Results from a first-in-human phase I safety trial to evaluate the use of a vascularized pericranial/temporoparietal fascial flap to line the resection cavity following resection of newly diagnosed glioblastoma.

PURPOSE: The efficacy of systemic therapies for glioblastoma (GBM) remains limited due to the constraints of systemic toxicity and blood-brain barrier (BBB) permeability. Temporoparietal fascial flaps (TPFFs) and vascularized peri cranial flaps (PCF) are not restricted by the blood-brain barrier (BBB), as they derive their vascular supply from branches of the external carotid artery. Transposition of a vascularized TPFF or PCF along a GBM resection cavity may bring autologous tissue not restricted by the BBB in close vicinity to the tumor bed microenvironment, permit ingrowth of vascular channels fed by the external circulation, and offer a mechanism of bypassing the BBB. In addition, circulating immune cells in the vascularized flap may have better access to tumor-associated antigens (TAA) within the tumor microenvironment. We conducted a first-in-human Phase I trial assessing the safety of lining the resection cavity with autologous TPFF/PCF of newly diagnosed patients with GBM. METHODS: 12 patients underwent safe, maximal surgical resection of newly diagnosed GBMs, followed by lining of the resection cavity with a pedicled, autologous TPFF or PCF. Safety was assessed by monitoring adverse events. Secondary analysis of efficacy was examined as the proportion of patients experiencing progression-free disease (PFS) as indicated by response assessment in neuro-oncology (RANO) criteria and overall survival (OS). The study was powered to determine whether a Phase II study was warranted based on these early results. For this analysis, subjects who were alive and had not progressed as of the date of the last follow-up were considered censored and all living patients who were alive as of the date of last follow-up were considered censored for overall survival. For simplicity, we assumed that a 70% PFS rate at 6 months would be considered an encouraging response and would make an argument for further investigation of the procedure. RESULTS: Median age of included patients was 57 years (range 46-69 years). All patients were Isocitrate dehydrogenase (IDH) wildtype. Average tumor volume was 56.6 cm3 (range 14-145 cm3). Resection was qualified as gross total resection (GTR) of all of the enhancing diseases in all patients. Grade III or above adverse events were encountered in 3 patients. No Grade IV or V serious adverse events occurred in the immediate post-operative period including seizure, infection, stroke, or tumor growing along the flap. Disease progression at the site of the original tumor was identified in only 4 (33%) patients (median 23 months, range 8-25 months), 3 of whom underwent re-operation. Histopathological analyses of those implanted flaps and tumor bed biopsy at repeat surgery demonstrated robust immune infiltrates within the transplanted flap. Importantly, no patient demonstrated evidence of tumor infiltration into the implanted flap. At the time of this manuscript preparation, only 4/12 (33%) of patients have died. Based on the statistical considerations above and including all 12 patients 10/12 (83.3%) had 6-month PFS. The median PFS was 9.10 months, and the OS was 17.6 months. 4/12 (33%) of patients have been alive for more than two years and our longest surviving patient currently is alive at 60 months. CONCLUSIONS: This pilot study suggests that insertion of pedicled autologous TPFF/PCF along a GBM resection cavity is safe and feasible. Based on the encouraging response rate in 6-month PFS and OS, larger phase II studies are warranted to assess and reproduce safety, feasibility, and efficacy. TRIAL REGISTRATION NUMBER AND DATE OF REGISTRATION FOR PROSPECTIVELY REGISTERED TRIALS: ClinicalTrials.gov ID NCT03630289, dated: 08/02/2018.

Stimulated Raman histology facilitates accurate diagnosis in neurosurgical patients: a one-to-one noninferiority study.

OBJECTIVE: Stimulated Raman histology (SRH) offers efficient and accurate intraoperative neuropathological tissue analysis without procedural alteration to the diagnostic specimen. However, there are limited data demonstrating one-to-one tissue comparisons between SRH and traditional frozen sectioning. This study explores the non-inferiority of SRH as compared to frozen section on the same piece of tissue in neurosurgical patients. METHODS: Tissue was collected over a 1-month period from 18 patients who underwent resection of central nervous system lesions. SRH and frozen section analyses were compared for diagnostic capabilities as well as assessed for quality and condition of tissue via a survey completed by pathologists. RESULTS: SRH was sufficient for diagnosis in 78% of specimens as compared to 94% of specimens by frozen section of the same specimen. A Fisher's exact test determined there was no significant difference in diagnostic capability between the two groups. Additionally, both quality of SRH and condition of tissue after SRH were deemed to be non-inferior to frozen section. CONCLUSIONS: This study provides further evidence for the non-inferiority of SRH techniques. It is also the first study to demonstrate SRH accuracy using one-to-one tissue analysis in neuropathological specimens.

Genomic comparison of paired primary breast carcinomas and lymph node macrometastases using the Oncotype DX Breast Recurrence Score® test.

PURPOSE: Adjuvant therapy decisions may in part be based on results of Oncotype DX Breast Recurrence Score® (RS) testing of primary tumors. When necessary, lymph node metastases may be considered as a surrogate. Here we evaluate the concordance in gene expression between primary breast cancers and synchronous lymph node metastases, based on results from quantitative RT-PCR-based RS testing between matched primary tumors and synchronous nodal metastases. METHODS: This retrospective, exploratory study included patients (≥ 18 years old) treated at our center (2005-2009) who had ER+ , HER2-negative invasive breast cancer and synchronous nodal metastases with available tumor blocks from both sites. Paired tissue blocks underwent RS testing, and RS and single-gene results for ER, PR, and HER2 were explored between paired samples. RESULTS: A wide distribution of RS results in tumors and in synchronous nodal metastases were modestly correlated between 84 paired samples analyzed (Pearson correlation 0.69 [95% CI 0.55-0.78]). Overall concordance in RS group classification between samples was 63%. ER, PR, and HER2 by RT-PCR between the primary tumor and lymph node were also modestly correlated (Pearson correlation [95% CI] 0.64 [0.50-0.75], 0.64 [0.49-0.75], and 0.51 [0.33-0.65], respectively). Categorical concordance (positive or negative) was 100% for ER, 77% for PR, and 100% for HER2. CONCLUSIONS: There is modest correlation in continuous gene expression, as measured by the RS and single-gene results for ER, PR, and HER2 between paired primary tumors and synchronous nodal metastases. RS testing for ER+ breast cancer should continue to be based on analysis of primary tumors.

Needle-based confocal endomicroscopy for evaluation of malignant lymph nodes - a feasibility study.

BACKGROUND AND AIMS: Current modalities for lymph node staging in cancer can be limited. We sought to evaluate the feasibility of needle-based confocal laser endomicroscopy (nCLE) at the time of endoscopic ultrasound (EUS) and to describe the nCLE features that distinguish between benign, malignant, and inflammatory lymph nodes. METHODS: We collected data on 28 consecutive patients during EUS staging of malignancy or assessment of enlarged lymph nodes. Patients underwent nCLE at the time of EUS followed by fine needle biopsy. nCLE images were correlated with the patients' final histopathology. RESULTS: All 28 patients successfully underwent nCLE during EUS without adverse events. There were 17 cases of carcinoma, 4 lymphoid malignancies, and 7 benign lymph nodes. We characterized the various nCLE features of the lymph node capsule and cortex. Features of carcinoma, such as clusters of dark pleomorphic tumor cells, were identified and found to correlate well with the final pathology. Lymphoid malignancies often had enlarged follicles, but this was inconsistent. CONCLUSIONS: nCLE of lymph nodes at the time of EUS is feasible and appears to be safe. Dark pleomorphic cells were readily identified in all of the malignant lymph nodes and correlated with tumor cells seen on histology.

Papillary Thyroid Carcinoma With Lymphoepithelial Features and Lacking Association With Epstein-Barr Virus (EBV): A Rare Case.

Papillary thyroid carcinoma (PTC) is the most common primary thyroid malignancy. PTC is diagnosed based on its hallmark nuclear characteristics, but a myriad of histological variants has been identified some of which can be diagnostically challenging due to its rarity and overlapping histomorphology with other entities. We report a rare variant of PTC with lymphoepithelial features which lacked association with Epstein-Barr Virus (EBV). In such cases, a thorough workup to rule out metastasis from other sites should be undertaken.

Symptomatic infratentorial ependymal cyst arising from the medulla: a case report with review of literature.

BACKGROUND: Ependymal cysts (EC) typically present supra-tentorially near the lateral ventricle, juxta ventricular, or temporoparietal regions. Previous cases have also identified infratentorial EC of the brainstem, cerebellum, and subarachnoid spaces. They are mostly asymptomatic. In this paper, we present the first-ever case of a symptomatic medullary ependymal cyst treated with surgery, along with a comprehensive review of the literature on EC of other parts of the brain stem. CASE DESCRIPTION: This 51-year-old female presented with hearing loss, dizziness, diplopia, and ataxia. Radiographic imaging indicated the presence of a non-enhancing lesion in the medulla with a mass effect on the brainstem. Pathological examination confirmed its characterization as an ependymal cyst. The patient underwent a suboccipital craniotomy for the fenestration of the medullary ependymal cyst under neuro-navigation, Intra-op ultrasound and intra-operative neuro-monitoring. Histopathological examination confirmed the diagnosis of an ependymal cyst. At one month follow-up, her KPS is 90, ECOG PS 1, and her ataxia has improved with complete resolution of diplopia. CONCLUSION: Due to their rarity and potential similarity to other cystic structures, EC may be overlooked or incorrectly diagnosed resulting in mismanagement and surgical disaster. Therefore, a comprehensive understanding and awareness of their distinct characteristics are essential for accurate diagnosis and appropriate management.

Sarcomatous Change of Cerebellopontine Angle Ependymoma Following Radiosurgery: A Case Report.

Sarcomatous change in ependymal tumors is rare and has been poorly described. We report on a cerebellopontine angle lesion that demonstrated rapid progression two years after radiosurgery in a 73-year-old female patient. Histopathological diagnosis at clinical progression showed an ependymoma with sarcomatous change ("ependymosarcoma") that was believed to be due to radiation. The patient underwent a complex tumor resection without complications using an exhaustive multi-modal neuromonitoring paradigm throughout the dissection and resection of the tumor. Given the limited available data on these rare tumors, we review their presentation, imaging, and histopathology in the context of the previous literature, and also discuss the management of these lesions in the cerebellopontine angle.

A 33-Year-Old Man With Chest Pain.

CASE PRESENTATION: A 33-year-old man was admitted with a 4-week history of intermittent, right-sided chest pain. Two weeks before the incident, he had completed a 10-day course of levofloxacin for a presumed right-sided pneumonia without much improvement. He denied any dyspnea, cough, sputum production, hemoptysis, night sweats, or weight loss. He was an active smoker with a 20-pack-year smoking history and 1-year history of vaping nicotine.

Calcifying Pseudoneoplasm of the Neuraxis in the Posterior Fossa: A Case Report and Literature Review.

Calcifying pseudoneoplasm of the neuraxis are rare fibro-osseous lesions that can occur throughout the central nervous system. This paper reports one case of this lesion within the posterior fossa and contains a literature review of all cases documented within the posterior fossa to date. A 53-year-old female patient with a history of epiphora, facial irritation, and headaches was found to have a mass centered in the posterior fossa. The patient underwent surgical resection for removal of the mass. Upon review by pathology, the final diagnosis was consistent with calcifying pseudoneoplasm of the neuraxis.

Breast involvement in mixed connective tissue disease.

To date, mammographic involvement in mixed connective tissue disease has not been described in the literature to the authors' knowledge. In addition, only 2 case reports have described panniculitis in mixed connective tissue disease. We present a patient with mixed connective tissue disease with coarse sheet-like calcifications on mammography bilaterally, which increased over time corresponding to rise in levels of anti-dsDNA. Biopsy showed fat necrosis with calcifications, chronic inflammation and fibrosis, vasculitis, as well as CD3, CD4, and CD8+ T cells and CD20+ B cells. These findings are similar histologically and mammographically to "lupus mastitis."

Cytological features of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP).

INTRODUCTION: The noninvasive encapsulated follicular variant of papillary carcinoma (EFVPC) was recently renamed a noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) because of its unique genetic alterations and biological behavior. The objective of this report is to help cytopathologists and cytotechnologists improve diagnostic accuracy and determine the need for cytogenetic studies during adequacy evaluation of thyroid fine-needle aspirations. MATERIALS AND METHODS: Fifty-five cases of surgery-proven noninvasive EFVPC with corresponding cytology material were reviewed. These cases were collected over 17 years, from 1999 to 2016. RESULTS: Thirty-four of 55 (61.8%) cases were diagnosed as follicular neoplasm or suspicious for follicular neoplasm on cytology. Eighty to ninety percent of cases showed scant colloid, cellular smears with small clusters of follicular cells with nuclear atypia including enlarged nuclei, oval-shaped nuclei, nuclear grooves, mild chromatin powdering, and rare nuclear pseudo-inclusions. CONCLUSIONS: NIFTP has unique features: cytologically similar to follicular neoplasms, and nuclear atypia falling between atypia of undetermined significance (category III) and suspicious for/and papillary thyroid carcinoma (category V/VI) (The Bethesda System for Reporting Thyroid Cytopathology).

Macrocystic (Mammary Analogue) Secretory Carcinoma: An Unusual Variant and a Pitfall in the Differential Diagnosis of Cystic Lesions in the Head and Neck.

Mammary analogue secretory carcinoma (MASC) is a relatively recently described salivary gland adenocarcinoma characterized by ETV6-NTRK3 gene fusion and in most cases indolent clinical behavior. The majority of tumors show an admixture of microcystic, solid, and tubular growth patterns but only a few cases with dominant macrocystic growth have been reported. We report 15 cases of macrocystic MASC. There were 11 men and 4 women (17 to 88 y age range, average 47 y). The patients presented with a painless cystic mass, the majority in the region of the parotid gland (n=13), as well as in submandibular gland (n=1) and the neck (n=1). All tumors were circumscribed measuring 1.0 to 4.0 cm in greatest diameter (mean: 1.75 cm). Twelve tumors were unilocular, while 3 were multilocular. The cystic spaces were predominantly lined by a single epithelial cell layer with focal areas in which the epithelium was multilayered with papillary and hobnail features. In 3 of the cases there were more solid foci of intracystic tumor characterized by papillary and/or microcystic growth. The neoplastic cells were round to oval with hyperchromatic to vesicular nuclei with centrally located nucleoli and eosinophilic or vacuolated cytoplasm. Tumor cells showed strong positivity for S100 protein and mammaglobin, while DOG1 was uniformly negative. A minority of cases showed focal p63 reactivity predominantly limited to the periphery of the cystic lining. ETV6 gene rearrangement was identified in 9 cases. Macrocystic MASC can simulate benign and malignant salivary gland lesions and needs to be included in the differential diagnosis of cystic lesions in the head and neck. To the best of our knowledge, our report represents the first series of macrocystic MASCs wholly focusing on this unusual variant.

A Rare Case of Isolated Pancreatic Tuberculosis.

Pancreatic tuberculosis (TB) is a rare but important entity to consider when evaluating a pancreatic mass, especially in patients from endemic areas. Its clinical and radiologic features may mimic those of a pancreatic neoplasm, making it a difficult clinical diagnosis. We present a case of a 31-year-old Indian man who presented with fevers, night sweats, weight loss, and epigastric pain. Abdominal magnetic resonance imaging (MRI) showed a pancreatic head mass. Biopsy of the mass was consistent with pancreatic tuberculosis.

Papillary thyroid carcinoma with atypical histiocytoid cells on fine-needle aspiration.

Although papillary thyroid carcinoma (PTC) usually has classic cytological characteristics on fine-needle aspiration (FNA), it can present rarely with aberrant features resembling those of histiocytes in a cystic nodule. The aim of the current study was to describe PTC with atypical histiocytoid cells and distinguish it from benign histiocytes. A retrospective computerized search for FNAs with atypical features suggestive of PTC and cystic degeneration was performed, and if available, the corresponding resection specimens were compared. Four cases met the criteria for FNAs and three had surgical pathology follow-up, which showed PTC. One aspirate had some features typical of PTC, but the remaining FNAs had atypical histiocytoid cells, which had traits intermediate between those of PTC and histiocytes. Large cell size, pseudoinclusions, nuclear grooves, and multiple well-defined vacuoles in atypical histiocytoid cells favor PTC over benign histiocytes. Ancillary immunocytochemical studies can also be useful in confirming the diagnosis. Histiocytic cells are frequently present in thyroid aspirates, and occasionally, they have atypical features that represent an unusual presentation of PTC. Closer examination of these cells can provide diagnostic clues for preventing false-negative diagnosis of PTC.

The Bethesda System 2001 recommendation for reporting of benign appearing endometrial cells in Pap tests of women age 40 years and older leads to unwarranted surveillance when followed without clinical qualifiers.

OBJECTIVES: The purpose of this study is to determine the impact of the Bethesda System 2001 recommendation of reporting cytologically benign appearing endometrial cells (BEC) seen in Papanicolaou (Pap) tests of all women age 40 years and older, and to determine the significance of such finding. METHODS: Pap tests of women age 40 years and older containing BEC outside of the first half of menstrual cycle reported before and after the Bethesda System 2001 implementation were included. 300 postmenopausal women without BEC were included as control group. Clinical follow-up was reviewed and significant endometrial pathology was defined as simple hyperplasia or a higher diagnosis. RESULTS: BEC reporting rate increased from 0.17% to 0.49% before and after the Bethesda System 2001 (P=0.0001), due to reporting in women with premenopausal status. Significant endometrial pathology was detected in 14 of 121 (11.6%) postmenopausal patients compared to 7 of 300 (2.3%) in the control group (P=0.0002, relative risk=4.96, 95% confidence interval 2.05-11.98), and in none of premenopausal patients. 12 of 14 women with significant endometrial pathology had either postmenopausal bleeding or hormone replacement therapy use. CONCLUSIONS: The Bethesda System 2001 led to increased reporting of BEC only in premenopausal women, leading to biopsies performed solely for BEC in these women with no pathology detected. Presence of BEC in Pap tests of postmenopausal women warrants a thorough clinical review, and immediate biopsy is a valid consideration. Presence of hormone therapy or postmenopausal bleeding may be modifiers of risk.