Joel Thibodeaux

A transistor-like pH nanoprobe for tumour detection and image-guided surgery

Because of profound genetic and histological differences in cancerous tissue, it is challenging to detect a broad range of malignant tumours at high resolution. Here, we report the design and performance of a fluorescent nanoprobe with transistor-like responses (transition pH = 6.9) for the detection of the deregulated pH that drives many of the invasive properties of cancer. The nanoprobe amplifies fluorescence signal in the tumour over that in the surrounding normal tissues, resulting in a discretized, binary output signal with spatial resolution smaller than 1 mm. The nanoprobe allowed us to image a broad range of tumours in mouse models using a variety of clinical cameras, and to perform real-time tumour-acidosis-guided detection and surgery of occult nodules (< 1 mm3) in mice bearing head-and-neck or breast tumours, significantly lengthening mice survivability. We also show that the pH nanoprobe can be used as a reporter in a fast, quantitative assay to screen for tumour-acidosis inhibitors. The binary delineation of pH achieved by the nanoprobe promises to improve the accuracy of cancer detection, surveillance and therapy.

In vivo optical imaging of folate receptor-β in head and neck squamous cell carcinoma.

Folate receptor (FR) expression, although known to be elevated in many types of cancer and inflammatory cells, has not been well characterized in head and neck squamous cell carcinoma (HNSCC). We hypothesized that tumor infiltrating inflammatory cells expressing FR‐β could allow fluorescent visualization of HNSCC tumors using folate conjugated dyes even when FR expression in cancer cells is low.

NQO1-Mediated tumor-selective lethality and radiosensitization for head and neck cancer

Ionizing radiation (IR) is a key therapeutic regimen for many head and neck cancers (HNC). However, the 5-year overall survival rate for locally advanced HNCs is approximately 50% and better therapeutic efficacy is needed. NAD(P)H:quinone oxidoreductase 1 (NQO1) is overexpressed in many cancers, and β-lapachone (β-lap), a unique NQO1 bioactivatable drug, exploits this enzyme to release massive reactive oxygen species (ROS) that synergize with IR to kill by programmed necrosis. β-Lap represents a novel therapeutic opportunity in HNC leading to tumor-selective lethality that will enhance the efficacy of IR. Immunohistochemical staining and Western blot assays were used to assess the expression levels of NQO1 in HNC cells and tumors. Forty-five percent of endogenous HNCs expressed elevated NQO1 levels. In addition, multiple HNC cell lines and tumors demonstrated elevated levels of NQO1 expression and activity and were tested for anticancer lethality and radiosensitization by β-lap using long-term survival assays. The combination of nontoxic β-lap doses and IR significantly enhanced NQO1-dependent tumor cell lethality, increased ROS, TUNEL-positive cells, DNA damage, NAD+, and ATP consumption, and resulted in significant antitumor efficacy and prolonged survival in two xenograft murine HNC models, demonstrating β-lap radiosensitization of HNCs through a NQO1-dependent mechanism. This translational study offers a potential biomarker-driven strategy using NQO1 expression to select tumors susceptible to β-lap–induced radiosensitization. Mol Cancer Ther; 15(7); 1757–67. ©2016 AACR.

Skull Base Osteomyelitis and Bisphosphonate Use in Multiple Myeloma: Report of Two Cases and Literature Review

OBJECTIVES Although osteoradionecrosis of the mandible is a well known entity, skull base osteomyelitis involving the temporal bone unrelated to otitis externa in patients with multiple myeloma using bisphosphonates has not been reported. We described a new entity of skull base erosion resulting from osteonecrosis, presenting with malignant features in patients using bisphosphonates for multiple myeloma. METHODS Two patients with multiple myeloma and prior zolendronic acid use were referred to our cancer center for management of maxillary and temporal bone masses with skull base erosion. Both patients were in remission and not immunocompromised. Clinical symptoms included pain, cranial nerve deficits, and vertigo. An oroantral fistula developed in the maxillary patient. In both cases, repeat CT and MRI revealed an eroding mass consistent with malignancy. After repeated biopsies, however, no malignancy was seen, and pathology revealed chronic inflammation with bacterial colonization. RESULTS Imaging with technetium and gallium revealed osteomyelitis of the skull base in the temporal bone patient and actinomyces in the maxillary patient. Prolonged intravenous antibiotics resulted insignificant improvement in symptoms and imaging after eight weeks of treatment. CONCLUSION Bisphosphonate-associated osteomyelitis and necrosis of the mandible has been described in recent literature as a diagnostic and management dilemma. However, skull base osteomyelitis from the temporal bone has not been reported, and few cases from the maxilla have been reported. Early recognition and differentiation from similarly presenting malignant disease may prevent intracranial complications resulting from delayed treatment.

Teenage cervical screening in a high risk American population

Background: The new 2009 ACOG guideline for cervical cytology screening changed the starting age to 21 years regardless of the age of onset of sexual intercourse. However, many recent studies have shown a dramatic increase in the incidence of cervical epithelial abnormalities among adolescents within the past two decades. Materials and Methods: For this study, the reports of 156,342 cervical cytology were available of which 12,226 (7.8%) were from teenagers. A total of 192 teenagers with high grade intraepithelial lesion (HSIL) cervical cytology were identified. The ages ranged from 13 to 19 years with a mean of 17.7 years and a median of 18 years. Among them, 31.3% were pregnant, 12.0% were postpartum, and 13.5% were on oral contraceptive. Ninety-eight had prior cervical cytology. Results: The teenagers had statistically significant higher detection rates of overall abnormal cervical cytology (23.6% vs. 6.6%, P = 0), with 15.4% vs. 3.2% (P = 0) of low grade intraepithelial lesion (LSIL) and 1.8% vs. 1.0% (P = 2.56 × 10-13 ) of HSIL compared to women ≥20 years. The teenage group had the highest abnormal cytology among all age groups. The LSIL/HSIL ratio was 8.5:1 for teenagers and 3.1:1 for women ≥20 years. A total of 131 teenagers had cervical biopsies within 12 months of the HSIL cytology, with diagnoses of 39 CIN 3, 1 VAIN 3, 15 CIN 2, 62 CIN 1, and 14 had a negative histology (CIN 0). Only in 19 of these 39 women, the CIN 2/3 lesion proved to be persistent. Conclusion: We conclude that cytology screening of high risk teenagers is effective in detecting CIN 2/3 lesions. Moreover, treatment and careful follow-up can be realized.

The diagnostic utility of Merkel cell polyomavirus immunohistochemistry in a fine needle aspirate of metastatic Merkel cell carcinoma of unknown primary to the pancreas

Merkel cell carcinoma (MCC) is an aggressive skin tumor with a high tendency for metastases. We report a case of MCC initially presenting as axillary and pancreatic metastases. A 33‐year‐old HIV‐positive Hispanic male presented with a history of a rapidly growing axillary mass. A needle core biopsy demonstrated an epithelioid neoplasm composed of small to medium‐sized cells with high nuclear‐cytoplasmic ratio, nuclear molding, and frequent mitotic figures. A subsequent PET scan revealed a 1.5 cm FDG avid mass in the pancreas. Endoscopic ultrasound‐guided FNA of the pancreatic mass showed neoplastic cells with similar morphology to those of the axillary mass. The tumor cells were positive with pancytokeratin AE1/AE3, CK20, CD56, synatophysin, chromogranin, and Merkel cell polyomavirus (MCPyV). This case of MCC most likely originated from a resolved primary skin lesion drained by the involved axillary lymph node with subsequent metastases to the pancreas and distant lymph nodes.

Pyogenic Granuloma of the Esophagus A Cause of Dysphagia

and chemotherapy. Major causes of deaths related to head and neck squamous cell carcinoma (HNSCC) are cervical node and distant metastasis. Epithelial-mesenchymal transition (EMT) was identified to be the key role for mediating tumor invasion and metastasis of carcinomas. METHOD: The authors investigated the relationship between proinflammatory mediator and EMT in HNSCC. The author evaluated the immunohistochemical expression of interleukin-1 (IL-1 ), cyclooxygenase-2 (COX-2), Slug and E-cadherin in relationship with histologic differentiation, clinical stage and nodal status in 146 surgical specimens of HNSCC. RESULTS: There was a correlation of increased expression of IL-1 with nodal status, increased expression of COX-2 with histologic differentiation, clinical stage, and nodal status. Increased Slug expression was correlated to histologic differentiation and clinical stage. Decreased E-cadherin expression was correlated to histologic differentiation and nodal status. Significant relation was observed between IL-1 and COX-2. However, significant inverse correlation was observed between Slug and E-cadherin. Significant relation was observed between increased proinflammatory mediator IL-1 /COX-2 expression and increased EMT marker Slug/ E-cadherin expression. CONCLUSION: These results indicate that proinflammatory mediators IL-1 and COX-2 induce EMT through increase of Slug and decrease of E-cadherin. The present findings suggest some anti-inflammatory agents could be used as an adjuvant treatment modality with anti-cancer chemotherapeutic drugs in HNSCC.

The value of duplicate slides on atypical squamous cells, cannot exclude high-grade intraepithelial lesion

Atypical squamous cells, cannot exclude high‐grade squamous intraepithelial lesion (ASC‐H) category was added to the 2001 Bethesda System. ASC‐H accounts for a small percentage (0.2–0.6%) of abnormal Pap smears and includes heterogenous group of lesions. There are more high‐grade cervical lesions (30–50%) in ASC‐H than ASC‐US (10–15%). An accurate Pap diagnosis is crucial for appropriate patient follow‐up and treatment.