Prolonged Survival of NUT Midline Carcinoma and Current Approaches to Treatment.

NUT midline carcinoma is a rare malignancy most commonly seen in adolescents and young adults. The disease presents most often in the lung or head and neck area but can be seen occasionally elsewhere. The diagnosis can be difficult and requires a high degree of suspicion with demonstration of the classic fusion rearrangement mutation of the NUTM1 gene with one of a variety of partners by immunohistochemistry, fluorescent in situ hybridization, or genomic analysis. Survival is usually only a number of months with few long-term survivors. Here we report one of the longest-known survivors of this disease treated with surgery and radiation without additional therapy. Systemic treatment approaches including the use of chemotherapy and BET and histone deacetylase inhibitors have yielded modest results. Further studies of these, as well as p300 and CDK9 inhibitors and combinations of BET inhibitors with chemotherapy or CDK 4/6 inhibitors, are being evaluated. Recent reports suggest there may be a role for immune checkpoint inhibitors, even in the absence of high tumor mutation burden or PD-L1 positivity. RNA sequencing of this patient's tumor demonstrated overexpression of multiple potentially targetable genes. Given the altered transcription that results from the causative mutation multi-omic evaluation of these tumors may uncover druggable targets for treatment.

Epidemiology and aetiology of chronic rhinosinusitis in Asia-A narrative review.

BACKGROUND: Despite having a similar prevalence to Western populations, literature on chronic rhinosinusitis (CRS) in the Asian population is sparse. There is limited data on the epidemiology and aetiology of CRS in Asia. OBJECTIVES: To review the current literature on the epidemiology and aetiology of CRS in Asia. METHODS: This is a narrative review of published data on the epidemiology and aetiology of CRS. Studies on CRS in Asian countries, published in English and indexed on PubMed or Google Scholar were reviewed. Where available, data extracted included epidemiology, endotype and cytokine profiles and genetic profiles. RESULTS AND CONCLUSION: The prevalence of CRS in Asia ranges widely from 2.1% to 28.4%. Type 2 inflammation has been reported in 5%-55% of Asian patients, with lower levels of Type 2 cytokines reported in head to head comparisons of Western versus Asian patients. Notably, there exists marked heterogeneity in criterion of the tissue eosinophilic infiltration for diagnosis of type 2 CRS. Our review suggests that differences in prevalence of CRS and proportion of eosinophilic CRS between Asia and Europe and the Americas requires further study. Large-scale Asian studies utilising standardised definitions are needed to bridge this gap. Head to head genetic and microbiomal analysis may also be useful in understanding differences in CRS between the Asian and Western populations.

A Phase II Study Investigating Cabozantinib in Patients with Refractory Metastatic Colorectal Cancer (AGICC 17CRC01).

Purpose: Multi-tyrosine kinase inhibitors (TKI) have shown clinical activity in patients with metastatic colorectal cancer. Cabozantinib, a multi-TKI, exhibited potent antitumor activity superior to regorafenib in preclinical colorectal cancer patient-derived tumor xenograft models. This phase II study aimed to investigate cabozantinib, a multi-TKI, in patients with refractory, metastatic colorectal cancer (mCRC). Experimental Design: A nonrandomized, two-stage, phase II clinical trial evaluating 12-week progression-free survival (PFS) was conducted in eight cancer centers across the United States between May 2018 and July 2020. Results: A total of 44 patients were enrolled between May 2018 and May 2019, 40 of which were response evaluable. Of the total 769 reported adverse events (AE), 93 (12%) were ≥ grade 3. Five grade 5 AEs were reported of which four were unrelated to study drug and one was reported as possibly related due to bowel perforation. Eighteen patients (45%) achieved 12-week PFS with stable disease or better (confidence interval, 0.29-0.62; P < 0.001). One patient (3%) had a partial response, and 27 other patients achieved stable disease as best response per RECISTv1.1. Median PFS was 3.0 months, and median overall survival was 8.3 months. Of the 18 patients who achieved 12-week PFS, 12 had left-sided primary tumors, 11 were RAS wild type, 11 were PIK3CA wild type, and 6 had previous regorafenib therapy. The 12-week PFS rate was higher in RAS wild-type tumors compared with RAS mutant tumors (0.61 vs. 0.32; P = 0.11). Conclusions: This phase II study demonstrated clinical activity of cabozantinib in heavily pretreated, patients with refractory mCRC, and supports further investigation. Significance: Targeting angiogenesis through VEGF axis blockade provides incremental survival benefit in patients with mCRC. The hepatocyte growth factor/MET signal transduction pathway has been observed as a mechanism for acquired resistance. Dual inhibition of VEGF plus MET is an attractive therapeutic strategy. This phase II trial demonstrated clinical activity with cabozantinib, a multi-TKI targeting VEGFR2 and MET, in patients with refractory, mCRC.

The Role of Endonasal Endoscopic Optic Nerve Decompression as the Initial Management of Primary Optic Nerve Sheath Meningiomas.

Background The management of optic nerve sheath meningiomas (ONSMs) remains controversial. Surgical decompression through traditional resective techniques has been associated with significant morbidity. While radiation therapy, the current modality of choice is not exempt of risks. Transnasal endoscopic optic nerve decompression (EOND) offers a direct route to the orbit, optic canal, and orbital apex, providing a minimally invasive alternative. Objective The main objective of this article is to assess EOND as the initial management of symptomatic patients with primary ONSM. Methods Patients with ONSMs without a history of radiotherapy who underwent EOND were retrospectively reviewed. Postoperative imaging, duration of follow-up, and visual outcomes at the last ophthalmology visit were assessed. Results Four women (age range 25-63 years) with primary ONSMs that underwent EOND were identified. All patients displayed subjective and objective baseline signs of vision loss. Additionally, baseline proptosis, diplopia, optic nerve atrophy, and ocular pain were identified. In none of the cases, the optic nerve sheath was breached. Following EOND, all patients deferred treatment with adjuvant radiotherapy. At a mean postoperative follow-up of 14 months, all patients were clinically stable without evidence of disease progression on imaging or physical examination. At last ophthalmologic evaluation, three out of four showed objective improvements from baseline visual acuity and visual field (remaining patient had baseline optic nerve atrophy). Conclusion These results suggest that EOND could be a viable initial treatment modality of selected primary ONSM cases. Further studies are warranted to determine long-term efficacy and its role in a stepwise progression of management, preceding radiotherapy.

Phase I/II trial of nano-camptothecin CRLX101 with capecitabine and radiotherapy as neoadjuvant treatment for locally advanced rectal cancer.

CRLX101 is a nanoparticle-drug conjugate with a camptothecin payload. We assessed the toxicity and pathologic complete response (pCR) rate of CRLX101 with standard neoadjuvant chemoradiotherapy (CRT) in locally advanced rectal cancer. A single-arm study was conducted with a 3 + 3 dose escalation phase Ib followed by phase II at the maximum tolerated dose (MTD). Thirty-two patients were enrolled with 29 (91%) patients having T3/4 and 26 (81%) N1/2 disease. In phase Ib, no patient experienced a dose limiting toxicity (DLT) with every other week dosing, while 1/9 patients experienced a DLT with weekly dosing. The weekly MTD was identified as 15 mg/m2. The most common grade 3-4 toxicity was lymphopenia, with only 1 grade 4 event. pCR was achieved in 6/32 (19%) patients overall and 2/6 (33%) patients at the weekly MTD. CRLX101 at 15 mg/m2 weekly with neoadjuvant CRT is a feasible combination strategy with an excellent toxicity profile. Clinicaltrials.gov registration NCT02010567.

The Eustachian Tube as a Landmark for Early Identification of the Abducens Nerve During Endonasal Transclival Approaches.

BACKGROUND: Expanded endonasal approaches have the potential to injure the abducens nerve (cranial nerve [CN] VI). The nerve's root entry zone (REZ) and cisternal segment (CS) are particularly prone to injury during the clivus resection and dural incision of transclival approaches. OBJECTIVE: To investigate the role of the eustachian tube (ET) as a surgical landmark for the REZ and CS of CN VI. METHODS: Transclival expanded endonasal approaches were performed bilaterally in 6 fresh-frozen cadaveric specimens (12 sides). Anatomic relationships between ET and CN VI were documented with neuronavigation. RESULTS: The mean vertical distance from the inferior brainstem point to the horizontal projection of CN VI REZ, CS midpoint, and interdural segment (ID) were 26.38 mm (95% confidence interval [CI] 17.36-35.4), 38.61 mm (95% CI 25.61-51.61), and 42.68 mm (95% CI 30.14-55.22), respectively. The relative vertical distance from the ET to the horizontal projections of the REZ, CS midpoint, and its ID were 6.43 mm (95% CI 3.25-9.61), 18.66 mm (95% CI 11.52-25.8), and 22.72 mm (95% CI 16.02-29.42), respectively. In the axial plane the angles between the ET and (1) the REZ and its midline horizontal projection point, (2) the midpoint and its midline horizontal projection point, and (3) ID and its midline horizontal projection point were 9.81 ± SD 5.20°, 18.50 ± SD 4.87°, and 24.71 ± SD 6.21°, respectively. CONCLUSION: The ET may serve as a constant landmark to reliably predict the position of the REZ and CS of CN VI.

Expanded Endoscopic Endonasal Approach to the Inframeatal Area: Anatomic Nuances with Surgical Implications.

BACKGROUND/OBJECTIVE: The inframeatal area represents a challenging region for skull base surgeons. Various surgical corridors have been described to access this area and frequently are used in combination. Recent studies describe the expanded endoscopic endonasal approach (EEA) as an established route for midline regions, particularly medial to the internal carotid arteries (ICA). We sought to evaluate the accessibility, maneuverability, and freedom of movement of the expanded endoscopic endonasal approach to the inframeatal region. METHODS: An EEA combining a middle and an inferior transclival corridor with an infrapetrous and a supracondylar lateral expansion was performed in 5 embalmed human cadaveric heads. The area of exposure and the surgical freedom to access the inframeatal area were calculated. The angle of attack and distances from the lacerum segment of the ICA to several anatomical targets also were measured. Our database was searched to select clinical case examples. RESULTS: The EEA provided an exposure area of 101.26 ± 16.66 mm2 and an area of surgical freedom of 1208.50 ± 507.01 mm2. The angles of attack in both the sagittal and axial planes were wider at the lacerum segment of the ICA and narrower at the dural entrance zone of cranial nerves VII/VIII. Three chondrosarcomas are presented as case illustrations. CONCLUSIONS: The EEA is a feasible route to the inframeatal area. This approach provides a safe working corridor for lesions in this region, as shown by the anatomical and clinical findings presented here. Comparative studies and large case series are warranted to further establish its clinical value.

Art and Challenges of Precision Medicine: Interpreting and Integrating Genomic Data Into Clinical Practice.

Precision medicine is at the forefront of innovation in cancer care. With the development of technologies to rapidly sequence DNA from tumors, cell-free DNA, proteins, and even metabolites coupled with the rapid decline in the cost of genomic sequencing, there has been an exponential increase in the amount of data generated for each patient diagnosed with cancer. The ability to harness this explosion of data will be critical to improving treatments for patients. Precision medicine lends itself to big data or "informatics" approaches and is focused on storing, accessing, sharing, and studying these data while taking necessary precautions to protect patients' privacy. Major cancer care stakeholders have developed a variety of systems to incorporate precision medicine technologies into patient care as soon as possible and also to provide the ability to store and analyze the omics and clinical data aggregately in the future. Scaling these precision medicine programs within the confines of health care system silos is challenging, and research consortiums are being formed to overcome these limitations. Incorporating and interpreting the results of precision medicine sequencing is complex and rapidly changing, necessitating reliance on a group of experts. This is often performed at molecular tumor boards at large academic and research institutions with available in-house expertise, but alternative models clinical decision support software or of virtual tumor boards potentially expand these advances to almost any patient, regardless of site of care. The promises of precision medicine will be more quickly realized by expanding collaborations to rapidly process and interpret the growing volumes of omics data.

Myrtol standardized affects mucociliary clearance.

BACKGROUND: Myrtol standardized (Gelomyrtol forte) has been shown to be effective in controlling nasal symptoms of rhinosinusitis by promoting mucociliary clearance. Our aim was to evaluate the short- and long-term effects of myrtol on ciliated columnar cells and goblet cells in an in-vitro setting. METHODS: Nasal epithelial cells were harvested (42 days) from an air-liquid interface (ALI) culture of human nasal epithelial stem/progenitor cells (hNESPCs), which was derived from biopsies of nasal inferior turbinate mucosa. Myrtol 0.1% was applied to the ALI culture system at 2 different time-points (day 0 and day 35) on progenitor and differentiated cells. Ciliary beat frequency (CBF), supernatant fluid, and ciliated and goblet cell markers were evaluated after short- (7 days) and long-term (42 days) treatment. RESULTS: In the long-term treatment with myrtol, there was an increase in cilia area (type IV ß-tubulin+ , 1.53-fold, p = 0.031) and ciliogenesis-related markers (Foxj1 and CP110) with no change in CBF, as compared with control. In addition, the short-term myrtol treatment group exhibited greater mucin secretion compared with control. CONCLUSION: This study demonstrates, through cellular and molecular mechanisms, that myrtol standardized enhances the mucus production from goblet cells in the short term, and promotes ciliated cell differentiation in the long term.

Differential Expression Patterns of EGF, EGFR, and ERBB4 in Nasal Polyp Epithelium.

Epidermal growth factor receptors play an important role in airway epithelial cell growth and differentiation. The current study investigates the expression profiles of EGF, EGFR and ERBB4 in patients with nasal polyps (NP), and their response to glucocorticosteroid (GC) treatment. Fifty patients with NP (40 without GC treatment and 10 with oral GC) and 20 control subjects with septal deviation were recruited into the study. Protein levels of EGF, EGFR, and ERBB4 were evaluated by immune-staining. In healthy nasal epithelium, EGF and EGFR localized within p63+ basal cells, while ERBB4 localized within ciliated cells. GC-naïve NP epithelium showed weak expression of EGF in 90% of samples versus 5% of controls. EGFR was significantly increased in the epithelium with basal cell hyperplasia from GC-naïve NPs (78%, 31/40) compared to controls (23%, 4/17). EGFR was also found in some degranulating goblet cells. ERBB4 expression was significantly higher in hyperplastic epithelium from GC-naïve NPs (65%, 26/40) than in controls (6%, 1/17). GC treatment restored the EGF expression and normalized the EGFR and ERBB4 expression in NPs. Differential expression patterns of EGF, EGFR, and ERBB4 are essential in epithelial restitution and remodeling in nasal epithelium.

Everolimus causing severe hypertriglyceridemia and acute pancreatitis.

Everolimus is an mTOR inhibitor commonly used to treat metastatic pancreatic neuroendocrine tumors (pNETs) and renal cell carcinoma, and for posttransplant immunosuppression. This report presents a case of a 36-year-old man being treated with everolimus for a metastatic pNET who developed severe hypertriglyceridemia and acute pancreatitis. The incidence of hypertriglyceridemia reported in large prospective randomized trials is reviewed and the management of hypertriglyceridemic pancreatitis is discussed. Careful monitoring of triglyceride levels and dose adjustments of everolimus together with lipid-lowering therapy can allow patients to continue this medication. Because there are increasing indications for the use of everolimus, prescribing oncologists must be cognizant of the common and serious side effects.

A review of hepatocellular carcinoma (HCC) staging systems.

Accurately staging patients is essential to oncology practice. Cancer staging contributes to prognostication, guides management decisions, and informs clinical, epidemiologic, and health services research. In hepatocellular carcinoma (HCC), staging poses unique challenges due to the geographic and biological heterogeneity of the disease and lack of consensus on how to best classify patients. The features included in various HCC classifications systems have evolved over the last 50 years, but in general, need to account for both tumor characteristics as well as the burden of underlying liver disease.In this review, we discuss the Child-Turcotte-Pugh and Model for End-Stage Liver Disease, two practical systems that reflect the degree of hepatic dysfunction. We then describe several HCC staging systems, reviewing their development, and applicability to clinical practice, with a critical look at their validation. Finally, we look ahead to novel systems utilizing molecular markers. It is hoped this review will provide context regarding the use of current staging and scoring methods and a glimpse of what we can expect with future systems.

Bilateral enlarged vestibular aqueduct with associated bilateral Mondini's dysplasia.

Enlarged Vestibular Aqueduct (EVA) and Mondini's dysplasia (incomplete partitioning type II) are entitites that have been fairly well described in the literature as potential causes of hearing loss in the young. However, it is uncommon for this condition to be detected bilaterally, especially so for both conditions to coexist bilaterally in the same patient. This is a brief description of a patient with the above bilateral condition with attached high resolution CT scan images of the temporal bone to illustrate the case.

Endoscopic surgery for fronto-ethmoidal mucoceles: a 15-year experience.

OBJECTIVE: To add to the existing knowledge of endoscopic surgery for fronto-ethmoidal mucoceles and to determine factors that influence the outcomes of endoscopic surgery. STUDY DESIGN: Case series with chart review. SETTING: University adult tertiary care institution. SUBJECTS AND METHODS: A database of patients treated surgically for mucoceles of the paranasal sinus has been kept by the senior author since 1995. It was used to identify those who have had endoscopic surgery for fronto-ethmoidal mucoceles from 1995 to 2010. All adult patients with 6 months or more of follow-up were included. The database was reviewed and assessed for variables that may affect outcome after surgery. RESULTS: Forty patients underwent 44 endoscopic procedures for treatment of fronto-ethmoidal mucoceles and the complications of surgery. The mean age was 46.3 years, and mean follow-up time was 74.9 months. Two patients had a history of head trauma. A total of 28 Draf IIa procedures, 13 Draf IIb, and 3 Draf III procedures were performed. Three patients had combined open approaches. Two patients had bilateral surgery, and 2 patients required revision surgery: 1 for restenosis after a Draf IIa procedure (1/28) and 1 for disease recurrence. Stenosis was found in a further 3 patients who had Draf IIb surgery (3/13). CONCLUSION: The current series represents one of the largest for the endoscopic management of fronto-ethmoidal mucoceles. Endoscopic approaches are suitable for most mucoceles. The most common complication, restenosis of the frontal recess, was more likely following Draf IIb procedures (23%) than Draf IIa (3.6%) procedures.