Real-World Data: Applications and Relevance to Cancer Clinical Trials.

Randomized controlled trials (RCTs) are the gold standard for comparative-effectiveness research (CER). Since the 1980s, there has been a rise in the creation and utilization of large national cancer databases to provide readily accessible "real-world data" (RWD). This review article discusses the role of RCTs in oncology, and the role of RWD from the national cancer database in CER. RCTs remain the preferred study type for CER because they minimize confounding and bias. RCTs have challenges to conduct, including extensive time and resources, but these factors do not impact the internal validity of the result. Generalizability and external validity are potential limitations of RCTs. RWD is ideal for studying cancer epidemiology, patterns of care, disparities in care delivery, quality-of-care evaluation, and applicability of RCT data in specific populations excluded from RCTs. However, retrospective databases with RWD have limitations in CER due to unmeasured confounders and are often suboptimal in identifying causal treatment effects.

Partial Breast Reirradiation for Patients With Ipsilateral Breast Tumor Recurrence After Initial Treatment With Breast Conservation for Early Stage Breast Cancer.

PURPOSE: Accelerated partial breast irradiation (APBI), including intraoperative radiation therapy (IORT), is an evidence-based treatment option in patients undergoing breast conserving surgery (BCS) for early-stage breast cancer. However, literature regarding reirradiation for patients with ipsilateral breast tumor recurrences (IBTR) is limited. This prospective study assessed the feasibility and efficacy of using APBI in patients who had prior whole breast irradiation. METHODS AND MATERIALS: This was a single institution, prospective study of patients who were previously treated with BCS and adjuvant whole breast radiation. At the time of enrollment, all had unifocal IBTR, histologically confirmed invasive ductal carcinoma with negative margins after repeat BCS. Patients received either IORT in a single fraction at time of BCS or MammoSite brachytherapy twice daily over 5 days. Follow-up data and patient surveys were collected at 1, 3, 6, 9, and 12 months, then annually for at least a 5-year period. RESULTS: From 2008 to 2014, 13 patients were enrolled. Median time to recurrence after initial course of radiation was 12.5 years. Median follow-up after retreatment was 7.8 years. One patient in the IORT group had a subsequent tumor bed recurrence, yielding a local control of 92%. One patient had distant recurrence. At baseline, 680 reported excellent-good cosmesis compared with 42% at 5 years. All patients indicated total satisfaction with overall treatment experience. CONCLUSIONS: APBI using IORT was well tolerated with excellent local control and may be a reasonable alternative to mastectomy for IBTR. Further study is needed to determine the most suitable candidates for this approach.

Stem cell therapy for preventing neonatal diseases in the 21st century: Current understanding and challenges.

Diseases of the preterm newborn such as bronchopulmonary dysplasia, necrotizing enterocolitis, cerebral palsy, and hypoxic-ischemic encephalopathy continue to be major causes of infant mortality and long-term morbidity. Effective therapies for the prevention or treatment for these conditions are still lacking as recent clinical trials have shown modest or no benefit. Stem cell therapy is rapidly emerging as a novel therapeutic tool for several neonatal diseases with encouraging pre-clinical results that hold promise for clinical translation. However, there are a number of unanswered questions and facets to the development of stem cell therapy as a clinical intervention. There is much work to be done to fully elucidate the mechanisms by which stem cell therapy is effective (e.g., anti-inflammatory versus pro-angiogenic), identifying important paracrine mediators, and determining the timing and type of therapy (e.g., cellular versus secretomes), as well as patient characteristics that are ideal. Importantly, the interaction between stem cell therapy and current, standard-of-care interventions is nearly completely unknown. In this review, we will focus predominantly on the use of mesenchymal stromal cells for neonatal diseases, highlighting the promises and challenges in clinical translation towards preventing neonatal diseases in the 21st century.

Human Breast Milk-Derived Extracellular Vesicles in the Protection Against Experimental Necrotizing Enterocolitis.

PURPOSE: Necrotizing enterocolitis (NEC) is a leading cause of death in premature infants. Breast feeding decreases the incidence of NEC but, even with aggressive promotion of nursing in Neonatal Intensive Care Units, morbidity and mortality remain high. Previous studies from our laboratory have demonstrated that extracellular vesicles (EVs) purified from mouse and rat stem cells can protect the intestines from NEC. The aim of this study was to determine whether human breast milk (BM)-derived EVs could prevent NEC. METHODS: EVs were purified from human donor breast milk. NEC was induced in premature rat pups by exposure to asphyxia/hypothermia/hypercaloric feeds. Pups were randomized to: (1) breast fed, no injury, (2) NEC, (3) NEC + BM-derived EVs once intraperitoneally (IP), (4) NEC + BM-derived EVs enterally (PO) with each feed. Intestinal tracts were examined for histologic damage. Additionally, the effect of BM-derived EVs on intestinal epithelial cells (IEC) subjected to hypoxia/reoxygenation injury in vitro was examined. RESULTS: NEC incidence was 0% in breast-fed pups and 62% in pups subjected to NEC. IP administration of BM-derived EVs decreased NEC incidence to 29% and enteral administration further decreased NEC incidence to 11.9%. (p < 0.05). BM-derived EVs significantly increased cell proliferation and decreased apoptosis in IEC in vitro. CONCLUSION: Breast milk-derived EVs delivered either IP or enterally significantly decrease the incidence and severity of experimental NEC, protect IEC from injury in vitro, and may represent an innovative therapeutic option for NEC in the future. TYPE OF STUDY: Basic science study. LEVEL OF EVIDENCE: N/A.

Pediatric Colorectal Surgery: A Collaborative Approach From a Single Institution.

BACKGROUND: Inflammatory bowel disease encompasses relapsing gastrointestinal disorders commonly presenting in pediatric patients, with 25% of diagnoses made before age 20 and 4% before age 5. Considering the need for life-long surgical follow-up, a collaborative system involving both pediatric and colorectal surgeons could improve overall patient experiences. We hypothesized that cases performed in collaboration with both pediatric and adult colorectal surgeons may lead to better outcomes. METHODS: Data were gathered retrospectively for 116 patients 18 y old or younger who underwent colorectal resections for inflammatory bowel disease between 2010 and 2017 at our institution. Data included patient demographics, type of procedure, surgical approach, specimen extraction site, surgeon involvement (pediatric, colorectal, or collaborative), operative time, and estimated blood loss. We analyzed days until passage of flatus and bowel movement, length of stay, type of surgical procedure, and surgical complications. RESULTS: Our data showed that days until flatus (2.27 ± 0.47, P = 0.049), first bowel movement (2.64 ± 0.67, P = 0.006), and length of stay (4.45 ± 1.51, P = 0.006) were the shortest in the collaborative group. We also found that single-incision laparoscopic surgery was significantly more common in the collaborative group (77.8%, P = 0.002). We did not see a difference in surgical complication rates among any of the groups. CONCLUSIONS: Our study showed short-term beneficial outcomes in a single institution associated with the collaboration of pediatric surgeons and colorectal surgeons on pediatric colorectal cases in comparison to those performed by pediatric surgeons or adult colorectal surgeons alone.

Potential role of stem cells in disease prevention based on a murine model of experimental necrotizing enterocolitis.

BACKGROUND: Necrotizing enterocolitis (NEC) is a devastating disease of newborns, and despite years of research, there is no known cure. The mortality rate of infants with NEC remains as high as 20%-30%. Babies who survive NEC frequently have long term complications including short gut syndrome, developmental delays and neurological sequelae. Unfortunately, despite much research over the past years, the precise pathogenesis of the disease is still not completely understood. METHODS: Our laboratory has focused on identifying novel therapies to prevent the disease, including the use of stem cells (SC), heparin-binding epidermal growth factor-like growth factor (HB-EGF) and recently, stem cell derived-exosomes, a type of nanovesicle, to combat this illness. RESULTS: We have outlined the major SC lines and data suggesting potential benefit as a curative or preventive approach for NEC as well as describing several new therapeutic strategies, including stem cell derived- exosomes and HB-EGF for decreasing the incidence and severity of this disease in rat models in our lab. CONCLUSION: Overall, our lab has demonstrated that these different types of SC equivalently reduce the incidence and severity of NEC and equally preserve intestinal barrier function during NEC. We have previously demonstrated that AF-MSC can protect the intestines from intestinal injury and may therefore hold strong therapeutic potential for the prevention of NEC. Most recently, our work with stem cell derived-exosomes has shown them to be equivalent to their derived SC lines in decreasing the incidence of this disease.