Trial of Electronic Medical Record Integrated Next-Generation Sequencing Ordering in Veterans Affairs Cancer Care.

PURPOSE: Previous studies document underuse of next-generation sequencing (NGS). We examined the impact to oncology care for veterans of incorporating NGS ordering into the Veterans Affairs (VA) electronic medical record (EMR) at two New York City VA Medical Centers. METHODS: We identified patients with non-small cell lung cancer and prostate cancer with oncology clinic visits and NGS testing indications between January and December 2021. Patients were divided into external ordering (EO) with visits before we implemented an EMR ordering system for NGS in July 2021, and internal ordering (IO) with visits after this date. The primary outcome was proportion of NGS testing performed in EO versus IO groups. Secondary outcomes were time between metastatic disease diagnosis to receipt of test by vendor, time of metastatic diagnosis to result, and proportion of testing by race. RESULTS: A total of 168 patients were identified, 116 EO and 52 IO patients. Between IO and EO periods, testing significantly increased from 52% to 87% (P ≤ .01); it was conducted more quickly, with time from metastatic diagnosis to sample receipt by the NGS vendor improving to median 37 days from 299 days (P = .03); and the time from documented metastatic disease to a test result improved to median 56 days from 309 days (P = .03). The proportion of tissue received by the vendor was not significantly different between the two groups. There were no significant differences in testing according to self-reported race. CONCLUSION: Integration of NGS ordering in the EMR led to increased proportion and speed of testing for a vulnerable patient population served by the country's largest health system.

Benefits and Pitfalls of a Glycosylation Inhibitor Tunicamycin in the Therapeutic Implication of Cancers.

The aberrant glycosylation is a hallmark of cancer progression and chemoresistance. It is also an immune therapeutic target for various cancers. Tunicamycin (TM) is one of the potent nucleoside antibiotics and an inhibitor of aberrant glycosylation in various cancer cells, including breast cancer, gastric cancer, and pancreatic cancer, parallel with the inhibition of cancer cell growth and progression of tumors. Like chemotherapies such as doxorubicin (DOX), 5'fluorouracil, etoposide, and cisplatin, TM induces the unfolded protein response (UPR) by blocking aberrant glycosylation. Consequently, stress is induced in the endoplasmic reticulum (ER) that promotes apoptosis. TM can thus be considered a potent antitumor drug in various cancers and may promote chemosensitivity. However, its lack of cell-type-specific cytotoxicity impedes its anticancer efficacy. In this review, we focus on recent advances in our understanding of the benefits and pitfalls of TM therapies in various cancers, including breast, colon, and pancreatic cancers, and discuss the mechanisms identified by which TM functions. Finally, we discuss the potential use of nano-based drug delivery systems to overcome non-specific toxicity and enhance the therapeutic efficacy of TM as a targeted therapy.

Comparative accuracy of endosonographic shear wave elastography and transcutaneous liver stiffness measurement: a pilot study.

BACKGROUND AND AIMS: Vibration-controlled transient elastography (VCTE) is a validated test for assessing liver fibrosis but may be unreliable in select patients, including those with morbid obesity. The limitations of VCTE may be overcome by EUS-guided shear wave elastography (EUS-SWE). METHODS: This single-center, prospective, nonrandomized tandem study compared the diagnostic accuracy of EUS-SWE and VCTE in consecutive patients undergoing liver biopsy sampling because of unreliable noninvasive testing. EUS-SWE of the left and right lobes were separately performed and then compared with VCTE. Liver elasticity cutoffs for different stages of fibrosis were estimated in 3 ways: optimized sensitivity and specificity using the Youden index; and with sensitivity and specificity fixed at 90% each, Diagnostic accuracy for fibrosis was compared with liver histology using the area under the receiver-operating characteristic curve (AUROC). The primary outcome was the diagnostic accuracy of EUS-SWE for advanced fibrosis. Secondary outcomes were diagnostic accuracy of VCTE, EUS-SWE for left and right hepatic lobes for significant/advanced fibrosis, and cirrhosis. RESULTS: Forty-two patients (39 men, aged 54.5 ± 12.1 years) underwent EUS-SWE, VCTE, and liver biopsy sampling. The cross-validated AUROCs for advanced fibrosis were as follows: VCTE, .87 (95% confidence interval [CI], .76-.97); EUS-SWE left lobe, .8 (95% CI, .64-.96); and EUS-SWE right lobe, .78 (95% CI, .62-.95). The corresponding AUROCs for cirrhosis were as follows: VCTE, .9 (95% CI, .83-.97); EUS-SWE left lobe, .96 (95% CI, .9-1); and EUS-SWE right lobe, .9 (95% CI, .8-1). VCTE was unreliable in 8 patients who successfully underwent EUS-SWE. There was no statistically significant difference in the AUROCs for EUS-SWE and VCTE. CONCLUSIONS: EUS-SWE correlates well with liver histology and is a safe and reliable diagnostic test for assessing liver fibrosis with accuracy comparable with VCTE. (Clinical trial registration number: NCT04533932.).

Intraoperative sentinel lymph node evaluation in patients with node-positive breast cancer status post neoadjuvant systemic therapy - An institutional experience.

Recent studies have shown the feasibility and utility of sentinel lymph node (SLN) biopsy in patients with biopsy proven node-positive breast cancer after neoadjuvant chemotherapy. We reviewed our experience in intraoperative SLN evaluation in such cases and its effect on axillary management. A retrospective analysis of breast cancer patients (2015-2018) with a biopsy-proven positive axillary lymph node, who received neoadjuvant systemic therapy and underwent intraoperative SLN assessment was performed. Intraoperative SLN assessment results were compared with final pathology. Its accuracy and effect on axillary management is summarized. We identified 106 patients with positive axillary lymph node and neoadjuvant systemic therapy between the ages of 28 and 75 years who had SLN biopsy and lumpectomy (33) or mastectomy (73). Three or more SLNs were identified in 91 cases (86 %). The previously biopsied lymph node was identified as one of the sentinel lymph nodes in 93 cases (88 %). There is a high concordance rate between frozen section diagnosis and final diagnosis on sentinel lymph nodes. No false positive case and seven false negative frozen section diagnosis cases (diagnosed as negative on frozen section and positive on permanent sections) were identified. False-negative frozen section diagnosis correlated with low-volume nodal disease and obscuring tumor bed changes. Almost half of the positive lymph nodes were converted to negative after neoadjuvant chemotherapy. SLN biopsy with intraoperative frozen section evaluation after neoadjuvant systemic therapy in node-positive patients is an effective way to minimize axillary surgery.

Refined pancreatobiliary UroVysion criteria and an approach for further optimization.

Pancreatobiliary strictures are a common source of false negatives for malignancy detection. UroVysion is more sensitive than any other method but remains underutilized because of conflicting sensitivities and specificities due to a lack of standardized cutoff criteria and confusion in interpreting results in the context of primary sclerosing cholangitis. We set out to determine the sensitivities and specificities of UroVysion, brushing cytology, forceps biopsies, and fine needle aspiration (FNAs) for pancreatobiliary stricture malignancy detection. A retrospective review was performed of all biopsied pancreatobiliary strictures at our institution over 5 years. UroVysion was unquestionably the most sensitive method and all methods were highly specific. Sensitivity was highest while maintaining specificity when a malignant interpretation was limited to cases with 5+ cells with the same polysomic signal pattern and/or loss of one or both 9p21 signals. Only UroVysion detected the metastases and a neuroendocrine tumor. In reviewing and analyzing the signal patterns, we noticed trends according to location and diagnosis. Herein we describe our method for analyzing signal patterns and propose cutoff criteria based upon observations gleaned from such analysis.

The utility of immunohistochemical testing for mismatch repair proteins in fine needle aspiration specimens of pancreatic adenocarcinoma.

INTRODUCTION: Microsatellite instability (MSI) testing is recommended for all colonic and endometrial carcinomas to screen for Lynch syndrome. The role of MSI testing in pancreatic adenocarcinoma has not been well-established. Screening can be done via immunohistochemical (IHC) staining for mismatch repair (MMR) proteins (MLH1, MSH2, MSH6, PMS2). We report our experience and the clinical utility of MMR IHC on pancreatic adenocarcinomas in fine-needle aspiration (FNA) specimens. MATERIALS AND METHODS: We performed a retrospective review to identify all patients diagnosed with pancreatic adenocarcinoma by FNA at our institution between December 2017 and September 2019. For cases with sufficient tumor cells for testing, the MMR results and morphology were summarized, as well as corresponding clinical information, including age, clinical stage, treatment, and concurrent other cancers. RESULTS: From December 2017 to September 2019, there were a total of 184 pancreatic FNAs with a diagnosis of adenocarcinoma. Of these 184 FNAs, 65 (35%) contained sufficient material in the cell block to perform IHC for MMR. The cell block material was collected in either RPMI or CytoLyt. Poor technical quality precluded interpretation of PMS2 in 4 cases and MSH6 in 2 cases. All other cases showed intact expression of all four proteins. CONCLUSIONS: IHC for MMR proteins can be done on specimens collected in RPMI or CytoLyt, but RPMI appears to be more reliable. None of the pancreatic adenocarcinomas in this study showed loss of MMR protein expression. Routine testing of MMR loss may not be indicated in pancreatic adenocarcinomas in the general patient population.

Risk of RBC alloimmunization in multiple myeloma patients treated by Daratumumab.

BACKGROUND: Daratumumab (DARA) is a human monoclonal antibody for the treatment of multiple myeloma (MM). DARA binds to CD38 on RBCs and interferes with detection of RBC alloantibodies. The objective of this study was to evaluate the risk of RBC alloimmunization in MM patients treated with DARA. MATERIALS AND METHODS: A retrospective study of the complete serological profile and transfusion history of 45 MM patients received transfusion and treated with DARA from July 2015 to December 2018 was undertaken. All cases with positive Ab screens were treated with DTT to identify RBC alloantibodies. RBC transfusion history was monitored between the first DARA dose to the last or extending to the first negative Ab screen after the last DARA dose if the Ab screen was ever positive. Forty-six MM patients received transfusion but not DARA were studied as control group. RESULTS: Totally 184 Ab screens were done on 45 patients transfused with ABO-Rh compatible RBCs, phenotypically matched units or both. None of them showed detectable alloantibodies after DTT treatment. The duration of Ab screening positivity varied markedly, ranging from 25 days to 5 months after the last dose. Two of 46 patients in the control group had preexisting alloantibodies but no new alloantibodies were detected during study period. CONCLUSIONS: Our results indicate that the risk of forming new RBC alloantibodies after transfusion in MM patients treated with current regimens is very low and no DARA-associated difference in the alloimmunization risk. No significant difference in alloimmunization is detected between ABO-Rh compatible and phenotypically matched transfusion.

Liposclerosing Myxofibrous Tumor in a Patient with Prostate Cancer: A Case Report.

CASE: A 64-year-old man diagnosed with prostate cancer was incidentally found to have a lesion in his distal femur. Although initially concerning for metastatic prostate cancer, after biopsy by an orthopaedic oncology specialist, a diagnosis of liposclerosing myxofibrous tumor (LSMFT) was confirmed. The lesion was treated with curettage and demineralized bone matrix grafting with close follow-up. CONCLUSIONS: This case report illustrates that LSMFT is not confined to the proximal femur and highlights the differences in radiographic appearance between LSMFT and more common metastatic bone lesions.

Immunodeficiency-Associated Lymphoid Hyperplasia As a Cause of Intussusception in a Case of Activated PI3K-δ Syndrome.

Activated PI3K-δ syndrome refers to a recently described primary immunodeficiency syndrome consisting of recurrent sinopulmonary infections, lymphadenopathy, mucosal lymphoid aggregates, increased susceptibility to Epstein-Barr virus and cytomegalovirus, and increased incidence of B-cell lymphomas. Variants in PIK3CD, which encodes the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta isoform, enhance membrane association and kinase activity, resulting in increased signal transduction through the PI3K-Akt pathway. Whole-exome sequencing revealed a pathogenic PIK3CD variant in a patient with history of immunologic impairment, recurrent sinopulmonary infections, and lymphoid hyperplasia presenting as intussusception. This case illustrates that while lymphoid hyperplasia secondary to immunodeficiency is most often unsurprising and non-threatening, it can present as an emergency-like intussusception.

A preliminary case study of androgen receptor gene polymorphism association with impulsivity in women with alcoholism.

OBJECTIVE: The androgen receptor (AR) gene, located on the X chromosome, contains a common polymorphism involving cytosine-adenine-guanine (CAG) repeats, which impacts disease and could contribute to the unequal sex ratio in alcoholism. CAG repeats in the AR gene are known to correlate with impulsivity in males. We report the first preliminary study examining the association between the number of CAG repeats and measures of impulsivity in females with chronic alcoholism. METHODS: A total of 35 women and 85 men with chronic alcoholism were previously recruited for a nutritional clinical trial, and 26 well-characterized females (19 African-American and seven Caucasian) with alcoholism agreed to participate for genetic testing. Genomic deoxyribonucleic acid (DNA) was isolated from peripheral blood and CAG repeats determined by analyzing polymerase chain reaction (PCR)-amplified products, using the polymorphic AR gene assay. CAG repeat length was correlated with raw scores from the Barratt Impulsivity Scale, version 11 and the Alcoholism Severity Scale. RESULTS: CAG repeat lengths were significantly longer in Caucasian alcoholic women compared with African-Americans, and the average number of CAG repeats were significantly, positively correlated (P<0.05) with impulsivity scores. Women with average CAG repeat length (CAGave) ≥18, representing the upper quartile of the repeat range, showed significantly greater mean raw impulsivity scores. CAG repeat length appeared to have less effect in African-American compared with Caucasian women, possibly due to a shorter average repeat length. CONCLUSION: We found an association between the number of CAG repeats and impulsivity in females with chronic alcoholism, specifically in women with CAGave ≥18, seen more commonly in Caucasian compared with African-American women.