Hyperbilirubinemia and Choledocholithiasis in an Extremely Premature Neonate.

Cholestasis affects 2% of newborns admitted to the neonatal intensive care unit and 20% of premature infants and requires a thoughtful evaluation and diagnostic workup.There may be a single responsible etiology, or its development may be multifactorial. Premature neonates are especially predisposed because of their increased risk of infections and acute illness, need for parenteral nutrition, and exposure to certain medications. Clinically, an infant may present with jaundice, evidence of hepatic injury, or worsening hepatic function. Diagnosis may be made in consultation with various pediatric subspecialists including gastroenterology, genetics, and surgery. Treatment depends on the etiology but may include medications or surgical interventions. Timely recognition and intervention improve outcomes. [Pediatr Ann. 2023;52(8):e297-e302.].

Radiation Therapy Improves Local Control in Juvenile Nasopharyngeal Angiofibroma following Disease Progression after Embolization and Surgical Resection: A Case Report.

Juvenile nasopharyngeal angiofibroma (JNA) is a relatively uncommon, benign neoplasm of the nasopharynx that can be very difficult to diagnose early due to inconspicuous and seemingly harmless presenting symptoms. Early diagnosis and treatment of JNA are essential for a good prognosis. JNA typically responds well to radiation therapy (RT), but when it does not, the most appropriate next course of action has not been readily defined due to the limited occurrence and experience with this neoplasm. Herein, we describe a JNA patient, who continued to progress after surgery and 36 Gy of adjuvant radiation, but after an additional 14.4 Gy, he has remained in remission for over 2 years. An 11-year-old boy who presented with JNA underwent treatment with embolization and surgical resection. Unfortunately, the tumor progressed within 2 months of surgical intervention and he required RT for adequate local control. While undergoing RT, he again demonstrated signs of progression; so his radiation regimen was increased from 3,600 cGy in 20 fractions to 5,040 cGy in 28 fractions. Since completing RT, the tumor has continued to decrease in size, and the patient is stable and has been without signs of disease progression for over 24 months now. Thus, escalating the radiation regimen to 5,040 cGy may improve local control in rapidly progressive JNA.

Pathologic Characteristics Associated With Local Recurrence of Atypical Meningiomas Following Surgical Resection.

BACKGROUND: Optimal management of grade II meningiomas following resection remains controversial, owing mostly to the heterogeneity of post-operative (post-op) recurrence patterns across studies. Improved risk stratification of these patients would ensure that only those most at risk of recurrence would undergo appropriate post-op radiation therapy (RT). METHODS: Medical records from patients who underwent resection for grade II meningiomas were retrospectively reviewed. Demographic, disease characteristics, treatment, and clinical course data were retrospectively collected. Logistic regression, Cox proportional hazards modeling, and Kaplan-Meier curves with log rank testing were conducted to describe any potential relationships with time of recurrence. RESULTS: Of the 49 patients identified, 18 (36.7%) suffered a local recurrence following resection with a median follow-up of 3.1 years (range: 0.23 - 17.1 years). Past recurrence of the meningioma (P = 0.002) and extent of resection (P = 0.02) were significantly associated with local recurrence. On multivariable analysis, only prior meningioma recurrence was associated with time to local failure (P = 0.021). No histopathologic factors were found to be associated with the initial local failure. Of those who suffered a local recurrence, the presence of bone invasion (hazard ratio: 0.069, P = 0.008) and lack of salvage RT (P = 0.02) were associated with subsequent local failure. CONCLUSIONS: Currently considered histopathologic factors appear not to be helpful in guiding initial treatment course. History of prior local failure and bone invasion appear to be associated with multiple recurrences. Optimal surgical resection is critical to improving outcomes, and salvage RT may reduce subsequent local failure.

Percentage of Hormone Receptor Positivity in Breast Cancer Provides Prognostic Value: A Single-Institute Study.

BACKGROUND: A majority of breast cancer tumors express estrogen receptor (ER) and/or progesterone receptor (PR); however, the percentage of cancer cells expressing these receptors can range from 0-100%. The prognostic and therapeutic impact of the percentage of cells expressing hormone receptors in breast cancer is not fully understood. METHODS: A retrospective analysis of 411 breast cancer patients who were treated at the University of Nebraska Medical Center between 2010 and 2017 was performed. Patient tumors were evaluated for percentage of cells expressing ER and PR in conjunction with clinical outcomes. RESULTS: Patient tumors demonstrated a highly bimodal pattern of ER and PR staining with a majority of tumors demonstrating either a high percentage (> 80% of cells) or lack of cells (0%) staining for ER or PR. An increase in the percentage of ER positivity correlated with decreased local recurrence and improved overall survival. An increase in the percentage of PR positivity demonstrated a trend towards decreased local recurrence and improved overall survival, but was not statistically significant. CONCLUSIONS: Results based on both continuous and categorical evaluation of ER expression revealed that increasing expression correlated with improved patient outcomes. Similar evaluation of PR expression demonstrated a trend towards improved patient outcomes though not statistically significant. These findings suggest that the degree of hormone receptor positivity and not a Boolean representation of positivity could provide additional prognostic value in the treatment and management of breast cancer.

Diffuse lesions secondary to sarcoidosis mimicking widespread metastatic breast cancer: A case report.

This case of sarcoidosis mimicking metastatic breast cancer serves as a reminder of the need to consider differential diagnoses even when the clinical scenario and imaging findings are highly suggestive of metastases.

A rapid and sensitive bioanalytical LC-MS/MS method for the quantitation of a novel CDK5 inhibitor 20-223 (CP668863) in plasma: Application to in vitro metabolism and plasma protein-binding studies.

A rapid, selective, and sensitive liquid chromatography coupled with tandem mass spectrometry (MS/MS) method was developed and validated for the quantitation of the novel CDK5 inhibitor '20-223' in mouse plasma. Separation of analytes was achieved by a reverse-phase ACE Excel C18 column (1.7 µm, 100 × 2.1 mm) with gradient elution using 0.1% formic acid (FA) in methanol and 0.1% FA as the mobile phase. Analytes were monitored by MS/MS with an electrospray ionization source in the positive multiple reaction monitoring mode. The MS/MS response was linear over the concentration range 0.2-500 ng/mL for 20-223. The within- and between-batch precision were within the acceptable limits as per Food and Drug Administration guidelines. The validated method was successfully applied to plasma protein binding and in vitro metabolism studies. Compound 20-223 was highly bound to mouse plasma proteins (>98% bound). Utilizing mouse S9 fractions, in vitro intrinsic clearance (CLint ) was 24.68 ± 0.99 µL/min/mg protein. A total of 12 phase I and II metabolites were identified with hydroxylation found to be the major metabolic pathway. The validate method required a low sample volume, was linear from 0.2 to 500 ng/mL, and had acceptable accuracy and precision.

Correlation of dosimetric factors with the development of symptomatic radiation pneumonitis in stereotactic body radiotherapy.

BACKGROUND: The development of radiation pneumonitis (RP) after Stereotactic Body Radiotherapy (SBRT) is known to be associated with many different factors, although historical analyses of RP have commonly utilized heterogeneous fractionation schemes and methods of reporting. This study aims to correlate dosimetric values and their association with the development of Symptomatic RP according to recent reporting standards as recommended by the American Association of Physicists in Medicine. METHODS: We performed a single-institution retrospective review for patients who received SBRT to the lung from 2010 to 2017. Inclusion criteria required near-homogeneous tumoricidal (α/ß = 10 Gy) biological effective dose (BED10) of 100-105 Gy (e.g., 50/5, 48/4, 60/8), one or two synchronously treated lesions, and at least 6 months of follow up or documented evidence of pneumonitis. Symptomatic RP was determined clinically by treating radiation oncologists, requiring radiographic evidence and the administration of steroids. Dosimetric parameters and patient factors were recorded. Lung volumes subtracted gross tumor volume(s). Wilcoxon Rank Sums tests were used for nonparametric comparison of dosimetric data between patients with and without RP; p-values were Bonferroni adjusted when applicable. Logistic regressions were conducted to predict probabilities of symptomatic RP using univariable models for each radiation dosimetric parameter. RESULTS: The final cohort included 103 treated lesions in 93 patients, eight of whom developed symptomatic RP (n = 8; 8.6%). The use of total mean lung dose (MLD) > 6 Gy alone captured five of the eight patients who developed symptomatic RP, while V20 > 10% captured two patients, both of whom demonstrated a MLD > 6 Gy. The remaining three patients who developed symptomatic RP without exceeding either metric were noted to have imaging evidence of moderate interstitial lung disease, inflammation of the lungs from recent concurrent chemoradiation therapy to the contralateral lung, or unique peri-tumoral inflammatory appearance at baseline before treatment. CONCLUSIONS: This study is the largest dosimetric analysis of symptomatic RP in the literature, of which we are aware, that utilizes near-homogenous tumoricidal BED fractionation schemes. Mean lung dose and V20 are the most consistently reported of the various dosimetric parameters associated with symptomatic RP. MLD should be considered alongside V20 in the treatment planning process. TRIAL REGISTRATION: Retrospectively registered on IRB 398-17-EP.

Stromal Modulation and Treatment of Metastatic Pancreatic Cancer with Local Intraperitoneal Triple miRNA/siRNA Nanotherapy.

Nanomedicines achieve tumor-targeted delivery mainly through enhanced permeability and retention (EPR) effect following intravenous (IV) administration. Unfortunately, the EPR effect is severely compromised in pancreatic cancer due to hypovascularity and dense desmoplastic stroma. Intraperitoneal (IP) administration may be an effective EPR-independent local delivery approach to target peritoneal tumors. Besides improved delivery, effective combination delivery strategies are needed to improve pancreatic cancer therapy by targeting both cancer cells and cellular interactions within the tumor stroma. Here, we described simple cholesterol-modified polymeric CXCR4 antagonist (PCX) nanoparticles (to block cancer-stroma interactions) for codelivery of anti-miR-210 (to inactivate stroma-producing pancreatic stellate cells (PSCs)) and siKRASG12D (to kill pancreatic cancer cells). IP administration delivered the nanoparticles to an orthotopic syngeneic pancreatic tumors as a result of preferential localization to the tumors and metastases with disrupted mesothelium and effective tumor penetration. The local IP delivery resulted in nearly 15-fold higher tumor accumulation than delivery by IV injection. Through antagonism of CXCR4 and downregulation of miR-210/KRASG12D, the triple-action nanoparticles favorably modulated desmoplastic tumor microenvironment via inactivating PSCs and promoting the infiltration of cytotoxic T cells. The combined therapy displayed improved therapeutic effect when compared with individual therapies as documented by the delayed tumor growth, depletion of stroma, reduction of immunosuppression, inhibition of metastasis, and prolonged survival. Overall, we present data that a local IP delivery of a miRNA/siRNA combination holds the potential to improve pancreatic cancer therapy.

Efficacy of sequential radiation and chemotherapy in treating glioblastoma with poor performance status.

INTRODUCTION: While the current standard of care after maximal safe resection for glioblastoma (GBM) is concomitant radiation and chemotherapy, the ideal therapy for patients with poor performance status remains in question due to concerns about treatment tolerance. We sought to evaluate an alternative regimen, sequential radiation and chemotherapy, to assess its efficacy as a treatment option for poorly performing patients. METHODS: We performed a retrospective analysis using the 2015 National Cancer Database in which the survival of patients with a KPS ≤ 70 who received sequential radiation and chemotherapy were compared to those who received radiation therapy alone. Survival outcomes were compared using Kaplan-Meier curves with log rank testing and Cox proportional hazard regression. RESULTS: There were 84 patients analyzed in this study, all of whom had a KPS between 10 and 70. Of those analyzed, 73.8% received radiation therapy alone, and 26.2% received sequential radiation and chemotherapy. There was no difference in survival between the two treatment groups (p = 0.84). Patient age of 70 years or older (n = 31) was associated with decreased survival (HR 1.06 per year, p < 0.0001), regardless of KPS and a KPS of < 70 correlated with a near-significant trend toward worse survival (HR 1.63, p = 0.06). CONCLUSIONS: Treatment with sequential radiation and chemotherapy in poorly performing patients is not associated with an advantage in survival outcome when compared to radiation alone in GBM patients with poor performance status.

Factors Predictive of Reoperation After Pancreaticoduodenectomy for Pancreatic Cancer.

While mortality is low, morbidity remains high for patients undergoing pancreas resections, especially for those who return to the operating room (RTOR). The aim of this study is to identify risk factors for RTOR following pancreaticoduodenectomy (PD) for ductal adenocarcinoma. Logistic regression models were constructed using the 2014 and 2015 National Surgical Quality Improvement Program (NSQIP) Pancreas Targeted database. Preoperative and procedure-related risk factors predictive of RTOR for patients undergoing either classic or pylorus-preserving pancreaticoduodenectomy for pancreatic ductal adenocarcinoma (PDAC) were identified. A total of 1736 patients were included. Multivariable analysis of patients undergoing classic PD demonstrated that an abnormally low preoperative WBC count was significantly associated with RTOR (OR 2.78, 95% CI 1.27-6.06, p = 0.010). For patients who underwent pylorus-preserving PD, the wound classification (OR 3.99, 95% CI 1.75-9.11, p = 0.001) and arterial resection (OR 26.3, 95% CI 7.96-87.20, p < 0.001) were associated with a higher rate of RTOR. When analyzing both approaches (classic and pylorus-preserving PD) together, only isolated arterial (OR 9.98, 95% CI 3.81-26.18, p < 0.001) and isolated venous (OR 1.79, 95% CI 1.05-3.05, p = 0.032) resections were independently associated with RTOR. The results of our study demonstrate that few factors are predictive of RTOR. Knowledge of these few variables in combination with a focus on the components of medical care in the immediate postoperative period may help identify individuals at risk for RTOR and improve patient care.

Highly Aggressive and Radiation-Resistant, "Atypical" and Silent Pituitary Corticotrophic Carcinoma: A Case Report and Review of the Literature.

BACKGROUND: Pituitary tumors typically remain silent unless interaction with nearby structures occurs. Rare subsets of pituitary tumors display aggressive phenotypes: highly mitotic, locally invasive, metastatic, chemotherapy and radiation resistant, etc. Disease progression and response to therapy is ill-defined in these subtypes, and their true prognostic potential is debated. Thus, identifying tumor characteristics with prognostic value and efficacious treatment options remains a challenge in aggressive pituitary tumors. CASE PRESENTATION: A 45-year-old female presented with a nonfunctioning corticotropic pituitary macroadenoma with biomarkers suggestive of an "atypical" subtype: Ki-67 of 8-12%, increased mitosis, and locally invasive. Despite resections and radiation, growth continued, eventually affecting her vision. Although histologically ACTH positive, the patient remained clinically asymptomatic. Twelve months later, an episode of Cushing's disease-induced psychosis prompted a PET-CT scan, identifying sites of metastasis. Temozolomide was added to her medical regimen, and her metastatic liver lesions and boney metastases were treated with radiofrequency ablation and stereotactic body radiation therapy, respectively. Systemic treatment resulted in a drop in her ACTH levels, with her most recent scans/labs at 12 months following RFA suggesting remission. CONCLUSIONS: This is a unique presentation of a pituitary tumor, displaying characteristics of both clinically silent corticotropic and "atypical" macroadenoma subtypes. Although initially ACTH positive while clinically silent, the patient's disease ultimately recurred metastatically with manifestations of Cushing's disease and psychosis. With the addition of temozolomide to her treatment plan, her primary and metastatic sites have responded favorably to radiation therapy. Thus, the addition of temozolomide may be beneficial in the treatment of aggressive pituitary tumors.

Stereotactic Body Radiation Therapy Versus Nonradiotherapeutic Ablative Procedures (Laser/Cryoablation and Electrocautery) for Early-Stage Non-Small Cell Lung Cancer.

BACKGROUND: Despite the fact that stereotactic body radiation therapy (SBRT) is the only recommended first-line therapy for inoperable early-stage non-small cell lung cancer (NSCLC), several thermal ablative procedures (TAPs; defined herein as laser/cryoablation and electrocautery) are available. Studies showing outcomes of these procedures and how they compare with SBRT are scarce. We sought to evaluate the comparative efficacy of SBRT versus TAPs using the National Cancer Database (NCDB). METHODS: The NCDB was queried for patients with early-stage NSCLC who did not undergo surgical resection. Treatment-specific inclusion criteria were applied to select for patients receiving either TAPs or SBRT. Univariate logistic regression and Cox proportional hazards modeling were performed, and Kaplan-Meier curves were generated. Serial propensity matches were performed using a modified greedy 8→n matching 1:1 algorithm. RESULTS: A total of 27,734 patients were analyzed; 26,725 underwent SBRT and 1,009 underwent TAPs. Patients who received SBRT were older and more likely to have clinical stage IB (vs IA) disease. Despite this, SBRT was associated with longer median overall survival (mOS; 37.7 vs 33.5 months; P=.001) and 1-, 2-, and 5-year OS rates compared with the TAPs cohort (86.7% vs 83.1%, 67.5% vs 62.7%, and 30.6% vs 26.9%, respectively; P=.001). Upon propensity matching, improved OS with SBRT remained, with a mOS of 40.4 versus 33.4 months and 1-, 2-, and 5-year OS rates of 89.0% versus 82.9%, 69.7% versus 62.7%, and 34.4% versus 26.4%, respectively (P=.003). CONCLUSIONS: Despite being associated with more higher-risk factors, SBRT was associated with higher OS compared with TAPs for treatment of nonoperative patients diagnosed with early-stage NSCLC. However, causation cannot be implied owing to the inherent limitations of large heterogeneous datasets such as the NCDB.

A 47-year-old woman with nuclear protein in testis midline carcinoma masquerading as a sinus infection: a case report and review of the literature.

BACKGROUND: Nuclear protein in testis midline carcinoma is a rare, highly metastatic undifferentiated carcinoma that typically arises in midline structures and is characterized by having a fusion involving the nuclear protein in testis, NUT, gene. Nuclear protein in testis midline carcinoma has been identified in patients of all ages and is often initially misdiagnosed due to the rapid timeline of symptom onset. CASE PRESENTATION: Here we report the case of a 47-year-old Caucasian woman with a nuclear protein in testis midline carcinoma that was initially mistaken for a sinus infection. After symptom progression while on an aggressive antibiotic regimen, the source of her symptoms was correctly identified as a sella mass. Comprehensive analysis of the tumor was performed, and standard cytogenetic analysis identified a translocation of 15q and 19p. Further testing identified a NUT-BRD4 fusion and confirmed the diagnosis of nuclear protein in testis midline carcinoma. Despite definitive diagnosis and surgical, radiation, and, ultimately, systemic therapy, she progressed rapidly, developing widespread metastases, and ultimately died from the disease 5 months after diagnosis. CONCLUSIONS: Based on this and other previous reports, aggressive therapy should be initiated once nuclear protein in testis midline carcinoma is diagnosed and close surveillance employed in an attempt to prevent and/or recognize metastases as early as possible. Aggressive therapy has shown little efficacy such that the average overall survival for patients with nuclear protein in testis midline carcinoma is very short, often less than 6 months. Thus, early enrollment into clinical trials testing novel therapies for the treatment of nuclear protein in testis midline carcinoma should be considered. Finally, additional reports of nuclear protein in testis midline carcinoma are needed to fully characterize this rare and highly aggressive cancer.

Morbidity and Mortality Rates Following Cytoreductive Surgery Combined With Hyperthermic Intraperitoneal Chemotherapy Compared With Other High-Risk Surgical Oncology Procedures.

Importance: Currently, rates of referral of patients with peritoneal metastasis in the United States who qualify for cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) are low, in part because of the misperception of high morbidity and mortality rates. However, patients requiring major gastrointestinal surgical procedures with similar complication rates are routinely referred. Objective: To evaluate the relative safety of CRS/HIPEC. Design, Setting, and Participants: Retrospective cohort study of 34 114 patients who underwent CRS/HIPEC, right lobe hepatectomy, trisegmental hepatectomy, pancreaticoduodenectomy, and esophagectomy between January 1, 2005, and December 31, 2015, included in the American College of Surgeons National Surgical Quality Improvement Project (NSQIP) database. Data analysis was performed in 2018. Main Outcomes and Measures: Data from the NSQIP database were used to compare perioperative and 30-day postoperative morbidity and mortality rates of CRS/HIPEC (1822 patients) with other, well-accepted, high-risk surgical oncology procedures: right lobe hepatectomy (5109 patients), trisegmental hepatectomy (2449 patients), pancreaticoduodenectomy (Whipple) (16 793 patients), and esophagectomy (7941 patients). Results: For 34 114 patients, median (interquartile range [IQR]) age was 63 (55-71) years and 42% were female. Patients undergoing CRS/HIPEC tended to be younger, with a median age of 57 years, and esophagectomy had the highest median (IQR) American Society of Anesthesiologists classification (3 [3-3]). When compared with CRS/HIPEC, higher complication rates were reported in the following categories: (1) superficial incisional infection in Whipple and esophagectomy (5.4% [95% CI, 4.4%-6.4%] vs 9.7% [95% CI, 9.3%-10.1%] and 7.2% [95% CI, 6.6%-7.8%], respectively; P < .001); (2) deep incisional infection in Whipple (1.7% [95% CI, 1.1%-2.3%] vs 2.7% [95% CI, 2.5%-2.9%]; P < .01); (3) organ space infection in right lobe hepatectomy (7.2% [95% CI, 6.0%-8.4%] vs 9.0% [95% CI, 8.2%-9.8%]; P = .02), trisegmental hepatectomy (12.4% [95% CI, 11.1%-13.7%]; P < .001), and Whipple (12.9% [95% CI, 12.4%-13.4%]; P < .001); and (4) return to the operating room for esophagectomy (6.8% [95% CI, 5.6%-8.0%] vs 14.4% [95% CI, 13.6%-15.2%]; P < .001). Median (IQR) length of hospital stay was lower in CRS/HIPEC (8 [5-11] days) than Whipple (10 [7-15] days) and esophagectomy (10 [8-16] days) (P < .001). Overall 30-day mortality was lower in CRS/HIPEC (1.1%; 95% CI, 0.6%-1.6%) compared with Whipple (2.5%; 95% CI, 2.3%-2.7%), right lobe hepatectomy (2.9%; 95% CI, 2.4%-3.4%), esophagectomy (3.0%; 95% CI, 2.6%-3.4%), and trisegmental hepatectomy (3.9%; 95% CI, 3.1%-4.7%) (P < .001). Conclusions and Relevance: Comparative analysis revealed CRS/HIPEC to be safe, often safer across the spectrum of NSQIP safety metrics when compared with similar-risk oncologic procedures. Patient selection was important in achieving observed outcomes. High complication rates are a misperception from early CRS/HIPEC experience and should no longer deter referral of patients to experienced centers or impede clinical trial development in the United States.

Incidence and Patterns of Locoregional Failure After Stereotactic Body Radiation Therapy for Pancreatic Adenocarcinoma.

PURPOSE: Stereotactic body radiation therapy (SBRT) is increasingly utilized in the neoadjuvant and definitive settings for pancreatic adenocarcinoma. The risk of local and regional recurrence after this treatment remains largely unknown. Because of the lack of elective nodal treatment and high fractional dose, we hypothesized that the incidence of regional out-of-field recurrence would predominate after SBRT. METHODS AND MATERIALS: Electronic medical records of all patients treated in our department with SBRT for pancreatic adenocarcinoma were retrospectively reviewed. Patients were separated into those who converted or did not convert to surgical resectability. Demographic, treatment, and outcome data were collected and analyzed. Recurrence was assessed based on the Response Evaluation Criteria In Solid Tumors version 1.1. Treatment plans were reviewed to determine the locations of failure with respect to treatment volume. Statistical comparisons were made using Mann-Whitney U testing for continuous variables and χ2 testing for dichotomous variables. RESULTS: Data on 69 patients was available for analysis. After treatment, 18 patients (26.1%) suffered in-field recurrence and 11 patients (15.9%) recurred regionally out of field. The median time to in-field and out-of-field failures were similar at 120.5 and 108.0 days, respectively (P = .65). Of those who failed out-of-field, 4 of 11 patients (36.4%) were without in-field failure prior to death. In-field failure rates were less in patients who subsequently underwent surgical resection compared with those who did not (2 of 22 patients [9.1%] vs 16 of 47 patients [34.0%]; P = .028), but out-of-field recurrence was unaffected by subsequent surgical resection (3 of 22 patients [13.6%] vs 8 of 47 patients [17.0%]; P = .720). All out-of-field failures occurred in areas that received <2600 cGy. CONCLUSIONS: The incidence of out-of-field failure remains acceptable after SBRT for pancreatic adenocarcinoma. Despite the high biological equivalent dose allowed by SBRT, in-field control remains problematic and continues to signal relative radiation resistance that is associated with bulky disease.

Bioanalytical method development and validation of moxidectin in plasma by LC-MS/MS: Application to in vitro metabolism.

Moxidectin (MOX) has recently been approved by the US Food and Drug Administration for the treatment of river blindness in select populations. It is also being evaluated as an alternative for the use of ivermectin, widespread resistance to which is becoming a global health issue. Moreover, MOX is becoming increasingly used as a prophylactic antiparasitic in the cattle industry. In this study, we developed and validated an LC-MS/MS method of MOX in human, monkey and mouse plasma. The separation was achieved on an ACE C18 (50 × 3.0 mm, 3 µm) column with isocratic elution using 0.1% acetic acid and methanol-acetonitrile (1:1, v/v) as mobile phase. MOX was quantitated using MS/MS with an electrospray ionization source operating in negative multiple reaction monitoring mode. The multiple reaction monitoring precursor ion → product ion transitions for MOX and abamectin (IS) were m/z 638.40 â†’ 236.30 and m/z 871.50 â†’ 565.35 respectively. The MS/MS response was linear over the concentration range 0.1-1000 ng/mL in plasma with a correlation coefficient (r2 ) of 0.997 or better. The within- and between-day precision (relative standard deviation, RSD) and accuracy were within the acceptable limits per US Food and Drug Administration guidelines. The method was successfully applied to an in vitro metabolic stability study of MOX.

Comprehensive genetic alteration profiling in primary and recurrent glioblastoma.

INTRODUCTION: Glioblastoma (GBM) is heterogeneous and underlying genomic profiles influence evolution, resistance, and therapeutic responses. While extensive knowledge regarding genomic profiling of primary GBM exists, there remains a lack of understanding of genomic differences in recurrent GBM. METHODS: We used the FoundationOne® comprehensive genomic profiling assay (CGP) to analyze ten matched primary and recurrent GBM. Genomic alterations (GA) were compared to the cancer database Catalogue of Somatic Mutations in Cancer (COSMIC). RESULTS: All matched tumor pairs demonstrated differences in GA between the primary and recurrence including one resected without any intervening therapy. This suggests that time and/or therapeutic intervention contribute to GA. Although mutations were common to both the primary and recurrence, the percent reads varied substantially suggesting clonal expansions and contractions. For example, EGFR mutations were significantly expanded in three patients, and CNAs were increased in two patients at recurrence. Four genes that were commonly altered in both primary and recurrent GBM were more prevalent in our cohort than reported in COSMIC: CDKN2A (86% vs. 53%) and CDKN2B (86% vs. 54%) deletions, EGFR activating mutation (52% vs. 10%) or amplification (81% vs. 45%), and TERT mutation (95% vs. 51%). Lastly, PI3K pathway activating mutations were also commonly seen in our cohort (67%). CONCLUSIONS: CGP revealed that GA identified in GBM changed over time and with treatment. Mutations in TERT, CDKN2A/CDKN2B, EGFR, and PI3K pathway were commonly observed in both primary and recurrent GBM revealing their prognostic and therapeutic potential. This may have important implications for individualized therapies and needs further evaluation.

National Cancer Database report of nonmetastatic esophageal small cell carcinoma.

BACKGROUND: Esophageal small cell carcinoma (ESCC) is a rare malignancy for which there is no consensus management approach. This is the largest known analysis of nonmetastatic ESCC patients to date, evaluating national practice patterns and outcomes of surgical-based therapy vs chemoradiotherapy (CRT) vs chemotherapy alone. METHODS: The National Cancer Data Base was queried for esophageal cancer patients with histologically confirmed nonmetastatic ESCC. Univariable and multivariable logistic regression ascertained factors associated with receipt of surgical-based management. Kaplan-Meier analysis evaluated overall survival (OS) and the log-rank test is used to compare OS between groups; Cox univariate and multivariate analyses determined variables associated with OS. RESULTS: Altogether, 323 patients were analyzed; 64 (20%) patients underwent surgical-based therapy, 211 (65%) CRT, and 48 (15%) chemotherapy alone. On multivariable analysis, no single factor significantly predicted for administration of surgery. Despite no OS differences between the surgery-based (median OS 21 months) and CRT arms (18 months), both were superior to CT alone (10 months) (P < 0.001). Among other factors, receiving any local therapy independently predicted for higher OS over chemotherapy alone on Cox multivariate analysis (P < 0.001). CONCLUSIONS: This study of a large, contemporary national database demonstrates that most ESCC is treated with CRT in the United States; adding local therapy to systemic therapy may be beneficial to these patients, although individualized multidisciplinary management is still recommended.