To determine local control according to clinical variables for patients with intermediate-risk rhabdomyosarcoma (RMS) treated on Children's Oncology Group protocol D9803.
Of 702 patients enrolled, we ...analyzed 423 patients with central pathology-confirmed group III embryonal (n=280) or alveolar (group III, n=102; group I-II, n=41) RMS. Median age was 5 years. Patients received 42 weeks of VAC (vincristine, dactinomycin, cyclophosphamide) or VAC alternating with VTC (T = topotecan). Local therapy with 50.4 Gy radiation therapy with or without delayed primary excision began at week 12 for group III patients. Patients with group I/II alveolar RMS received 36-41.4 Gy. Local failure (LF) was defined as local progression as a first event with or without concurrent regional or distant failure.
At a median follow-up of 6.6 years, patients with clinical group I/II alveolar RMS had a 5-year event-free survival rate of 69% and LF of 10%. Among patients with group III RMS, 5-year event-free survival and LF rates were 70% and 19%, respectively. Local failure rates did not differ by histology, nodal status, or primary site, though there was a trend for increased LF for retroperitoneal (RP) tumors (P=.12). Tumors ≥5 cm were more likely to fail locally than tumors <5 cm (25% vs 10%, P=.0004). Almost all (98%) RP tumors were ≥5 cm, with no difference in LF by site when the analysis was restricted to tumors ≥5 cm (P=.86).
Local control was excellent for clinical group I/II alveolar RMS. Local failure constituted 63% of initial events in clinical group III patients and did not vary by histology or nodal status. The trend for higher LF in RP tumors was related to tumor size. There has been no clear change in local control over RMS studies, including IRS-III and IRS-IV. Novel approaches are warranted for larger tumors (≥5 cm).
Background:
The gut microbiome plays a critical role in modulating the therapeutic effect of immune checkpoint inhibitors (ICIs). Proton pump inhibitors (PPIs) are commonly used in cancer patients ...and may affect the gut microbiome by altering gut pH.
Objective:
To evaluate if concurrent use of PPI is associated with overall survival (OS) and progression-free survival (PFS) in patients with stage IV non–small-cell lung cancer (NSCLC), melanoma, renal cell carcinoma, transitional cell carcinoma, or head and neck squamous cell carcinoma.
Methods:
This was a single-center retrospective cohort study of advanced cancer adult patients who received nivolumab or pembrolizumab between September 1, 2014, and August 31, 2019. Concomitant PPI exposure was defined as PPI use 0 to 30 days before or after initiation of ICIs. Treatment outcome was OS and PFS.
Results:
A total of 233 patients were included in our study. Concomitant PPI use was not significantly associated with OS (hazard ratio HR = 1.22; 95% CI = 0.80-1.86) or PFS (HR = 1.05; 95% CI = 0.76-1.45) in patients with ICI use. The effect estimates were robust after adjusting for covariates in multivariate analysis and in patients with NSCLC.
Conclusion and Relevance:
Concomitant PPI use was not associated with the effectiveness of nivolumab or pembrolizumab. Certain predictors of survival outcomes related to PPI use in patients receiving immunotherapy, such as the time window and indication of PPI exposure and autoimmune disorders, should be explored in the future to better carve out the impact of PPI on the effectiveness of ICI use.
Several anti-viral drugs have demonstrated efficacy in preventing Cytomegalovirus (CMV) infections in solid organ transplant (SOT) patients. The recently approved valganciclovir is the most commonly ...used and most expensive drug for CMV prevention. The safety and efficacy data have been drawn from a single trial. We hypothesized that valganciclovir may not be as safe as nor more effective than other therapies for CMV prevention.
All experimental and analytical studies that compared valganciclovir with other therapies for prevention of CMV infection after SOT were selected. Based on meta-analytic and multivariate regression methodologies we critically analyzed all available evidence.
Nine studies were included (N = 1,831). In trials comparing valganciclovir with ganciclovir, the risk for CMV disease is 0.98 (95% Confidence Interval (95%CI) 0.67 to 1.43; P = 0.92; I(2) = 0%). Valganciclovir was significantly associated with the risk of absolute neutropenia (<1,500/mm(3)) compared with all therapies (Odds Ratio (OR) 3.63 95%CI 1.75 to 7.53; P = 0.001; I(2) = 0%); with ganciclovir only (OR 2.88, 95%CI 1.27 to 6.53; P = 0.01; I(2) = 0%); or with non-ganciclovir therapies (OR 8.30, 95%CI 1.51 to 45.58; P = 0.01; I(2) = 10%). For a neutropenia cut-off of <1,000/mm(3), the risk remained elevated (OR 1.97, 95%CI 1.03 to 3.67; P = 0.04; I(2) = 0%). For every 24 patients who receive valganciclovir prophylaxis, one more will develop neutropenia compared to other therapies. The risk of late-onset CMV disease with valganciclovir was similar to ganciclovir and higher than those with non-ganciclovir therapies (OR 8.95, 95%CI 1.07 to 74.83; P = 0.04; I(2) = 0%. One more patient will develop late-onset CMV disease for every 25 who receive valganciclovir compared to treatment with non-ganciclovir therapies. The risk of CMV tissue-invasive disease in liver recipients receiving valganciclovir was 4.5 times the risk seen with ganciclovir 95%CI 1.00 to 20.14 (p = 0.04). All results remained consistent across different study designs, valganciclovir doses, and CMV serostatus.
Valganciclovir shows no superior efficacy and significantly higher risk of absolute neutropenia, CMV late-onset disease, and CMV tissue-invasive disease compared to other standard therapies. Due to the availability of efficacious, safer, and lower cost drugs (high-dose acyclovir, valacyclovir, ganciclovir), our results do not favor the use of valganciclovir as a first-line agent for CMV preemptive or universal prophylaxis in SOT patients.
To simplify the recommended staging evaluation by correlating tumor and clinical features with patterns of distant metastasis in newly diagnosed patients with embryonal rhabdomyosarcoma (ERMS) or ...alveolar rhabdomyosarcoma (ARMS).
Patient data from the Intergroup Rhabdomyosarcoma Study Group and the Children's Oncology Group over two periods were analyzed: 1991 to 1997 and 1999 to 2004. We used recursive partitioning analyses to identify factors (including histology, age, regional nodal and distant metastatic status, tumor size, local invasiveness, and primary site) that divided patients into subsets with the most different rates of metastatic disease.
Of the 1,687 patients analyzed, 5.7% had lung metastases, 4.8% had bone involvement, and 6% had bone marrow (BM) involvement. Rhabdomyosarcoma (RMS) without local invasion (T1) had a low rate of metastasis for all distant sites, especially ERMS (0% bone, 0% BM). ARMS with local invasion (T2) had a higher rate of metastasis for all distant sites (13% lung, 18% bone, 23% BM). ERMS, T2 also had a higher rate of metastatic lung involvement (9%). The likelihood of bone or BM involvement increased in the presence of lung metastases (41% with, 6% without). Regional nodal metastases (N1) predicted a high rate of metastasis in all distant sites (14% lung, 14% bone, 18% BM). A staging algorithm was developed.
Staging studies in childhood RMS can be tailored to patients' presenting characteristics. Bone marrow aspirate and biopsy and bone scan are unnecessary in at least one third of patients with RMS.
Neonatal brain injury is a potentially devastating cause of neurodevelopmental impairment. There is no consensus, however, on the appropriate timing and frequency of routine head ultrasound (HUS) ...screening for such injuries. We evaluated the diagnostic utility of routine HUS screening at 30 days of life ("late HUS") for detecting severe intraventricular hemorrhage (IVH) or cystic periventricular leukomalacia (c-PVL) in preterm infants with a negative HUS before 14 days of life ("early HUS").
Single-center retrospective cohort analysis of infants born at ≤ 32 weeks gestational age (GA) admitted to the University of Nebraska Medical Center NICU from 2011-2018. Demographics, HUS and MRI diagnoses were abstracted from clinical records. Fisher's exact test and t-test assessed associations between categorical and continuous variable, respectively.
205 infants were included-120 very preterm (28-32 weeks GA) and 85 extremely preterm (<28 weeks GA). Negative predictive value of early HUS for predicting any clinically significant anomalies (severe IVH or c-PVL) on late HUS was 100% for extremely and 99.2% for very preterm infants. Term-equivalent MRI detected previously undiagnosed c-PVL in 16.7% of the 24 patients that received MRI; all infants with new c-PVL on MRI had severe IVH on early HUS.
Following negative early HUS, late HUS detected significant new abnormalities in one infant. These data suggest that in a unit with low prevalence of c-PVL, 30-day HUS may have limited clinical utility following negative screening. In infants with abnormal early HUS, clinicians should consider obtaining term-equivalent MRI screening to detect c-PVL.
Oxidized zirconium (OxZi) and highly cross-linked polyethylene (HXLPE) were developed to minimize wear and risk of osteolysis in total hip arthroplasty (THA). However, retrieval studies have shown ...that scratched femoral heads may lead to runaway wear, and few reports of long-term results have been published. The purpose of this investigation is to report minimum ten-year wear rates and clinical outcomes of THA with OxZi femoral heads on HXLPE, and to compare them with a retrospective control group of cobalt chrome (CoCr) or ceramic heads on HXLPE.
From 2003 to 2006, 108 THAs were performed on 96 patients using an OxZi head with a HXLPE liner with minimum ten-year follow-up. Harris Hip Scores (HHS) were collected preoperatively and at the most recent follow-up (mean 13.3 years). Linear and volumetric liner wear was measured on radiographs of 85 hips with a minimum ten-year follow-up (mean 14.5 years). This was compared to a retrospective control group of 45 THAs using ceramic or CoCr heads from October 1999 to February 2005, with a minimum of ten years' follow-up.
Average HHS improved from 50.8 to 91.9 and 51.0 to 89.8 in the OxZi group and control group, respectively (p = 0.644), with no osteolysis in either group. Linear and volumetric wear rates in the OxZi group averaged 0.03 mm/year and 3.46 mm
/year, respectively. There was no statistically significant difference in HHS scores, nor in linear or volumetric wear rate between the groups, and no revision for any indication.
The radiological and clinical outcomes, and survivorship of THA with OxZi femoral heads and HXLPE liners, were excellent, and comparable to CoCr or ceramic heads at minimum ten-year follow-up. Wear rates are below what would be expected for development of osteolysis. OxZi-HXLPE is a durable bearing couple with excellent long-term outcomes.
Very low birth weight (VLBW) infants may be at risk for late-onset circulatory collapse (LCC) where otherwise stable infants develop hypotension resistant to vasoactive agents. The risk factors for ...LCC development are poorly defined, and it has been theorized that it may be in part due to withdrawal from exogenous prenatal steroids. The goal of this study was to define the clinical characteristics of LCC and investigate its association with antenatal steroid administration.
This is a retrospective cohort study of infants born ≤1500 g. LCC was retrospectively diagnosed in infants requiring glucocorticoids for circulatory instability at >1 week of life. Demographic and clinical characteristics were compared between groups using Mann-Whitney test.
Three hundred and ten infants were included; 19 (6.1%) developed LCC. Infants with LCC were born at a median 4.6 weeks' lower gestation, 509 g lower birth weight than those without LCC. There was no difference in antenatal steroid delivery between the groups.
LCC occurs in a distinct subset of VLBW infants, suggesting the need for monitoring in this high-risk population. Antenatal steroids did not significantly increase the risk of LCC development in this study.
Late-onset circulatory collapse (LCC) is a life-threatening clinical entity occurring in around 6% in VLBW infants and is likely underdiagnosed in the United States. Targeting specific demographic characteristics such as birth weight (<1000 g) and gestational age at birth (<26 weeks) may allow for early identification of high-risk infants, allowing close monitoring and prompt treatment of LCC. No significant association was found between antenatal steroid administration and LCC development, suggesting that the theoretical risks of antenatal steroids on the fetal HPA axis does not outweigh the benefits of antenatal steroids in fetal lung maturity. To date, no studies characterizing LCC have originated outside of Asia. Therefore, providing a description of LCC in a U.S.-based cohort will provide insight into both its prevalence and presentation to inform clinicians about this potentially devastating disorder and foster early diagnosis and treatment. This study validates LCC characteristics and prevalence previously outlined by Asian studies in a single-center U.S.-based cohort while also identifying potential risk factors for LCC development. This manuscript will provide education for U.S. physicians about the risk factors and clinical presentation of LCC to facilitate early diagnosis and treatment, potentially decreasing neonatal mortality. With prompt recognition and treatment of LCC, infants may have decreased exposure to vasoactive medications that have significant systemic effects.
Although growing evidence supports the inclusion of social media in education, no studies to date have investigated the potential role of Instagram in anatomy education for dental students. ...Anatomists at University of Texas School of Dentistry (UTSD) and University of Nebraska Medical Center (UNMC) College of Dentistry created unique Instagram pages supplemental to traditional pedagogy, aiming to provide easily‐accessible, interactive content for our tech‐savvy students. The aim of this study was to evaluate students’ perspectives of the use of social media in education and their respective professor's Instagram page. In the fall of 2020, 170 students (86 from UTSD and 84 from UNMC) voluntarily participated in a survey via Qualtrics. The majority of respondents (85.1%) had seven or more years of experience with social media, and 96.9% of students reported using social media as a source of information with 92.5% using for educational purposes. All students agreed that their respective professor's page has been helpful for anatomy study and review, added to their understanding of anatomy, is convenient, engaging, and professional. While consistent themes emerged between cohorts, UNMC students had a higher level of agreement regarding their page's added relevance to learning in the class/clinic (p = 0.0016), while UTSD students reported feeling more comfortable asking their professor questions through Instagram (p = 0.015). Among all variables, female students and Generation Z students responded more favorably than male or Generation Y counterparts. Here, the authors describe benefits and considerations for others interested in using Instagram as an educational tool.
B-cell chronic lymphocytic leukemia (CLL) results from intrinsic genetic defects and complex microenvironment stimuli that fuel CLL cell growth through an array of survival signaling pathways. Novel ...small-molecule agents targeting the B-cell receptor pathway and anti-apoptotic proteins alone or in combination have revolutionized the management of CLL, yet combination therapy carries significant toxicity and CLL remains incurable due to residual disease and relapse. Single-molecule inhibitors that can target multiple disease-driving factors are thus an attractive approach to combat both drug resistance and combination-therapy-related toxicities. We demonstrate that SRX3305, a novel small-molecule BTK/PI3K/BRD4 inhibitor that targets three distinctive facets of CLL biology, attenuates CLL cell proliferation and promotes apoptosis in a dose-dependent fashion. SRX3305 also inhibits the activation-induced proliferation of primary CLL cells in vitro and effectively blocks microenvironment-mediated survival signals, including stromal cell contact. Furthermore, SRX3305 blocks CLL cell migration toward CXCL-12 and CXCL-13, which are major chemokines involved in CLL cell homing and retention in microenvironment niches. Importantly, SRX3305 maintains its anti-tumor effects in ibrutinib-resistant CLL cells. Collectively, this study establishes the preclinical efficacy of SRX3305 in CLL, providing significant rationale for its development as a therapeutic agent for CLL and related disorders.
PDF
