dizziness. Are there nootropics that can improve learning behavior while having potential positive effect on health? Here, we reported that Atomoxetine (ATX) has sex-specific effect on prolonging the life span of female Drosophila melanogaster. Further study indicated that ATX enhanced female resistance to heat stress and their vertical climbing ability, but it did decrease the number of eggs laid. ATX increased food-intake and sleep time both of females and males, and significantly reduced the 24h spontaneous activity of females and males. Our results present the sex dimorphic effect of ATX on life span regulation in Drosophila, and support further research on the beneficial role of ATX and the mechanisms in other animal models.

Depot medroxyprogesterone acetate (DMPA) is a highly-effective, injectable contraceptive method that requires injections every 12 to 15 weeks. The need for return visits to a healthcare provider may present barriers to access, use, and continuation of DMPA. Studies demonstrate that self-administration of subcutaneous DMPA (DMPA-SC) outside clinical settings is safe, effective, feasible, acceptable, and can improve continuation. Based on existing evidence and potential to improve contraceptive access and autonomy, the Society of Family Planning recommends that DMPA-SC self-administration be made widely available as an additional option for patients. Provider-administered DMPA must also remain available to meet patients' individual needs and preferences.

Cancer cell plasticity due to the dynamic architecture of interactome networks provides a vexing outlet for therapy evasion. Here, through chemical biology approaches for systems level exploration of protein connectivity changes applied to pancreatic cancer cell lines, patient biospecimens, and cell- and patient-derived xenografts in mice, we demonstrate interactomes can be re-engineered for vulnerability. By manipulating epichaperomes pharmacologically, we control and anticipate how thousands of proteins interact in real-time within tumours. Further, we can essentially force tumours into interactome hyperconnectivity and maximal protein-protein interaction capacity, a state whereby no rebound pathways can be deployed and where alternative signalling is supressed. This approach therefore primes interactomes to enhance vulnerability and improve treatment efficacy, enabling therapeutics with traditionally poor performance to become highly efficacious. These findings provide proof-of-principle for a paradigm to overcome drug resistance through pharmacologic manipulation of proteome-wide protein-protein interaction networks., Joshi, Gomes et al. employ a chemical modulation approach of the cellular interactome to a hyperconnectivity state and show association with the increased response of pancreatic cancer cell lines to specific drugs, including those that target the MAPK-pathways and PI3K-mTOR pathway. To achieve this, the authors employ chemical modulation of the interactome via epichaperome inhibition with the small molecule PU-H71.

Background Community health workers (CHWs) are essential field-based personnel and increasingly used to deliver priority interventions to achieve universal health coverage. Existing literature allude to the potential for detrimental effects of multi-tasking CHWs. This study objective was to assess the impact of integrating cervical cancer screening and prevention therapy (CCSPT) with family planning (FP) on time utilization among CHWs. Methods A time and motion study was conducted in 7 health facilities in Malawi. Data was collected at baseline between October-July 2019, and 12 months after CCSPT implementation between July and August 2021. CHWs trained to deliver CCSPT were continuously observed in real time while their activities were timed by independent observers. We used paired sample t-test to assess pre-post differences in average hours CHWs spent on the following key activities, before and after CCSPT implementation: clinical and preventive care; administration; FP; and non-work-related tasks. Regression models were used to ascertain impact of CCSPT on average durations CHWs spent on key activities. Results Thirty-seven (n = 37) CHWs were observed. Their mean age and years of experience were 42 and 17, respectively. Overall, CHWs were observed for 323 hours (inter quartile range: 2.8–5.5). Compared with the period before CCSPT, the proportion of hours CHWs spent on clinical and preventive care, administration and non-work-related activities were reduced by 13.7, 8.7 and 34.6%, respectively. CHWs spent 75% more time on FP services after CCSPT integration relative to the period before CCSPT. The provision of CCSPT resulted in less time that CHWs devoted towards clinical and preventive care but this reduction was not significant. Following CCPST, CHWs spent significantly few hours on non-work-related activities. Conclusion Introduction of CCSPT was not very detrimental to pre-existing community services. CHWs managed their time ensuring additional efforts required for CCSPT were not at the expense of essential activities. The programming and policy implications are that multi-tasking CHWs with CCSPT will not have substantial opportunity costs.

BACKGROUND: Limited information exists about relationship dynamics and their role in HIV acquisition, HIV disclosure, hormonal contraceptive uptake, and condom use among women in Malawi. METHODS: Ninety-seven women aged 18–45 years were randomly assigned to initiate the depot medroxyprogesterone acetate injectable or levonorgestrel implant from May 2014 to April 2015 in Lilongwe, Malawi. Women were recruited after randomisation to participate in semi-structured interviews about HIV and family planning using purposive sampling. Interviews were thematically analysed using within and between group comparisons. RESULTS: We conducted individual interviews and/or focus group discussions with 41 women: 30 (73%) women living with HIV and 11 (27%) women not living with HIV. Most women living with HIV who participated in in-depth interviews disclosed their status to their partners, and most partners agreed to get HIV tested only after disclosure. Nearly all women said their partners agreed to use condoms, but few used them consistently. Nearly all women believed their current and former partners had outside partners. Most women living with HIV who participated in in-depth interviews believed their current or other serious partners were the source of their infection. Some women thought their partner’s infidelity was due to their partner’s disinterest in sex with them during menstrual/breakthrough bleeding. Some women included their partners in contraceptive decision-making when the partner was supportive. DISCUSSION: Relationship dynamics affected decision-making for contraceptive and condom use, as well as serodisclosure for the women living with HIV in the study. All women reported challenges with consistent condom use with their male partners, although contraceptive use was generally more acceptable. Women included their partners in their decision-making concerning contraceptive use when they were supportive.

Primary hypothyroidism can lead to delayed growth and pseudoprecocious puberty in juvenile patients, which was known as Van Wyk-Grumbach's syndrome (VWGS). There have been very few clinical case reports of primary juvenile hypothyroidism presenting with concurrent huge bilateral cystic ovaries. Here, we report the case of a 14-year-old female patient suffering from primary hypothyroidism in combination with bilateral cystic ovaries. Remarkable improvement of symptoms was observed after one month of hormone replacement therapy and an unnecessary surgical treatment was avoided. A comprehensive literature review of VWGS is summarised here to illustrate the presentation, diagnosis, and treatment of VWGS in pediatric patients. The present study aims to improve the current clinical knowledge of VWGS.

Rheumatoid arthritis (RA) is a chronic inflammatory disease with fluctuating course of progression. Despite substantial improvement in treatments in recent years, treatment response is still not guaranteed. The aim of this study was to identify variation in Disease Activity Score 28 (DAS28) of RA patients in response to Tocilizumab, and to investigate both molecular and clinical factors influencing response. Clinical and biochemical data for 485 RA patients receiving Tocilizumab in combination with methotrexate were extracted from the LITHE phase III clinical study (NCT00106535), and post-hoc analysis conducted. Latent class mixed models were used to identify statistically distinct trajectories of DAS28 after the initiation of treatment. Biomarker measurements were then analysed cross-sectionally and temporally, to characterise patients by serological biomarkers and clinical factors. We identified three distinct trajectories of drug response: class 1 (n = 85, 17.5%), class 2 (n = 338, 69.7%) and class 3 (n = 62, 12.8%). All groups started with high DAS28 on average (DAS28 > 5.1). Class 1 showed the least reduction in DAS28, with significantly more patients seeking escape therapy (p p

Overlap in metabolism pathways of endogenous female sex hormones and antiretroviral drugs may lead to altered exposure to these compounds. In a family planning clinic in Lilongwe, Malawi, blood, blood cell, and cervicovaginal fluid (CVF) samples from seventy-three HIV positive Malawian women taken in follicular and luteal menstrual phases were assessed for estradiol and progesterone by chemiluminescent immunoassay, and for antiretroviral concentration by liquid chromatography-mass spectrometry. In both follicular and luteal phases, estradiol concentrations were lower in women receiving efavirenz compared with women on non-efavirenz regimens or no antiretroviral therapy (p

Aims: We sought to compare the efficiency of the novel EuroCTO (CASTLE) score with the commonly used Multicentre CTO registry in Japan (J-CTO) score in predicting procedural success of percutaneous recanalization (PCI) for coronary chronic total occlusions (CTOs). Methods and results: We evaluated 660 consecutive CTO PCIs (mean age: 66±11 years, 84% male). The mean J-CTO and EuroCTO (CASTLE) scores were 1.86 ± 1.2 and 1.74 ± 1.2, respectively. Antegrade wire escalation, antegrade dissection re-entry and retrograde approach were used in 82%, 14% and 37% of cases, respectively. Receiver-operator characteristic analysis demonstrated equal overall discriminatory capacity between the two scores (AUC: 0.698, 95%CI: 0.653-0.742 p

To explore the protective immune effect induced by mucosal delivery heparin-binding hemagglutinin (HBHA)-a candidate vaccine antigen of为探讨疫苗候选抗原—结核分枝杆菌肝素结合血凝素（HBHA）通过黏膜接种诱导的保护性免疫效应。动物实验均使用6~8周龄雌性C57BL/6小鼠。30只小鼠接受不同的免疫接种策略，采用随机数字表法分为对照组、早期分泌抗原靶蛋白-6（ESAT-6）滴鼻组、HBHA滴鼻组、BCG初免PBS对照组、BCG初免HBHA加强组，每组6只。通过检测免疫后小鼠血浆白细胞介素17A（IL-17A）等细胞因子水平；肺IL-17A mRNA相对表达量（RQ）；肺三级淋巴结构的形成，及与其形成相关的趋化因子的检测；脾Th1、Th17细胞比例比较，从而分析免疫效应。BCG初免PBS对照组和BCG初免HBHA加强组（每组各30只小鼠），用BCG滴鼻模拟感染。在感染后预设的时间点做肺组织菌落计数，以评估细菌清除效率。多组间比较采用单因素方差分析，事后分析采用

OBJECTIVE: To investigate the effects of melatonin on the growth and metastasis of MDA-MB-231 breast cancer cells and explore the mechanism. METHODS: MDA-MB-231 cells were treated with 1, 3 or 5 mmol/L melatonin, and the changes in cell proliferation were examined using CCK-8 assay. Colony-forming assay and wound healing assay were used to assess the effects of melatonin treatmnent on colony-forming ability and migration of the cells. Flow cytometry and immunofluoresnce assay were employed to examine apoptosis and positive staining for autophagy-related proteins in the cells treated with 3 mmol/L melatonin. The effects of melatonin treatment alone or in combination with 3-methyladenine (3-MA) on the expressions of the proteins associated with autophagy (LC3, P62 and Beclin1), apoptosis (Bcl2 and Bax) and epithelial-mesenchymal transition (E-cadherin and Snail) were examined with Western blotting. RESULTS: Melatonin treatment significantly inhibited the proliferation of breast cancer cells in a concentration- and time-dependent manner (P < 0.05), suppressed colony-forming ability and migration (P < 0.01), and promoted apoptosis of the cells (P < 0.01). Melatonin treatment alone significantly increased the expressions of Bax (P < 0.05), E-cadherin, LC3-II/LC3-I, and Beclin1 and lowered the expressions of Bcl2 (P < 0.05), Snail, P62 (P < 0.05), and Bcl2/Bax ratio (P < 0.01) in the cells, and caused enhanced positive staining of Beclin1 protein and attenuated staining of P62 protein. Compared with melatonin treatment alone, melatonin treatment combined with 3-MA significantly decreased the expressions of Beclin1 (P < 0.001), LC3-II/LC3-I (P < 0.05), Bax (P < 0.01), and E-cadherin (P < 0.001) and increased the expressions of Bcl2 (P < 0.05), Snail, and Bcl2/Bax ratio (P < 0.01). CONCLUSION: Melatonin can induce autophagy of MDA-MB-231 breast cancer cells to inhibit cell proliferation and metastasis and promote cell apoptosis, and suppressing autophagy can weaken the inhibitory effect of melatonin on the growth and metastasis of breast cancer cells.

Plenty of studies have examined the long term effect of weight loss on bone mineral density. This study aimed to explore the effects of 10% weight loss on early changes in bone metabolism as well as the possible influencing factors.Overweight and obese outpatients (BMI 24.0 kg/mA total of 75 participants were enrolled and 37 participants achieved a weight loss of at least 10%. It was found that PINP decreased (p = 0.000) and the β-Crosslaps increased (p = 0.035) in female participants. Decreases in PTH (p = 0.001), serum IL-2 (p = 0.013), leptin (p = 0.001) and increases in 25(OH) VitD (p = 0.001), serum ghrelin (p = 0.033) were found in 37 participants after 10% of their weight had been lost. Change in PINP was detected to be significantly associated with change in lean body mass (r = 0.418, p = 0.012) and change in serum ghrelin(r = - 0.374, p = 0.023).Bone formation was suppressed and bone absorption was increased in female subjects after a 10% weight loss. Bone turnover was found to be associated with lean body mass and affected by the circulating ghrelin level.

1. The Wnt signalling pathway is centred on the fact that catenin beta-1(

Roux-en-Y gastric bypass (RYGB) has been widely reported to be safe and feasible, and has a powerful effect on improving metabolism and weight loss in patients with a high body mass index (BMI). A few studies have focused on the comparison of RYGB with medical treatment in type 2 diabetes (T2D) patients with a lower BMI.To compare the metabolic effects and safety of RYGB versus medical treatment during a 2 years follow-up in T2D patients with a BMI of 25 to 32.5 kg/mThis retrospective and multicenter cohort study participants were extracted from the T2D patients with a lower BMI (25-32.5 kg/mIn total, 213 patients (mean age of 47.4 ± 9.5 years, 70.4% male, mean BMI of 28.6 ± 2.2 kg/mAmong T2D patients with a BMI between 25.0 and 32.5 kg/m

Globe perforation following retrobulbar or peribulbar anesthetic injection is a rare but dreaded complication that often results in suboptimal visual outcomes. This video describes a 72-year-old woman who sustained a globe perforation during retrobulbar block in the setting of cataract extraction and later developed a retinal detachment. The retina was repaired with pars plana vitrectomy and silicone oil, resulting in a favorable visual outcome. The authors discuss various modes of local anesthesia for vitreoretinal surgery, risks for globe perforations, and how to approach retinal detachment secondary to needle perforations, which are complex cases at high risk for proliferative vitreoretinopathy.

By the strictest of definitions, a genetic driver of tumorigenesis should fulfill two criteria: it should be altered in a high percentage of patient tumors, and it should also be able to cause the same type of tumor to form in mice. No gene that fits either of these criteria has ever been found for ileal neuroendocrine tumors (I-NETs), which in humans are known for an unusual lack of recurrently mutated genes, and which have never been detected in mice. In the following report, we show that I-NETs can be generated by transgenic RT2 mice, which is a classic model for a genetically unrelated disease, pancreatic neuroendocrine tumors (PNETs). The ability of RT2 mice to generate I-NETs depended upon genetic background. I-NETs appeared in a B6AF1 genetic background, but not in a B6 background nor even in an AB6F1 background. AB6F1 and B6AF1 have identical nuclear DNA but can potentially express different allelic forms of imprinted genes. This led us to test human I-NETs for loss of imprinting, and we discovered that the IGF2 gene showed loss of imprinting and increased expression in the I-NETs of 57% of patients. By increasing IGF2 activity genetically, I-NETs could be produced by RT2 mice in a B6 genetic background, which otherwise never developed I-NETs. The facts that IGF2 is altered in a high percentage of patients with I-NETs and that I-NETs can form in mice that have elevated IGF2 activity, define IGF2 as the first genetic driver of ileal neuroendocrine tumorigenesis.

BACKGROUND AND OBJECTIVE: To describe a case series of three patients in one family with Von Hippel-Lindau (VHL) disease who presented with vitreoretinal neovascularization and resulting tractional retinal detachments (TRDs). This vitreoretinal phenotype of VHL may benefit from early surgical intervention. PATIENTS AND METHODS: Descriptive case series of three patients in one family with VHL disease. A review of the literature regarding surgical intervention for VHL was performed. RESULTS: All three patients developed prominent intravitreal neovascularization with fibrovascular growth within the vitreous secondary to a retinal capillary hemangioma. Two subjects with intravitreal neovascularization were treated with laser and cryotherapy but eventually developed a TRD. The final vision in these two patients was light perception and 20/300. The eye that was preemptively treated with vitrectomy to remove the vitreous sustaining the neovascularization had visual acuity of 20/50 after surgery. CONCLUSION: Intravitreal neovascularization with fibrovascular proliferation may be an indication for vitrectomy prior to the development of retinal detachment. [ Ophthalmic Surg Lasers Imaging Retina . 2020;51:109–115.]

Introduction In the first-line (1L) setting, pazopanib (PAZ) has been recommended by the National Comprehensive Cancer Network for the treatment of advanced renal cell carcinoma (aRCC). In 2018, immuno-oncology (IO) therapy became a commonly used 1L treatment option for aRCC. We report the real-world clinical outcomes of PAZ after IO therapy for patients with aRCC. Materials and Methods We performed a longitudinal, retrospective medical record review study. The included patients were aged ≥ 18 years, had initiated second-line and/or beyond PAZ after IO therapy for clear cell aRCC on or before October 2017, and had complete medical records available from the diagnosis of aRCC to the discontinuation of PAZ, death, or the medical record extraction date (May 2018), whichever occurred first. The primary outcome variable was the PAZ duration of therapy. The secondary outcomes were progression-free survival and overall survival since PAZ initiation, the reasons for PAZ discontinuation, and the occurrence of adverse events (AEs). Results A total of 258 eligible patients had initiated IO therapies before PAZ as follows: nivolumab (68%), nivolumab plus ipilimumab (14%), pembrolizumab (12%), and ipilimumab (3%). Overall, the median PAZ duration of therapy was 13.4 months (95% confidence interval [CI], 10.1-16.0 months). The median progression-free survival with PAZ after IO therapy was 13.5 months (95% CI, 11.8 months to not reached). The estimated overall survival rate of PAZ after IO therapy at 6 and 12 months was 93% and 89%, respectively. A total of 109 patients (42%) had reported an AE. The most frequently reported AEs were fatigue (29%) and diarrhea (14%). No additional safety signal of hepatotoxicity was observed (increased aspartate aminotransferase, 5%; increased alanine transaminase, 6%). Conclusions In the present real-world study, second-line and/or beyond PAZ after previous IO therapy was well-tolerated and effective for patients with aRCC.

Objective To compare medroxyprogesterone acetate (MPA) concentrations between HIV-positive women on antiretroviral therapy (ART) and HIV-negative women initiating depot medroxyprogesterone (DMPA) injectable. Study design Secondary analysis of 28 HIV-positive women on non-nucleoside reverse transcriptase inhibitor-containing ART regimens and 10 HIV-negative women randomized to initiate DMPA in a clinical trial of progestin contraception in Malawi. Results MPA concentrations were significantly lower among HIV-positive women on ART, compared with HIV-negative women, at week 4 and week 13 (p=.03 for both), but not at day 3 or week 26 post-DMPA initiation. Conclusions Antiretroviral medications may affect MPA metabolism in HIV-positive African women.

Purpose: Immune checkpoint inhibitors (ICI) are effective in only a minority of patients with esophagogastric cancer (EGC). Here, we aimed to identify predictors of durable clinical benefit to ICI in EGC. Experimental Design: Patients with advanced EGC treated with ICIs at Memorial Sloan Kettering Cancer Center (New York, NY) were identified. Clinicopathologic variables were assessed. In patients profiled by MSK-IMPACT–targeted sequencing, outcomes were correlated with tumor genomic features. Results: One-hundred sixty-one patients were treated with ICIs (110 with anti–PD-1/PD-L1 antibodies and 51 with anti–CTLA-4 and PD-1/PD-L1 antibodies). The median progression-free survival (PFS) and overall survival (OS) were 1.7 and 4.9 months, respectively. Greater number of disease sites (≥3), liver metastases, treatment with ≥3 prior therapies and ECOG performance status ≥2 were associated with poorer PFS and OS. Patients treated with combination ICI and those with PD-L1–positive tumors had improved outcomes. There was no difference in outcomes between patients treated with antibiotics during or in the 2 months preceding ICI treatment versus those who were not. Occurrence of irAEs was associated with improved OS. In genomically profiled tumors (n = 89), survival was associated with increasing tumor mutation burden (TMB). However, in multivariable analyses and when microsatellite unstable (MSI) patients were excluded, a significant association was no longer observed. Conclusions: In patients with advanced EGC, heavily pretreated patients, those with high-volume disease and/or poor PS were less likely to benefit from ICI. irAEs were associated with improved OS. TMB correlated with improved survival, but this association was not observed when MSI-high patients were excluded.

Objective: \ud To develop a nomogram estimating the probability of recurrence free at 5 years after resection for localized grade 1 (G1)/ grade 2 (G2) pancreatic neuroendocrine tumors (PanNETs).\ud \ud Background: \ud Among patients undergoing resection of PanNETs, approximately 17% experience recurrence. It is not established which patients are at risk, with no consensus on optimal follow-up.\ud \ud Method: \ud A multi-institutional database of patients with G1/G2 PanNETs treated at 2 institutions was used to develop a nomogram estimating the rate of freedom from recurrence at 5 years after curative resection. A second cohort of patients from 3 additional institutions was used to validate the nomogram. Prognostic factors were assessed by univariate analysis using Cox regression model. The nomogram was internally validated using bootstrap resampling method and on the external cohort. Performance was assessed by concordance index (c-index) and a calibration curve.\ud \ud Results: \ud The nomogram was constructed using a cohort of 632 patients. Overall, 68% of PanNETs were G1, the median follow-up was 51 months, and we observed 74 recurrences. Variables included in the nomogram were the number of positive nodes, tumor diameter, Ki-67, and vascular/perineural invasion. The model bias-corrected c-index from the internal validation was 0.85, which was higher than European Neuroendocrine Tumors Society/American Joint Committee on Cancer 8th staging scheme (c-index 0.76, P =

Discarding unused drugs after dose changes or discontinuation can significantly affect pharmacy budgets. This is especially concerning for expensive oncology agents. However, few economic studies account for drug wastage, providing an inaccurate estimate of a drug's actual economic cost, cost-effectiveness, and value.To (a) compare the economic impact of drug wastage between ribociclib and palbociclib-clinically similar oral medications for metastatic breast cancer-using 3 approaches (Markov model, pharmacy acquisition cost model, and a retrospective claims analysis) and (b) compare the modeling results with a published estimate of drug wastage for palbociclib from a claims analysis.A Markov model and a pharmacy acquisitions cost model were developed to evaluate the economic impact of dose reductions for ribociclib and palbociclib over a 1-year time period. Data inputs were pharmacy costs (RED BOOK wholesale acquisition cost) and proportion of patients experiencing dose reductions from either ribociclib randomized clinical trials (MONALEESA-2, -3, or -7) or real-world observational data (Symphony Health retrospective claims analysis). The latter constituted the third approach for quantifying drug wastage. The economic impact of dose reductions for ribociclib and palbociclib in postmenopausal women with previously untreated HR-positive/HER2-negative advanced breast cancer was assessed. Drug wastage was defined as drug doses that could not be used by a patient following a dose reduction. The cost of drug wastage was defined as the cost associated with an unused drug resulting from a dose reduction. The predicted results from the 2 models were compared with a previously published claims analysis that estimated the effect of treatment costs and drug wastage for palbociclib based on the observed dosing patterns from the Symphony Health Solutions database.In the Markov model, relative to ribociclib, palbociclib users experienced drug wastage of $112,382 total, or $1,124 per treated patient, per year due to dose changes. In the pharmacy acquisition cost model, relative to ribociclib, palbociclib usage was associated with an increased cost of $7,196 per patient per year (based on a mid-cycle dose reduction) comprising dosing-based cost differences and drug wastage cost for palbociclib of $3,727. The previously published claims analysis found that palbociclib users experiencing a dose reduction had drug wastage costs of $5,471 per patient.In both models, dose reductions for ribociclib patients resulted in no wastage, since unused tablets could be administered in subsequent cycles, while dose reductions for palbociclib resulted in drug wastage and increased costs. The results from both models were consistent with previously published results from the claims analysis, demonstrating drug wastage costs for palbociclib.This study received financial support from Novartis Pharmaceuticals, which has products approved for treatment of breast cancer. Tang was employed by Novartis during this study; Zacker and Dalal are employed by Novartis and own company stock. Biskupiak, Brixner, and Oderda received payment from Novartis for this study. Brixner serves as a consultant for Millcreek Outcomes Group and also declares consulting fees from Abbvie, AstraZeneca, Abbott, Becton Dickinson, and Xcenda, unrelated to this study.

Purpose: VEGFR2-directed therapy is commonly used to treat metastatic esophagogastric cancer, but disease progresses in most patients within months. Therapeutic resistance is likely mediated in part by co-occurring amplifications of the genes for multiple oncogenic receptor tyrosine kinases (RTK). We therefore tested the efficacy of combined inhibition of VEGFR1-3, PDGFα/β, and FGFR1-3 using nintedanib. Patients and Methods: Patients with metastatic esophagogastric adenocarcinoma and disease progression on first-line chemotherapy were treated with nintedanib 200 mg twice daily. The primary endpoint was progression-free survival (PFS) at 6 months; secondary endpoints included tumor response and safety. Tumor biopsies were profiled by targeted capture next-generation sequencing (NGS) to identify molecular predictors of drug response. Results: The study achieved its primary endpoint; 6 of 32 patients (19%) were progression-free at 6 months. With a median follow-up of 14.5 months among survivors, median overall survival (OS) was 14.2 months [95% confidence interval (CI), 10.8 months–NR]. Nintedanib was well tolerated; grade ≥ 3 toxicities were uncommon and included grade 3 hypertension (15%) and liver enzyme elevation (4%). FGFR2 alterations were identified in 18% of patients but were not predictive of clinical outcome on nintedanib therapy. Alterations in cell-cycle pathway genes were associated with worse median PFS (1.61 months for patients with cell-cycle pathway alterations vs. 2.66 months for patients without, P = 0.019). Conclusions: Nintedanib treatment resulted in modest disease stabilization in patients with metastatic esophagogastric cancer. Alterations in cell-cycle pathway genes and increased global copy-number alteration (CNA) burden warrant further study as prognostic or predictive biomarkers.

As immune checkpoint inhibitors are rapidly developing into the standard of care for patients with advanced melanoma, the value of diagnostic metrics to predict response to immunotherapy is steadily increasing. Next-generation sequencing based parameters include tumor mutation burden (TMB) as well as genomic amplification of PD-L1/PD-L2/JAK2 at 9p24.1. At present, there are limited studies documenting response to checkpoint blockade in 9p24.1 amplified solid tumors. Herein, we have compared a cutaneous melanoma with a mucosal melanoma, both with 9p24.1 amplifications and durable response to immunotherapy. While the cutaneous melanoma had a high TMB, the mucosal melanoma had a lower TMB compared to the mean TMB for all melanomas within the institutional clinical sequencing cohort. In summary, PD-L1/PD-L2/JAK2 amplification was associated with durable response to therapy for both cases and this genomic signature is a potential valuable metric in predicting response to immunotherapy.

BACKGROUND: Immune checkpoint inhibition is effective in a subset of patients with advanced gastric cancer. Genomic profiling has revealed the heterogeneity of gastric adenocarcinomas, but the immune microenvironment and predictors of immunotherapy response remain poorly understood. We aimed to better characterize the underlying immune response to gastric cancer. METHODS: Retrospective review of a prospectively maintained institutional database was performed to identify patients who underwent curative intent resection of gastric adenocarcinoma from 2006–2016. Tumors were classified according to modified TCGA subtype: Epstein-Barr virus-associated (EBV), microsatellite instability-high (MSI), intestinal as a surrogate for chromosomal instability (CIN), diffuse as a surrogate for genomically stable (GS). Tumor infiltrating leukocytes (TIL) were measured using immunohistochemistry. RESULTS: Forty-three patients were identified: 6 EBV, 11 MSI, 14 intestinal, 12 diffuse. The most prevalent TIL were CD8(+) T lymphocytes and CD68(+) macrophages, comprising 15% and 13% of all tumor cells. EBV and MSI tumors were the most infiltrated, harboring 30–50% T cells and 20% macrophages. Intestinal tumors contained fewer T cells but disproportionately more macrophages. Diffuse tumors were the least infiltrated. Programmed cell death protein 1 (PD1) was most frequently expressed in intestinal tumors, whereas 70% of EBV and MSI tumors expressed programmed death-ligand 1 (PDL1). CONCLUSION: We herein demonstrate a heterogeneous immune response to gastric cancer, which varies by tumor subtype and has implications for future immunotherapy trials. Checkpoint inhibition is unlikely to be effective as single-agent therapy against intestinal and diffuse tumors lacking prominent T cell infiltration or substantial PDL1 expression.

Background The purpose of this study is to evaluate the content validity of the National Comprehensive Cancer Network – Functional Assessment of Cancer Therapy – Breast Cancer Symptom Index (NFBSI-16) and the Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function Short Form 10b among patients with hormone receptor positive (HR+)/human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer. Methods Cognitive debriefing interviews sought to evaluate patients’ ability to read, understand, and meaningfully respond to the questionnaires, as well as to evaluate the questionnaires’ relevance in the target patient population. Interviews were conducted by telephone and lasted approximately 90 min. Audio recordings were transcribed, anonymized, and analyzed using qualitative data analysis software. Results Fifteen cognitive debriefing interviews were conducted with women (mean age 66.0 years [standard deviation = 12.4]). Patients reported metastases in the bone (86.7%), liver (20.0%), lung (13.3%), skin (6.7%), and lymph node (6.7%) (not mutually exclusive). All patients for whom data were available demonstrated understanding of the instructions and the recall period of the NFBSI-16 (n = 14/14, 100.0%) and the PROMIS (n = 14/14, 100.0%). Greater than 90% of patients demonstrated understanding of each of the items in the NFBSI-16 and the PROMIS. Greater than 70% of patients demonstrated understanding of the response options of the NFBSI-16, > 90% understood response options of PROMIS Items 1–6, and ≥ 50% understood response options of PROMIS Items 7–10. Conceptual relevance was supported for most items in both questionnaires based on patients’ reports of experiencing the concepts as part of their breast cancer experience. Conclusions The results of the cognitive debriefing interviews provide evidence that the NFBSI-16 and PROMIS Physical Function Short Form 10b have content validity in the HR+/HER2- advanced breast cancer patient population. Patients may benefit from additional instructions at the point the response options reverse direction in the PROMIS.

IntroductionCervical cancer is the leading cause of cancer deaths among women in Malawi, but preventable through screening. Malawi primarily uses visual inspection with acetic acid (VIA) for screening, however, a follow-up for positive screening results remains a major barrier, in rural areas. We interviewed women who underwent a community-based screen-and-treat campaign that offered same-day treatment with thermocoagulation, a heat-based ablative procedure for VIA-positive lesions, to understand the barriers in accessing post-treatment follow-up and the role of male partners in contributing to, or overcoming these barriers.MethodsWe conducted in-depths interviews with 17 women recruited in a pilot study that evaluated the safety and acceptability of community-based screen-and-treat programme using VIA and thermocoagulation for cervical cancer prevention in rural Lilongwe, Malawi. Ten of the women interviewed presented for post-treatment follow-up at the healthcare facility and seven did not. The interviews were analysed for thematic content surrounding barriers for attending for follow-up and role of male partners in screening.ResultsTransportation was identified as a major barrier to post-thermocoagulation follow-up appointment, given long distances to the healthcare facility. Male partners were perceived as both a barrier for some, that is, not supportive of 6-week post-thermocoagulation abstinence recommendation, and as an important source of support for others, that is, encouraging follow-up attendance, providing emotional support to maintaining post-treatment abstinence and as a resource in overcoming transportation barriers. Regardless, the majority of women desired more male partner involvement in cervical cancer screening.ConclusionDespite access to same-day treatment, long travel distances to health facilities for post-treatment follow-up visits remained a major barrier for women in rural Lilongwe. Male partners were identified both as a barrier to, and an important source of support for accessing and completing the screen-and-treat programme. To successfully eliminate cervical cancer in Malawi, it is imperative to understand the day-to-day barriers women face in accessing preventative care.

Purpose The ability of the T‐cell–inflamed gene expression profile (GEP) to predict clinical outcome in esophageal cancer (EC) is unknown. This retrospective observational study assessed the prognostic value of GEP and programmed death ligand 1 (PD‐L1) expression in patients with EC treated in routine clinical practice. Methods Tumor samples of 294 patients from three centers in Denmark, South Korea, and the United States, collected between 2005 and 2017, were included. T‐cell–inflamed GEP score was defined as non‐low or low using a cutoff of −1.54. A combined positive score (CPS) ≥10 was defined as PD‐L1 expression positivity. Associations between overall survival (OS) and GEP status and PD‐L1 expression were explored by Cox proportional hazards models adjusting for age, sex, histology, stage, and performance status. Results Median age was 65 years; 63% of patients had adenocarcinoma (AC) and 37% had squamous cell carcinoma (SCC). Thirty‐six percent of tumors were GEP non‐low, with higher prevalence in AC (46%) than SCC (18%). Twenty‐one percent were PD‐L1–positive: 32% in South Korean samples versus 16% in non‐Asian samples and 26% in SCC versus 18% in AC. GEP scores and PD‐L1 CPS were weakly correlated (Spearman’s R = 0.363). OS was not significantly associated with GEP status (non‐low vs low; adjusted hazard ratio, 0.91 [95% CI, 0.69–1.19]) or PD‐L1 expression status. Conclusion Neither GEP nor PD‐L1 expression was a prognostic marker in Asian and non‐Asian patients with EC., In a cohort of 294 patients with esophageal adenocarcinoma and esophageal squamous cell carcinoma from Denmark, South Korea, and the United States, T‐cell–inflamed gene expression profile (GEP) score (non‐low vs low) and PD‐L1 expression status (CPS ≥10 vs CPS

Purpose: To determine whether unilateral multifocal uveal melanomas (UM) in the setting of ocular melanosis (melanosis oculi) represent genetically independent tumors. Design: Clinical case series. Methods: Two patients with unilateral multifocal UM in the setting of melanosis oculi were included. Tumors were evaluated for gene expression profile (GEP) and next generation sequencing (NGS) for uveal melanoma-associated mutations. Histopathologic analysis of enucleated specimens was also performed when available. Results: Patients were both female, ages 73 and 83 years. In Patient #1, the tumors both exhibited Class 2 GEP but each harbored a unique BAP1 mutation. In Patient #2, one tumor was Class 1 and harbored an SF3B1 mutation, whereas the other tumor was Class 2 and harbored a BAP1 mutation. Conclusions: Unilateral multifocal UM in the setting of melanosis oculi can arise due to the development of genetically independent primary tumors, which is detectable based on the mutation profile of each tumor. This is the first report of genetically-confirmed independent primary tumors in the setting of unilateral multifocal UM.

Background Umbilical hernias are a frequent and well-known pathology in children or adults. Congenital umbilical hernias are commonly diagnosed in childhood, and in adulthood such a hernia is usually acquired. Umbilical hernia in pregnancy may result in serious obstetric complications including antepartum hemorrhage, intrauterine fetal demise, and preterm labor, particularly if incarcerated. Case presentation We present a rare case of a congenital umbilical hernia in a term pregnancy. The patient was a 34-year-old African (Malawian) woman, living with human immunodeficiency virus (HIV) and on antiretroviral treatment, gravida 4, with three previous vaginal deliveries, and with two babies weighing 4 kg at birth. We performed herniorrhaphy at caesarean section, and at 3 months of follow-up she had no evidence of a recurrent hernia. Conclusion Congenital umbilical hernias are commonly diagnosed in childhood but might first be seen by medical practitioners in adulthood. A patient-centered approach addressing patient complaints, associated risk factors, and possible complications is recommended. Primary repair at caesarean section is a feasible option.

Background Malawi has the world’s highest cervical cancer incidence and mortality due to high rate of HIV coupled with inadequate screening and treatment services. The country’s cervical cancer control program uses visual inspection with acetic acid (VIA) and cryotherapy, but screening is largely limited by poor access to facilities, high cost of cryotherapy gas, and high loss-to-follow-up. To overcome these limitations, we implemented a community-based screen-and-treat pilot program with VIA and thermocoagulation. Through a qualitative study, we explore the experiences of women who underwent this community-based pilot screening program. Methods We implemented our pilot program in rural Malawi and conducted an exploratory qualitative sub-study. We conducted in-depth interviews with women who were treated with thermocoagulation during the program. We used semi-structured interviews to explore screen-and-treat experience, acceptability of the program and attitudes towards self-sampling for HPV testing as an alternative screening method. Content analysis was conducted using NVIVO v12. Results Between July – August 2017, 408 participants eligible for screening underwent VIA screening. Thirty participants had VIA positive results, of whom 28 underwent same day thermocoagulation. We interviewed 17 of the 28 women who received thermocoagulation. Thematic saturation was reached at 17 interviews. All participants reported an overall positive experience with the community-based screen-and-treat program. Common themes were appreciation for bringing screening directly to their villages, surprise at the lack of discomfort, and the benefits of access to same day treatment immediately following abnormal screening. Negative experiences were rare and included discomfort during speculum exam, long duration of screening and challenges with complying with postprocedural abstinence. Most participants felt that utilizing self-collected HPV testing could be acceptable for screening in their community. Conclusions Our exploratory qualitative sub-study demonstrated that the community-based screen-and-treat with VIA and thermocoagulation was widely accepted. Participants valued the accessible, timely, and painless thermocoagulation treatment and reported minimal side effects. Future considerations for reaching rural women can include community-based follow-up, cervical cancer education for male partners and self-sampling for HPV testing.

Malawi has the highest invasive cervical cancer (ICC) mortality rate worldwide, and ICC is the leading cause of cancer death among women. In 2004, Malawi adopted visual inspection with acetic acid (VIA) and ablative treatment with cryotherapy. However, screening coverage has remained low (

Introduction Long-term care engagement of women on antiretroviral therapy (ART) is essential to effective HIV public health measures. We sought to explore factors associated with a history of HIV treatment interruption among pregnant women living with HIV presenting to an antenatal clinic in Lilongwe, Malawi. Methods We performed a cross-sectional study of pregnant women living with HIV who had a history of ART interruption presenting for antenatal care. Women were categorized as either retained in HIV treatment or reinitiating care after loss-to-follow up (LTFU). To understand factors associated with treatment interruption, we surveyed socio-demographic and partner relationship characteristics. Crude and adjusted prevalence ratios (aPR) for factors associated with ART interruption were estimated using modified Poisson regression with robust variance. We additionally present patients’ reasons for ART interruption. Results We enrolled 541 pregnant women living with HIV (391 retained and 150 reinitiating). The median age was 30 years (interquartile range (IQR): 25–34). Factors associated with a history of LTFU were age Conclusions Interventions that simplify the ART clinic transfer process, facilitate partner disclosure, and provide counseling about the importance of lifelong ART beyond pregnancy and breastfeeding should be further evaluated for improving retention in ART treatment of women living with HIV in Malawi.

Trials typically group cancers of the gastro-oesophageal junction (GOJ) with oesophageal or gastric cancer when studying neoadjuvant chemoradiation and perioperative chemotherapy, so the results may not be fully applicable to GOJ cancer. Because optimal neoadjuvant treatment for GOJ cancer remains controversial, outcomes with neoadjuvant chemoradiation versus chemotherapy for locally advanced GOJ adenocarcinoma were compared retrospectively.Data were collected from all patients who underwent neoadjuvant treatment followed by surgery for adenocarcinoma located at the GOJ at a single high-volume institution between 2002 and 2017. Postoperative major complications and mortality were compared between groups using Fisher's exact test. Overall survival (OS) and disease-free survival (DFS) were assessed by log rank test and multivariable Cox regression analyses. Cumulative incidence functions were used to estimate recurrence, and groups were compared using Gray's test.Of 775 patients, 650 had neoadjuvant chemoradiation and 125 had chemotherapy. These groups were comparable in terms of clinical tumour and lymph node categories, although the chemoradiation group had greater proportions of white men, complete pathological response to chemotherapy, and smaller proportions of diffuse cancer, poor differentiation, and neurovascular invasion. Postoperative major complications (20.0 versus 17.6 per cent) and 30-day mortality (1.7 versus 1.6 per cent) were not significantly different between the chemoradiation and chemotherapy groups. After adjustment, type of therapy (chemoradiation versus chemotherapy) was not significantly associated with OS (hazard ratio (HR) 1.26, 95 per cent c.i. 0.96 to 1.67) or DFS (HR 1.27, 0.98 to 1.64). Type of recurrence (local, regional, or distant) did not differ after neoadjuvant chemoradiation versus chemotherapy.In patients undergoing surgical resection for locally advanced adenocarcinoma of the GOJ, OS and DFS did not differ significantly between patients who had neoadjuvant chemoradiation compared with chemotherapy.Treating advanced cancer of the gastro-oesophageal junction (GOJ) poses a challenge given its location in the distal oesophagus and proximal stomach, and whether it should be treated as oesophageal or gastric cancer. Given the indistinct location, it is unclear whether GOJ cancer should be treated with neoadjuvant chemoradiation, which is the treatment of choice for advanced oesophageal cancers, or perioperative chemotherapy, which is the treatment of choice for advanced gastric cancers. Few studies have addressed treatment options specifically for GOJ cancers. This study investigated whether there was a difference in survival between patients with GOJ cancer who were treated with chemoradiation versus chemotherapy.

OBJECTIVES Pancreatic neuroendocrine neoplasms include well-differentiated tumors (PanNETs) and poorly differentiated carcinomas (PanNECs). Previous reports suggested a role for platinum-based therapy largely in PanNEC. We sought to investigate the role of platinum-based therapy in pancreatic neuroendocrine neoplasms regardless of tumor grade and differentiation. METHODS Patients with pancreatic neuroendocrine neoplasms treated with platinum-based therapy at Memorial Sloan Kettering (1994-2016) and Verona University Hospital (2008-2016) were retrospectively identified. Response to treatment by RECIST v1.1, overall survival, and progression-free survival were defined. Among patients with available tissue, DAXX, ATRX, Rb, and p53 expression was evaluated to support the histologic grade of differentiation. RESULTS Fifty PanNETs, 29 PanNECs, and 22 high-grade tumors with undeterminable differentiation were included. No patients achieved complete response. Overall rate of partial response was 31%, 41% for PanNEC, and 20% for PanNETs. Among PanNETs, partial response was achieved in 33% of G1 (2/6), 10% of G2 (2/19), and 24% of G3 (6/25) tumors. Median overall survival was 29.3 months for PanNETs and 10.9 months for PanNEC (P < 0.001). There was no significant difference in median progression-free survival (P = 0.2). CONCLUSIONS Platinum-based therapies demonstrated increased activity in PanNEC; however, promising efficacy was also observed in PanNETs, irrespective of grade.

Background In stable coronary artery disease, medications are used for 2 purposes: cardiovascular risk reduction and symptom improvement. In clinical trials and clinical practice, medication use is often not optimal. The ORBITA (Objective Randomised Blinded Investigation With Optimal Medical Therapy of Angioplasty in Stable Angina) trial was the first placebo‐controlled trial of percutaneous coronary intervention. A key component of the ORBITA trial design was the inclusion of a medical optimization phase, aimed at ensuring that all patients were treated with guideline‐directed truly optimal medical therapy. In this study, we report the medical therapy that was achieved. Methods and Results After enrollment into the ORBITA trial, all 200 patients entered a 6‐week period of intensive medical therapy optimization, with initiation and uptitration of risk reduction and antianginal therapy. At the prerandomization stage, the median number of antianginals established was 3 (interquartile range, 2–4). A total of 195 patients (97.5%) reached the prespecified target of ≥2 antianginals; 136 (68.0%) did not stop any antianginals because of adverse effects, and the median number of antianginals stopped for adverse effects per patient was 0 (interquartile range, 0–1). Amlodipine and bisoprolol were well tolerated (stopped for adverse effects in 4/175 [2.3%] and 9/167 [5.4%], respectively). Ranolazine and ivabradine were also well tolerated (stopped for adverse effects in 1/20 [5.0%] and 1/18 [5.6%], respectively). Isosorbide mononitrate and nicorandil were stopped for adverse effects in 36 of 172 (20.9%) and 32 of 141 (22.7%) of patients, respectively. Statins were well tolerated and taken by 191 of 200 (95.5%) patients. Conclusions In the 12‐week ORBITA trial period, medical therapy was successfully optimized and well tolerated, with few drug adverse effects leading to therapy cessation. Truly optimal medical therapy can be achieved in clinical trials, and translating this into longer‐term clinical practice should be a focus of future study. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02062593.

Background: Fractional flow reserve (FFR) uses pressure-based measurements to assess the severity of a coronary stenosis. Distal pressure (Pd) is often at a different vertical height to that of the proximal aortic pressure (Pa). The difference in pressure between Pd and Pa due to hydrostatic pressure, may impact FFR calculation. Methods: One hundred computed tomography coronary angiographies were used to measure height differences between the coronary ostia and points in the coronary tree. Mean heights were used to calculate the hydrostatic pressure effect in each artery, using a correction factor of 0.8 mmHg/cm. This was tested in a simulation of intermediate coronary stenosis to give the “corrected FFR” (cFFR) and percentage of values, which crossed a threshold of 0.8. Results: The mean height from coronary ostium to distal left anterior descending (LAD) was +5.26 cm, distal circumflex (Cx) –3.35 cm, distal right coronary artery-posterior left ventricular artery (RCA-PLV) –5.74 cm and distal RCA-posterior descending artery (PDA) +1.83 cm. For LAD, correction resulted in a mean change in FFR of +0.042, –0.027 in the Cx, –0.046 in the PLV and +0.015 in the PDA. Using 200 random FFR values between 0.75 and 0.85, the resulting cFFR crossed the clinical treatment threshold of 0.8 in 43% of LAD, 27% of Cx, 47% of PLV and 15% of PDA cases. Conclusions: There are significant vertical height differences between the distal artery (Pd) and its point of normalization (Pa). This is likely to have a modest effect on FFR, and correcting for this results in a proportion of values crossing treatment thresholds. Operators should be mindful of this phenomenon when interpreting FFR values.