Russell B. Smith

Sentinel lymph node biopsy accurately stages the regional lymph nodes for T1-T2 oral squamous cell carcinomas: results of a prospective multi-institutional trial.

PURPOSEnThe validity of sentinel lymph node biopsy (SLNB) for T1 or T2, clinically N0, oral cancer was tested by correlation of sentinel node pathologic status with that of nodes within the completion neck dissection.nnnMETHODSnThis prospective, cooperative group trial involved 25 institutions over a 3-year period. One hundred forty patients with invasive oral cancers, stage T1 and T2, N0 including 95 cancers of the tongue, 26 of the floor of mouth, and 19 other oral cancers were studied. The study excluded lesions with diameter smaller than 6 mm or minimal invasion. Imaging was used to exclude nonpalpable gross nodal disease. Patients underwent injection of the lesion with (99m)Tc-sulfur colloid, nuclear imaging, narrow-exposure SLNB, and completion selective neck dissection. The major end point was the negative-predictive value (NPV) of SLNB.nnnRESULTSnIn the 106 SLNBs, which were found to be pathologically and clinically node-negative by routine hematoxylin and eosin stain, 100 patients were found to have no other pathologically positive nodes, corresponding to a NPV of 94%. With additional sectioning and immunohistochemistry, NPV was improved to 96%. In the forty patients with proven cervical metastases, the true-positive rate was 90.2% and was superior for tongue tumors relative to floor of mouth. For T1 lesions, metastases were correctly identified in 100%.nnnCONCLUSIONnFor T1 or T2 N0 oral squamous cell carcinoma, SLNB with step sectioning and immunohistochemistry, performed by surgeons of mixed experience levels, correctly predicted a pathologically negative neck in 96% of patients (NPV, 96%).

Clinical Significance of Postradiotherapy [18F]-Fluorodeoxyglucose Positron Emission Tomography Imaging in Management of Head-and-Neck Cancer—A Long-Term Outcome Report

PURPOSEnTo determine the accuracy and prognostic significance of post-treatment [(18)F]-fluorodeoxyglucose positron emission tomography (FDG-PET) in head-and-neck squamous cell carcinoma after radiotherapy (RT).nnnMETHODS AND MATERIALSnThis was a retrospective study of 188 patients with head-and-neck squamous cell carcinoma who had undergone FDG-PET within 12 months after completing RT. All living patients had >/=1 year of follow-up after FDG-PET. All patients had undergone intensity-modulated RT, 128 with definitive and 60 with postoperative intensity-modulated RT.nnnRESULTSnFor all patients, the median follow-up after RT completion was 32.6 months and after FDG-PET was 29.2 months. For the neck, 171 patients had negative FDG-PET findings. Of these results, two were falsely negative. Seventeen patients had positive FDG-PET findings, of which 12 were true-positive findings. The sensitivity, specificity, positive predictive value, and negative predictive value for FDG-PET in the assessment of the treatment response in the neck was 86%, 97%, 71%, and 99%, respectively. For the primary site, 151 patients had negative FDG-PET findings, of which two were falsely negative. Thirty-seven patients had positive FDG-PET findings, of which 12 were true-positive findings. The sensitivity, specificity, positive predictive value, and negative predictive value for FDG-PET in the assessment of the treatment response in the primary site was 86%, 86%, 32.4%, and 98.7%, respectively. Patients with positive post-RT PET findings had significantly worse 3-year overall survival and disease-free survival.nnnCONCLUSIONnThe results of our study have shown that the findings of post-RT FDG-PET have a high negative predictive value and are a significant prognostic factor. It can provide guidance for the management of head-and-neck cancer after definitive treatment.

[99mTc]Tilmanocept Accurately Detects Sentinel Lymph Nodes and Predicts Node Pathology Status in Patients with Oral Squamous Cell Carcinoma of the Head and Neck: Results of a Phase III Multi-institutional Trial

Background[99mTc]Tilmanocept, a novel CD206 receptor-targeted radiopharmaceutical, was evaluated in an open-label, phase III trial to determine the false negative rate (FNR) of sentinel lymph node biopsy (SLNB) relative to the pathologic nodal status in patients with intraoral or cutaneous head and neck squamous cell carcinoma (HNSCC) undergoing tumor resection, SLNB, and planned elective neck dissection (END). Negative predictive value (NPV), overall accuracy of SLNB, and the impact of radiopharmaceutical injection timing relative to surgery were assessed.Methods and FindingsThis multicenter, non-randomized, single-arm trial (ClinicalTrials.gov identifier NCT00911326) enrolled 101 patients with T1–T4, N0, and M0 HNSCC. Patients received 50xa0µg [99mTc]tilmanocept radiolabeled with either 0.5xa0mCi (same day) or 2.0xa0mCi (next day), followed by lymphoscintigraphy, SLNB, and END. All excised tissues were evaluated for tissue type and tumor presence. [99mTc]Tilmanocept identified one or more SLNs in 81 of 83 patients (97.6xa0%). Of 39 patients identified with any tumor-positive nodes (SLN or non-SLN), one patient had a single tumor-positive non-SLN in whom all SLNs were tumor-negative, yielding an FNR of 2.56xa0%; NPV was 97.8xa0% and overall accuracy was 98.8xa0%. No significant differences were observed between same-day and next-day procedures.ConclusionsUse of receptor-targeted [99mTc]tilmanocept for lymphatic mapping allows for a high rate of SLN identification in patients with intraoral and cutaneous HNSCC. SLNB employing [99mTc]tilmanocept accurately predicts the pathologic nodal status of intraoral HNSCC patients with low FNR, high NPV, and high overall accuracy. The use of [99mTc]tilmanocept for SLNB in select patients may be appropriate and may obviate the need to perform more extensive procedures such as END.

OUTCOMES AFTER THYROIDECTOMY AND PARATHYROIDECTOMY

Previous reports on postoperative outcomes following thyroid and parathyroid surgery are limited by relatively small sample size. We report 30‐day outcomes following thyroid and parathyroid surgery and analyze factors affecting length of stay (LOS) and postoperative adverse events (AEs).

The Small Round Blue Cell Tumors of the Sinonasal Area

The diagnostic classification of small round blue cell tumors of the sinonasal area to include diverse malignancies of epithelial, hematolymphoid, neuroectodermal, and mesenchymal origin is challenging to the surgical pathologist using conventional histopathologic approaches because the cytomorphologic features are often overlapping or indistinctive. Rare or occasional clinical presentations in atypical age groups or unusual locations, as well as small biopsy samples may further complicate the differential diagnosis. Immunohistochemistry represents an extensively investigated ancillary technique that may aid in the provision of a definitive diagnosis. In recent years, certain small round blue cell tumors have been shown by cytogenetic analysis to have specific and primary chromosomal alterations, providing clinicians with a valuable tool to enhance their diagnostic armamentarium. The addition of molecular cytogenetic [fluorescence in situ hybridization (FISH), comparative genomic hybridization (CGH)] and molecular pathologic [polymerase chain reaction (PCR) and reverse transcriptase (RT)-PCR] approaches has further enhanced the sensitivity and accuracy of detecting these genetic alterations including assessment in formalin-fixed, paraffin-embedded tissues. Establishing an accurate diagnosis of a small round blue cell tumor of the sinonasal tract frequently requires adjunctive studies including immunohistochemical and molecular analyses.

Immunoglobulin G4–related sclerosing disease of the paranasal sinus

Immunoglobulin G4 (IgG4)–related sclerosing disease is a systemic disease characterized by extensive IgG4‐positive plasma cells and T‐lymphocyte infiltration of various organs. We present a case of a 69‐year‐old man with maxillary sinus IgG4 sclerosing disease, with orbital invasion treated with rituximab and dexamethasone pulse therapy. Surgery was used as well to debulk the disease and to obtain tissue for diagnosis.

MUC4 regulates cellular senescence in head and neck squamous cell carcinoma through p16/Rb pathway.

The limited effectiveness of therapy for patients with advanced stage head and neck squamous cell carcinoma (HNSCC) or recurrent disease is a reflection of an incomplete understanding of the molecular basis of HNSCC pathogenesis. MUC4, a high molecular weight glycoprotein, is differentially overexpressed in many human cancers and implicated in cancer progression and resistance to several chemotherapies. However, its clinical relevance and the molecular mechanisms through which it mediates HNSCC progression are not well understood. Thisxa0study revealed a significant upregulation of MUC4 in 78% (68/87) of HNSCC tissues compared withxa010% positivity (1/10) in benign samples (P=0.006, odds ratioxa0(95% confidence interval)=10.74 (2.0–57.56). MUC4 knockdown (KD) in SCC1 and SCC10B HNSCC cell lines resulted in significant inhibition of growth in vitro and in vivo, increased senescence as indicated by an increase in the number of flat, enlarged and senescence-associated β-galactosidase (SA-β-Gal)-positive cells. Decreased cellular proliferation was associated with G0/G1 cell cycle arrest and decrease expression of cell cycle regulatory proteins like cyclin E, cyclin D1 and decrease in BrdU incorporation. Mechanistic studies revealed upregulation of p16, pRb dephosphorylation and its interaction with histone deacetylase 1/2. This resulted in decreased histone acetylation (H3K9) at cyclin E promoter leading to its downregulation. Orthotopic implantation of MUC4 KD SCC1 cells into the floor of the mouth in nude mice resulted in the formation of significantly smaller tumors (170±18.30u2009mg) compared to those (375±17.29u2009mg) formed by control cells (P=0.00007). In conclusion, our findings showed that MUC4 overexpression hasxa0a critical role by regulating proliferation and cellular senescence of HNSCC cells. Downregulation of MUC4 may be a promising therapeutic approach for treating HNSCC patients.

Modifiable Risk Factors and Thyroid Cancer

Objective To evaluate the association between modifiable patient risk factors including tobacco use, alcohol consumption, body mass index (BMI), and thyroid cancer. Study Design Retrospective study with chart review. Setting Midwest university hospital. Subjects and Methods Retrospective study comparing Midwest patients with thyroid cancer from our Thyroid Tumor and Cancer Registry with Midwest controls without a personal history of cancer. Descriptive statistics were created from patient questionnaires and chart reviews. Odds ratios (ORs) were reported for significant associations. Results There were 467 patients with cancer and 255 controls. The thyroid cancer group included 404 papillary, 47 follicular, 13 medullary, and 3 anaplastic cancers. When comparing all patients with cancer with controls, smoking more than 100 lifetime cigarettes was associated with a reduced cancer risk (OR, 0.68; 95% confidence interval [CI], 0.50-0.94). Secondhand smoke exposure did not show a statistically significant relationship to thyroid cancer. Compared with never drinking, current drinking was associated with a reduced cancer risk (OR, 0.46; 95% CI, 0.29-0.73) as was consuming 1 to 2 drinks daily compared to drinking <1 drink daily (OR, 0.58; 95% CI, 0.34-0.89). There was no difference between median BMI at age 20 years, lifetime maximum BMI, or current BMI between patients with cancer and controls. Conclusion Our data showed no positive correlation between tobacco use, alcohol consumption, or obesity and thyroid cancer risk. Our data suggest that tobacco use and mild alcohol consumption may be associated with a slightly reduced risk of thyroid cancer. There was no association between BMI and thyroid cancer in our study population.

Afatinib radiosensitizes head and neck squamous cell carcinoma cells by targeting cancer stem cells

The dismal prognosis of locally advanced and metastatic squamous cell carcinoma of the head and neck (HNSCC) is primarily due to the development of resistance to chemoradiation therapy (CRT). Deregulation of Epidermal Growth Factor Receptor (EGFR) signaling is involved in HNSCC pathogenesis by regulating cell survival, cancer stem cells (CSCs), and resistance to CRT. Here we investigated the radiosensitizing activity of the pan-EGFR inhibitor afatinib in HNSCC in vitro and in vivo. Our results showed strong antiproliferative effects of afatinib in HNSCC SCC1 and SCC10B cells, compared to immortalized normal oral epithelial cells MOE1a and MOE1b. Comparative analysis revealed stronger antitumor effects with afatinib than observed with erlotinib. Furthermore, afatinib enhanced in vitro radiosensitivity of SCC1 and SCC10B cells by inducing mesenchymal to epithelial transition, G1 cell cycle arrest, and the attenuating ionizing radiation (IR)-induced activation of DNA double strand break repair (DSB) ATM/ATR/CHK2/BRCA1 pathway. Our studies also revealed the effect of afatinib on tumor sphere- and colony-forming capabilities of cancer stem cells (CSCs), and decreased IR-induced CSC population in SCC1 and SCC10B cells. Furthermore, we observed that a combination of afatinib with IR significantly reduced SCC1 xenograft tumors (median weight of 168.25 ± 20.85 mg; p = 0.05) compared to afatinib (280.07 ± 20.54 mg) or IR alone (324.91 ± 28.08 mg). Immunohistochemical analysis of SCC1 tumor xenografts demonstrated downregulation of the expression of IR-induced pEGFR1, ALDH1 and upregulation of phosphorylated γH2AX by afatinib. Overall, afatinib reduces tumorigenicity and radiosensitizes HNSCC cells. It holds promise for future clinical development as a novel radiosensitizer by improving CSC eradication.

Postoperative respiratory failure after thyroid and parathyroid surgery: Analysis of national surgical quality improvement program†‡

The risk–benefit analysis of any operation is influenced by its perioperative complications. Our objective was to examine the relationship between preoperative clinical characteristics and postoperative respiratory failure (PRF: mechanical ventilation for >48 hours after surgery or reintubation) within 30 days of thyroid and parathyroid surgeries.