ABSTRACT
Mechanosensory hair cells located in the inner ear mediate the sensations of hearing and balance. If damaged, mammalian inner ear hair cells are unable to regenerate, resulting in permanent sensory deficits. Aquatic vertebrates like zebrafish (Danio rerio) have a specialized class of mechanosensory hair cells found in the lateral line system, allowing them to sense changes in water current. Unlike mammalian inner ear hair cells, lateral line hair cells can robustly regenerate following damage. In mammalian models, the transcription factor Foxg1 functions to promote normal development of the inner ear. Foxg1a is expressed in lateral line sensory organs in zebrafish larvae, but its function during lateral line development and regeneration has not been investigated. We find that loss of Foxg1a function results in reduced hair cell development and regeneration, as well as decreased cellular proliferation in the lateral line system. These data suggest that Foxg1 may be a valuable target for investigation of clinical hair cell regeneration. Summary statement: Our work demonstrates a role for Foxg1a in developing and regenerating new sensory cells through proliferation.
ABSTRACT
Mechanosensory hair cells in the inner ear mediate the sensations of hearing and balance, and in the specialized lateral line sensory system of aquatic vertebrates, the sensation of water movement. In mammals, hair cells lack the ability to regenerate following damage, resulting in sensory deficits. In contrast, non-mammalian vertebrates, such as zebrafish, can renew hair cells throughout their lifespan. Wnt signaling is required for development of inner ear and lateral line hair cells and regulates regeneration. Kremen1 inhibits Wnt signaling and hair cell formation, though its role in regeneration is unknown. We used a zebrafish kremen1 mutant line to show overactive Wnt signaling results in supernumerary support cells and hair cell regeneration without increased proliferation, in contrast with the previously described role of Wnt signaling during hair cell regeneration. This work allows us to understand the biology of mechanosensory hair cells and how regeneration might be promoted following damage.
ABSTRACT
Mechanosensory hair cells in the inner ear mediate the sensations of hearing and balance, and in a specialize lateral line sensory system of aquatic vertebrates, the sensation of water movement. In mammals, hair cells lack the ability of regenerate following damage, resulting in sensory deficits. In contrast, non-mammalian vertebrates, such zebrafish, can renew hair cells throughout the life of the animal. Wnt signaling is required for development of inner ear and lateral line hair cells and regulates regeneration. Kremen1 inhibits Wnt signaling and hair cell formation, though its role in regeneration has not been established. We use a zebrafish kremen1 mutant line, to show that when Wnt signaling is overactivated in the lateral line, excessive regeneration occurs in the absence of increased proliferation, due to an increase in support cells. This contrasts with the previously described role of Wnt signaling during hair cell regeneration. This work will allow us to understand the biology of mechanosensory hair cells, and how regeneration might be promoted following damage.
ABSTRACT
This review analyzes the seafood recalls registered by the United States Food and Drug Administration (USFDA) from October 2002 through March 2022. There were more than 2,400 recalls for seafood products over this 20-year period. Biological contamination was the listed root cause for about 40% of these recalls. Almost half were designated as Class I recalls, due to the high risk of the recalled seafood to cause disease or death. Independent of the recall classification, 74% of the recalls were due to violations of the Current Good Manufacturing Practices (cGMPs) regulations. The most common cause for these seafood recalls was due to undeclared allergens (34%). More than half of the undeclared allergen recalls were for undeclared milk and eggs. Recalls for Listeria monocytogenes accounted for 30% of all recalls and were all Class I. Finfish comprised 70% of the recall incidents, and salmon was the single most recalled species (22%). Improper cold smoking treatment that resulted in Listeria monocytogenes contamination was the most common reason reported for the salmon recalls. The goal of this review was to evaluate the main causes of food safety failures within the seafood manufacturing and distribution sectors. Human errors and failures to control food safety risks during the processing of food are the main driving factors for most reported recalls in the U.S. Properly applying the Hazard Analysis Critical Control Points (HACCP) approach and procedures are needed to identify the potential food safety risks. The key to reducing the risks of human error and loss of process control is the development and implementation of an effective food safety culture program at the manufacturing facility, which must require strong senior management support at corporate and enterprise levels.
Subject(s)
Food Contamination , Listeria monocytogenes , Animals , United States , Humans , Food Contamination/analysis , Food Safety , Seafood/analysis , Eggs/analysis , United States Food and Drug Administration , Allergens/analysis , SalmonABSTRACT
BACKGROUND: A textbook outcome (TO) is a composite indicator covering the entire intervention process in order to reflect the "ideal" intervention and be a surrogate for patient important outcomes. Selective internal radiation therapy (SIRT) is a complex multidisciplinary and multistep intervention facing the challenge of standardization. This expert opinion-based study aimed to define a TO for SIRT of hepatocellular carcinoma. METHODS: This study involved two steps: (1) the steering committee (4 interventional radiologists) first developed an extensive list of possible relevant items reflecting an optimal SIRT intervention based on a literature review and (2) then conducted an international and multidisciplinary survey which resulted in the final TO. This survey was online, from February to July 2021, and consisted three consecutive rounds with predefined settings. Experts were identified by contacting senior authors of randomized trials, large observational studies, or studies on quality improvement in SIRT. This study was strictly academic. RESULTS: A total of 50 items were included in the first round of the survey. A total of 29/40 experts (73%) responded, including 23 interventional radiologists (79%), three nuclear medicine physicians (10%), two hepatologists, and one oncologist, from 11 countries spanning three continents. The final TO consisted 11 parameters across six domains ("pre-intervention workup," "tumor targeting and dosimetry," "intervention," "post-90Y imaging," "length of hospital stay," and "complications"). Of these, all but one were applied in the institutions of > 80% of experts. CONCLUSIONS: This multidimensional indicator is a comprehensive standardization tool, suitable for routine care, clinical round, and research.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Humans , Carcinoma, Hepatocellular/diagnostic imaging , Carcinoma, Hepatocellular/radiotherapy , Carcinoma, Hepatocellular/pathology , Liver Neoplasms/diagnostic imaging , Liver Neoplasms/radiotherapy , Liver Neoplasms/drug therapy , Radiometry , Yttrium Radioisotopes/therapeutic useABSTRACT
Historically, selective internal radiation therapy (SIRT) with yttrium-90 (Y-90) requires a two-week interval between workup and treatment (map and treat). The intervening gap between workup and treatment is used to plan for the dose required and obtain delivery of the radioactive Y-90. During the coronavirus disease 2019 pandemic, the delivery of a robust SIRT service was challenging due to unprecedented demands on all hospital services. Emergent practice changes were required to ensure this service could still be delivered to patients while retaining sufficient inpatient hospital beds and services for acutely unwell patients. In response to this, the interventional radiology team proposed the retention of a full SIRT service by removing the historical two-week interval between map and treat, delivering both components of the SIRT procedure on the same day. A traditional approach using femoral access would require a prolonged period of immobility and potentially an overnight stay. By adopting a transradial approach without sedo-analgesia, an ambulatory day-case map and treat SIRT with no post-procedure immobilisation was performed. This case report demonstrates the technical feasibility of same-day 'map-and-treat' SIRT, highlighting a paradigm shift from the conventional femoral access method and immobilisation to an 'ambulatory' approach with immediate mobilisation post-procedure.
ABSTRACT
Sintering and microstructural development in ceramics has long been studied in a two-dimensional grain size-density space, with only texture (i.e. deviation of grain orientation from random) used to gain first insights into additional parametric spaces. Following an increased interest for grain boundary engineering and a deeper understanding of dopant effects on sintering and grain boundaries, the theory of complexion transitions for ceramics has been introduced over the last decade, providing a new base for advanced microstructure engineering in ceramics. With emergence of high entropy ceramics over the last 5 years, the combination of both yields new grounds for exploration and engineering of functional ceramic materials of the future.
ABSTRACT
ABSTRACT: This review covers 18 years of voluntary recalls of tuna sold commercially in the United States. Recall information is a valuable indicator of failure to implement procedures for food safety. The voluntary recalls involve tuna that was fresh, frozen, processed, hermetically sealed, retorted in a shelf-stable pack (i.e., canned), and formulated into other tuna products. U.S. Food and Drug Administration regulations address the capture, processing, transportation, and sale of raw and processed seafood. These regulations include current good manufacturing practices, the Food Modernization Act, emergency permit controls, and guidelines for low-acid canned foods, seafood hazard analysis and critical control points, food labeling, and sanitary food transportation. Traceability and the food safety culture are important for successfully preventing or implementing recalls. The recalls themselves were separated into product treatment groups: uncooked products, canned shelf-stable products, and products in which tuna was used as an ingredient. The recalls were further categorized and summarized by reason or cause, such as biological and chemical contamination, undeclared ingredients, underprocessing, and foreign materials. The primary causes of recalls of the reviewed tuna products were (in order) Listeria monocytogenes, undeclared allergens, elevated histamine concentrations, and underprocessing of retorted tuna products. The recalls for elevated histamine concentrations primarily affected uncooked (raw) tuna. Recalls for Listeria contamination and the presence of undeclared allergens were primarily class I recalls, and recalls for elevated histamine concentrations and underprocessing were almost always assigned to the less serious recall class II.
Subject(s)
Food Contamination , Tuna , Allergens/analysis , Animals , Food Contamination/analysis , Food Labeling , Food Safety , Seafood/analysis , United StatesABSTRACT
Chemosaturation with percutaneous hepatic perfusion (CS-PHP; Hepatic CHEMOSAT® Delivery System, Delcath Systems Inc, Wilmington, Delaware) is an interventional radiology procedure that delivers high doses of melphalan, a chemotherapeutic agent, directly to the liver in patients with unresectable primary and secondary liver tumours. Traditionally, CS-PHP is delivered by arterial access via the femoral artery. However, there can be many risks and adverse effects associated with femoral artery punctures, such as retroperitoneal haemorrhage and haematoma formation. The monitoring and bed rest required following the removal of a femoral arterial catheter may also cause significant distress to patients as they remain immobile, potentially prolonging their stay in hospital. The radial artery is an alternative access point, with fewer reported adverse events and increased patient tolerance when compared with femoral access. This case report details the first reported use of Hepatic CHEMOSAT® therapy being delivered via the radial artery. Two patients received hepatic chemosaturation with no reported complications. This report demonstrates that access via the radial artery is a feasible alternative for the delivery of chemotherapy, which may reduce morbidity and the risks usually associated with femoral access.
ABSTRACT
Histamine is a biogenic amine and a food safety hazard, and it is the only biogenic amine regulated by statute or hazard analysis and critical control point guidance. This article reviews the regulations for histamine levels in fish in countries around the world, including maximum limits or levels and sampling procedures in different fish preparations. The maximum histamine levels, sampling plans, and fish products are listed. The country-by-country regulations for maximum histamine acceptance levels in some food products vary by a factor of 8, from 50 ppm in some countries to a maximum of 400 ppm in other countries. For similar food products, the maximum histamine levels vary by a factor of 4 (from 50 ppm to 200 ppm) in, for example, fresh tuna. The country-by-country sampling plans vary widely as well, and these, too, are covered in detail.
Subject(s)
Biogenic Amines , Histamine , Animals , Fish Products/analysis , Fishes , TunaABSTRACT
INTRODUCTION: The aim of the study is to estimate the cost-effectiveness of TheraSphere against other embolic treatments in a population with early to intermediate stage hepatocellular carcinoma (HCC) who are unresectable at presentation and are eligible for transarterial embolization (TAE), conventional transarterial chemoembolization (cTACE) or drug-eluting bead TACE (DEB-TACE). MATERIALS AND METHODS: A Markov model was constructed using a UK National Health Service (NHS) perspective, a 20-year time horizon, and four-week cycles. The eight health states included 'watch and wait', 'transplantation' (pre-, post and post (No HCC)), 'resection', 'no HCC other', 'pharmacological management' and 'death'. Clinical data were sourced from literature and expert opinion. Resource use and costs were reflective of the NHS, and benefits were quantified using Quality-Adjusted Life Years (QALYs), with utility weights sourced from literature. Comparators were TAE, cTACE and DEB-TACE. The primary output was the Incremental Cost-Effectiveness Ratio (ICER) expressed as cost per QALY gained. An ICER of under £20,000/QALY gained for an intervention is cost-effective and represents efficient use of healthcare resources. Extensive deterministic and probabilistic sensitivity analyses were undertaken. RESULTS: TheraSphere patients were predicted to gain 0.7 additional QALYs compared to all other treatments. The base case ICERs for TheraSphere were £17,300, £17,279 and £23,020 per QALY gained compared to TAE, cTACE and DEB-TACE, respectively. In the TheraSphere cohort, 87% more patients were predicted to achieve downstaging compared to all other treatment options. CONCLUSIONS: This study indicates that treatment with TheraSphere is a potentially cost-effective option for patients with early to intermediate stage HCC.
Subject(s)
Carcinoma, Hepatocellular/therapy , Chemoembolization, Therapeutic/economics , Liver Neoplasms/therapy , Radiopharmaceuticals/administration & dosage , Aged , Carcinoma, Hepatocellular/diagnosis , Cost-Benefit Analysis , Female , Follow-Up Studies , Humans , Infusions, Intra-Arterial , Liver Neoplasms/diagnosis , Male , Microspheres , Treatment OutcomeABSTRACT
Selective internal radiotherapy (SIRT) is an established modality for the treatment of hepatic malignancy. The procedure is normally carried out in two parts. The first part involves a planning or "work-up" angiogram to delineate anatomy and plan safe yttrium-90 (Y90) delivery, and the second part for the administration of the Y90 microspheres. The work-up angiogram has three main purposes including delineation of hepatic and tumor vascular anatomy, which might influence the administration of the microbeads, identification, and embolization of blood vessels, which may complicate treatment or contribute to non-target Y90 microsphere deposition and administration of technetium 99 (metastable) labeled macroaggregated albumin (99mTcMAA) at the planned administration points prior to the same day single-photon emission computed tomography (SPECT) or planar SPECT to identify sites of 99mTcMAA uptake. We present the case of a SIRT procedure that demonstrated an anomalous artery arising from the left hepatic artery with supply to the pericardium, diaphragm, fundus of the stomach, and spleen. This is a rare vascular variant that highlights the importance of thorough assessment of both the planning angiograms and SPECT CT for the presence of anatomical variants and abnormal extrahepatic 99mTcMAA uptake to help reduce the need to recall patients for repeat work-up procedures.
ABSTRACT
Activated carbon (AC) exhibits superior sorption properties compared to other porous materials, due to well-developed porous structures and high surface areas. Therefore, it is widely applied in its various forms in water purification to remove a diverse range of contaminating species. The presence of viruses in fresh water bodies poses a serious issue for human health. However, AC has not yet been commonly applied to waterborne virus removal. In this study, we present oxidation and copper impregnation treatment procedures of activated carbon fibers (ACFs) that resulted in porous structure and surface chemistry modifications. The effect of these modifications on virus removal was investigated by experimental flow studies and revealed up to 2.8 log10 reduction value (LRV) and 3.6 LRV of MS2 bacterio-phages for non-modified and oxidized ACFs, respectively, emphasizing the advantages of ACF surface functionalization. Copper modified fibers demonstrated a high sensitivity to media composition, resulting in a release of metal and therefore limited virucidal capacity.
ABSTRACT
Peripheral intravenous catheters are frequently used devices in emergency departments. Many patients now present with difficult anatomy and are labeled as difficult intravenous access patients. A common technology to address this challenge is ultrasound. While studies have examined the ability to train emergency staff, few have addressed how this should be done and the outcomes associated with such training. No studies were found with dedicated vascular access specialist teams in emergency departments. An emergency department vascular access specialist team was formed at a hospital in Bangor, Maine, United States to train, validate, and proctor clinicians with ultrasound-guided peripheral intravenous devices. A quality review of this process was compiled and determined that appropriate clinicians with dedicated training and guidance can achieve higher levels of procedural success. Furthermore, evidence substantiates that frequent practice is linked to a higher quality of care and that a significant need for such teams is present. This review examines how a team was implemented and its impact both department- and facility-wide. It is possible that hospitals benefit from the services of vascular access specialists to provide higher quality care. Successful implementation of such specialist teams requires foundational knowledge and skills in vascular access with ongoing quality measures to ensure competency and compliance with evidence-based practices.
Subject(s)
Catheterization, Peripheral , Clinical Competence , Delivery of Health Care, Integrated/organization & administration , Emergency Service, Hospital/organization & administration , Outcome and Process Assessment, Health Care/organization & administration , Patient Care Team/organization & administration , Ultrasonography, Interventional , Humans , Maine , Program Development , Program Evaluation , Quality Improvement/organization & administration , Quality Indicators, Health Care/organization & administrationABSTRACT
PURPOSE: To report outcomes of yttrium-90 (90Y) radioembolization in patients with unresectable intrahepatic cholangiocarcinoma (ICC). MATERIALS AND METHODS: Retrospective review was performed of 115 patients at 6 tertiary care centers; 92 were treated with resin microspheres (80%), 22 were treated with glass microspheres (19%), and 1 was treated with both. Postintervention outcomes were compared between groups with χ2 tests. Survival after diagnosis and after treatment was assessed by Kaplan-Meier method. RESULTS: Grade 3 laboratory toxicity was observed in 4 patients (4%); no difference in toxicity profile between resin and glass microspheres was observed (P = .350). Clinical toxicity per Society of Interventional Radiology criteria was noted in 29 patients (25%). Partial response per Response Evaluation Criteria In Solid Tumors 1.1 was noted in 25% of patients who underwent embolization with glass microspheres and 3% of patients who were treated with resin microspheres (P = .008). Median overall survival (OS) from first diagnosis was 29 months (95% confidence interval [CI], 21-37 mo) for all patients, and 1-, 3-, and 5-year OS rates were 85%, 31%, and 8%, respectively. Median OS after treatment was 11 months (95% CI, 8-13 mo), and 1- and 3-year OS rates were 44% and 4%, respectively. These estimates were not significantly different between resin and glass microspheres (P = .730 and P = .475, respectively). Five patients were able to undergo curative-intent resection after 90Y radioembolization (4%). CONCLUSIONS: This study provides observational data of treatment outcomes after 90Y radioembolization in patients with unresectable ICC.
Subject(s)
Bile Duct Neoplasms/radiotherapy , Cholangiocarcinoma/radiotherapy , Embolization, Therapeutic , Radiopharmaceuticals/administration & dosage , Yttrium Radioisotopes/administration & dosage , Bile Duct Neoplasms/diagnostic imaging , Bile Duct Neoplasms/mortality , Bile Duct Neoplasms/pathology , Cholangiocarcinoma/diagnostic imaging , Cholangiocarcinoma/mortality , Cholangiocarcinoma/pathology , Embolization, Therapeutic/adverse effects , Embolization, Therapeutic/mortality , Female , Humans , Male , Radiopharmaceuticals/adverse effects , Retrospective Studies , Time Factors , Treatment Outcome , Yttrium Radioisotopes/adverse effectsSubject(s)
Carcinoma, Squamous Cell/diagnostic imaging , Magnetic Iron Oxide Nanoparticles , Penile Neoplasms/diagnostic imaging , Sentinel Lymph Node/diagnostic imaging , Aged , Aged, 80 and over , Carcinoma, Squamous Cell/pathology , Feasibility Studies , Humans , Image-Guided Biopsy , Inguinal Canal , Lymphatic Metastasis/diagnostic imaging , Male , Middle Aged , Penile Neoplasms/pathology , Sentinel Lymph Node Biopsy/methodsABSTRACT
PURPOSE: To evaluate the safety and efficacy of yttrium-90 transarterial radioembolization (TARE) for the treatment of unresectable, chemotherapy-refractory intrahepatic cholangiocarcinoma (ICC). METHODS: A prospective, observational study was carried out in 10 centers between 2013 and 2017. TARE plus standard care was delivered to patients with unresectable, chemotherapy-refractory or chemotherapy-intolerant ICC. Primary outcome was overall survival. Secondary outcomes included safety, progression-free survival (PFS), and liver-specific progression-free survival (LPFS). RESULTS: Sixty-one patients were treated with TARE. Patients were 53% male; median age was 64 years; 91% had performance status 0/1; 92% had received prior chemotherapy; and 59% had no extrahepatic disease. Median follow-up was 13.9 months (95% confidence interval [CI], 9.6-18.1). Overall survival was 8.7 months (95% CI, 5.3-12.1), and 37% of patients survived to 12 months. PFS was 2.8 months (95% CI, 2.6-3.1), and LPFS was 3.1 months (95% CI, 1.3-4.8). One severe complication (abdominal pain) occurred at the time of the TARE procedure. Thirty patients experienced a total of 49 adverse events, of which 8% were grade ≥3; most common were grade 1-2 fatigue and abdominal pain. A total of 77 abnormal laboratory value events were recorded, of which 4% were grade ≥3. CONCLUSIONS: Patients with advanced ICC have limited therapeutic options and a poor prognosis. This prospective study examined the survival of patients with unresectable, chemotherapy-refractory primary ICC treated with TARE in real-world practice. The results demonstrate that this treatment merits further investigation in this patient cohort in a larger study, including collection of patient-reported outcomes.
Subject(s)
Bile Duct Neoplasms/radiotherapy , Cholangiocarcinoma/radiotherapy , Drug Resistance, Neoplasm , Embolization, Therapeutic/methods , Radiopharmaceuticals/administration & dosage , Yttrium Radioisotopes/administration & dosage , Aged , Bile Duct Neoplasms/diagnostic imaging , Bile Duct Neoplasms/mortality , Bile Duct Neoplasms/pathology , Cholangiocarcinoma/diagnostic imaging , Cholangiocarcinoma/mortality , Cholangiocarcinoma/pathology , Disease Progression , Embolization, Therapeutic/adverse effects , Embolization, Therapeutic/mortality , England , Female , Humans , Male , Middle Aged , Progression-Free Survival , Prospective Studies , Radiopharmaceuticals/adverse effects , Risk Factors , Time Factors , Yttrium Radioisotopes/adverse effectsABSTRACT
The TheraSphere Global Dosimetry Steering Committee was formed in 2017 by BTG International to review existing data and address gaps in knowledge related to dosimetry. This committee is comprised of health care providers with diverse areas of expertise and perspectives on radiation dosimetry. The goal of these recommendations is to optimize glass microspheres radiation therapy for hepatocellular carcinoma while accounting for variables including disease presentation, tumour vascularity, liver function, and curative/palliative intent. The recommendations aim to unify glass microsphere users behind standardized dosimetry methodology that is simple, reproducible and supported by clinical data, with the overarching goal of improving clinical outcomes and advancing the knowledge of dosimetry.
Subject(s)
Consensus Development Conferences as Topic , Practice Guidelines as Topic , Radiometry/standards , Radiopharmaceuticals/standards , Radiotherapy/standards , Yttrium Radioisotopes/standards , Carcinoma, Hepatocellular/radiotherapy , Humans , Liver Neoplasms/radiotherapy , Microspheres , Radiopharmaceuticals/therapeutic use , Radiotherapy/methods , Radiotherapy Dosage , Yttrium Radioisotopes/therapeutic useABSTRACT
Authenticity is crucial to the seafood industry, as substitution and mislabeling have important economic, environmental, and food safety consequences. To address this problem, protein profiling and software algorithm techniques were developed to classify fish muscle samples by species. The method uses water-based protein extraction, chip-based microfluidic electrophoresis (Agilent 2100 Bioanalyzer) for the analysis of high abundance fish muscle proteins, and a novel data analysis method for species-specific protein pattern recognition. The method's performance in distinguishing commercially important fish from commonly reported substitutions was evaluated using sensitivity, specificity, and accuracy determinations with all three performance measures at >98% for common substitutions. This study demonstrates that uncooked seafood products of commercially important species of catfish, snapper, and grouper can be rapidly distinguished from commonly substituted species with a high level of confidence. A tiered testing approach to seafood species verification by sequentially applying a rapid screening method and DNA testing is proposed to more effectively ensure accurate product labeling.
Subject(s)
Electrophoresis, Capillary , Fish Proteins/analysis , Fishes/classification , Seafood/classification , Animals , Microfluidic Analytical Techniques , Species SpecificityABSTRACT
Cholangiocarcinoma is a rare form of gastrointestinal cancer with a poor prognosis. Patients often present with biliary obstruction or non-specific abdominal pain, and a high proportion of patients have advanced disease at initial diagnosis. The goal of this review is to discuss treatment options for patients with advanced bile duct tumours focusing on radioembolisation (RE) and its impact on overall survival. RE provides a therapeutic option for patients with unresectable cholangiocarcinoma. However, although systemic chemotherapy has demonstrated a survival benefit in randomised controlled trials, there is limited supporting evidence for the use of RE in this setting. Studies are mostly limited to single-centre, small cohorts with variable outcome measures. Additionally, patients included in these studies received a variety of previous therapies including chemotherapy, surgery or alternative intra-arterial therapy; therefore, a true assessment of overall survival benefit is difficult.