Global Standard Of Care Research Articles

The Role of Tranexamic Acid in Postpartum Hemorrhage: A Narrative Review.

Postpartum hemorrhage is the leading cause of preventable maternal illness and death globally, and carries a disproportionately high burden of mortality in low-to-middle income countries. Tranexamic acid, an antifibrinolytic drug, has been widely adopted to control bleeding in trauma and other surgical conditions. Within the last decade, the World Health Organization updated their guidelines for the treatment of postpartum hemorrhage to include the use of tranexamic acid in all cases of postpartum hemorrhage. However, despite these guidelines, and the proven utility of tranexamic acid to treat postpartum hemorrhage, widespread adoption of tranexamic acid into global standards of care across professional organizations has not been achieved. It is important for healthcare providers to understand the etiologies of postpartum hemorrhage, the mechanism of action and adverse effect profile of tranexamic acid, and the available literature regarding the use of tranexamic acid to prevent and treat postpartum hemorrhage to provide the best care for the pregnant patient.

Diagnosis and treatment challenges in lower resource countries: State-of-the-art.

The 2022 World Federation of Haemophilia Annual Global Survey (AGS) reports that 454,690 patients with inherited bleeding disorders (IBD) have been identified globally. While this represents noteworthy progress, haemophilia epidemiology data indicate that 75% of people with inherited bleeding disorders living in low-income and low-to-middle-income countries have yet to be diagnosed. The AGS also revealed that 11 billion clotting factor units are available to treat haemophilia A and B globally. Due to a lack of finance, these treatments are unavailable to haemophilia in low-income countries with a consequence lack of access equity for haemophilia treatment in these communities. This sobering reality is not limited to haemophilia but applies to von Willebrand Disease (VWD). While VWD is the most prevalent IBD, only 103,844 people living with this condition have been diagnosed globally. Of the diagnosed patients, only a fraction live in low- or middle-income countries. Moreover, the majority of VWD patients are still treated sub-optimally without replacement therapies or prophylaxis, both of which are now accepted as global standards of care. In this state-of-the-art review, the authors reflect on three issues. First, the minimum elements required to diagnose haemophilia in a resource-constrained setting are identified. Second, this review points to the critical stakeholders and outlines their roles in removing access to haemophilia treatment barriers. Finally, the authors examine von Willebrand disease's ongoing diagnostic and treatment challenges and compare these to haemophilia. With the rapidly evolving novel therapies, the therapeutic landscape of all IBD will likely change for the better.

Impact of Bevacizumab Being Skipped due to Adverse Events of Special Interest for Bevacizumab in Patients with Unresectable Hepatocellular Carcinoma Treated with Atezolizumab plus Bevacizumab: An Exploratory Analysis of the Phase III IMbrave150 Study

Introduction: The phase III IMbrave150 study established atezolizumab + bevacizumab as the global standard of care in patients with unresectable hepatocellular carcinoma (HCC). This exploratory analysis examined the impact of bevacizumab interruption due to bevacizumab adverse events of special interest (AESIs). Methods: Patients in IMbrave150 who were randomized to atezolizumab + bevacizumab and received treatment for ≥6 months (to reduce immortal time bias) were included in group A-1 if bevacizumab had ever been skipped due to bevacizumab AESIs or to group A-2 otherwise. Efficacy analyses included overall survival (OS) and progression-free survival (PFS) by whether bevacizumab was skipped (group A-1 vs. A-2). PFS was evaluated per independent review facility (IRF)-assessed Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 and HCC-modified RECIST (IRF-HCC mRECIST). Safety was also evaluated. Results: Of the 210 patients who received ≥6 months of atezolizumab + bevacizumab, 69 were assigned to group A-1 and 141 to A-2. At data cutoff (August 20, 2020), hazard ratio (HR) for OS was 1.04 (95% CI: 0.64, 1.69) for group A-1 versus A-2. HR for PFS was 1.07 (95% CI: 0.74, 1.55) per IRF-assessed RECIST 1.1 and 1.10 (95% CI: 0.76, 1.59; 15.5 vs. 9.7 months) per IRF-HCC mRECIST for group A-1 versus A-2. Safety profiles for atezolizumab and bevacizumab were largely similar between groups. More group A-1 patients had grade 3/4 adverse events. A separate analysis investigating the impact of immortal time bias in patients who received ≥3 months of atezolizumab + bevacizumab supported the appropriateness of the ≥6-month landmark analysis. Discussion/Conclusion: Efficacy was similar between patients who skipped bevacizumab due to bevacizumab AESIs and those who did not. Although this comparison was nonrandomized and exploratory, results suggest that skipping bevacizumab due to bevacizumab AESIs did not considerably impact the efficacy and safety of atezolizumab + bevacizumab.

(045) Standard of Care and Patient Perspectives Regarding Early Genital Surgery for Infants with Congenital Adrenal Hyperplasia

Abstract Introduction Opposition to normalizing genital surgeries for children with disorders of sex development (DSD) continues to grow. However, some have argued that congenital adrenal hyperplasia (CAH) should not be lumped in with other DSD conditions and therefore normalizing surgery for CAH infants with XX chromosomes and ambiguous genitalia is justifiable. Furthermore, patient and caregiver perspectives/satisfaction regarding early genital surgery varies greatly. The heterogeneity of views regarding early genital surgery in CAH infants may make navigating the treatment of CAH patients difficult and unique from the treatment of other DSD. Objective This project seeks to summarize the viewpoints regarding CAH and early genital surgery available in the biomedical literature. Methods We conducted a systematic literature review using the database Ovid MEDLINE using the terms “congenital adrenal hyperplasia,” “urogenital surgical procedures,” “sex reassignment surgery,” “genitalia surgery,” and “reconstructive surgical procedures.” We limited the search to English articles published from 2000 to October 2022. We limited the age range to children from birth to 23 months. We included articles with results that offered recommendations regarding decision making in early genital surgery, patient/parent perspectives or satisfaction regarding early surgery, and clinicians’ perspectives. We excluded articles that discussed the science of disease or surgical techniques and outcomes but did not address the complex perspectives regarding CAH surgery. Results Of the 118 articles initially retrieved, we included 53 articles. A variety of views were expressed regarding early genital surgery. Of the three articles that explicitly evaluated patient perspectives using a survey, most people with CAH seemed to approve of early genital surgery. In contrast, narrative pieces have highlighted the psychological trauma of receiving early genital surgery without their consent. Interestingly, many of the excluded articles discussed surgical techniques and their aesthetic outcomes for people with CAH, but failed to investigate the psychological impact that surgeries might have on the patient. Seven articles specifically evaluated the perspectives of the parent/caregiver in the decision making or possible regret process. One article addressed the effects of early surgery on fertility. Finally, genital surgeries and expectations also drastically vary from country to country. In more conservative countries such as Egypt, Sudan, and Nigeria, normalizing surgery is acceptable as a way to clearly define the child’s sex. In more progressive countries, such as Germany and Malta, these surgeries are not accepted or expected. Conclusions The biomedical literature is unclear about the global standard of care regarding CAH early genital surgery. Although there is a plethora of research regarding surgical technique, aesthetic outcomes, and even parental and caregiver decision making, there is less research regarding the long-term psychological impact of these surgeries. More research needs to amplify the voices of patients with CAH to inform the evolution of the standard of care. Disclosure No

Adverse events self-reported by patients (pts) with extensive-stage small cell lung cancer (ES-SCLC) treated with durvalumab (D) plus platinum-etoposide (EP) or EP in the CASPIAN study.

8571 Background: The CASPIAN phase 3 study established D+EP as a global standard of care in ES-SCLC. Patient-Reported Outcomes - Common Terminology Criteria for Adverse Events (PRO-CTCAE) was developed to complement standard adverse event (AE) reporting in oncology trials. Here we describe patient-reported symptomatic AEs using PRO-CTCAE in CASPIAN, the first time the PRO-CTCAE tool has been piloted in SCLC research. Methods: In CASPIAN, treatment-naïve pts (WHO PS 0/1) with ES-SCLC received 4 cycles of D+EP q3w followed by maintenance D q4w until progressive disease (PD), or up to 6 cycles of EP q3w. As part of exploratory analyses, where validated local language versions were available (in English, German, Japanese or Spanish), pts were asked to complete the PRO-CTCAE by e-device at baseline, q3w during EP (in both arms), then q4w until PD, followed by day 28 post-PD, 2 months post-PD, and q8w until second progression/death. Presence/absence, frequency or severity were examined during the first 24 weeks after starting treatment across 11 AEs selected as being relevant to pts with ES-SCLC (Table). Results: In total, 164 of the 537 pts randomized to D+EP and EP in CASPIAN (31%; D+EP: 83; EP: 81) were asked to complete the PRO-CTCAE. At baseline, the PRO-CTCAE was completed by 84% of these pts in the D+EP arm and 81% in the EP arm; compliance rates > 60% were achieved up to cycle 32 for D+EP and cycle 6 for EP. Examined AEs were reported by a minority of pts before starting treatment in both arms (range D+EP vs EP: 4% vs 3% for hand-foot syndrome to 34% vs 41% for dry mouth). Baseline AE rates were generally maintained in both arms up to 24 weeks after starting treatment, except for itchy skin, which showed a numerical increase from 13% at baseline to a peak of 34% at cycle 6 in the D+EP arm and 12% at baseline to a peak of 42% at cycle 8 in the EP arm; and dizziness, which showed a numerical increase from 16% at baseline to a peak of 40% at cycle 5 in the D+EP arm, while rates were maintained vs baseline in the EP arm. Most pts reporting these AEs indicated that they occurred rarely or occasionally, or were mild or moderate in severity. Conclusions: Self-reported data from pts in CASPIAN showed that the 11 AEs examined during the 24 weeks after starting treatment were reported by a minority of pts, mostly with rare or occasional occurrence, and mild to moderate severity. Rates and patterns of AEs over time were broadly similar in the D+EP and EP arms. These results complement the CASPIAN safety profile and give insight into pts’ experience of treatment. Clinical trial information: NCT03043872. [Table: see text]

The impact of improving haemophilia A management within the Spanish National Healthcare System: a social return on investment analysis

BackgroundHaemophilia A (HA) has been associated with poor health-related quality of life and a large economic burden, accentuated by severity, arthropathy, and inhibitors. To meet global standards of care, the management of HA should align with the principles of care outlined by the World Federation of Haemophilia. The aims of the present study were to establish a set of proposals to improve HA management within the Spanish National Health System (SNHS) and to estimate the impact its hypothetical implementation would generate from a clinical, healthcare, economic, and social perspective.MethodsA multidisciplinary group of experts agreed on a set of 15 proposals to improve HA management within the SNHS. Thereafter, a forecast-type Social Return on Investment analysis was carried out to estimate the impact of implementing this set of proposals within the SNHS over a one-year timeframe, in relation to the required investment.ResultsThis study estimated that the implementation of the complete set of 15 proposals would require a total investment of 2.34 M€ and have a total impact of 14.60 M€. Accordingly, every euro invested in the complete set of 15 proposals would yield a social return of €6.23 (€3.37 in the worst-case scenario and €9.69 in the best-case scenario) of both tangible and intangible nature in similar proportions (45.71 and 54.29%, respectively).ConclusionsThese results can be used to inform policy and practice such that interventions that may potentially improve current public health challenges associated with the management of HA may be implemented.

Opinion: The use of point-of-care sonography in primary care: An ethical perspective

The use of point-of-care ultrasound (PoCUS) is fast becoming a global standard of care. World over, training programmes are embracing the use of PoCUS to improve patient care, reduce risks to patients and reduce the burden of unnecessary referrals and investigations. The South African setting is particularly amenable to the benefits of this diagnostic modality to improve healthcare delivery to rural and marginalised populations. However, as with any technological advancements, the use of PoCUS is also not immune to deleterious consequences and patient harm from overdependence and over-zealous uptake. Family physicians, as the champions of primary care, should take the lead to ensure the effective and proper use of PoCUS in rural and primary care settings through advocacy, training and accreditation of clinicians to safely harness the benefits of PoCUS and minimise harm.

O-L06 The use of tumour marker Ca19.9 in the follow up of patients with resected biliary tract cancer: Results from the BILCAP randomised clinical trial

Abstract Background Even after resection biliary tract cancer has a poor outlook. Follow-up is commonly utalises and the sialyl-Lewis tetra saccharide antigen Ca19.9, a known tumour marker in pancreatic and biliary malignancy (upper limit of normal (ULN) 37U/ml). However, the evidence base for the utility of Ca19.9 is limited. The UK BILCAP trial examined the use of adjuvant capecitabine chemotherapy in resected biliary tract cancer and establishing a new global standard of care. Ca19.9 was regularly measured as part of the BILCAP protocol, this provides an opportunity to assess the use of this marker in a large trial with complete patient follow-up. Methods Between March 2006 and December 2014 447 patients underwent resectional surgery (R0 or R1) then were randomised to receive capecitabine chemotherapy or observation. CT imaging and Ca19.9 were performed 3 monthly in year 1, 6 monthly in year 2, and annually thereafter up to 5 years. Follow up was continued until all patients had 5 years follow-up. Recurrence was based mainly on imaging criteria combined with the clinical presentation. The cohort was divided into progression and non- progression groups and the Ca19. 9 values recorded were investigated using descriptive analyses with cut-off of 37 (ULN), 100 and 400U/ml. Results Of 447 study patients 440 had at least one Ca19.9 measurement from either post-operative baseline (394) or a follow-up visit (422). Baseline Ca19-9 was elevated above 37U/ml in 96 patients and 82 (85%) went on to develop recurrence. The sensitivity, specificity, positive predictive value (PPV) and negative predictive values (NPV) of the Ca19.9 on follow up are shown in the table. Conclusions Although high Ca19.9 levels predict recurrence as shown by acceptable positive predictive values at cut-offs of 100 and 400U/ml the negative predictive values are very poor as most patients develop recurrence without elevation of Ca19.9. Ca19.9 measurement is of very limited value in the follow up of patients with resected biliary cancer.

Navigating with logics: Care for women with hypertensive disorders of pregnancy in a tertiary hospital in Ghana

This paper explores how care for women with hypertensive disorders of pregnancy (HDP) is practiced in a tertiary hospital in Ghana. Partly in response to the persistently high maternal and neonatal mortality rates in Low- and Middle-income countries, efforts to improve quality of maternity care have increased. Quality improvement initiatives are shaped by the underlying conceptualisation of quality of care, often driven by global (WHO) standards and protocols. However, there are tensions between global standards of care and local clients' and providers' understandings of care practices and quality of care. Implementation of standards is further complicated by structural and organisational restrictions that influence providers' possibilities and priorities. Based on ethnographic fieldwork, we explore how clinical guidelines and professionals' and patients' perspectives converge and, more importantly, diverge. We illuminate local, situated care practices and show how professionals creatively deal with tensions that arise on the ground. In this middle-income setting, caring for women with HDP involves tinkering and navigating in contexts of uncertainty, scarcity, varying responsibilities and conflicting interests. We unravelled a complex web of, at times, contradictory logics, from which various forms of care arise and in which different notions of good care co-exist. While practitioners navigated through and with these varying logics of care, the logic of survival permeated all practices. This study provides important initial insights into how professionals might implement and innovatively adapt the latest quality of maternity care guidelines which seek to marry clinical standards and patients’ needs, preferences and experiences.

Phase III study of NUC-1031 + cisplatin versus gemcitabine + cisplatin for first-line treatment of patients with advanced biliary tract cancer (NuTide:121).

TPS4164 Background: Biliary tract cancer (BTC) is an aggressive disease with a poor prognosis. Gemcitabine + cisplatin (GemCis) is the accepted global standard of care (SoC), however key cancer resistance mechanisms associated with the transport, activation and breakdown of gemcitabine are known to limit its clinical activity across a range of tumor types, including BTC. NUC-1031 is a phosphoramidate transformation of gemcitabine designed to overcome these key resistance mechanisms and generate much higher levels of the active anti-cancer metabolite, dFdCTP, in cells. Promising efficacy has been observed with single-agent NUC-1031 in a phase I study in advanced solid tumors and in the phase Ib ABC-08 study of NUC-1031 + cisplatin for first-line treatment of advanced BTC. Of 21 patients enrolled in 2 dose cohorts (NUC-1031 625 mg/m2 or 725 mg/m2 + cisplatin 25 mg/m2 on Days 1 and 8 of 21-day cycle), 16 were considered to be efficacy evaluable. In this population, 1 patient had a CR and 6 patients had PRs, resulting in an ORR of 44% (7/16). This compares favorably to the 26% ORR reported for the SoC regimen. In addition, 6 patients had SD, resulting in a DCR of 81% (13/16). The combination was well tolerated with no unexpected AEs or DLTs. The recommended dose of NUC-1031 with cisplatin was 725 mg/m2. The tolerability profile, together with encouraging efficacy led to initiation of a global registrational study. Methods: NuTide:121 is a phase III, open-label, randomized study of NUC-1031 + cisplatin vs GemCis for first-line treatment of advanced BTC. Patients ≥18 years with histologically- or cytologically-confirmed BTC (including cholangiocarcinoma, gallbladder, or ampullary cancer), who have had no prior systemic chemotherapy for locally advanced/metastatic disease, are eligible. A total of 828 patients are being randomized (1:1) to either 725 mg/m2 NUC-1031 or 1000 mg/m2 gemcitabine, both with 25 mg/m2 cisplatin, administered on Days 1 and 8 of 21-day cycles. Primary endpoints are OS and ORR. Secondary endpoints include PFS, safety, PK and patient-reported quality of life. In addition to the final analysis, three interim analyses are planned. The study has passed an initial safety analysis, with no protocol changes required. NuTide:121 is being conducted at approximately 130 sites across North America, Europe and Asia Pacific. Clinical trial information: NCT04163900.

FRESCO-2: A global phase III study of the efficacy and safety of fruquintinib in patients (pts) with metastatic colorectal cancer (mCRC).

TPS154 Background: Pts with mCRC have limited treatment options following progression on standard therapies. Current standard of care (SOC) after pts progress on trifluridine/tipiracil (TAS-102) or regorafenib is re-challenge with previous systemic treatments, enrollment in a clinical trial, or best supportive care (BSC). Fruquintinib (Elunate) is a novel, highly selective, vascular endothelial growth factor (VEGF) receptor (VEGFR)-1, -2, and -3 tyrosine kinase inhibitor (TKI) ( Cancer Biol Ther 2014;15:1635-1645). Fruquintinib is approved in China to treat pts with mCRC who received or are intolerant to fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, anti-VEGF therapy, and, if RAS wild type, anti-epidermal growth factor receptor (EGFR) therapy. Approval was based on results of the phase 3 FRESCO study (2013-013-00CH1; NCT02314819; JAMA 2018;319:2486-2496), in which fruquintinib 5 mg daily (QD), 3 weeks on, 1 week off (3 on/1 off), significantly improved overall survival (OS) in pts with mCRC in the 3rd-line+ setting when compared to placebo (median OS 9.3 months [mo] versus 6.6 mo; hazard ratio [HR] 0.65; p < .001). Progression-free survival (PFS) was also superior (median PFS 3.7 mo versus 1.8 mo; HR 0.26; p < .001). The toxicities of fruquintinib were consistent with those of other VEGF TKIs and were manageable. At the time FRESCO was conducted in China, SOC for pts with mCRC differed from that in the US, EU, and Japan. We describe here a global phase 3 study (FRESCO-2; 2019-013-GLOB1; NCT04322539) being conducted to investigate fruquintinib’s efficacy and safety in pts with refractory mCRC and a treatment profile representative of the global SOC. Methods: FRESCO-2 is a randomized, double-blind, placebo-controlled study to compare fruquintinib + BSC to placebo + BSC. Key inclusion criteria are progression on or intolerance to treatment with TAS-102 and/or regorafenib; previous treatment with standard approved therapies including chemotherapy, anti-VEGF therapy, and, if RAS wild type, anti-EGFR therapy. Prior therapy with immune checkpoint or BRAF inhibitors is required for pts with corresponding tumor alterations. Pts (~522) will be randomized 2:1 to receive either fruquintinib 5 mg orally (PO) QD + BSC or placebo 5 mg PO QD + BSC, with a 3 on/1 off schedule. Randomization will be stratified by prior therapy, RAS status, and duration of metastatic disease. The primary endpoint is OS; secondary endpoints include PFS, disease control rate, objective response rate, duration of response, and safety. Final OS analyses will be performed when 364 OS events are observed; futility analysis will be conducted with 1/3 (121) OS events. If enrichment of post-regorafenib pts occurs, enrollment to that strata will be capped at approximately 262. FRESCO-2 will be activated in the US, EU, and Japan; global enrollment is anticipated over 13 mo. Clinical trial information: NCT04322539.

Rethinking the Protection of Vulnerable Groups in the Pandemic Situation (SARS-COVID 19): The Necessity to Implement the HRA and Human Security Framework into the Healthcare Professionals and Caregivers

Purpose: Changes caused by the COVID-19 pandemic in the organisation of medical care and medical social work provided to patients as part of end-of-life care, make it necessary to re-evaluate the ethical and legal obligations for the protection of this particularly vulnerable groups. Design/Methodology/Approach: This article draws attention to palliative care, a specific form of medical care, and in particular to end-of-life care. Changes in medical practice and medical social work caused by the pandemic, while epidemiologically justified, in many cases lead to violations of the selected European and global standards of care, including end-of-life care. The COVID-19 pandemic has clearly demonstrated, also in Europe, how difficult it is to meet social, medical, and legal standards of care for terminal patients while limiting the possibility of virus transmission. Findings: Patients and their relatives suffer great mental discomfort caused by violations of certain standards of care resulting from an elevated sanitary regime in medical facilities. Such violations can be regarded as violations of patients’ rights and of human rights in broader terms. Practical implications: We recommend standardising and popularising the following three parallel solutions to facilitate their funding: 1/ preparing and implementing technical infrastructure to make possible for patients to meet in person with their family and relatives, while preventing physical contact; 2/ extending the use of video chat technologies in hospitals and hospices; 3/ implementing educational activities addressed to patients, their families, and medical staff. These standards positively influence patients’ quality of life and, at the same time, make it possible to meet the ethical and legal requirements of medical care. Originality/value: This article included in our depth legal and axiological analyses, and will contribute to the overall strengthening of the value-based health policy of vulnerable groups as the implementation of HRA and human security framework for physician and social workers (caregivers) developed in response to the current pandemic crisis are now becoming an urgent global need.

Neoadjuvant (chemo)radiotherapy and Lateral Node Dissection: Is It Mutually Exclusive?

The importance of total mesorectal excision (TME) has been the global standard of care in patients with rectal cancer. However, there is no universal strategy for lateral lymph nodes (LLN). The treatment of the lateral compartment remains controversial and has gone to the opposite directions between Eastern and Western countries in the past decades. In the East, mainly Japan, surgeons consider LLN metastases as regional disease and have performed TME with lateral lymph node dissection (LLND) without neoadjuvant (chemo)radiotherapy ([C]RT) in patients with clinical Stage II/III rectal cancer below the peritoneal reflection. In the West, neoadjuvant radiotherapy or has been the standard, and surgeons do not perform LLND assuming the (C)RT can sterilize most lateral lymph node metastasis (LLNM). Recent evidences show that lateral nodes are the major cause of local recurrence after (C)RT plus TME, and LLND reduces local recurrence particularly from the lateral compartment. Probably a combination of the two strategies, that is, neoadjuvant (C)RT plus LLND, would be needed to improve outcomes in patients with lateral nodal disease.

Immunotherapy For Ovarian Cancer: Recent Advances And Combination Therapeutic Approaches.

Epithelial ovarian cancer (EOC) is the most lethal gynaecological cancer. Although many advances have been made in therapeutic strategies, the global standard of care still remains radical surgery plus chemotherapy, but new scenarios need to be explored to improve survival. The role of immunotherapy in EOC treatment is controversial. Results obtained from studies evaluating immunotherapy are contradictory: in particular data on survival are not as good as expected when immunotherapy was administered alone, and other data are still immature. Thus, significant efforts must be devoted to finding new strategies for the use of immunotherapy. The aim of this paper is to review the most recent findings of the use of immunotherapy in ovarian cancer, with a particular focus on combination approaches.

Survey of challenges in access to diagnostics and treatment for neuroendocrine tumor (NET) patients (SCAN): Awareness of specialized techniques and latest interventions.

e16708 Background: SCAN measured global readiness to provide diagnostics and treatments for NET patients in terms of awareness, availability, quality and affordability. This analysis focused on patient and healthcare professional (HCP) awareness of NET diagnostics and treatments. Methods: During Sept-Nov 2019, NET patients and HCPs completed an online survey (available in 14 languages). Results: There were 2795 respondents from 68 countries across 6 continents (2359 patients/carers; 436 HCPs). Primary NETs were most often gastroenteropancreatic NETs (GEP NET; 71% [1408/1983]), particularly small intestinal (35% [690/1983]) or pancreatic (20% [402/1983]). Biopsy was the most well-known diagnostic option in the overall NET patient group (82% [1917/2325]), the GEP NET patient subgroup (83% [1156/1395]) and HCPs (94% [411/435]), followed by CT (all patients: 81% [1874/2325]; GEP NET: 80% [1118/1395]; HCPs: 86% [376/435]). More HCPs were aware of specialized diagnostics, such as 68Ga-DOTA PET CT (HCP 81% [353/435]) and chromogranin A (CgA; 79% [344/435]), than patients (all: 68% [1574/2325] & 62% [1451/2325], respectively; GEP NET: 69% [962/1395] & 67% [936/1395]). The vast majority of all patients (87% [1983/2275]), GEP NET patients (89% [1215/1363]) and HCPs (91% [392/431]) knew surgery was a treatment option. Somastatin analogues were recognised as a treatment option by 90% of HCPs (387/431), but only 75% of GEP NET patients (1019/1363) and 70% of all NET patients (1599/2275). Nearly a quarter of HCPs (22% [95/431]) and one-third of patients (all: 33% [755/2275]; GEP NET: 30% [409/1363]) had not heard of peptide receptor radionuclide therapy (PRRT). The majority of patients (all: 88% [2007/2273]; GEP NET: 89% [1213/1370]) and HCPs (93% [396/425]) were aware of conventional imaging, such as CT/MRI/ultrasound, being used for ongoing monitoring of NETs. Approximately a third of all NET patients and a quarter of HCPs were unware CgA (patients: 32% [723/2273]; HCPs: 22% [94/425]) or 68Ga-DOTA PET CT (patients: 29% [670/2273]; HCPs: 24% [102/425]) were ongoing monitoring tools. Similarly, CgA and 68Ga-DOTA PET CT were not recognized by 27% of GEP NET patients (364/1370 & 371/1370, respectively). Conclusions: Increased awareness of NET diagnostics and treatments, particularly newer, more specialized tools, amongst both HCPs and patients is required to ensure continued advancements and improvements in the global standard of care for NETs.

Repurposing Molecular Imaging and Sensing for Cancer Image-Guided Surgery.

Gone are the days when medical imaging was used primarily to visualize anatomic structures. The emergence of molecular imaging (MI), championed by radiolabeled 18F-FDG PET, has expanded the information content derived from imaging to include pathophysiologic and molecular processes. Cancer imaging, in particular, has leveraged advances in MI agents and technology to improve the accuracy of tumor detection, interrogate tumor heterogeneity, monitor treatment response, focus surgical resection, and enable image-guided biopsy. Surgeons are actively latching on to the incredible opportunities provided by medical imaging for preoperative planning, intraoperative guidance, and postoperative monitoring. From label-free techniques to enabling cancer-selective imaging agents, image-guided surgery provides surgical oncologists and interventional radiologists both macroscopic and microscopic views of cancer in the operating room. This review highlights the current state of MI and sensing approaches available for surgical guidance. Salient features of nuclear, optical, and multimodal approaches will be discussed, including their strengths, limitations, and clinical applications. To address the increasing complexity and diversity of methods available today, this review provides a framework to identify a contrast mechanism, suitable modality, and device. Emerging low-cost, portable, and user-friendly imaging systems make the case for adopting some of these technologies as the global standard of care in surgical practice.

NUC-1031 in combination with cisplatin for first-line treatment of patients with advanced biliary tract cancer (NuTide:121).

TPS602 Background: Biliary tract cancer (BTC) carries a poor prognosis and has no approved treatments. Although gemcitabine + cisplatin (GemCis) is accepted as the global standard of care (SoC) for 1st-line treatment, the reported unconfirmed ORR and OS from randomized studies of this combination are low at 18.5-26.1% and 11.2-11.7 months, respectively. NUC-1031, a phosphoramidate transformation of gemcitabine, is designed to overcome key cancer resistance mechanisms associated with gemcitabine. Promising signs of efficacy have been observed with single-agent NUC-1031 in a Phase I study in advanced solid tumors (Blagden et al 2018) and in the Phase Ib ABC-08 study of NUC-1031 + cisplatin 25 mg/m2 on days 1 and 8 of a 21-day cycle for the 1st-line treatment of advanced BTC. Of 14 patients (pts) enrolled in 2 cohorts (NUC-1031: 625 mg/m2 and 725 mg/m2), 1 pt achieved a CR and 6 pts achieved PR, giving an unconfirmed ORR of 50% and representing an approximate doubling of ORR over SoC. The combination was well-tolerated with no unexpected adverse events or dose-limiting toxicities. The RP2D of NUC-1031 in combination with cisplatin is 725 mg/m2. The tolerability profile together with robust efficacy signals suggested NUC-1031 + cisplatin may represent a more effective therapy than GemCis for BTC and led to initiation of a global Phase III study. Methods: A Phase III, open-label, randomized head-to-head study of NUC-1031 + cisplatin versus GemCis for 1st-line treatment of advanced BTC will include pts ≥18 years with histologically- or cytologically-proven BTC (including cholangiocarcinoma, gallbladder, or ampullary cancer), who have had no prior systemic chemotherapy for locally advanced/metastatic disease. A total of 828 pts will be randomized (1:1) to either 725 mg/m2 NUC-1031 + 25 mg/m2 cisplatin or 1000 mg/m2 gemcitabine + 25 mg/m2 cisplatin, administered on days 1 and 8 of a 21-day cycle. Primary objectives are OS and ORR. Secondary objectives include further measurements of efficacy, safety, pharmacokinetics, and patient-reported quality of life. The study will be conducted at approximately 120 sites across North America, Europe and Asia Pacific countries. Clinical trial information: NCT04163900.

Tislelizumab (BGB-A317) + concurrent chemoradiotherapy (cCRT) followed by tislelizumab monotherapy for newly diagnosed locally advanced, unresectable, stage III non-small cell lung cancer (NSCLC) in a phase III study (RATIONALE 001).

TPS8574 Background: cCRT improves survival vs RT alone and is a global standard of care in patients (pts) with stage III NSCLC, but survival remains poor for these pts. Combining PD-1/PD-L1-targeting immunotherapies and cCRT may lead to synergistic activity and improved outcomes. Tislelizumab (anti–PD-1) demonstrated clinical activity and tolerability in solid tumors, including NSCLC. This phase III, randomized, double-blind, placebo-controlled study (RATIONALE 001) will evaluate efficacy and safety of tislelizumab + cCRT. Methods: Pts (N ≈ 840) will be randomized 1:1:1 in a 3-arm study design to evaluate whether the timing of giving tislelizumab earlier upfront with cCRT in addition to as consolidation (Arm 1) or giving tislelizumab as consolidation only (Arm 2) will improve outcomes vs cCRT alone (Arm 3; Table). RT will be given in 2 Gy fractions to a target dose of 60 Gy (30 fractions). Chemotherapy will be investigator’s choice of cisplatin + etoposide or carboplatin + paclitaxel. A safety analysis specific to the cisplatin + etoposide component of the cCRT + tislelizumab combination is planned. All sites must pass a radiation quality assurance review process. The primary endpoint is PFS. Secondary endpoints include ORR, OS, OS at 24 months, and safety. As an exploratory endpoint, blood and tumor biomarkers will be assessed for correlations with clinical benefit. With a one-sided α of 1.25%, a total of 580 PFS events are required to allow ≈ 90% power to detect a HR for progression or death of 0.7 for either pairwise comparison (Arm 1 vs Arm 3 or Arm 2 vs Arm 3). Key eligibility criteria are locally advanced, unresectable, stage III NSCLC; FDG-PET and brain imaging confirmation of stage III status; no prior treatment; and ECOG PS ≤ 1. PD-L1 expression assessment is not required prior to randomization. EudraCT number 2018-001132-22. Clinical trial information: NCT03745222. [Table: see text]

NUC-1031 in combination with cisplatin for first-line treatment of advanced biliary tract cancer.

TPS4156 Background: Cisplatin and gemcitabine (CisGem) is the global standard of care for 1st-line treatment of patients (pts) with advanced biliary tract cancer (BTC). No agents have regulatory approval for this disease. CisGem achieves an objective response rate (ORR) of 26% and median overall survival (OS) of 11.7 months (ABC-02). Key cancer resistance mechanisms limit gemcitabine efficacy. NUC-1031, a phosphoramidate transformation of gemcitabine, is designed to overcome resistance mechanisms associated with poor gemcitabine response. Promising signs of efficacy have been observed with single agent in a phase I study in solid tumors (Blagden et al 2018) and in the phase Ib ABC-08 study of NUC-1031 + cisplatin 25 mg /m2 d1, d8 q 21 days for the 1st-line treatment of advanced BTC. 14 pts have been enrolled across 2 cohorts (NUC-1031: 625 mg/m2 and 725 mg/m2). In 11 pts evaluable for response ORR was 64% (1 CR, 6 PRs) and DCR was 73%. PFS/OS data is maturing. The combination was very well-tolerated with no unexpected adverse events or dose-limiting toxicities. The RP2D in combination with cisplatin is 725 mg/ m2. Safety, coupled with encouraging efficacy signal has led to initiation of a global Phase III development program. Methods: A Phase III, open-label, randomized head-to-head study of NUC-1031 + cisplatin versus CisGem for the 1st-line treatment of advanced BTC will include pts ≥18 years with histologically- or cytologically-proven BTC (including cholangiocarcinoma, gallbladder, or ampullary cancer), that is not resectable and who have had no prior systemic chemotherapy for locally advanced/metastatic disease. A total of 828 pts will be randomized (1:1) to either 725 mg/m2 NUC-1031 + 25 mg/m2 cisplatin or 1000 mg/m2 gemcitabine + 25 mg/m2 cisplatin, administered on Days 1 and 8 of a 21-day cycle, respectively. Primary objectives are OS and ORR. Secondary objectives include further measurements of efficacy, safety, pharmacokinetics, and patient-reported quality of life. The study will be conducted at approximately 120 sites across North America, Europe and Asia Pacific countries. Clinical trial information: NCT02351765.

Birth Outcomes for Pregnant Women With HIV Using Tenofovir-Emtricitabine

(Abstracted from N Engl J Med 2018;378:1593–1603) Three-drug antiretroviral therapy (ART) during pregnancy has reduced the risk of perinatal transmission of HIV to less than 1% and has become the global standard of care. The Promoting Maternal and Infant Survival Everywhere (PROMISE) trial recently found that pregnant women in multiple sites of sub-Saharan Africa and India receiving tenofovir, disoproxil fumarate, emtricitabine, and ritonavir-boosted lopinavir (TDF-FTC-LPV/r) were more than twice as likely to deliver very prematurely (<34 weeks of gestation), at very low birth weight (<1500 g), and were significantly more likely to have infants that died within 14 days after delivery compared with those assigned to receive zidovudine, lamivudine, and ritonavir-boosted lopinavir (ZDV-3TC-LPV/r).