Adjuvant Radiotherapy for Surgically Resected Stage III Merkel Cell Carcinoma.

This case-control study evaluates whether adjuvant radiotherapy is associated with overall survival among patients with surgically resected stage III Merkel cell carcinoma.

Optimal Timing of Inguinal Hernia Repair in Premature Infants: A NSQIP-P Study.

INTRODUCTION: Among premature infants, the incidence of inguinal hernias is reported to be as high as 30%. Despite being one of the most commonly performed procedures, the optimal setting of inguinal hernia repair (IHR) that is inpatient versus outpatient remains debatable. We sought to compare the 30-day outcomes of each approach by querying the National Surgical Quality Improvement Program-Pediatric database. MATERIALS AND METHODS: A retrospective cohort study comparing inpatient versus outpatient IHR using the National Surgical Quality Improvement Program-Pediatric database from 2013 to 2019 was performed. Demographic and clinical data were initially compared using univariate analysis. Continuous variables are presented as median and interquartile range and categorical variables are presented as n (%). Subsequently, cohorts were propensity matched using clinically and statistically significant patient characteristics. RESULTS: 928 patients underwent IHR, 634 (68.3%) while inpatient, 294 (31.7%) following hospital discharge. Inpatient IHR was associated with lower age at the time of surgery (120 versus 147 d; P < 0.0001), younger gestational age (27 versus 33 wk; P < 0.0001), decreased probability of repair in elective setting (87.2% versus 97.3%; P < 0.0001), and increased preoperative supplemental oxygen need (42% versus 4.4%; P < 0.0001). Comparison of propensity matched cohorts revealed that inpatient IHR was associated with increased procedure time (82 versus 51 min; P < 0.0001) and anesthetic duration (146 versus 102 min; P < 0.0001), wound infection rates (3.8% versus 0%; P = 0.007), blood transfusions (4.2% versus 0.5%; P = 0.036), unplanned intubations (2.8% versus 0%; P = 0.03), ventilator days (0 versus 0; range [0,30 versus 0,2]; P = 0.002), reoperation rate (5.6% versus 0%; P < 0.001), postoperative hospital length of stay (4 versus 1 d; P < 0.0001), and unplanned readmissions (8.9% versus 0.9%; P = 0.002). CONCLUSIONS: Inpatient IHR in premature neonates were associated with different postoperative outcomes than outpatient IHR. At least in the elective setting among premature infants, outpatient IHR can be considered safe in select patients while we await higher quality prospective data.

Combined MEK/MDM2 inhibition demonstrates antitumor efficacy in TP53 wild-type thyroid and colorectal cancers with MAPK alterations.

Most tumors with activating MAPK (mitogen-activated protein kinase) pathway alterations respond poorly to MEK inhibitors alone. Here, we evaluated combination therapy with MEK inhibitor selumetinib and MDM2 inhibitor KRT-232 in TP53 wild-type and MAPK altered colon and thyroid cancer models. In vitro, we showed synergy between selumetinib and KRT-232 on cell proliferation and colony formation assays. Immunoblotting confirmed p53 upregulation and MEK pathway inhibition. The combination was tested in vivo in seven patient-derived xenograft (PDX) models (five colorectal carcinoma and two papillary thyroid carcinoma models) with different KRAS, BRAF, and NRAS mutations. Combination therapy significantly prolonged event-free survival compared with monotherapy in six of seven models tested. Reverse-phase protein arrays and immunohistochemistry, respectively, demonstrated upregulation of the p53 pathway and in two models cleaved caspase 3 with combination therapy. In summary, combined inhibition of MEK and MDM2 upregulated p53 expression, inhibited MAPK signaling and demonstrated greater antitumor efficacy than single drug therapy in both in vitro and in vivo settings. These findings support further clinical testing of the MEK/MDM2 inhibitor combination in tumors of epithelial origin with MAPK pathway alterations.

Recovery of Screening Mammogram Cancellations During COVID-19.

BACKGROUND: In response to the COVID-19 pandemic, the American Society of Breast Surgeons and American College of Radiology released a joint statement recommending that all breast screening studies be postponed effective March 26, 2020. STUDY DESIGN: A retrospective review of all canceled mammograms at a single tertiary care institution from January 1-August 31, 2020 was performed to evaluate the effect of this recommendation by quantifying both the number and reason for mammogram cancellations before and after March 26, 2020. Utilization of the electronic patient portal for appointment cancellation as a surrogate for telehealth uptake was noted. RESULTS: During the study period, 5340 mammogram appointments were kept and 2784 mammogram appointments were canceled. From a baseline of 30 (10.8%) canceled mammograms in January, cancellations peaked in March (576, 20.6%) and gradually decreased to a low in August (197, 7%). Reasons for cancellations varied significantly by month (P < .0001) and included COVID-19 related (236, 8.5%), unspecified patient reasons (1,210, 43.5%), administrative issues (147, 5.3%), provider requests (46, 1.7%), sooner appointments available (31, 1.1%), and reasons not given (486, 17.5%). In addition, compared to a baseline in January (51, 16.5%), electronic patient portal access peaked in August (67, 34.0%). CONCLUSION: Screening mammogram cancellations have gradually recovered after early COVID-19 restrictions were lifted and increasing use of electronic patient access appears to be sustained. Consequences for future staging at the time of diagnosis remain unknown. Understanding to what extent the pandemic affected screening may help surgeons plan for post-pandemic breast cancer care.

Thoracoscopic segmentectomy for a large previously undiagnosed CPAM presenting as a spontaneous pneumothorax: A case report.

INTRODUCTION: Incidentally found congenital pulmonary airway malformations (CPAM) in older children are extremely rare and have traditionally been managed with minimally invasive versus open lobectomy of the affected lobe. PRESENTATION OF CASE: In this report, we present a 11-year-old male who presented with a recurrent spontaneous pneumothorax and was found to have a large symptomatic CPAM confined to a single segment of the right lower lobe. The patient was successfully treated with thoracoscopic segmentectomy without any residual disease seen on follow up imaging. DISCUSSION: Minimally invasive thoracoscopic approach has many advantages over open approach including better pain control, reduced hospital length of stay, and decreased intraoperative blood loss. With increasing use of minimally invasive approaches, lung-sparing surgery has demonstrated to be a viable and an attractive option for definitive resection of CPAM, without compromising resection margins and/or future lung function. CONCLUSION: This report demonstrates that minimally invasive lung-sparing surgical treatment of a large CPAM is feasible in older children.

First in class dual MDM2/MDMX inhibitor ALRN-6924 enhances antitumor efficacy of chemotherapy in TP53 wild-type hormone receptor-positive breast cancer models.

BACKGROUND: MDM2/MDMX proteins are frequently elevated in hormone receptor-positive (ER+) breast cancer. We sought to determine the antitumor efficacy of the combination of ALRN-6924, a dual inhibitor of MDM2/MDMX, with chemotherapy in ER+ breast cancer models. METHODS: Three hundred two cell lines representing multiple tumor types were screened to confirm the role of TP53 status in ALRN-6924 efficacy. ER+ breast cancer cell lines (MCF-7 and ZR-75-1) were used to investigate the antitumor efficacy of ALRN-6924 combination. In vitro cell proliferation, cell cycle, and apoptosis assays were performed. Xenograft tumor volumes were measured, and reverse-phase protein array (RPPA), immunohistochemistry (IHC), and TUNEL assay of tumor tissues were performed to evaluate the in vivo pharmacodynamic effects of ALRN-6924 with paclitaxel. RESULTS: ALRN-6924 was active in wild-type TP53 (WT-TP53) cancer cell lines, but not mutant TP53. On ER+ breast cancer cell lines, it was synergistic in vitro and had enhanced in vivo antitumor activity with both paclitaxel and eribulin. Flow cytometry revealed signs of mitotic crisis in all treatment groups; however, S phase was only decreased in MCF-7 single agent and combinatorial ALRN-6924 arms. RPPA and IHC demonstrated an increase in p21 expression in both combinatorial and single agent ALRN-6924 in vivo treatment groups. Apoptotic assays revealed a significantly enhanced in vivo apoptotic rate in ALRN-6924 combined with paclitaxel treatment arm compared to either single agent. CONCLUSION: The significant synergy observed with ALRN-6924 in combination with chemotherapeutic agents supports further evaluation in patients with hormone receptor-positive breast cancer.

Cell-free Circulating Tumor DNA Variant Allele Frequency Associates with Survival in Metastatic Cancer.

PURPOSE: Physicians are expected to assess prognosis both for patient counseling and for determining suitability for clinical trials. Increasingly, cell-free circulating tumor DNA (cfDNA) sequencing is being performed for clinical decision making. We sought to determine whether variant allele frequency (VAF) in cfDNA is associated with prognosis. EXPERIMENTAL DESIGN: We performed a retrospective analysis of 298 patients with metastatic disease who underwent clinical comprehensive cfDNA analysis and assessed association between VAF and overall survival. RESULTS: cfDNA mutations were detected in 240 patients (80.5%). Median overall survival (OS) was 11.5 months. cfDNA mutation detection and number of nonsynonymous mutations (NSM) significantly differed between tumor types, being lowest in appendiceal cancer and highest in colon cancer. Having more than one NSM detected was associated with significantly worse OS (HR = 2.3; P < 0.0001). VAF was classified by quartiles, Q1 lowest, Q4 highest VAF. Higher VAF levels were associated with a significantly worse overall survival (VAF Q3 HR 2.3, P = 0.0069; VAF Q4 HR = 3.8, P < 0.0001) on univariate analysis. On multivariate analysis, VAF Q4, male sex, albumin level <3.5 g/dL, number of nonvisceral metastatic sites >0 and number of prior therapies >4 were independent predictors of worse OS. CONCLUSIONS: Higher levels of cfDNA VAF and a higher number of NSMs were associated with worse OS in patients with metastatic disease. Further study is needed to determine optimal VAF thresholds for clinical decision making and the utility of cfDNA VAF as a prognostic marker in different tumor types.

Percutaneous Needle Biopsies of the Breast in Women Younger than 35 Years: Minimally or Excessively Invasive?

Percutaneous needle biopsy (PNB) of the breast is commonly used for diagnosis of breast pathology, but has been less studied in young women. We sought to determine the effectiveness and necessity of PNB in patients younger than 35 years of age. The charts of sequential patients <35 years who underwent PNB between February 2013 and May 2016 were reviewed; 181 PNB were performed in 127 patients. Median age was 30 years (13-34). Indications for PNB were Breast Imaging Reporting and Data System (BIRADS) ≥4 in 137 (75.7%) cases, with mass on imaging in 139 (76.8%). Carcinoma was diagnosed in 12 (6.6%), PNB in eight unique patients (6.3%). Other PNB pathology included atypia in four (2.2%) patients; papillary lesion, five (2.8%); benign lymph node, 10 (5.5%); fibroepithelial lesion, 15 (8.3%); benign breast tissue, 63 (34.8%); and fibroadenoma, 72 (39.8%). Women with atypia or malignancy were older than those with benign findings (30.9 vs 28.0 years, P = 0.002). No other patient or imaging factors were significantly associated with pathologic diagnosis on PNB. Routine PNB for all BIRADS 4 findings may be over-used in young women as most results are benign and subsequent surgical findings are concordant. Improved diagnostic accuracy of breast imaging is warranted to reduce unnecessary procedures.

Outcomes of Nipple-Sparing Mastectomy: Role of Anatomic Measurements.

Nipple-sparing mastectomy (NSM) offers improved cosmesis for women undergoing mastectomy; however, there is increased risk for complications with this technique. We sought to determine if standard anatomic measurements could be used to predict complications of NSM. We performed a retrospective review of NSM for which anthropometric measurements of sternal notch to nipple distance, base width, and inframammary fold to nipple distance were available, and compared outcomes by anatomic measurements. We identified 102 cases of NSM with measurements available for study performed in 55 patients. Areola necrosis was associated with base width of greater than 15 cm (42.9% vs 10.9%, P = 0.02), infections were more likely with inframammary fold to nipple distance of more than 10 cm (29.2% vs 10.3%, P = 0.02), hematomas were more likely with sternal notch to nipple distance more than 30 cm (22.2% vs 4.3%, P = 0.03), and delayed wound healing was more likely with sternal notch to nipple distance of more than 25 cm (10.3% vs 1.6%, P = 0.03). There were no significant differences in nipple necrosis, skin flap necrosis, wound care requirements, or operative intervention based on anatomic measurement. Standard anatomic measurements are inconsistent predictors of outcome from NSM and should not be used alone to exclude attempts at NSM.

Percutaneous Sentinel Node Biopsy in Breast Cancer: Results of a Phase 1 Study.

BACKGROUND: While sentinel lymph node dissection (SLND) provides axillary staging, recent trials question the necessity of removing positive nonsentinel axillary lymph nodes (LN) in breast cancer. We sought to determine the technical feasibility of percutaneous core needle biopsy (PNB) of axillary sentinel lymph nodes (SLNs). METHODS: After dual tracer injection, 25 patients underwent intraoperative axillary ultrasound and ultrasound guided per PNB of the axillary LN at the site of radiotracer uptake, followed by standard SLND. The primary outcome measure was successful correlation of PNB with SLN, defined as: (1) similar final pathology in core and SLN and (2) presence of blue staining and/or radiotracer in the core or gross evidence of PNB at the SLN (e.g., transected SLN). RESULTS: Preincision axillary ultrasound identified a LN (mean size 1.15 ± 0.67 cm) at the site of radioactive tracer in 92 % (23 of 25) of cases. Gross evidence of PNB at the SLN was found in 76 % (19 of 25) of cases. Blue staining, radioisotope, and pathology matched in core and SLN specimens in 36 % (9 of 25), 64 % (16 of 25), and 72 % (18 of 25) of cases, respectively. Overall, successful correlation of core biopsy with SLN occurred in 72 % (18 of 25) of cases. CONCLUSIONS: Results of this phase I study demonstrate that PNB of the SLN is technically feasible, but further refinement of technique is warranted to improve correlation of core biopsy to SLND.

The Effect of Breast Implants on Mammogram Outcomes.

Breast cancer detection in women with implants has been questioned. We sought to evaluate the impact of breast implants on mammographic outcomes. A retrospective review of women undergoing mammography between March 1 and October 30, 2013 was performed. Demographic characteristics and mammogram results were compared between women with and without breast implants. Overall, 4.8 per cent of 1863 women identified during the study period had breast implants. Median age was 59 years (26-93). Women with implants were younger (53.9 vs 59.2 years, P < 0.0001), had lower body mass index (25.4 vs 28.9, P < 0.0001), and were more likely to have dense breast tissue (72.1% vs 56.4%, P = 0.004) than those without. There were no statistically significant differences with regards to Breast Imaging Recording and Data System 0 score (13.3% with implants vs 21.4% without), call back exam (18.9% with vs 24.1% without), time to resolution of abnormal imaging (58.6 days with vs 43.3 without), or cancer detection rate (0% with implants vs 1.0% without). Because implants did not significantly affect mammogram results, women with implants should be reassured that mammography remains useful in detecting cancer. However, future research is required to determine whether lower call back rates and longer time to resolution of imaging findings contribute to delays in diagnosis in patients with implants.