The Role of Adjuvant Radiotherapy for the Treatment of Resected High-Risk Stage III Cutaneous Melanoma in the Era of Modern Systemic Therapies.

Modern adjuvant systemic therapies (STs) have revolutionized the management of stage III melanoma. Currently, the role of adjuvant radiotherapy (RT) remains unclear. In this single-center retrospective study, patients with clinically detectable stage III melanoma with high-risk features for lymph node basin (LNB) recurrence and whose tumors were fully resected with complete lymphadenectomy (CLD) between 2010 and 2019 were assessed. We determined the cumulative incidence (CIF) of LNB recurrence and any disease recurrence or progression using competing risk analysis. A total of 108 patients were identified; the median age was 59 years (24-92), and 74 (69%) were men. A total of 51 (42%) received adjuvant RT, 22 (20%) received adjuvant ST, and 35 (32%) received no adjuvant therapy. The advent of ST changed clinical practice, with a significant increase in the use of adjuvant ST and a decrease in the use of RT when comparing practice patterns before and after 2015 (p < 0.001). The 3-year CIF of LNB recurrence was similar in patients treated with adjuvant RT (6.3%) and adjuvant ST (9.8%). The 3-year CIF of any disease recurrence or progression was lower in patients receiving adjuvant ST (24%) compared to those receiving adjuvant RT (52%) or no adjuvant therapy (55%, p = 0.06). Three-year overall survival (OS) was not significantly different in patients treated with ST compared to those not treated with any ST (p = 0.118). Despite ST replacing RT as the dominant adjuvant treatment modality, this change in practice has not resulted in increased LNB recurrence for patients at high risk of LNB recurrence following CLD.

Low grade endometrial stromal sarcoma in pregnancy: A case in support of safe abortion access.

Background: Endometrial stromal sarcoma (ESS) is extremely rare in pregnancy. It shares clinical and imaging features with more common pregnancy findings such as leiomyoma and molar gestations, which makes diagnosis challenging. Case: A 36-year-old patient presented at 8 weeks and 1 day gestation for vaginal bleeding. An intrauterine pregnancy with an appropriately sized embryo with heart motion and a 9.5 cm complex uterine mass was found on ultrasound. MRI showed an 11.4 cm cystic mass with nodular septations causing mass effect on the endometrial cavity. After extensive counseling, the patient underwent a gravid abdominal hysterectomy and bilateral salpingectomy. Final pathology showed low grade ESS. Conclusion: This case highlights the importance of evaluating suspicious uterine masses in pregnancy and the necessity for safe abortion access.

Analysis of the Circulating Metabolome of Patients with Cutaneous, Mucosal and Uveal Melanoma Reveals Distinct Metabolic Profiles with Implications for Response to Immunotherapy.

Cutaneous melanoma (CM) patients respond better to immune checkpoint inhibitors (ICI) than mucosal and uveal melanoma patients (MM/UM). Aiming to explore these differences and understand the distinct response to ICI, we evaluated the serum metabolome of advanced CM, MM, and UM patients. Levels of 115 metabolites were analyzed in samples collected before ICI, using a targeted metabolomics platform. In our analysis, molecules involved in the tryptophan-kynurenine axis distinguished UM/MM from CM. UM/MM patients had higher levels of 3-hydroxykynurenine (3-HKyn), whilst patients with CM were found to have higher levels of kynurenic acid (KA). The KA/3-HKyn ratio was significantly higher in CM versus the other subtypes. UM, the most ICI-resistant subtype, was also associated with higher levels of sphingomyelin-d18:1/22:1 and the polyamine spermine (SPM). Overall survival was prolonged in a cohort of CM patients with lower SPM levels, suggesting there are also conserved metabolic factors promoting ICI resistance across melanoma subtypes. Our study revealed a distinct metabolomic profile between the most resistant melanoma subtypes, UM and MM, compared to CM. Alterations within the kynurenine pathway, polyamine metabolism, and sphingolipid metabolic pathway may contribute to the poor response to ICI. Understanding the different metabolomic profiles introduces opportunities for novel therapies with potential synergic activity to ICI, to improve responses of UM/MM.

Integrated, Longitudinal Analysis of Cell-free DNA in Uveal Melanoma.

Uveal melanomas are rare tumors arising from melanocytes that reside in the eye. Despite surgical or radiation treatment, approximately 50% of patients with uveal melanoma will progress to metastatic disease, most often to the liver. Cell-free DNA (cfDNA) sequencing is a promising technology due to the minimally invasive sample collection and ability to infer multiple aspects of tumor response. We analyzed 46 serial cfDNA samples from 11 patients with uveal melanoma over a 1-year period following enucleation or brachytherapy (n = ∼4/patient) using targeted panel, shallow whole genome, and cell-free methylated DNA immunoprecipitation sequencing. We found detection of relapse was highly variable using independent analyses (P = 0.06-0.46), whereas a logistic regression model integrating all cfDNA profiles significantly improved relapse detection (P = 0.02), with greatest power derived from fragmentomic profiles. This work provides support for the use of integrated analyses to improve the sensitivity of circulating tumor DNA detection using multi-modal cfDNA sequencing. Significance: Here, we demonstrate integrated, longitudinal cfDNA sequencing using multi-omic approaches is more effective than unimodal analysis. This approach supports the use of frequent blood testing using comprehensive genomic, fragmentomic, and epigenomic techniques.

Pre-encoded responsiveness to type I interferon in the peripheral immune system defines outcome of PD1 blockade therapy.

Type I interferons (IFN-Is) are central regulators of anti-tumor immunity and responses to immunotherapy, but they also drive the feedback inhibition underlying therapeutic resistance. In the present study, we developed a mass cytometry approach to quantify IFN-I-stimulated protein expression across immune cells and used multi-omics to uncover pre-therapy cellular states encoding responsiveness to inflammation. Analyzing peripheral blood cells from multiple cancer types revealed that differential responsiveness to IFN-Is before anti-programmed cell death protein 1 (PD1) treatment was highly predictive of long-term survival after therapy. Unexpectedly, IFN-I hyporesponsiveness efficiently predicted long-term survival, whereas high responsiveness to IFN-I was strongly associated with treatment failure and diminished survival time. Peripheral IFN-I responsive states were not associated with tumor inflammation, identifying a disconnect between systemic immune potential and 'cold' or 'hot' tumor states. Mechanistically, IFN-I responsiveness was epigenetically imprinted before therapy, poising cells for differential inflammatory responses and dysfunctional T cell effector programs. Thus, we identify physiological cell states with clinical importance that can predict success and long-term survival of PD1-blocking immunotherapy.

Establishing ranked priorities for future hydrocephalus research.

OBJECTIVE: The aim of this initiative was to develop a ranked list of hydrocephalus research priorities as determined by the hydrocephalus patient community in conjunction with the healthcare and scientific community. METHODS: Using the validated methodology published by the James Lind Alliance (JLA), the Hydrocephalus Association (HA) administered two surveys and hosted a final prioritization workshop. Survey One solicited open-ended responses from the community. From these responses, a long list of priority statements was developed. This list was then consolidated into a short list of research priority statements, which, after a nonsystematic literature review, were verified as being research uncertainties. Survey Two asked the community members to select their top 10 priorities from the short list. The final prioritization leading to a final ranked top 20 list of hydrocephalus research priorities took place at a virtual workshop led by a team of trained facilitators, by means of an iterative process of consensus building. RESULTS: From Survey One, 3703 responses from 890 respondents were collected, leading to a long list of 146 priority statements. The consolidated short list contained 49 research priority statements, all of which were verified as uncertainties in hydrocephalus research. From an analysis of Survey Two responses, the top 21 research priority statements were determined. A consensus on these statements was reached at the virtual workshop, leading to a final ranked top 20 list of hydrocephalus research priorities, within which needs were apparent in several areas: development of noninvasive and/or one-time therapies, reduction of the burden of current treatments, improvement of the screening and diagnosis of hydrocephalus, improved quality of life, and improved access to care. CONCLUSIONS: By gathering extensive input from the hydrocephalus community and using an iterative process of consensus building, a ranked list of the top 20 hydrocephalus research priorities was developed. The HA will use this ranked list to guide future research programs and encourages the healthcare and scientific community to do the same.

Correction: Work-Related and Personal Factors Associated With Mental Well-Being During the COVID-19 Response: Survey of Health Care and Other Workers.

[This corrects the article DOI: 10.2196/21366.].

Work-Related and Personal Factors Associated With Mental Well-Being During the COVID-19 Response: Survey of Health Care and Other Workers.

BACKGROUND: The response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has created an unprecedented disruption in work conditions. This study describes the mental health and well-being of workers both with and without clinical exposure to patients with coronavirus disease (COVID-19). OBJECTIVE: The aim of this study is to measure the prevalence of stress, anxiety, depression, work exhaustion, burnout, and decreased well-being among faculty and staff at a university and academic medical center during the SARS-CoV-2 pandemic and describe work-related and personal factors associated with their mental health and well-being. METHODS: All faculty, staff, and postdoctoral fellows of a university, including its medical school, were invited in April 2020 to complete an online questionnaire measuring stress, anxiety, depression, work exhaustion, burnout, and decreased well-being. We examined associations between these outcomes and factors including work in high-risk clinical settings and family/home stressors. RESULTS: There were 5550 respondents (overall response rate of 34.3%). Overall, 34% of faculty and 14% of staff (n=915) were providing clinical care, while 61% of faculty and 77% of staff were working from home. Among all workers, anxiety (prevalence ratio 1.37, 95% CI 1.09-1.73), depression (prevalence ratio 1.28, 95% CI 1.03-1.59), and high work exhaustion (prevalence ratio 1.24, 95% CI 1.13-1.36) were independently associated with community or clinical exposure to COVID-19. Poor family-supportive behaviors by supervisors were also associated with these outcomes (prevalence ratio 1.40, 95% CI 1.21-1.62; prevalence ratio 1.69, 95% CI 1.48-1.92; and prevalence ratio 1.54, 95% CI 1.44-1.64, respectively). Age <40 years and a greater number of family/home stressors were also associated with these poorer outcomes. Among the subset of clinicians, caring for patients with COVID-19 and working in high-risk clinical settings were additional risk factors. CONCLUSIONS: Our findings suggest that the pandemic has had negative effects on the mental health and well-being of both clinical and nonclinical employees. Mitigating exposure to COVID-19 and increasing supervisor support are modifiable risk factors that may protect mental health and well-being for all workers.

An interim report on the investigator-initiated phase 2 study of pembrolizumab immunological response evaluation (INSPIRE).

BACKGROUND: Immune checkpoint inhibitors (ICIs) demonstrate unprecedented efficacy in multiple malignancies; however, the mechanisms of sensitivity and resistance are poorly understood and predictive biomarkers are scarce. INSPIRE is a phase 2 basket study to evaluate the genomic and immune landscapes of peripheral blood and tumors following pembrolizumab treatment. METHODS: Patients with incurable, locally advanced or metastatic solid tumors that have progressed on standard therapy, or for whom no standard therapy exists or standard therapy was not deemed appropriate, received 200 mg pembrolizumab intravenously every three weeks. Blood and tissue samples were collected at baseline, during treatment, and at progression. One core biopsy was used for immunohistochemistry and the remaining cores were pooled and divided for genomic and immune analyses. Univariable analysis of clinical, genomic, and immunophenotyping parameters was conducted to evaluate associations with treatment response in this exploratory analysis. RESULTS: Eighty patients were enrolled from March 21, 2016 to June 1, 2017, and 129 tumor and 382 blood samples were collected. Immune biomarkers were significantly different between the blood and tissue. T cell PD-1 was blocked (≥98%) in the blood of all patients by the third week of treatment. In the tumor, 5/11 (45%) and 11/14 (79%) patients had T cell surface PD-1 occupance at weeks six and nine, respectively. The proportion of genome copy number alterations and abundance of intratumoral 4-1BB+ PD-1+ CD8 T cells at baseline (P < 0.05), and fold-expansion of intratumoral CD8 T cells from baseline to cycle 2-3 (P < 0.05) were associated with treatment response. CONCLUSION: This study provides technical feasibility data for correlative studies. Tissue biopsies provide distinct data from the blood and may predict response to pembrolizumab.

Phase II clinical trial of adoptive cell therapy for patients with metastatic melanoma with autologous tumor-infiltrating lymphocytes and low-dose interleukin-2.

Adoptive cell therapy using autologous tumor-infiltrating lymphocytes (TIL) has shown significant clinical benefit, but is limited by toxicities due to a requirement for post-infusion interleukin-2 (IL-2), for which high dose is standard. To assess a modified TIL protocol using lower dose IL-2, we performed a single institution phase II protocol in unresectable, metastatic melanoma. The primary endpoint was response rate. Secondary endpoints were safety and assessment of immune correlates following TIL infusion. Twelve metastatic melanoma patients were treated with non-myeloablative lymphodepleting chemotherapy, TIL, and low-dose subcutaneous IL-2 (125,000 IU/kg/day, maximum 9-10 doses over 2 weeks). All but one patient had previously progressed after treatment with immune checkpoint inhibitors. No unexpected adverse events were observed, and patients received an average of 6.8 doses of IL-2. By RECIST v1.1, two patients experienced a partial response, one patient had an unconfirmed partial response, and six had stable disease. Biomarker assessment confirmed an increase in IL-15 levels following lymphodepleting chemotherapy as expected and a lack of peripheral regulatory T-cell expansion following protocol treatment. Interrogation of the TIL infusion product and monitoring of the peripheral blood following infusion suggested engraftment of TIL. In one responding patient, a population of T cells expressing a T-cell receptor Vß chain that was dominant in the infusion product was present at a high percentage in peripheral blood more than 2 years after TIL infusion. This study shows that this protocol of low-dose IL-2 following adoptive cell transfer of TIL is feasible and clinically active. (ClinicalTrials.gov identifier NCT01883323.).

Smaller fetal size in singletons after infertility therapies: the influence of technology and the underlying infertility.

OBJECTIVE: To determine whether fetal size differences exist between matched fertile and infertile women and among women with infertility achieving pregnancy through various treatment modalities. DESIGN: Retrospective cohort study with propensity score analysis. SETTING: Tertiary care center and affiliated community hospitals. PATIENT(S): 1,246 fertile and 461 infertile healthy women with singleton livebirths over a 10-year period. INTERVENTION(S): Infertile women conceiving without medical assistance, with ovulation induction, or with in vitro fertilization. MAIN OUTCOME MEASURE(S): Birthweight; secondary outcomes included crown-rump length, second-trimester estimated fetal weight, and incidence of low birth weight and preterm delivery. RESULT(S): Compared with matched fertile women, infertile women had smaller neonates at birth (3,375 ± 21 vs. 3,231 ± 21 g) and more low-birth-weight infants (relative risk = 1.68, 95% confidence interval, 1.06, 2.67). Neonates conceived via ovulation induction were the smallest among the infertility subgroups compared with the neonates of fertile women (3,092 ± 46 vs. 3,397 ± 44 g). First-trimester fetal size was smaller in infertile versus fertile women (crown-rump length 7.9 ± 0.1 vs. 8.5 ± 0.1 mm). Within the infertility subgroups, no differences in fetal or neonatal size were found. CONCLUSION(S): The inherent pathologic processes associated with infertility may have a larger impact on fetal growth than infertility therapies.

Predicting the risk of pre-eclampsia between 11 and 13 weeks' gestation by combining maternal characteristics and serum analytes, PAPP-A and free ß-hCG.

OBJECTIVE: To determine if a simplified model for predicting pre-eclampsia (PEC) can be developed by combining first-trimester serum analytes, pregnancy-associated plasma protein A (PAPP-A) and free beta human chorionic gonadotrophin (ß-hCG), and maternal characteristics. METHODS: A retrospective cohort study of patients seen for first-trimester aneuploidy screening from 2003 to 2009. The 5th, 10th, 90th, and 95th percentiles for the analyte multiples of the medians (MoMs) for our population were determined and evaluated for association with PEC. Univariate and backward stepwise logistic regression analyses were performed and the area under the receiver operating characteristic (ROC) curves [area under curve (AUC)] used to determine the best models for predicting PEC. RESULTS: Among 4020 women meeting the inclusion criteria, outcome data was available for 3716 (93%). There were 293 cases of PEC. The final model identified a history of pre-gestational diabetes [aOR 2.6, 95% confidence interval (CI) 1.7-3.9], chronic hypertension (cHTN) (aOR 2.6, 95% CI 1.7-3.9), maternal body mass index (BMI) > 25 (aOR 2.5, 95% CI 1.9-3.4), African American race (aOR 1.8, 95% CI 1.3-2.6), and PAPP-A MoM < 10th percentile (aOR 1.6, 95% CI 1.1-2.4) to be significant predictors of PEC (AUC = 0.70, 95% CI 0.65-0.72). CONCLUSION: Low first-trimester PAPP-A levels are associated with the development of PEC; however, the model was only modestly efficient in its predictive ability.

The effect of fetal gender in predicting Down syndrome using long bone ultrasonographic measurements.

OBJECTIVE: To determine if fetal gender affects the screening efficiency of short femur and humerus lengths in the prediction of trisomy 21. METHODS: Retrospective cohort study of 62 111 patients presenting for ultrasound from 1990 to 2006. Short humerus and femur lengths were defined using (1) biparietal diameter (BPD) to femur/humerus length (FL/HL) ratios > 1.5 standard deviations above the mean, (2) the observed to expected (O/E) ratio of femur length ≤ 0.91 or humerus length ≤ 0.89, and (3) femur and humerus lengths < 5th percentile. The sensitivity, specificity, and likelihood ratios were calculated for the association of short FL/HL and trisomy 21 stratified by gender. RESULTS: Both BPD/long bone ratios as well as O/E ratios demonstrated a statistically significant higher specificity for the detection of trisomy 21 in female fetuses. This difference was most clinically significant when using the O/E ratio, which yielded a specificity of 82.6% in males and 90.6% in females for short femur, and 69.7% in males and 77.9% in females for short humerus, when these markers were evaluated as isolated findings. CONCLUSION: Gender-specific differences in the effectiveness of both short femur and humerus lengths for the prediction of trisomy 21 may exist, but their presence and magnitude are largely dependent on the formula used.

Do race-specific definitions of short long bones improve the detection of down syndrome on second-trimester genetic sonograms?

OBJECTIVE: The purpose of this study was to determine whether the use of race-specific definitions of short femur and humerus lengths improves Down syndrome detection. METHODS: This was a retrospective cohort study over 16 years. For each self-reported maternal race (white, African American, Hispanic, and Asian), we evaluated the efficiency of Down syndrome detection using published race-specific formulas compared with a standard formula for short femur and humerus lengths (observed versus expected lengths < or =0.91 and < or =0.89, respectively). The sensitivity, specificity, and 95% confidence intervals for each parameter were compared. Screening performance was compared by areas under the receiver operating characteristic curves. RESULTS: Of 58,710 women, 209 (0.3%) had a diagnosis of a fetus with Down syndrome. Although the race-based formula increased sensitivity in each population, the increase was statistically significant only in the white population, whereas a decrease in specificity was statistically significant in all 4 populations, as denoted by nonoverlapping confidence intervals. The area under the receiver operating characteristic curve for the model using the race-specific definition of short femur length was 0.67 versus 0.65 compared with the standard definition, and for humerus length it was 0.70 versus 0.71. CONCLUSIONS: The use of race-based formulas for the determination of short femur and humerus lengths did not significantly improve the detection rates for Down syndrome.

Is chorionic villus sampling associated with hypertensive disorders of pregnancy?

OBJECTIVE: Our objective is to evaluate for potential associations between chorionic villus sampling (CVS) and hypertensive disorders of pregnancy. METHODS: Using our genetic database, we compared the rates of hypertensive disorders between women who underwent CVS at 10-13 and 6/7 weeks with those seen for other indications at similar gestational ages who had no invasive procedure. Only singleton and euploid pregnancies were included. Statistical methods including univariable and multivariable logistic regression, supplemented by stratified analyses were used for comparisons. RESULTS: Among 11 012 pregnant women seen between 1990 and 2006 in our center and meeting the inclusion criteria, information on hypertensive disorders of pregnancy were available in 9386, and 9098 met the inclusion criteria. The overall incidence of hypertensive disorders was 421/9098 (4.6%), with 138/5096 (2.7%) in the CVS group and 283/4002 (7.1%) in the control group [adjusted odds ratio (adjOR) 0.47, 95% confidence interval (CI), 0.38-0.59]. Similar findings were seen on stratified analyses for gestational age of procedure and the type or severity of hypertensive disorder, and other potential confounders. CONCLUSION: The rate of hypertensive disorders of pregnancy is significantly lower in women having CVS compared with the control group. Placental disruption from CVS is not associated with preeclampsia or gestational hypertension.

Echogenic intracardiac foci: associated with increased risk for fetal trisomy 21 or not?

OBJECTIVE: The purpose of this study was to evaluate the impact of an echogenic intracardiac focus (EIF) on the risk for fetal trisomy 21 (T21) in populations with differing prevalence of T21. METHODS: A retrospective cohort study of pregnancies presenting to our prenatal ultrasound units over 16 years (1990-2006) was conducted. Contingency table analysis of the presence of an EIF and diagnosis of fetal T21 was performed. The groups analyzed included the following: (1) all fetuses with EIF plus other sonographic markers, (2) EIF as an isolated sonographic marker, (3) those younger than 35 years with an isolated finding of EIF, and (4) a group with an isolated finding of EIF excluding those at increased risk for T21 on serum screening. RESULTS: Echogenic intracardiac foci were found in 2223 of 62,111 pregnancies (3.6%), and T21 was diagnosed in 218 pregnancies (0.4%). The presence of an EIF along with other markers was associated with a statistically significant risk for T21 (positive likelihood ratio [LR], 4.4; 95% confidence interval [CI], 3.2-6.0; P < .05). An isolated EIF was not associated with a statistically significant increased risk for T21 in patients younger than 35 years (positive LR, 1.7; 95%, CI 0.7-4.1) and those without abnormal serum screening results for aneuploidy (positive LR, 1.6; 95% CI, 0.8-3.1). CONCLUSIONS: The finding of an isolated EIF on prenatal sonography does not significantly increase the risk for fetal T21 in populations not otherwise at an increased risk for the disorder. An isolated EIF should be considered an incidental finding in patients younger than 35 years and in those without abnormal serum aneuploidy screening results.

Prevalence and likelihood ratios for aneuploidy in fetuses diagnosed prenatally with isolated congenital cardiac defects.

OBJECTIVE: To determine the prevalence and likelihood ratios for aneuploidy in fetuses diagnosed prenatally with isolated congenital cardiac defects. STUDY DESIGN: Retrospective cohort study over a 16-year period using our computerized perinatal database. Cardiac diagnosis was confirmed before establishing karyotype by prenatal diagnosis or postnatal chromosome testing. The screening efficiency and likelihood ratios for any aneuploidy and for trisomy 21, 18, 13, and 45, X were calculated with 95% confidence intervals. RESULTS: A total of 233 (0.4%) isolated congenital cardiac defects were diagnosed among 62,111 patients who had obstetric ultrasounds during the study period. The likelihood ratio (LR+) for any aneuploidy was 24.9 (95% confidence interval [CI], 17.8-35.0). The corresponding likelihood ratio for trisomy 21, 18, and 13 were 29.8 (95% CI, 19.6-45.4), 26 (95% CI, 10.5-64.6), and 19.7 (95% CI, 4.7-82.2), respectively. CONCLUSION: Prenatal diagnosis of congenital cardiac defects is highly associated with aneuploidy.

Predicting adverse neonatal outcomes in fetuses with abdominal wall defects using prenatal risk factors.

OBJECTIVE: The aim of this study was to determine whether prenatal variables can predict adverse neonatal outcomes in fetuses with abdominal wall defects. STUDY DESIGN: A retrospective cohort study that used ultrasound and neonatal records for all cases of gastroschisis and omphalocele seen over a 16-year period. Cases with adverse neonatal outcomes were compared with noncases for multiple candidate predictive factors. Univariable and multivariable statistical methods were used to develop the prediction models, and effectiveness was evaluated using the area under the receiver operating characteristic curve. RESULTS: Of 80 fetuses with gastroschisis, 29 (36%) had the composite adverse outcome, compared with 15 of 33 (47%) live neonates with omphalocele. Intrauterine growth restriction was the only significant variable in gastroschisis, whereas exteriorized liver was the only predictor in omphalocele. The areas under the curve for the prediction models with gastroschisis and omphalocele are 0.67 and 0.74, respectively. CONCLUSION: Intrauterine growth restriction and exteriorization of the liver are significant predictors of adverse neonatal outcome with gastroschisis and omphalocele.