Phase I/II trial of Durvalumab plus Tremelimumab and stereotactic body radiotherapy for metastatic head and neck carcinoma.

BACKGROUND: The efficacy of immunotherapy targeting the PD-1/PD-L1 pathway has previously been demonstrated in metastatic head and neck squamous cell carcinoma (HNSCC). Stereotactic Body Radiotherapy (SBRT) aims at ablating metastatic lesions and may play a synergistic role with immunotherapy. The purpose of this study is to assess the safety and efficacy of triple treatment combination (TTC) consisting of the administration of durvalumab and tremelimumab in combination with SBRT in metastatic HNSCC. METHOD: This is a phase I/II single arm study that will include 35 patients with 2-10 extracranial metastatic lesions. Patients will receive durvalumab (1500 mg IV every 4 weeks (Q4W)) and tremelimumab (75 mg IV Q4W for a total of 4 doses) until progression, unacceptable toxicity or patient withdrawal. SBRT to 2-5 metastases will be administered between cycles 2 and 3 of immunotherapy. The safety of the treatment combination will be evaluated through assessment of TTC-related toxicities, defined as grade 3-5 toxicities based on Common Terminology Criteria for Adverse Events (v 4.03), occurring within 6 weeks from SBRT start, and that are definitely, probably or possibly related to the combination of all treatments. We hypothesize that dual targeting of PD-L1 and CTLA-4 pathways combined with SBRT will lead to < 35% grade 3-5 acute toxicities related to TTC. Progression free survival (PFS) will be the primary endpoint of the phase II portion of this study and will be assessed with radiological exams every 8 weeks using the RECIST version 1.1 criteria. DISCUSSION: The combination of synergistic dual checkpoints inhibition along with ablative radiation may significantly potentiate the local and systemic disease control. This study constitutes the first clinical trial combining effects of SBRT with dual checkpoint blockade with durvalumab and tremelimumab in the treatment of metastatic HNSCC. If positive, this study would lead to a phase III trial testing this treatment combination against standard of care in metastatic HNSCC. TRIAL REGISTRATION: NCT03283605 . Registration date: September 14, 2017; version 1.

Four PTEN-targeting co-expressed miRNAs and ACTN4- targeting miR-548b are independent prognostic biomarkers in human squamous cell carcinoma of the oral tongue.

The purpose of this study was to determine the prognostic value and oncogenic pathways associated to miRNA expression in squamous cell carcinoma of the oral tongue and to link these miRNA candidates with potential gene targets. We performed a miRNA screening within our institutional cohort (n = 58 patients) and reported five prognostic targets including a cluster of four co-expressed miRNAs (miR-18a, miR-92a, miR-103, and miR-205). Multivariate analysis showed that expression of miR-548b (p = 0.007) and miR-18a (p = 0.004, representative of co-expressed miRNAs) are independent prognostic markers for squamous cell carcinoma of the oral tongue. These findings were validated in The Cancer Genome Atlas (TCGA) cohort (n = 131) for both miRNAs (miR-548b: p = 0.027; miR-18a: p = 0.001). Bioinformatics analysis identified PTEN and ACTN4 as direct targets of the four co-expressed miRNAs and miR-548b, respectively. Correlations between the five identified miRNAs and their respective targeted genes were validated in the two merged cohorts and were concordantly significant (miR-18a/PTEN: p < 0.0001; miR-92a/PTEN: p = 0.0008; miR-103/PTEN: p = 0.008; miR-203/PTEN: p = 0.019; miR-548b/ACTN4: p = 0.009).

Tri-modal microscope for head and neck tissue identification.

A novel tri-modal microscope combining optical coherence tomography (OCT), spectrally encoded confocal microscopy (SECM) and fluorescence imaging is presented. This system aims at providing a tool for rapid identification of head and neck tissues during thyroid surgery. The development of a dual-wavelength polygon-based swept laser allows for synchronized, co-registered and simultaneous imaging with all three modalities. Further ameliorations towards miniaturization include a custom lens for optimal compromise between orthogonal imaging geometries as well as a double-clad fiber coupler for increased throughput. Image quality and co-registration is demonstrated on freshly excised swine head and neck tissue samples to illustrate the complementarity of the techniques for identifying signature cellular and structural features.

Predicting depression and quality of life among long-term head and neck cancer survivors.

OBJECTIVE: The aim of this study is to identify clinical factors that are predictive of depression and quality of life (QOL) among long-term survivors of head and neck squamous cell carcinoma and to develop predictive scores using these factors. STUDY DESIGN: Cohort study SETTING: Tertiary referral center. SUBJECTS AND METHODS: A total of 209 posttreatment (median follow-up, 38.7 months) head and neck cancer patients were prospectively evaluated using the Hospital Anxiety Depression Scale (HADS), the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30, and the EORTC Quality of Life Questionnaire Head and Neck 35, and pretreatment patient-related, tumor-related, and treatment-related predictors were identified using chart review. Bivariate (χ(2) and t test) and multivariate (linear regression) analyses were used to construct predictive models. RESULTS: Significant pretreatment predictors of depression were identified on multivariate analysis as smoking at diagnosis, >14 alcoholic drinks per week, T3 or T4 status, and >3 medications (P < .001). Two or more of these factors yielded an 82.3% sensitivity in detecting significant depressive symptoms (defined as a HADS cutoff score of 5). Significant predictors of fatigue, global health/QOL, social contact, speech, pain, swallowing, and xerostomia were also identified. CONCLUSION: Pretreatment predictors of long-term depression and QOL have been defined using multivariate models, and an easily applicable predictive score of long-term depression is proposed. Potential eventual clinical applications include prophylactic intervention in at-risk patients.

Preoperative serum thyroglobulin as an adjunct to fine-needle aspiration in predicting well-differentiated thyroid cancer.

BACKGROUND/PURPOSE: when fine-needle aspiration biopsy (FNAB) of a thyroid nodule yields indeterminate pathology, management decisions become complex, and other preoperative predictors of thyroid cancer must be employed to assess the risk of malignancy. Although thyroglobulin (Tg) is currently accepted as the serum marker of choice in the detection of well-differentiated thyroid cancer (WDTC) recurrence, its preoperative role in the workup of a thyroid nodule remains controversial. The purpose of this study was to evaluate the potential role for Tg as a preoperative indicator of primary WDTC, specifically in patients with indeterminate FNAB. METHODS: this was a retrospective review of 861 consecutive thyroidectomy patients; 297 patients had indeterminate FNAB, of which 68 had serum levels of Tg measured prior to surgery. The predictive value of various threshold levels of preoperative Tg for WDTC was evaluated. Patients with nonindeterminate FNAB or final pathology containing medullary carcinoma, anaplastic carcinoma, or lymphoma were excluded. RESULTS: eighty-one percent (25 of 31) of patients with both indeterminate FNAB and preoperative Tg ≥ 75 microg/L had well-differentiated cancer on final pathology compared to 58% (172 of 297) of patients with indeterminate cytology alone (p = .014, RR = 1.4). In addition, mean preoperative Tg levels were found to be significantly higher in patients with WDTC compared to those with benign pathology (223 vs 53 microg/L, p = .007). DISCUSSION/CONCLUSION: our results imply that elevated preoperative serum Tg levels may be predictive of WDTC. This marker may be useful as an aid when making management decisions in patients with indeterminate cytology.

Body mass index in the evaluation of thyroid cancer risk.

BACKGROUND: Obesity has been linked to numerous diseases including thyroid cancer, but the exact nature of the relationship, especially with respect to patients with thyroid nodules, remains unclear. The objective of this study was to evaluate the impact of body mass index (BMI) on thyroid cancer risk in a population of patients with indeterminate cytology on fine-needle aspiration biopsy (FNAB). METHODS: A total of 253 consecutive patients with indeterminate thyroid nodule FNABs who underwent total thyroidectomy in a tertiary care teaching hospital between 2002 and 2007 were reviewed. Height and weight reported on the anesthesia summary were recorded for each patient. Malignancy rates were calculated for the underweight, normal, overweight, and obese groups stratified according to their BMI. Subanalyses according to age and sex were also performed. RESULTS: The risk of malignancy tended to be lower in obese patients compared to patients with BMIs in the underweight, normal, and overweight ranges (52% vs. 61%, p = 0.195). In men, a BMI classified as obese was associated with a significantly lower rate of malignancy (36% vs. 72%, p = 0.003). Women older than 45 years were a subgroup in which higher malignancy rates were associated with obesity (65% vs. 54%, p = 0.293). Conversely, in men over the age of 45 years and women under 45 years, a BMI in the obesity range was linked to a lower incidence of malignancy (20% vs. 68% p = 0.009 and 36% vs. 68% p = 0.043, respectively). When older women were excluded from the population studied, the rate of malignancy in obese patients was 36% versus 70% in nonobese patients (p = 0.002) with an associated reduction of 5% in the risk of malignancy per increased unit of BMI. CONCLUSIONS: For patients with FNAB results of indeterminate significance, a higher BMI correlates with lower rates of thyroid malignancy for all patients except women over the age of 45 years.

Fine-needle aspiration biopsy of the thyroid: review of cytopathologic features predictive of malignancy.

OBJECTIVE: To determine the value of specific cytopathologic features on fine-needle aspiration biopsies (FNABs) at predicting thyroid malignancy. DESIGN: Retrospective review of consecutive patients undergoing thyroidectomy between 2005 and 2007 following FNAB of thyroid nodules. SETTING: Two McGill University teaching hospitals in Montreal. METHODS: One hundred forty-seven patients were reviewed and further categorized into two groups (benign vs malignant) based on the final histopathologic diagnosis. The frequency of specific cytopathologic features from the preoperative FNAB samples was recorded for 106 patients from the first hospital and 41 patients from the second. RESULTS: The presence of atypical cells (30% vs 72%; p = 3.23 x 10(-7)), nuclear grooves (5% vs 23%; p = .002), anisonucleosis (8% vs 36%; p = .00011), variable chromatin staining (10% vs 28%; p = .007), hypochromasia (11% vs 47%; p = 7.19 x 10(-6)), nuclear overlapping/crowding (8% vs 29%; p = .0019), irregular nuclear membranes (15% vs 52%, p = 3.22 x 10(-6)), micronucleoli (15% vs 60%, p = .003), and powdery chromatin (8% vs 47%, p = .004) correlates with an increased risk of malignancy. Alternatively, siderophages (44% vs 23%; p = .007) and honeycomb arrangements (92% vs 60%; p = .012) were more associated with benign processes. HBME-1 staining (n = 53) was positive or focally positive on 61% of the malignant cases (p = .0002), with a specificity of 100%. All biopsies demonstrating intranuclear inclusions, papillary fragments, or atypical architecture were malignant. CONCLUSION: Some cytopathologic features are more significantly associated with thyroid malignancy. The cytopathologic features listed in FNAB reports and HBME-1 immunoreactivity are, alone or in combination, additional tools available to the physician to guide management of thyroid nodules.

Predictors of malignancy in preoperative nondiagnostic biopsies of the thyroid.

OBJECTIVE: To determine whether preoperative variables can be used to predict malignancy for thyroid nodules with follicular, Hürthle, or nondiagnostic cytology on fine-needle aspiration biopsy (FNAB). MATERIALS AND METHODS: Retrospective analysis of 77 consecutive patients selected for total or subtotal thyroidectomy for follicular, Hürthle, or nondiagnostic lesions of the thyroid in two university hospitals. Eleven clinical variables, as well as nodule size, multiplicity, and ultrasound calcifications, were correlated with final histopathologic diagnosis of benign or malignant disease. Analysis was preformed using the Pearson chi-square test. RESULTS: The overall rate of malignancy in our series was 61% (n = 47). FNABs classified as follicular or Hürthle lesions without cellular atypia had a significantly lower risk of malignancy (49% vs 71%; p = .05). Patients who presented with a solitary nodule and FNAB cellular atypia displayed an increased risk of malignancy (92% vs 55%; p = .011). The rate of malignancy was higher for patients with a positive family history (100% vs 59%), a solitary nodule (73% vs 53%), cellular atypia (76% vs 54%), or intrathyroidal calcifications on ultrasonography (71% vs 57%), although none were found to be statistically significant (p > .05). Male gender, age > 45 years, nodule size > 3 cm, mass effect symptoms, and radiation exposure to the neck were not associated with malignancy in our series. CONCLUSION: When presented with follicular, Hürthle, or nondiagnostic biopsies for thyroid nodules, thyroid surgeons should rely systematically on sonographic findings and cytopathologic features to guide their management approach.

Fine-needle aspiration biopsies in the management of indeterminate follicular and Hurthle cell thyroid lesions.

OBJECTIVES: To determine the value of fine-needle aspiration biopsies (FNABs) of the thyroid and stratify the risk of malignancy within the indeterminate FNAB diagnostic category at our institution. STUDY DESIGN: Case series with chart review of preoperative FNABs of consecutive patients who underwent total thyroidectomy between 2005 and 2007. SUBJECTS AND METHODS: A total of 115 cases were reviewed, and FNABs were categorized into four groups: benign, positive or suspicious for malignancy, indeterminate (follicular or Hurthle cell lesions), and nondiagnostic. Cytohistologic correlation was then established. RESULTS: The accuracy of FNAB in detecting thyroid malignancy was 88 percent with false-negative and false-positive rates of 13 percent and 7 percent, respectively. Overall, 52 percent of the indeterminate cases were carcinomas (48 percent of follicular lesions and 62 percent of Hurthle cell lesions). In the presence of cytologic atypia, the rate of malignancy increased to 75 percent and 83 percent for the follicular and Hurthle cell lesions, respectively. CONCLUSIONS: FNAB is an accurate and helpful method for the evaluation of thyroid nodules with results directly correlating with management. Surgery should be considered for FNABs categorized as indeterminate, especially in the presence of cytologic atypia. Because of the high false-negative rate, benign FNABs require close follow-up with ultrasound examination and periodic biopsies.

Incidence and histopathological behavior of papillary microcarcinomas: study of 429 cases.

OBJECTIVE: We aim to present papillary microcarcinoma (PMC) incidence at a university teaching hospital, to compare characteristics of PMC in relation to size, and to assess for significant difference in PMC incidence among patients with non-PMC thyroid malignancies. MATERIALS AND METHODS: Pathology results were reviewed for consecutive total thyroidectomies between 2002 and 2007 (n = 860). Statistical significance was calculated using chi(2) or, when unavailable, Fisher exact test. RESULTS: PMC was found in 429 cases, which is 49.9 percent of all total thyroidectomies. In PMC > or =5 mm, 25.1 percent had extrathyroidal extension vs 9.1 percent for <5 mm (P < 0.001). When 4 mm is used as a threshold, P value was 300-fold smaller. Incidence in patients with any non-PMC thyroid malignancy was 51.6 percent against 47.2 percent in all other patients (P = 0.203). CONCLUSIONS: In this study, PMC was found in 49.9 percent of patients, which, to our knowledge, is higher than any other reported incidence. A threshold of > or =4 mm was more significant than 5 mm for carrying increased risk for extrathyroidal spread. There was no significant difference in PMC incidence in patients with malignant vs benign disease.

Determination of sequential mutation accumulation in pancreas and bile duct brushing cytology.

Neoplastic progression is characterized by clonal expansion of tumor cells associated with accumulation of mutational damage. The timing of mutation acquisition could be of value in distinguishing preneoplastic conditions from early and advanced cancer as well as characterizing tumor aggressiveness and treatment response. Using quantitative methods applied to microdissected cell clusters selected according to cytomorphologic features, we sought to demonstrate the feasibility and efficacy for determining the time and course of mutation accumulation in pancreatobiliary cytology specimens. In all, 40 pancreatic duct and 21 biliary brushing cytology specimens were retrieved from the cytology database. Xylene-resistant markings were placed on the slide underside and coverslips removed. Clusters of benign, atypical and malignant cells were manually microdissected and DNA extracted. Mutations (allelic imbalance) (loss of heterozygosity) were quantitatively determined for a broad panel of 15 markers (1p, 3p, 5q, 9p, 10q, 17p, 17q, 21q, 22q) as well as point mutation in K-ras-2 using PCR/capillary electrophoresis. Time course was based on earlier mutations having a higher proportion of mutant DNA for a particular marker. The descending frequency of detectable mutational involvement in pancreatic cytology was K-ras-2 point mutation (58%), 3p25-26 and 17q21 (35%), 5q23 (33%), 1p36 (28%), followed by the remaining molecular markers. The descending frequency of mutational content in bile duct cytology was 17p13, 1p36, 3p25-26, and 5q23 followed by remaining molecular markers. K-ras-2 point mutation was not seen in bile duct specimens. While there was overlap in the spectrum of mutational markers in pancreatic duct and biliary brushing cytology, the temporal profile was significantly different (P<0.001). Pancreatic and biliary neoplasia progression involves distinct subset of accumulated defined mutations. Determination of timing of the mutational damage in cytologic material could be incorporated in the work-up and help in making a more definitive diagnosis of malignancy in pancreatobiliary cytology specimens.

Potential diagnostic use of p16INK4A, a new marker that correlates with dysplasia in oral squamoproliferative lesions.

Protein products of tumor suppressor genes are often involved in regulating the cell cycle, and aberrant expression can correlate with underlying genetic mutations. Mutations in the p16 gene have been detected at relatively high rates in squamous cell carcinomas of the oral cavity. However, immunohistochemical staining for the protein product has not been examined as a diagnostic tool for identifying dysplastic lesions in the oral cavity. Sixty cases of biopsies of reactive, inflammatory, and dysplastic lesions of all grades were stained with an antibody to p16INK4A and analyzed for which layer of the epithelium had positive cells. Staining was seen only in the basal or lower third in keratoses and mild dysplasias and was seen in the mid and upper thirds in moderate to severe dysplasia. The staining across larger fragments of biopsied epithelium highlighted skip lesions, with strong staining restricted to dysplastic regions. Inflammatory lesions, including chronic ulcers, showed absent or minimal basal layer staining with p16INK4A. In this preliminary study, p16INK4A shows promise as to a potential marker to aid in recognizing the presence of dysplasia in squamous mucosa of the head and neck, particularly in subtle lesions, and in an inflammatory or ulcerated background.