Combining PARP Inhibition and Immunotherapy in BRCA-Associated Cancers.

Poly (ADP-ribose) polymerase (PARP) inhibitors have significantly improved treatment outcomes of homologous recombination (HR) repair-deficient cancers. While the activity of these agents is largely linked to multiple mechanisms underlying the synthetic lethality of PARP inhibition and HR deficiency, emerging data suggest that their efficacy is also tied to their effects on the immune microenvironment and dependent upon cytotoxic T-cell activation. Effects observed in preclinical models are currently being validated in on-treatment biopsy samples procured from patients enrolled in clinical trials. Although this work has stimulated the development of combinations of PARP inhibitors with immunomodulatory agents, results to date have not demonstrated the superiority of combined PARP inhibition and immune checkpoint blockade compared with PARP inhibition alone. These results have stimulated a more comprehensive assessment of the immunosuppressive components of the tumor microenvironment that must be addressed so that the efficacy of PARP inhibitor agents can be maximized.

Transvaginal Migration of Ventriculoperitoneal Shunts in Children: Review of Literature.

Ventriculo-peritoneal shunt placement is the most commonly performed procedure for the treatment of hydrocephalus. The complication of migration of the distal ventriculo-peritoneal shunt is one of the many complications that occur after ventriculo-peritoneal shunt placement. The migration of the ventriculo-peritoneal shunt through the vagina is infrequently reported in children. The aim of this review is to help all the providers caring for children with ventriculo-peritoneal shunts to identify issues early when encountered with this complication and thus limit morbidity and mortality. We reviewed all cases of migration of ventriculo-peritoneal shunt through the vagina in children less than 18 years of age that were published in the literature using PubMed, Google Scholar, Web of Science, and Cochrane Library. A total of 11 articles met the eligibility criteria and were included in this review among the 93 articles obtained with title and abstract screening. Previous non-shunt-related abdominal operations and shunt revisions are consistent risk factors in all cases. We did not recognize specific approaches to catheter placement or management that could have prevented this complication. Ventriculitis necessitating shunt removal and therapies requiring additional procedures and prolonged hospitalization are the major consequences identified. Awareness of this unusual complication is very important among health care providers such as emergency care health providers who are likely to be the first to encounter these children on initial presentation.

MatchMiner: an open-source platform for cancer precision medicine.

Widespread, comprehensive sequencing of patient tumors has facilitated the usage of precision medicine (PM) drugs to target specific genomic alterations. Therapeutic clinical trials are necessary to test new PM drugs to advance precision medicine, however, the abundance of patient sequencing data coupled with complex clinical trial eligibility has made it challenging to match patients to PM trials. To facilitate enrollment onto PM trials, we developed MatchMiner, an open-source platform to computationally match genomically profiled cancer patients to PM trials. Here, we describe MatchMiner's capabilities, outline its deployment at Dana-Farber Cancer Institute (DFCI), and characterize its impact on PM trial enrollment. MatchMiner's primary goals are to facilitate PM trial options for all patients and accelerate trial enrollment onto PM trials. MatchMiner can help clinicians find trial options for an individual patient or provide trial teams with candidate patients matching their trial's eligibility criteria. From March 2016 through March 2021, we curated 354 PM trials containing a broad range of genomic and clinical eligibility criteria and MatchMiner facilitated 166 trial consents (MatchMiner consents, MMC) for 159 patients. To quantify MatchMiner's impact on trial consent, we measured time from genomic sequencing report date to trial consent date for the 166 MMC compared to trial consents not facilitated by MatchMiner (non-MMC). We found MMC consented to trials 55 days (22%) earlier than non-MMC. MatchMiner has enabled our clinicians to match patients to PM trials and accelerated the trial enrollment process.

SARS-CoV-2 With Concurrent Respiratory Viral Infection as a Risk Factor for a Higher Level of Care in Hospitalized Pediatric Patients.

OBJECTIVE: As of early 2021, there have been over 3.5 million pediatric cases of SARS-CoV-2, including 292 pediatric deaths in the United States. Although most pediatric patients present with mild disease, they are still at risk for developing significant morbidity requiring hospitalization and intensive care unit (ICU) level of care. This study was performed to evaluate if the presence of concurrent respiratory viral infections in pediatric patients admitted to the hospital with SARS-CoV-2 was associated with an increased rate of ICU level of care. DESIGN: A multicenter, international, noninterventional, cross-sectional study using data provided through The Society of Critical Care Medicine Discovery Network Viral Infection and Respiratory Illness Universal Study database. SETTING: The medical ward and ICU of 67 participating hospitals. PATIENTS: Pediatric patients younger than 18 years hospitalized with SARS-CoV-2. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 922 patients were included. Among these patients, 391 required ICU level care and 31 had concurrent non-SARS-CoV-2 viral coinfection. In a multivariate analysis, after accounting for age, positive blood culture, positive sputum culture, preexisting chronic medical conditions, the presence of a viral respiratory coinfection was associated with need for ICU care (odds ratio, 3.6; 95% confidence interval, 1.6-9.4; P < 0.01). CONCLUSIONS: This study demonstrates an association between concurrent SARS-CoV-2 infection with viral respiratory coinfection and the need for ICU care. Further research is needed to identify other risk factors that can be used to derive and validate a risk-stratification tool for disease severity in pediatric patients with SARS-CoV-2.

A 28-Year-Old Man With Diffuse Bilateral Pulmonary Nodules.

CASE PRESENTATION: A 28-year-old man with a history of congenital HIV sought treatment at the ED with a chief symptom of generalized malaise and confusion of 3 days' duration. He had mild dyspnea, but no respiratory distress, and he reported no fever, chest pain, or headache. We were unable to obtain past medical, family, or social history because of encephalopathy and we had no available contact person. Review of the patient's medical record revealed he made an initial clinic visit to the Department of Pediatric Infectious Disease 5 years previously. At the time of that visit, CD4 count was 250 cells/mm3 and no known complications of HIV were documented. He was prescribed Stribild (elvitegravir-cobicistat-emtricitabine-tenofovir disoproxil fumarate) and darunavir; however, pharmacy records revealed he did not fill the prescriptions. He underwent no further clinic follow-up examinations. He grew up in California and moved to upstate New York 5 years previously.

Characterization and Outcomes of Hospitalized Children With Coronavirus Disease 2019: A Report From a Multicenter, Viral Infection and Respiratory Illness Universal Study (Coronavirus Disease 2019) Registry.

OBJECTIVES: Multicenter data on the characteristics and outcomes of children hospitalized with coronavirus disease 2019 are limited. Our objective was to describe the characteristics, ICU admissions, and outcomes among children hospitalized with coronavirus disease 2019 using Society of Critical Care Medicine Discovery Viral Infection and Respiratory Illness Universal Study: Coronavirus Disease 2019 registry. DESIGN: Retrospective study. SETTING: Society of Critical Care Medicine Viral Infection and Respiratory Illness Universal Study (Coronavirus Disease 2019) registry. PATIENTS: Children (< 18 yr) hospitalized with coronavirus disease 2019 at participating hospitals from February 2020 to January 2021. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was ICU admission. Secondary outcomes included hospital and ICU duration of stay and ICU, hospital, and 28-day mortality. A total of 874 children with coronavirus disease 2019 were reported to Viral Infection and Respiratory Illness Universal Study registry from 51 participating centers, majority in the United States. Median age was 8 years (interquartile range, 1.25-14 yr) with a male:female ratio of 1:2. A majority were non-Hispanic (492/874; 62.9%). Median body mass index (n = 817) was 19.4 kg/m2 (16-25.8 kg/m2), with 110 (13.4%) overweight and 300 (36.6%) obese. A majority (67%) presented with fever, and 43.2% had comorbidities. A total of 238 of 838 (28.2%) met the Centers for Disease Control and Prevention criteria for multisystem inflammatory syndrome in children, and 404 of 874 (46.2%) were admitted to the ICU. In multivariate logistic regression, age, fever, multisystem inflammatory syndrome in children, and pre-existing seizure disorder were independently associated with a greater odds of ICU admission. Hospital mortality was 16 of 874 (1.8%). Median (interquartile range) duration of ICU (n = 379) and hospital (n = 857) stay were 3.9 days (2-7.7 d) and 4 days (1.9-7.5 d), respectively. For patients with 28-day data, survival was 679 of 787, 86.3% with 13.4% lost to follow-up, and 0.3% deceased. CONCLUSIONS: In this observational, multicenter registry of children with coronavirus disease 2019, ICU admission was common. Older age, fever, multisystem inflammatory syndrome in children, and seizure disorder were independently associated with ICU admission, and mortality was lower among children than mortality reported in adults.

Use of esophageal balloon manometry in the management of pediatric acute respiratory distress syndrome.

There is paucity of literature regarding the use of esophageal balloon manometry in the management of Pediatric Acute Respiratory Distress Syndrome. We describe our first ever experience of successful usage of esophageal balloon pressure manometry in a child with acute respiratory distress syndrome. This is a six-year-old girl who presented with shortness of breath and fever and was found to be in severe acute respiratory distress syndrome due to septic shock secondary to group A streptococcus. The patient was managed using an esophageal balloon manometry for positive end-expiratory pressure titration. She was liberated from invasive mechanical ventilation on day 7 of hospital course. Esophageal balloon manometry guided positive end-expiratory pressure for 103 out of 155 hours of ventilation with no obvious sequelae. Our case shows the feasibility of transpulmonary pressure measurements in pediatric patients. This practice may be useful to optimize management in pediatric acute respiratory distress syndrome to improve outcomes.

Risk Factors for Delayed Enteral Nutrition in Critically Ill Children.

OBJECTIVE: Delayed enteral nutrition, defined as enteral nutrition started 48 hours or more after admission to the PICU, is associated with an inability to achieve full enteral nutrition and worse outcomes in critically ill children. We reviewed nutritional practices in six medical-surgical PICUs and determined risk factors associated with delayed enteral nutrition in critically ill children. DESIGN: Retrospective cross-sectional study using medical records as source of data. SETTING: Six medical-surgical PICUs in northeastern United States. PATIENTS: Children less than 21 years old admitted to the PICU for 72 hours or more excluding those awaiting or recovering from abdominal surgery. MEASUREMENTS AND MAIN RESULTS: A total of 444 children with a median age of 4.0 years were included in the study. Enteral nutrition was started at a median time of 20 hours after admission to the PICU. There was no significant difference in time to start enteral nutrition among the PICUs. Of those included, 88 children (19.8%) had delayed enteral nutrition. Risk factors associated with delayed enteral nutrition were noninvasive (odds ratio, 3.37; 95% CI, 1.69-6.72) and invasive positive-pressure ventilation (odds ratio, 2.06; 95% CI, 1.15-3.69), severity of illness (odds ratio for every 0.1 increase in pediatric index of mortality 2 score, 1.39; 95% CI, 1.14-1.71), procedures (odds ratio, 3.33; 95% CI, 1.67-6.64), and gastrointestinal disturbances (odds ratio, 2.05; 95% CI, 1.14-3.68) within 48 hours after admission to the PICU. Delayed enteral nutrition was associated with failure to reach full enteral nutrition while in the PICU (odds ratio, 4.09; 95% CI, 1.97-8.53). Nutrition consults were obtained in less than half of the cases, and none of the PICUs used tools to assure the adequacy of energy and protein nutrition. CONCLUSIONS: Institutions in this study initiated enteral nutrition for a high percentage of patients by 48 hours of admission. Noninvasive positive-pressure ventilation was most strongly associated with delay enteral nutrition. A better understanding of these risk factors and assessments of nutritional requirements should be explored in future prospective studies.