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Importance: The combination of immune checkpoint inhibitors with antiangiogenic agents has revolutionized the treatment landscape of advanced hepatocellular carcinoma (HCC). However, due to rapid publication of new studies that attained their predefined primary end points, a lack of robust cross-trial comparison of first-line therapies, and diverging clinical guidelines, no clear-cut treatment flowchart and sequence of therapies are available. This critical analysis of the recommendations for the management of advanced HCC from the main scientific societies in the US and Europe adopted an integrated approach to provide information on the clinical benefit (overall survival and progression-free survival) and safety profile of these therapies using the European Society for Medical Oncology (ESMO)-Magnitude of Clinical Benefit Scale (MCBS) score and an ad hoc network meta-analysis. Observations: There is a major consensus among guidelines that atezolizumab plus bevacizumab has a primacy as the recommended first-line treatment of choice in advanced HCC. On progression after immunotherapy-containing regimens and for patients with contraindications for immunotherapies, most guidelines maintain the established treatment hierarchy, recommending lenvatinib or sorafenib as the preferred options, followed by either regorafenib, cabozantinib, or ramucirumab. Thus far, the first-line immune-based regimen of tremelimumab plus durvalumab has been integrated only in the American Association for the Study of Liver Diseases guidance document and the latest National Comprehensive Cancer Network guidelines and has particular utility for patients with a high risk of gastrointestinal bleeding. Overall, in the first-line setting, both atezolizumab plus bevacizumab and sintilimab plus IBI305 (a bevacizumab biosimilar) and durvalumab plus tremelimumab received the highest ESMO-MCBS score of 5, indicating a substantial magnitude of clinical benefit. In a network meta-analysis, no significant differences in overall survival were found among the various combination regimens. However, the newly reported combination of camrelizumab plus rivoceranib was associated with a significantly higher risk of treatment-related adverse events compared with atezolizumab plus bevacizumab (relative risk, 1.59; 95% CI, 1.25-2.03; P < .001). Conclusions and Relevance: This narrative review found that atezolizumab plus bevacizumab is regarded as the primary standard of care for advanced HCC in the first-line setting. These findings from integrating the recommendations from scientific societies' guidelines for managing advanced HCC along with new data from cross-trial comparisons may aid clinicians in decision-making and guide them through a rapidly evolving and complex treatment landscape.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Bevacizumab/efectos adversos , Neoplasias Hepáticas/tratamiento farmacológico , Inmunoterapia , SorafenibRESUMEN
The TEM8 protein represents an emerging biomarker in many solid tumor histologies. Given the various roles it plays in oncogenesis, including but not limited to angiogenesis, epithelial-to-mesenchymal transition, and cell migration, TEM8 has recently served and will continue to serve as the target of novel oncologic therapies. We review herein the role of TEM8 in oncogenesis. We review its normal function, highlight the additional roles it plays in the tumor microenvironment, and synthesize pre-clinical and clinical data currently available. We underline the protein's prognostic and predictive abilities in various solid tumors by (1) highlighting its association with more aggressive disease biology and poor clinical outcomes and (2) assessing its associated clinical trial landscape. Finally, we offer future directions for clinical studies involving TEM8, including incorporating pre-clinical agents into clinical trials and combining previously tested oncologic therapies with currently available treatments, such as immunotherapy.
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Neoplasias , Receptores de Superficie Celular , Humanos , Receptores de Superficie Celular/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas de Microfilamentos , Neoplasias/terapia , Transformación Celular Neoplásica , Carcinogénesis , Biología , Microambiente TumoralRESUMEN
Oncolytic viruses have made a significant inroad in cancer drug development. Numerous clinical trials are currently investigating oncolytic viruses both as single agents or in combination with various immunomodulators. Oncolytic viruses (OV) are an integral pillar of immuno-oncology and hold potential for not only delivering durable anti-tumor responses but also converting "cold" tumors to "hot" tumors. In this review we will discuss one such promising oncolytic virus called Seneca Valley Virus (SVV-001) and its therapeutic implications. SVV development has seen seismic evolution over the past decade and now boasts of being the only OV with a practically applicable biomarker for viral tropism. We discuss relevant preclinical and clinical data involving SVV and how bio-selecting for TEM8/ANTXR1, a negative tumor prognosticator can lead to first of its kind biomarker driven oncolytic viral cancer therapy.
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The treatment paradigm for hepatocellular carcinoma (HCC) had been stagnant until recently, with new combinations of targeted and immunotherapies entering the first- and second-line setting for patients with advanced disease. This improvement in therapeutic options is well timed given the rise in rates of HCC globally; additionally, screening high-risk patients has also led to an increase in detection of early HCC lesions, identifying patients who can be treated with curative intent approaches such as surgery. Unfortunately, the vast majority of patients who undergo surgical resection develop recurrent HCC, either due to disease recurrence from residual micrometastatic disease or de novo primaries, and there are no perioperative therapies that have demonstrated the ability to significantly improve survival for these patients. Given the survival benefit that immunotherapy has imparted to patients with advanced HCC, and recent studies in other tumor types demonstrating perioperative-in particular neoadjuvant-immunotherapy significantly improves outcomes, there is substantial interest in neoadjuvant immunotherapy for patients with resectable HCC. Three recently reported small studies looking at anti-PD-1 antibodies alone or in combination have demonstrated significant pathologic response to brief pre-operative interventions, and support exploring this approach in larger registrational studies. With these developments the clinical outlook for HCC patients, with both early and advanced disease, is rapidly improving.
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Neoplasms that secrete ectopic adrenocorticotropin (ACTH) may cause severe, life-threatening hypercortisolism. These tumors are often difficult to localize and treat, requiring a comprehensive and systematic management plan orchestrated by a multidisciplinary team. The Mount Sinai Adrenal Center hosted an interdisciplinary retreat of experts in adrenal disorders and neuroendocrine tumors (NETs) with the aim of developing a clinical pathway for the management of Cushing syndrome due to ectopic ACTH production. The result was institutional recommendations for the diagnosis, localization, surgical approaches to intrathoracic tumors and bilateral adrenalectomy, and perioperative and postoperative medical management of hypercortisolism and its sequelae. Specific recommendations were made regarding the timing and selection of therapies based on the considerations of our team as well as a review of the current literature. Our clinical pathway can be applied by other institutions directly or serve as a guide for institution-specific management.
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BACKGROUND: Large cell neuroendocrine carcinoma (LCNEC) is a rare, aggressive cancer with a dismal prognosis. The majority of cases occur in the lung and the gastrointestinal tract; however, it can occur throughout the body. Recently advances in the understanding of the molecular underpinnings of this disease have paved the way for additional novel promising therapies. This review will discuss the current best evidence for management of LCNEC and new directions in the classification and treatment of this rare disease. METHODS: We performed a PubMed search for "Large cell neuroendocrine carcinoma" and "High grade neuroendocrine carcinoma." All titles were screened for relevance to the management of LCNEC. Papers were included based on relevance to the management of LCNEC. RESULTS: Papers were included reviewing both pulmonary and extra pulmonary LCNEC. We summarized the data driven best practices for the management of both early and advanced stage LCNEC. We describe emerging therapies with promising potential. DISCUSSION: LCNEC are rare and aggressive neoplasms. In advanced disease, the historical regimen of platinum based therapy in combination with etoposide or irinotecan remains among the commonly used first line therapies, however for extra thoracic LCNEC regimens like FOLFOX, FOLFOIRI and CAPTEM can also be used. Further effective and safe treatment options are desperately needed. Recently, new advances including a new understanding of the genetic subcategories of LCNEC and immunotherapy agents may guide further treatments.
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Síndrome Torácico Agudo/etiología , Infecciones por Coronavirus/complicaciones , Neumonía Viral/complicaciones , Rasgo Drepanocítico/complicaciones , Talasemia beta/complicaciones , Síndrome Torácico Agudo/terapia , Betacoronavirus , COVID-19 , Prueba de COVID-19 , Técnicas de Laboratorio Clínico , Infecciones por Coronavirus/diagnóstico , Diagnóstico Tardío , Recambio Total de Sangre , Necrosis de la Cabeza Femoral/complicaciones , Heterocigoto , Humanos , Masculino , Terapia por Inhalación de Oxígeno , Pandemias , Neumonía Viral/diagnóstico , SARS-CoV-2 , Rasgo Drepanocítico/genética , Adulto Joven , Talasemia beta/genéticaRESUMEN
The goal of this paper is to review and describe the characteristics and outcomes of ethics consultations on a gastrointestinal oncology service and to identify areas for systems improvement and staff education. This is a retrospective case series derived from a prospectively-maintained database (which includes categorization of the primary issues, contextual ethical issues, and other case characteristics) of the ethics consultation service at Memorial Sloan Kettering Cancer Center. The study analyzed all ethics consultations requested for patients on the gastrointestinal medical oncology service from September 2007 to January 2016. A total of 64 patients were identified. The most common primary ethical issue was the DNR order (39%), followed by medical futility (28%). The most common contextual issues were dispute/conflict between staff and family (48%), dispute/conflict intra-family (16%), and cultural/ethnic/religious issues (16%). The majority of ethical issues leading to consultation were resolved (84%); i.e., the patient, surrogate, and/or healthcare team followed the recommendation of the ethics consultant. 22% had a DNR order prior to the ethics consult and 69% had a DNR order after the consult. In this population of patients on a gastrointestinal oncology service, ethics consultations are most often called regarding patients with advanced cancers and the most common ethical conflicts arose between families and the health care team over goals of care at the end of life, specifically related to the DNR order and perceived futility of continued/escalation of treatment. Ethics consultations assisted with conflict resolution. Conflicts might be reduced with improved communication about prognosis and earlier end of life care planning.
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Consultoría Ética/normas , Neoplasias Gastrointestinales/terapia , Oncología Médica/ética , Adulto , Anciano , Anciano de 80 o más Años , Instituciones Oncológicas/organización & administración , Estudios de Casos y Controles , Toma de Decisiones/ética , Femenino , Neoplasias Gastrointestinales/psicología , Humanos , Masculino , Oncología Médica/normas , Persona de Mediana Edad , Negociación , Estudios RetrospectivosRESUMEN
PURPOSE: Identifying at-risk adolescent and young adult (AYA) cancer patients and referring them to age-appropriate psychosocial support services may be instrumental in reducing psychological distress and promoting psychosocial adaptation. The purpose of this study is to identify trajectories of clinically significant levels of distress throughout the first year following diagnosis and to distinguish factors, including supportive care service use, that predict the extent to which AYAs report distress. METHODS: In this prospective multisite study, 215 AYAs aged 15-39 years were assessed for psychological distress and psychosocial support service use within the first 4 months of diagnosis and again 6 and 12 months later. On the basis of distress scores, respondents were assigned to one of four distress trajectory groups (Resilient, Recovery, Delayed, and Chronic). Multiple logistic regression analyses examined whether demographics, clinical variables, and reports of unsatisfied need for psychosocial support were associated with distress trajectories over 1 year. RESULTS: Twelve percent of AYAs reported clinically significant chronic distress throughout the first 12 months following diagnosis. An additional 15% reported delayed distress. Substantial proportions of AYAs reported that needs for information (57%), counseling (41%), and practical support (39%) remained unsatisfied at 12 months following diagnosis. Not getting counseling needs met, particularly with regard to professional mental health services, was observed to be significantly associated with distress over time. CONCLUSIONS: Substantial proportions of AYAs are not utilizing psychosocial support services. Findings suggest the importance of identifying psychologically distressed AYAs and addressing their needs for mental health counseling throughout a continuum of care.
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Ansiedad/psicología , Depresión/psicología , Evaluación de Necesidades , Neoplasias/psicología , Resiliencia Psicológica , Apoyo Social , Estrés Psicológico/psicología , Adaptación Psicológica , Adolescente , Adulto , Ansiedad/terapia , Estudios de Cohortes , Depresión/terapia , Femenino , Humanos , Modelos Logísticos , Estudios Longitudinales , Masculino , Servicios de Salud Mental/estadística & datos numéricos , Análisis Multivariante , Estudios Prospectivos , Estrés Psicológico/terapia , Adulto JovenRESUMEN
OBJECTIVE: This study was designed to validate a slow-sweep real-time 4-dimensional (4D) spatiotemporal image correlation method for producing quantitatively accurate dynamic fetal heart images using an in vitro pulsatile balloon model and apparatus. METHODS: To model fetal heart chambers, asymmetric double-walled finger stalls (tips of surgical latex gloves) were used and attached to a laboratory-designed circuit that allowed calibrated changes in the inner balloon volume as well as an intermediate gel mass interposed between the 2 layers. The water-submerged model was attached to a small-volume pulsatile pump to produce phasic changes in volume within the inner balloon at a fixed rate. A sonography system with 4D spatiotemporal image correlation (STIC) capabilities was used for 3-dimensional (3D) and 4D data acquisition. Volume data were analyzed by customized radial summation techniques with 4D data analysis software and compared with known volumes and masses. RESULTS: Fifty-six individual volumes ranging from 2.5 to 10 mL were analyzed. Volume and mass measurements with 4D STIC were highly correlated (R2 > 0.90). The mean percentage error was better (<6%) for volumes exceeding 4 mL and was as low as 0.3% for 6-mL estimations. Measurements in the diastolic phase were the most accurate, followed by mass estimations equivalent to chamber walls. There was a wider range of percentage error in the lowest volumes tested (2.5 mL), which might have arisen from difficulties in spatial resolution or distortions from within the model apparatus itself. Resolution limitations of 4D technology in combination with extremely small volume targets may explain higher error rates at these small volumes. CONCLUSIONS: Four-dimensional STIC is an acceptably accurate method for volume and mass estimations in the ranges comparable with mid- and late-gestation fetal hearts. It is particularly accurate for diastolic estimations, for chamber wall mass measurements, and at volumes of greater than 2.5 mL. This study validates use of 4D STIC technology to overcome the limitations of nongated 3D technology for phasic and quantitative assessments in fetal echocardiography.
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Ecocardiografía Tetradimensional , Corazón Fetal/diagnóstico por imagen , Modelos Cardiovasculares , Ultrasonografía Prenatal , Humanos , Procesamiento de Imagen Asistido por Computador , Técnicas In Vitro , Volumen SistólicoRESUMEN
BACKGROUND: Estimation of ventricular volume and mass is important for baseline and serial evaluation of fetuses with normal or abnormal hearts. Direct measurement of chamber wall volumes and mass can be made without geometric assumptions by 3D fetal echocardiography. Our goals were to determine the feasibility of using fast nongated 3D echocardiography for fetal volumetric and mass assessments, to validate the accuracy of the ultrasound system and the measurement technique, and if satisfactory, to develop normal values for fetal ventricular mass during the second and third trimesters. METHODS AND RESULTS: This was a prospective outpatient study of 90 consecutive normal pregnancies during routine obstetric services at Oregon Health & Science University (Portland). Optimized 3D volumes of the fetal thorax and cardiac chambers were rapidly acquired and later analyzed for right and left ventricular mass by radial summation technique from manual epicardial and endocardial traces. Experiments to validate the ultrasound system and measurement technique were performed with modified small balloon models and in vivo and ex vivo small animal experiments. Our study established the feasibility of fetal ventricular mass measurements with 3D ultrasound technology and developed normal values for right and left ventricular mass from 15 weeks' gestation to term. CONCLUSIONS: Nongated fast 3D fetal echocardiography is an acceptable modality for determination of cardiac chamber wall volume and mass with good accuracy and acceptable interobserver variability. The method should be especially valuable as an objective serial measurement in clinical fetal studies with structurally or functionally abnormal hearts.