Jeffrey Mueller

Phase III Randomized Trial of Induction Chemotherapy in Patients With N2 or N3 Locally Advanced Head and Neck Cancer

PURPOSE Induction chemotherapy (IC) before radiotherapy lowers distant failure (DF) rates in locally advanced squamous cell carcinoma of the head and neck (SCCHN). The goal of this phase III trial was to determine whether IC before chemoradiotherapy (CRT) further improves survival compared with CRT alone in patients with N2 or N3 disease. PATIENTS AND METHODS Treatment-naive patients with nonmetastatic N2 or N3 SCCHN were randomly assigned to CRT alone (CRT arm; docetaxel, fluorouracil, and hydroxyurea plus radiotherapy 0.15 Gy twice per day every other week) versus two 21-day cycles of IC (docetaxel 75 mg/m(2) on day 1, cisplatin 75 mg/m(2) on day 1, and fluorouracil 750 mg/m(2) on days 1 to 5) followed by the same CRT regimen (IC + CRT arm). The primary end point was overall survival (OS). Secondary end points included DF-free survival, failure pattern, and recurrence-free survival (RFS). RESULTS A total of 285 patients were randomly assigned. The most common grade 3 to 4 toxicities during IC were febrile neutropenia (11%) and mucositis (9%); during CRT (both arms combined), they were mucositis (49%), dermatitis (21%), and leukopenia (18%). Serious adverse events were more common in the IC arm (47% v 28%; P = .002). With a minimum follow-up of 30 months, there were no statistically significant differences in OS (hazard ratio, 0.91; 95% CI, 0.59 to 1.41), RFS, or DF-free survival. CONCLUSION IC did not translate into improved OS compared with CRT alone. However, the study was underpowered because it did not meet the planned accrual target, and OS was higher than predicted in both arms. IC cannot be recommended routinely in patients with N2 or N3 locally advanced SCCHN.

Axillary Lymph Nodes Suspicious for Breast Cancer Metastasis: Sampling with US-guided 14-Gauge Core-Needle Biopsy—Clinical Experience in 100 Patients

PURPOSE To study the clinical usefulness of ultrasonography (US)-guided core-needle biopsy (CNB) of axillary lymph nodes and the US-depicted abnormalities that may be used to predict nodal metastases. MATERIALS AND METHODS This retrospective study was HIPAA compliant and institutional review board approved; the requirement for informed patient consent was waived. US-guided 14-gauge CNB of abnormal axillary lymph nodes was performed in 100 of 144 patients with primary breast cancer who underwent US assessment of axillary lymph nodes. A biopsy needle with controllable action rather than a traditional throw-type needle was used. US findings were considered suspicious for metastasis if cortical thickening and/or nonhilar blood flow (NHBF) to the lymph node cortex was present. The absence of any discernible fatty hilum was also noted. RESULTS Nodal metastases were documented at CNB in 64 (64%) of the 100 patients. All 36 patients with negative biopsy results underwent subsequent sentinel lymph node biopsy (SLNB), which yielded negative findings in 32 (89%) patients and revealed metastasis in four (11%). All 44 patients who did not undergo CNB because of negative US results subsequently underwent SLNB, which revealed lymph node metastasis in 12 (27%) patients. Cortical thickening was found in 63 (79%) of the total of 80 metastatic nodes, but only a minority (n = 26 [32%]) of the nodes had an absent fatty hilum. NHBF to the cortex was detected in 52 (65%) metastatic nodes. Both absence of a fatty hilum (metastasis detected in 26 [93%] of 28 nodes) and cortical thickening combined with NHBF (metastasis detected in 52 [81%] of 64 nodes) had a high positive predictive value. No clinically important complications were encountered with the biopsy procedures. CONCLUSION Axillary lymph nodes with abnormal US findings can be sampled with high accuracy and without major complications by using a modified 14-gauge CNB technique.

Dramatic Antitumor Effects of the Dual MET/RON Small-Molecule Inhibitor LY2801653 in Non–Small Cell Lung Cancer

Lung cancer is a heterogeneous disease encompassing a wide array of genetic abnormalities. The MET receptor tyrosine kinase is altered in many lung cancers, especially non-small cell lung cancer (NSCLC), and clinical trials of MET inhibitors that are under way are documenting cases of acquired resistance. On the basis of the evidence that the RON tyrosine kinase receptor can also be overexpressed in NSCLC, we evaluated the potent MET/RON dual kinase inhibitor LY2801653 in this setting. LY2801653 was more efficacious than the MET/ALK/RON/ROS inhibitor crizotinib with a distinct pattern of downstream signaling effects. Using the PamGene platform, we found that inhibition of MET and RON was associated with decreased phosphorylation of CBL, PI3K, and STAT3. In classic and orthotopic mouse xenograft models of lung cancer, LY2801653 decreased tumor growth, dramatically inhibiting mitotic events and angiogenesis. Taken together, our results argued that specific targeting of the MET/RON kinases could provide robust inhibition of cell proliferation and tumor outgrowth in multiple in vitro and in vivo models of NSCLC. These findings offer a robust preclinical proof of concept for MET/RON targeting by LY2801653 as a promising small-molecule modality to treat NSCLC.

Diagnostic Utility of Cd10 in Benign and Malignant Extrahepatic Bile Duct Lesions

CD10, a cell surface enzyme with neutral metalloendopeptidase activity, is a marker for intestinal epithelial brush border. It is also present in normal bile ducts and gallbladder epithelia but is absent in cholangiocarcinomas. However, the expression profile of CD10 in benign and malignant extrahepatic biliary lesions has not been studied. In this study, 69 biopsies, 9 resections, and 9 cell blocks prepared from fine-needle aspirations of the extrahepatic bile ducts from 86 patients were studied immunohistochemically for CD10 expression. The majority of cases contained normal biliary epithelium (NL, n=64), along with foci of benign or malignant lesions in various combinations. Benign lesions included reactive atypia (n=35), low-grade dysplasia of unknown significance (n=21), and bile duct adenoma (BDA, n=1). Malignant lesions included high-grade dysplasia (HGD, n=45) and invasive adenocarcinoma (IC, n=30). As expected, the NL showed strong continuous staining at the apical surface in all cases. Benign lesions were also CD10 positive in all but 3 cases; however, the staining pattern was discontinuous, with positive cells varying from 20% to 80%. None of the malignant lesions showed CD10 immunoreactivity, except for 2 HGD cases and 1 IC case, which exhibited focal staining. The Pearson &khgr;2 and Fisher exact tests showed significant statistical difference in CD10 expression among the study groups (P<0.001). Our findings suggest that absence of CD10 expression in strips of atypical biliary epithelial cells may be a phenotype associated with malignant transformation and may serve as a useful marker to aid in the evaluation of bile duct biopsies, in which distinction between benign and malignant lesions on biopsies or cytology specimens can be extremely challenging because of limited sampling, crush artifact, and frequent inflammatory/reactive changes.

Value of rapid assessment cytology in the surgical management of head and neck tumors in a Nigerian mission hospital.

Fine‐needle aspiration (FNA) or touch preparation with rapid assessment is a valuable diagnostic tool with a reported accuracy of diagnosis similar to intraoperative frozen section consultation. The Nigeria Christian Hospital partners with health care professionals from the United States to provide surgical care for rural residents of Aba, Nigeria. Frozen section diagnosis is impractical in this setting because of very limited resources. Therefore, intraoperative rapid assessment FNA or touch preparation to guide surgical management was performed on all mass lesions, and the results were evaluated.

Programmed death-ligand 1 testing of lung cancer cytology specimens obtained with bronchoscopy

Programmed death‐ligand 1 (PD‐L1) expression testing is recommended by guidelines for patients with advanced non–small cell lung cancer (NSCLC). The primary objective of the current study was to determine the success rate of PD‐L1 testing from cytology cell block samples obtained by bronchoscopic needle aspiration. The secondary objective was the assessment of the difference in specimen adequacy acquired via needles of different gauges.

Comprehensive genetic testing identifies targetable genomic alterations in most patients with non-small cell lung cancer, specifically adenocarcinoma, single institute investigation

This study reviews extensive genetic analysis in advanced non-small cell lung cancer (NSCLC) patients in order to: describe how targetable mutation genes interrelate with the genes identified as variants of unknown significance; assess the percentage of patients with a potentially targetable genetic alterations; evaluate the percentage of patients who had concurrent alterations, previously considered to be mutually exclusive; and characterize the molecular subset of KRAS. Thoracic Oncology Research Program Databases at the University of Chicago provided patient demographics, pathology, and results of genetic testing. 364 patients including 289 adenocarcinoma underwent genotype testing by various platforms such as FoundationOne, Caris Molecular Intelligence, and Response Genetics Inc. For the entire adenocarcinoma cohort, 25% of patients were African Americans; 90% of KRAS mutations were detected in smokers, including current and former smokers; 46% of EGFR and 61% of ALK alterations were detected in never smokers. 99.4% of patients, whose samples were analyzed by next-generation sequencing (NGS), had genetic alterations identified with an average of 10.8 alterations/tumor throughout different tumor subtypes. However, mutations were not mutually exclusive. NGS in this study identified potentially targetable genetic alterations in the majority of patients tested, detected concurrent alterations and provided information on variants of unknown significance at this time but potentially targetable in the future.

Immunohistochemical analysis of E‐cadherin and zeste homolog 2 expression in endoscopic ultrasound‐guided fine‐needle aspiration of pancreatic adenocarcinoma

Recent studies have demonstrated that partial or complete loss of E‐cadherin (EC) and nuclear accumulation of zeste homolog 2 (EZH2) are hallmarks of poorly differentiated pancreatic adenocarcinoma (PAC). Depletion of EZH2 sensitizes cancer cells to chemotherapy in vitro. The objective of this study was to determine EC and EZH2 expression by immunohistochemistry (IHC) in samples obtained by endoscopic ultrasound‐guided fine‐needle aspiration (EUS‐FNA) as potential biomarkers for treatment and disease prognosis.

MRI accurately identifies early murine mammary cancers and reliably differentiates between in situ and invasive cancer: correlation of MRI with histology

MRI methods that accurately identify various stages of mouse mammary cancer could provide new knowledge that may have a direct impact on the management of breast cancer in patients. This research investigates whether we can accurately follow the progression from in situ to invasive cancer by the evaluation of in vivo and ex vivo MRI, and in comparison with histology as the gold standard for the diagnosis and staging of cancer. Six C3(1)SV40Tag virgin female mice, aged 12–16 weeks, were studied. At this age, these mice develop in situ cancer that resembles human ductal carcinoma in situ (DCIS). Fast spin‐echo images of inguinal mammary glands were acquired at 9.4 T. After in vivo MRI, mice were sacrificed; inguinal mammary glands were excised and fixed in formalin for ex vivo MRI. Three‐dimensional, volume‐rendered, in vivo and ex vivo MR images were then correlated with histology. High‐resolution ex vivo scans facilitated the comparison of in vivo scans with histology. The sizes of mammary cancers classified as in situ on the basis of histology ranged from 150 to 400 µm in largest diameter, and the average signal intensity relative to muscle was 1.40 ± 0.18 on T2‐weighted images. Cancers classified as invasive on the basis of histology were >400 µm in largest diameter, and the average intensity relative to muscle on T2‐weighted images was 2.34 ± 0.26. Using a cut‐off of 400 µm in largest diameter to distinguish between in situ and invasive cancers, a T2‐weighted signal intensity of at least 1.4 times that of muscle for in situ cancer, and at least 2.3 times that of muscle for invasive cancer, 96% of in situ and 100% of invasive cancers were correctly identified on in vivo MRI, using histology as the gold standard. Precise MRI–histology correlation demonstrates that MRI reliably detects early in situ cancer and differentiates in situ from invasive cancers in the SV40Tag mouse model of human breast cancer. Copyright

Mammary cancer initiation and progression studied with magnetic resonance imaging.

IntroductionPrevious work from this laboratory demonstrated that magnetic resonance imaging (MRI) detects early murine mammary cancers and reliably differentiates between in situ and invasive cancer. Based on this previous work, we used MRI to study initiation and progression of murine mammary cancer, and monitor the transition from the in situ to the invasive phase.MethodsIn total, seven female C3(1) SV40 Tag mice were imaged every two weeks between the ages of 8 to 23 weeks. Lesions were identified on T2-weighted images acquired at 9.4 Tesla based on their morphology and growth rates. Lesions were traced manually on MR images of each slice. Volume of each lesion was calculated by adding measurements from individual slices. Plots of lesion volume versus time were analyzed to obtain the specific growth rate (SGR). The time at which in situ cancers (referred to as ‘mammary intraepithelial neoplasia (MIN)’) and invasive cancers were first detected; and the time at which in situ cancers became invasive were recorded.ResultsA total of 121 cancers (14 to 25 per mouse) were identified in seven mice. On average the MIN lesions and invasive cancers were first detected when mice were 13 and 18 weeks old, respectively. The average SGR was 0.47 ± 0.18 week-1 and there were no differences (P >0.05) between mice. 74 lesions had significantly different tumor growth rates before and after ~17 weeks of age; with average doubling times (DT) of 1.88 and 1.27 weeks, respectively. The average DT was significantly shorter (P <0.0001) after 17 weeks of age. However, the DT for some cancers was longer after 17 weeks of age, and about 10% of the cancers detected did not progress to the invasive stage.ConclusionsA wide range of growth rates were observed in SV40 mammary cancers. Most cancers transitioned to a more aggressive phenotype at approximately 17 weeks of age, but some cancers became less aggressive. The results suggest that the biology of mammary cancers is extremely heterogeneous. This work is a first step towards use of MRI to improve understanding of factors that control and/or signal the development of aggressive breast cancer.