Neuroimaging findings in 4342 hospitalized COVID-19 subjects: A multicenter report from the United States and Europe.

BACKGROUND AND PURPOSE: To determine the incidence of acute neuroimaging (NI) findings and comorbidities in the coronavirus disease of 2019 (COVID-19)-infected subjects in seven U.S. and four European hospitals. METHODS: This is a retrospective study of COVID-19-positive subjects with the following inclusion criteria: age >18, lab-confirmed COVID-19 infection, and acute NI findings (NI+) attributed to COVID-19 on CT or MRI brain. NI+ and comorbidities in total hospitalized COVID-19-positive (TN) subjects were assessed. RESULTS: A total of 37,950 COVID-19-positive subjects were reviewed and 4342 underwent NI. NI+ incidence in subjects with NI was 10.1% (442/4342) including 7.9% (294/3701) in the United States and 22.8% (148/647) in Europe. NI+ incidence in TN was 1.16% (442/37,950). In NI (4342), incidence of ischemic stroke was 6.4% followed by intracranial hemorrhage (ICH) (3.8%), encephalitis (0.5%), sinus venous thrombosis (0.2%), and acute disseminated encephalomyelitis (ADEM) (0.2%). White matter involvement was seen in 57% of NI+. Hypertension was the most common comorbidity (54%) before cardiac disease (28.8%) and diabetes mellitus (27.7%). Cardiac disease (p < .025), diabetes (p < .014), and chronic kidney disease (p < .012) were more common in the United States. CONCLUSION: This multicenter, multinational study investigated the incidence and spectrum of NI+ in 37,950 hospitalized adult COVID-19 subjects including regional differences in incidences of NI+, associated comorbidities, and other demographics. NI+ incidence in TN was 1.16% including 0.95% in the United States and 2.09% in Europe. ICH, encephalitis, and ADEM were common in Europe, while ischemic strokes were more common in the United States. In this cohort, incidence and distribution of NI+ helped characterize the neurological complications of COVID-19.

Acute Neurological Complications of Coronavirus Disease.

The coronavirus disease (COVID-19) pandemic has impacted many lives globally. Neurologic manifestations have been observed among individuals at various stages and severity of the disease, the most common being stroke. Prompt identification of these neurologic diagnoses can affect patient management and prognosis. This article discusses the acute neuroradiological features typical of COVID-19, including cerebrovascular disease, intracerebral hemorrhage, leukoencephalopathy, and sensory neuropathies.

Impact of pathological response after neoadjuvant chemotherapy on adjuvant therapy decisions and patient outcomes in gastrointestinal cancers.

BACKGROUND: Neoadjuvant chemotherapy (NAC) is frequently used in gastrointestinal cancers (GIC), and pathological, radiological, and tumor marker responses are assessed during and after NAC. AIM: To evaluate the relationship between pathologic, radiologic, tumor marker responses and recurrence-free survival (RFS), overall survival (OS), adjuvant chemotherapy (AC) decisions, and the impact of changing to a different AC regimen after poor response to NAC. METHODS AND RESULTS: Medical records of GIC patients treated with NAC at Mount Sinai between 1/2012 and 12/2018 were reviewed. One hundred fifty-six patients (58.3% male, mean age 63 years) were identified. Primary tumor sites were: 43 (27.7%) pancreas, 62 (39.7%) gastroesophageal, and 51 (32.7%) colorectal. After NAC, 31 (19.9%) patients had favorable pathologic response (FPR; defined as College of American Pathologists [CAP] score 0-1). Of 107 patients with radiological data, 59 (55.1%) had an objective response, and of 113 patients with tumor marker data, 61 (54.0%) had a ≥50% reduction post NAC. FPR, but not radiographic or serological responses, was associated with improved RFS (HR 0.28; 95% CI 0.11-0.72) and OS (HR 0.13; 95% CI 0.2-0.94). Changing to a different AC regimen from initial NAC, among all patients and specifically among those with unfavorable pathological response (UPR; defined as CAP score 2-3) after NAC, was not associated with improved RFS or OS. CONCLUSIONS: GIC patients with FPR after NAC experienced significant improvements in RFS and OS. Patients with UPR did not benefit from changing AC. Prospective studies to better understand the role of pathological response in AC decisions and outcomes in GIC patients are needed.

Overall Survival Trends and Clinical Characteristics of Plasmacytoma in the United States: A National Cancer Database Analysis.

BACKGROUND: Given the rarity of plasmacytoma, large-scale database analysis can provide useful information regarding the clinical presentation and patient-related factors impacting overall survival (OS). MATERIALS AND METHODS: The National Cancer Data Base was queried for patients with plasmacytoma between 2004 and 2013, excluding patients with systemic disease. Plasmacytomas were classified as originating in bone (P-bone), in extramedullary tissue (P-EM), or unspecified. Survival was estimated using the Kaplan-Meier and log-rank test method. We used Cox regression to determine specific outcomes adjusting for demographic, socioeconomic, geographic, facility type, year of diagnosis, and comorbid factors. RESULTS: In total, 6225 patients were identified, of which 61.5% were men. The median age at diagnosis was 64 years (range, 18-90 years), and the median follow-up was 58 months. The primary site of disease was P-bone in 4056 (65.1%) patients and P-EM in 1468 (23.6%), and the remaining 701 patients were P-unspecified. The unadjusted median survival for solitary P-bone was 89 months (95% confidence interval, 82.9-95.0 months), and for solitary P-EM was 117.3 months (95% confidence interval, 108.8 months to not reached). Factors associated with improved OS include younger age, private insurance, higher income, solitary lesion, and lower comorbidity score. Patients with P-bone disease treated at academic facilities had improved OS. Only 65% of patients with solitary plasmacytoma lesions received radiation treatment. Age greater than 75 years and increased distance to treatment facility was associated with a decreased likelihood of receiving radiation. CONCLUSIONS: This is the largest study examining outcomes of patients with plasmacytoma using a large database analysis, revealing unique aspects of P-EM versus P-bone and underutilization of radiation treatment.

Utilization Patterns of Single Fraction Radiation Therapy for Multiple Myeloma.

BACKGROUND: Patients with multiple myeloma (MM) are living longer than ever before thanks to new therapies. As a consequence, radiation therapy (RT) is increasingly important in the management of bone lesions from MM. Current American Society for Radiation Oncology guidelines recommend greater usage of 8 Gy in 1 fraction for treatment of these lesions. The objective of this study is to analyze utilization of 8 Gy in 1 fraction for treatment of MM bone lesions in the United States utilizing the National Cancer Data Base (NCDB). MATERIALS AND METHODS: The NCDB was used to identify patients with MM treated with palliative RT for painful bony lesions in the period between 2004 and 2014. Utilization rate of RT in this patient population as well as single-fraction (SFRT) versus multiple-fraction RT (MFRT) was compared according to demographic, socioeconomic, and logistic details. RESULTS: A total of 95,190 patients met our inclusion criteria. Of these, 10,261 (10.8%) patients received RT, and a total of 243 (2.4%) of these patients received SFRT over the 10-year period. There was an 11.73% annual increase (P = .0001) in SFRT utilization from 2004 to 2014. Older age, black race, longer distance from the treatment facility, lower degree of education, treatment at an academic or integrated healthcare network, worse comorbidities, and more recent diagnoses were all associated with increased usage of SFRT. CONCLUSION: SFRT for the management of MM painful bony metastases remains underutilized. Trends show that radiation oncologists do not appear to be changing their approach to treating this disease.

The Safety Profile of Concurrent Therapy for Multiple Myeloma in the Modern Era.

PURPOSE: The management of multiple myeloma has evolved in the modern era, partially owing to the increasing number of biologic therapeutics. Nonetheless, radiation remains an important treatment in the management of painful lytic lesions from multiple myeloma. The goal of this study is to evaluate the side effect profile of radiation therapy (RT) while patients are concurrently treated with biologic agents. METHODS AND MATERIALS: We conducted a retrospective study based on data collected from patients receiving RT at our institute from 2007 to 2017. A total of 130 patients (279 treatment sites) were included in this study with a median follow-up time of 14 months. Patients were required to be receiving a biological agent at least within 1 month before starting and up to 1 month after RT. Generalized estimating equations with a log link function and binomial distribution were used to estimate the prevalence ratio (PR) and corresponding 95% confidence interval (CI) and compare the side effects between patients with RT alone and RT + biologic agent. RESULTS: The median age of all patients in our cohort was 64 years, with 53 men (58.9%) and 37 women (41.1%). The mean Karnofsky performance status score of all cohorts was 80. No significant difference in incidence of acute (PR: 1.33; 95% CI, 0.80-2.22; P = .2660) or subacute (PR: 0.90; 95% CI, 0.49-1.67; P = .7464) toxicities was found between patients with or without biologic agents who were treated concurrently with RT. No significant difference was found in reduction in laboratory values between patients with or without biologic agents treated concurrently with RT for white blood cells (P = .6916), platelets (P = .7779), or hematocrit (P = .0858). CONCLUSIONS: Our study did not detect any significant toxicity rates from palliative radiation while patients were concurrently treated with biologic agents.

Dose Selection for Multiple Myeloma in Modern Era.

PURPOSE: The management of multiple myeloma (MM) has evolved over the past 20 years, secondary to novel biologic therapeutics. Radiation therapy remains an important intervention in the management of painful lytic bone lesions. However, the currently used radiation therapy regimens were developed in the pre-biologic therapy era. The goal of this study is to assess the effects of dose and fractionation in pain control for patients with MM in the modern era. METHODS AND MATERIALS: We conducted a retrospective study based on data collected from patients who received radiation therapy at our institute between 2007 and 2017. A total of 130 patients (266 treatment sites) were included in this study. Univariate Cox proportional hazards models were used to analyze the association of risk of pain recurrence with treatment characteristics and compute the hazard ratios (HRs). RESULTS: The median follow-up time was 14 months. Patients who received a total dose of 20 to <30 Gy (including 20 Gy) had a significantly lower probability of pain recurrence when compared with those who received <20 Gy (HR, 0.36; 95% confidence interval, 0.14-0.94; P = .0365). There was no statistically significant difference in treatment response or pain recurrence between the different fraction numbers and sizes. However, we noted a trend indicating lower pain recurrence in the group that received 6 to 10 fractions of radiation therapy (P = .06). Among the most commonly used regimens, 8 Gy in a single fraction resulted in a statistically significant increased chance of pain recurrence compared with 20 Gy in 10 fractions and a borderline statistically significant increased chance of pain recurrence when compared with 30 Gy in 10 fractions. CONCLUSIONS: Radiation therapy remains highly effective at managing lytic bone lesions in patients with MM, and 6- to 10-fraction treatment courses are equally as effective as longer courses at treating these lesions. Treatment with 20 Gy in 10 fractions resulted in a significantly lower probability of pain recurrence when compared with 8 Gy in 1 fraction.

The impact of radiation treatment planning technique on unplanned hospital admissions.

PURPOSE: Treatment burdens and toxicities related to palliative radiation therapy (RT) may lead to unplanned hospital admissions (UHAs). The likelihood for these toxicities may be related to treatment technique. We compared rates of UHA between patients receiving nonconformal (2-dimensional) and conformal (3-dimensional or higher) radiation treatments to bone metastases involving the vertebral column. METHODS AND MATERIALS: We retrospectively analyzed patients treated with RT for bone metastases at a single tertiary care center between 2010 and 2017. We compared rates of RT-related UHA within 90 days of receiving radiation using Cox competing risk regression models. RESULTS: We identified 326 patients with bone metastases involving the vertebral column, 139 of whom received radiation by nonconformal technique and 187 by conformal technique. On multivariable analysis, conformal techniques were associated with a reduced risk of 90-day UHA (hazard ratio [HR]: 0.35; 95% confidence interval [CI], 0.14-0.88). Other significant factors include hematologic cancer (HR: 0.17; 95% CI, 0.03-0.82) and baseline Eastern Cooperative Oncology Group score ≥2 (HR: 3.02; 95% CI, 1.05-8.69). CONCLUSIONS: The utilization of conformal (non-2-dimensional) radiation treatment plans may help reduce treatment-related toxicities and consequently UHAs after palliation of bone metastases.

Trends of Earlier Palliative Care Consultation in Advanced Cancer Patients Receiving Palliative Radiation Therapy.

CONTEXT: The American Society of Clinical Oncology recommends that all patients with metastatic disease receive dedicated palliative care (PC) services early in their illness, ideally via interdisciplinary care teams. OBJECTIVES: We investigated the time trends of specialty palliative care consultations from the date of metastatic cancer diagnosis among patients receiving palliative radiation therapy (PRT). A shorter time interval between metastatic diagnosis and first PC consultation suggests earlier involvement of palliative care in a patient's life with metastatic cancer. METHODS: In this IRB-approved retrospective analysis, patients treated with PRT for solid tumors (bone and brain) at a single tertiary care hospital between 2010 and 2016 were included. Cohorts were arbitrarily established by metastatic diagnosis within approximately two-year intervals: 1) 1/1/2010-3/27/2012, 2) 3/28/2012-5/21/2014, and 3) 5/22/2014-12/31/2016. Cox proportional hazards regression modeling was used to compare trends of PC consultation among cohorts. RESULTS: Of 284 patients identified, 184 patients received PC consultation, whereas 15 patients died before receiving a PC consult. Median follow-up time until an event or censor was 257 days (range: 1900). Patients in the most recent cohort had a shorter median time to first PC consult (57 days) compared to those in the first (374 days) and second (186 days) cohorts. On multivariable analysis, patients in the third cohort were more likely to undergo a PC consultation earlier in their metastatic illness (hazard ratio: 1.8, 95% CI: 1.2-2.8). CONCLUSION: Over a six-year period, palliative care consultation occurred earlier for metastatic patients treated with PRT at our institution.

A Palliative Radiation Oncology Consult Service Reduces Total Costs During Hospitalization.

CONTEXT: Palliative radiation therapy (PRT) is a highly effective treatment in alleviating symptoms from bone metastases; however, currently used standard fractionation schedules can lead to costly care, especially when patients are treated in an inpatient setting. The Palliative Radiation Oncology Consult (PROC) service was developed in 2013 to improve appropriateness, timeliness, and care value from PRT. OBJECTIVES: Our primary objective was to compare total costs among two cohorts of inpatients with bone metastases treated with PRT before, or after, PROC establishment. Secondarily, we evaluated drivers of cost savings including hospital length of stay, utilization of specialty-care palliative services, and PRT schedules. METHODS: Patients were included in our observational cohort study if they received PRT for bone metastases at a single tertiary care hospital from 2010 to 2016. We compared total costs and length of stay using propensity score-adjusted analyses. Palliative care utilization and PRT schedules were compared by χ2 and Mann-Whitney U tests. RESULTS: We identified 181 inpatients, 76 treated before and 105 treated after PROC. Median total hospitalization cost was $76,792 (range $6380-$346,296) for patients treated before PROC and $50,582 (range $7585-$620,943) for patients treated after PROC. This amounted to an average savings of $20,719 in total hospitalization costs (95% CI [$3687, $37,750]). In addition, PROC was associated with shorter PRT schedules, increased palliative care utilization, and an 8.5 days reduction in hospital stay (95% CI [3.2,14]). CONCLUSION: The PROC service, a radiation oncology model integrating palliative care practice, was associated with cost-savings, shorter treatment courses and hospitalizations, and increased palliative care.

A Palliative Radiation Oncology Consult Service's Impact on Care of Advanced Cancer Patients.

INTRODUCTION: Palliative radiation therapy (PRT) is a commonly utilized intervention for symptom palliation among patients with metastatic cancer, yet it is under-recognized as a distinct area of subspecialty within radiation oncology. OBJECTIVE: We developed a multidisciplinary service model within radiation oncology called the Palliative Radiation Oncology Consult (PROC) service to improve the quality of cancer care for advanced cancer patients. We assessed the service's impact on patient-related and healthcare utilization outcomes. DESIGN: Patients were included in this observational cohort study if they received PRT at a single tertiary care hospital between 2009 and 2017. We compared outcomes of patients treated after (post-intervention group) to those treated before (control group) PROC's establishment using unadjusted and propensity score adjusted analyses. RESULTS: Of the 450 patients in the cohort, 154 receive PRT pre- and 296 after PROC's establishment. In comparison to patients treated pre-PROC, post-PROC patients were more likely to undergo single-fraction radiation (RR: 7.74, 95% CI: 3.84-15.57) and hypofraction (2-5 fraction) radiation (RR: 10.74, 95% CI: 5.82-19.83), require shorter hospital stays (21 vs. 26.5 median days, p = 0.01), and receive more timely specialty-level palliative care (OR: 2.65, 95% CI: 1.56-4.49). Despite shortened treatments, symptom relief was similar (OR: 1.35, 95% CI: 0.80-2.28). CONCLUSION: The PROC service was associated with more efficient radiation courses, substantially reduced hospital length of stays, and more timely palliative care consultation, without compromising symptom improvements. These results suggest that a multidisciplinary care delivery model can lead to enhanced quality of care for advanced cancer patients.

Managing an Older Adult with Cancer: Considerations for Radiation Oncologists.

Older adults with cancer present a unique set of management complexities for oncologists and radiation oncologists. Prognosis and resilience to cancer treatments are notably dependent on the presence or risk of "geriatric syndromes," in addition to cancer stage and histology. Recognition, proper evaluation, and management of these conditions in conjunction with management of the cancer itself are critical and can be accomplished by utilization of various geriatric assessment tools. Here we review principles of the geriatric assessment, common geriatric syndromes, and application of these concepts to multidisciplinary oncologic treatment. Older patients may experience toxicities related to treatments that impact treatment effectiveness, quality of life, treatment-related mortality, and treatment compliance. Treatment-related burdens from radiotherapy are increasingly important considerations and include procedural demands, travel, costs, and temporary or permanent loss of functional independence. An overall approach to delivering radiotherapy to an older cancer patient requires a comprehensive assessment of both physical and nonphysical factors that may impact treatment outcome. Patient and family-centered communication is also an important part of developing a shared understanding of illness and reasonable expectations of treatment.

Liver Stiffness Decreases Rapidly in Response to Successful Hepatitis C Treatment and Then Plateaus.

BACKGROUND AND AIM: To investigate the impact of a sustained virological response (SVR) to hepatitis C virus (HCV) treatment on liver stiffness (LS). METHODS: LS, measured by transient elastography (FibroScan), demographic and laboratory data of patients treated with interferon (IFN)-containing or IFN-free regimens who had an SVR24 (undetectable HCV viral load 24 weeks after the end of treatment) were analyzed using two-tailed paired t-tests, Mann-Whitney Wilcoxon Signed-rank tests and linear regression. Two time intervals were investigated: pre-treatment to SVR24 and SVR24 to the end of follow-up. LS scores ≥ 12.5 kPa indicated LS-defined cirrhosis. A p-value below 0.05 was considered statistically significant. RESULTS: The median age of the patients (n = 100) was 60 years [IQR (interquartile range) 54-64); 72% were male; 60% were Caucasian; and 42% had cirrhosis pre-treatment according to the FibroScan measurement. The median LS score dropped from 10.40 kPa (IQR: 7.25-18.60) pre-treatment to 7.60 kPa (IQR: 5.60-12.38) at SVR24, p <0.01. Among the 42 patients with LS-defined cirrhosis pre-treatment, 25 (60%) of patients still had LS scores ≥ 12.5 kPa at SVR24, indicating the persistence of cirrhosis. The median change in LS was similar in patients receiving IFN-containing and IFN-free regimens: -1.95 kPa (IQR: -5.75 --0.38) versus -2.40 kPa (IQR: -7.70 --0.23), p = 0.74. Among 56 patients with a post-SVR24 LS measurement, the LS score changed by an additional -0.90 kPa (IQR: -2.98-0.5) during a median follow-up time of 1.17 (IQR: 0.88-1.63) years, which was not a statistically significant decrease (p = 0.99). CONCLUSIONS: LS decreased from pre-treatment to SVR24, but did not decrease significantly during additional follow-up. Earlier treatment may be needed to reduce the burden of liver disease.

IGFBP3 promotes esophageal cancer growth by suppressing oxidative stress in hypoxic tumor microenvironment.

Insulin-like growth factor binding protein 3 (IGFBP3), a hypoxia-inducible gene, regulates a variety of cellular processes including cell proliferation, senescence, apoptosis and epithelial-mesenchymal transition (EMT). IGFBP3 has been linked to the pathogenesis of cancers. Most previous studies focus upon proapoptotic tumor suppressor activities of IGFBP3. Nevertheless, IGFBP3 is overexpressed in certain cancers including esophageal squamous cell carcinoma (ESCC), one of the most aggressive forms of squamous cell carcinomas (SCCs). The tumor-promoting activities of IGFBP3 remain poorly understood in part due to a lack of understanding as to how the tumor microenvironment may influence IGFBP3 expression and how IGFBP3 may in turn influence heterogeneous intratumoral cell populations. Here, we show that IGFBP3 overexpression is associated with poor postsurgical prognosis in ESCC patients. In xenograft transplantation models with genetically engineered ESCC cells, IGFBP3 contributes to tumor progression with a concurrent induction of a subset of tumor cells showing high expression of CD44 (CD44H), a major cell surface receptor for hyaluronic acid, implicated in invasion, metastasis and drug resistance. Our gain-of-function and loss-of-function experiments reveal that IGFBP3 mediates the induction of intratumoral CD44H cells. IGFBP3 cooperates with hypoxia to mediate the induction of CD44H cells by suppressing reactive oxygen species (ROS) in an insulin-like growth factor-independent fashion. Thus, our study sheds light on the growth stimulatory functions of IGFPB3 in cancer, gaining a novel mechanistic insight into the functional interplay between the tumor microenvironment and IGFBP3.

Notch receptor inhibition reveals the importance of cyclin D1 and Wnt signaling in invasive esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive forms of squamous cell carcinomas. Common genetic lesions in ESCC include p53 mutations and EGFR overexpression, both of which have been implicated in negative regulation of Notch signaling. In addition, cyclin D1 is overexpressed in ESCC and can be activated via EGFR, Notch and Wnt signaling. To elucidate how these genetic lesions may interact during the development and progression of ESCC, we tested a panel of genetically engineered human esophageal cells (keratinocytes) in organotypic 3D culture (OTC), a form of human tissue engineering. Notch signaling was suppressed in culture and mice by dominant negative Mastermind-like1 (DNMAML1), a genetic pan-Notch inhibitor. DNMAML1 mice were subjected to 4-Nitroquinoline 1-oxide-induced oral-esophageal carcinogenesis. Highly invasive characteristics of primary human ESCC were recapitulated in OTC as well as DNMAML1 mice. In OTC, cyclin D1 overexpression induced squamous hyperplasia. Concurrent EGFR overexpression and mutant p53 resulted in transformation and invasive growth. Interestingly, cell proliferation appeared to be regulated differentially between those committed to squamous-cell differentiation and those invading into the stroma. Invasive cells exhibited Notch-independent activation of cyclin D1 and Wnt signaling. Within the oral-esophageal squamous epithelia, Notch signaling regulated squamous-cell differentiation to maintain epithelial integrity, and thus may act as a tumor suppressor by preventing the development of a tumor-promoting inflammatory microenvironment.

Hypoxia induces IGFBP3 in esophageal squamous cancer cells through HIF-1α-mediated mRNA transcription and continuous protein synthesis.

Insulin-like growth factor binding protein (IGFBP)-3 regulates cell proliferation and apoptosis in esophageal squamous cell carcinoma (ESCC) cells. We have investigated how the hypoxic tumor microenvironment in ESCC fosters the induction of IGFBP3. RNA interference experiments revealed that hypoxia-inducible factor (HIF)-1α, but not HIF-2α, regulates IGFBP3 mRNA induction. By chromatin immunoprecipitation and transfection assays, HIF-1α was found to transactivate IGFBP3 through a novel hypoxia responsive element (HRE) located at 57 kb upstream from the transcription start site. Metabolic labeling experiments demonstrated hypoxia-mediated inhibition of global protein synthesis. 7-Methyl GTP-cap binding assays suggested that hypoxia suppresses cap-dependent translation. Experiments using pharmacological inhibitors for mammalian target of rapamycin (mTOR) suggested that a relatively weak mTOR activity may be sufficient for cap-dependent translation of IGFBP3 under hypoxic conditions. Bicistronic RNA reporter transfection assays did not validate the possibility of an internal ribosome entry site as a potential mechanism for cap-independent translation for IGFBP3 mRNA. Finally, IGFBP3 mRNA was found enriched to the polysomes. In aggregate, our study establishes IGFBP3 as a direct HIF-1α target gene and that polysome enrichment of IGFBP3 mRNA may permit continuous translation under hypoxic conditions.