Concept: Basal cell carcinoma
Nevoid basal cell carcinoma syndrome (Gorlin syndrome) is a rare autosomal dominant disorder characterized by numerous basal cell carcinomas, keratocystic odontogenic tumors of the jaws, and diverse developmental defects. This disorder is associated with mutations in tumor suppressor gene Patched 1 (PTCH1). We present two patients with Gorlin syndrome, one sporadic and one familial. Clinical examination, radiological and CT imaging, and mutation screening of PTCH1 gene were performed. Family members, as well as eleven healthy controls were included in the study. Both patients fulfilled the specific criteria for diagnosis of Gorlin syndrome. Molecular analysis of the first patient showed a novel frameshift mutation in exon 6 of PTCH1gene (c.903delT). Additionally, a somatic frameshift mutation in exon 21 (c.3524delT) along with germline mutation in exon 6 was detected in tumor-derived tissue sample of this patient. Analysis of the second patient, as well as two affected family members, revealed a novel nonsense germline mutation in exon 8 (c.1148 C>A).
UV radiation (UV) is classified as a “complete carcinogen” because it is both a mutagen and a non-specific damaging agent and has properties of both a tumor initiator and a tumor promoter. In environmental abundance, UV is the most important modifiable risk factor for skin cancer and many other environmentally-influenced skin disorders. However, UV also benefits human health by mediating natural synthesis of vitamin D and endorphins in the skin, therefore UV has complex and mixed effects on human health. Nonetheless, excessive exposure to UV carries profound health risks, including atrophy, pigmentary changes, wrinkling and malignancy. UV is epidemiologically and molecularly linked to the three most common types of skin cancer, basal cell carcinoma, squamous cell carcinoma and malignant melanoma, which together affect more than a million Americans annually. Genetic factors also influence risk of UV-mediated skin disease. Polymorphisms of the melanocortin 1 receptor (MC1R) gene, in particular, correlate with fairness of skin, UV sensitivity, and enhanced cancer risk. We are interested in developing UV-protective approaches based on a detailed understanding of molecular events that occur after UV exposure, focusing particularly on epidermal melanization and the role of the MC1R in genome maintenance.
Patients with cutaneous melanoma metastases have experienced excellent responses to intralesional interleukin (IL)-2. This has led to its recent inclusion into the US National Comprehensive Cancer Network guidelines for management of cutaneous melanoma metastases. Despite this, intralesional IL-2 has not been highlighted in the US literature nor have US physicians adopted it.
Irreversible destruction of bronchi and alveoli can lead to multiple incurable lung diseases. Identifying lung stem/progenitor cells with regenerative capacity and utilizing them to reconstruct functional tissue is one of the biggest hopes to reverse the damage and cure such diseases. Here we showed that a rare population of SOX9+ basal cells (BCs) located at airway epithelium rugae can regenerate adult human lung. Human SOX9+ BCs can be readily isolated by bronchoscopic brushing and indefinitely expanded in feeder-free condition. Expanded human SOX9+ BCs can give rise to alveolar and bronchiolar epithelium after being transplanted into injured mouse lung, with air-blood exchange system reconstructed and recipient’s lung function improved. Manipulation of lung microenvironment with Pirfenidone to suppress TGF-β signaling could further boost the transplantation efficiency. Moreover, we conducted the first autologous SOX9+ BCs transplantation clinical trial in two bronchiectasis patients. Lung tissue repair and pulmonary function enhancement was observed in patients 3-12 months after cell transplantation. Altogether our current work indicated that functional adult human lung structure can be reconstituted by orthotopic transplantation of tissue-specific stem/progenitor cells, which could be translated into a mature regenerative therapeutic strategy in near future.
Solar ultraviolet (UV) radiation is the second most prevalent carcinogenic exposure in Canada and is similarly important in other countries with large Caucasian populations. The objective of this article was to estimate the economic burden associated with newly diagnosed non-melanoma skin cancers (NMSCs) attributable to occupational solar radiation exposure. Key cost categories considered were direct costs (healthcare costs, out-of-pocket costs (OOPCs), and informal caregiver costs); indirect costs (productivity/output costs and home production costs); and intangible costs (monetary value of the loss of health-related quality of life (HRQoL)). To generate the burden estimates, we used secondary data from multiple sources applied to computational methods developed from an extensive review of the literature. An estimated 2,846 (5.3%) of the 53,696 newly diagnosed cases of basal cell carcinoma (BCC) and 1,710 (9.2%) of the 18,549 newly diagnosed cases of squamous cell carcinoma (SCC) in 2011 in Canada were attributable to occupational solar radiation exposure. The combined total for direct and indirect costs of occupational NMSC cases is $28.9 million ($15.9 million for BCC and $13.0 million for SCC), and for intangible costs is $5.7 million ($0.6 million for BCC and $5.1 million for SCC). On a per-case basis, the total costs are $5,670 for BCC and $10,555 for SCC. The higher per-case cost for SCC is largely a result of a lower survival rate, and hence higher indirect and intangible costs. Our estimates can be used to raise awareness of occupational solar UV exposure as an important causal factor in NMSCs and can highlight the importance of occupational BCC and SCC among other occupational cancers.
Alterations in hedgehog signaling are implicated in the pathogenesis of basal-cell carcinoma. Although most basal-cell carcinomas are treated surgically, no effective therapy exists for locally advanced or metastatic basal-cell carcinoma. A phase 1 study of vismodegib (GDC-0449), a first-in-class, small-molecule inhibitor of the hedgehog pathway, showed a 58% response rate among patients with advanced basal-cell carcinoma.
We previously reported modest clinical 3-year benefit for topical imiquimod compared with surgery for superficial or nodular basal cell carcinoma at low-risk sites in our noninferiority randomized controlled SINS trial. Here we report 5-year data. Participants were randomized to imiquimod 5% cream once daily (superficial basal cell carcinoma, 6 weeks; nodular basal cell carcinoma, 12 weeks) or excisional surgery (4-mm margin). The primary outcome was clinical absence of initial failure or signs of recurrence at the 3-year dermatology review. Five-year success was defined as 3-year success plus absence of recurrences identified through hospital, histopathology, and general practitioner records. Of 501 participants randomized, 401 contributed to the modified intention-to-treat analyses at year 3 (primary outcome), 383 (96%) of whom had data at year 5. Five-year success rates for imiquimod were 82.5% (170/206) compared with 97.7% (173/177) for surgery (relative risk of imiquimod success = 0.84, 95% confidence interval = 0.77-0.91, P < 0.001). These were comparable to year 3 success rates of 83.6% (178/213) and 98.4% (185/188) for imiquimod and surgery, respectively. Most imiquimod treatment failures occurred in year 1. Although surgery is clearly superior to imiquimod, this study shows sustained benefit for lesions that respond early to topical imiquimod.
Diagnosis of tumors during tissue-conserving surgery with integrated autofluorescence and Raman scattering microscopy
- Proceedings of the National Academy of Sciences of the United States of America
- Published almost 7 years ago
Tissue-conserving surgery is used increasingly in cancer treatment. However, one of the main challenges in this type of surgery is the detection of tumor margins. Histopathology based on tissue sectioning and staining has been the gold standard for cancer diagnosis for more than a century. However, its use during tissue-conserving surgery is limited by time-consuming tissue preparation steps (1-2 h) and the diagnostic variability inherent in subjective image interpretation. Here, we demonstrate an integrated optical technique based on tissue autofluorescence imaging (high sensitivity and high speed but low specificity) and Raman scattering (high sensitivity and high specificity but low speed) that can overcome these limitations. Automated segmentation of autofluorescence images was used to select and prioritize the sampling points for Raman spectroscopy, which then was used to establish the diagnosis based on a spectral classification model (100% sensitivity, 92% specificity per spectrum). This automated sampling strategy allowed objective diagnosis of basal cell carcinoma in skin tissue samples excised during Mohs micrographic surgery faster than frozen section histopathology, and one or two orders of magnitude faster than previous techniques based on infrared or Raman microscopy. We also show that this technique can diagnose the presence or absence of tumors in unsectioned tissue layers, thus eliminating the need for tissue sectioning. This study demonstrates the potential of this technique to provide a rapid and objective intraoperative method to spare healthy tissue and reduce unnecessary surgery by determining whether tumor cells have been removed.
High frequency ultrasonography (HFUS) is a non-invasive, low risk method which can provide real-time visual information regarding different processes in cutaneous tissue. The goal of this study is to compare the accuracy of HFUS in determining depth and width of basal cell carcinoma (BCC) lesions compared with histopathology as a reference standard.
Recognition of the multiple roles of Hedgehog signaling in cancer has prompted intensive efforts to develop targeted pathway inhibitors. Leading inhibitors in clinical development act by binding to a common site within Smoothened, a critical pathway component. Acquired Smoothened mutations, including SMO(D477G), confer resistance to these inhibitors. Here, we report that itraconazole and arsenic trioxide, two agents in clinical use that inhibit Hedgehog signaling by mechanisms distinct from that of current Smoothened antagonists, retain inhibitory activity in vitro in the context of all reported resistance-conferring Smoothened mutants and GLI2 overexpression. Itraconazole and arsenic trioxide, alone or in combination, inhibit the growth of medulloblastoma and basal cell carcinoma in vivo, and prolong survival of mice with intracranial drug-resistant SMO(D477G) medulloblastoma.