MicroRNA-135b Regulates Leucine Zipper Tumor Suppressor 1 in Cutaneous Squamous Cell Carcinoma.

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin malignancy and it presents a therapeutic challenge in organ transplant recipient patients. Despite the need, there are only a few targeted drug treatment options. Recent studies have revealed a pivotal role played by microRNAs (miRNAs) in multiple cancers, but only a few studies tested their function in cSCC. Here, we analyzed differential expression of 88 cancer related miRNAs in 43 study participants with cSCC; 32 immunocompetent, 11 OTR patients, and 15 non-lesional skin samples by microarray analysis. Of the examined miRNAs, miR-135b was the most upregulated (13.3-fold, 21.5-fold; p=0.0001) in both patient groups. Similarly, the miR-135b expression was also upregulated in three cSCC cell lines when evaluated by quantitative real-time PCR. In functional studies, inhibition of miR-135b by specific anti-miR oligonucleotides resulted in upregulation of its target gene LZTS1 mRNA and protein levels and led to decreased cell motility and invasion of both primary and metastatic cSCC cell lines. In contrast, miR-135b overexpression by synthetic miR-135b mimic induced further down-regulation of LZTS1 mRNA in vitro and increased cancer cell motility and invasiveness. Immunohistochemical evaluation of 67 cSCC tumor tissues demonstrated that miR-135b expression inversely correlated with LZTS1 staining intensity and the tumor grade. These results indicate that miR-135b functions as an oncogene in cSCC and provide new understanding into its pathological role in cSCC progression and invasiveness.

XPC initiation codon mutation in xeroderma pigmentosum patients with and without neurological symptoms.

Two unrelated xeroderma pigmentosum (XP) patients, with and without neurological abnormalities, respectively, had identical defects in the XPC DNA nucleotide excision repair (NER) gene. Patient XP21BE, a 27-year-old woman, had developmental delay and early onset of sensorineural hearing loss. In contrast, patient XP329BE, a 13-year-old boy, had a normal neurological examination. Both patients had marked lentiginous hyperpigmentation and multiple skin cancers at an early age. Their cultured fibroblasts showed similar hypersensitivity to killing by UV and reduced repair of DNA photoproducts. Cells from both patients had a homozygous c.2T>G mutation in the XPC gene which changed the ATG initiation codon to arginine (AGG). Both had low levels of XPC message and no detectable XPC protein on Western blotting. There was no functional XPC activity in both as revealed by the failure of localization of XPC and other NER proteins at the sites of UV-induced DNA damage in a sensitive in vivo immunofluorescence assay. XPC cDNA containing the initiation codon mutation was functionally inactive in a post-UV host cell reactivation (HCR) assay. Microsatellite markers flanking the XPC gene showed only a small region of identity ( approximately 30kBP), indicating that the patients were not closely related. Thus, the initiation codon mutation resulted in DNA repair deficiency in cells from both patients and greatly increased cancer susceptibility. The neurological abnormalities in patient XP21BE may be related to close consanguinity and simultaneous inheritance of other recessive genes or other gene modifying effects rather than the influence of XPC gene itself.

Behavior modification and risk perception in patients with nonmelanoma skin cancer.

CONTEXT: Nonmelanoma skin cancer (NMSC) is the most common cancer among humans, yet risk perceptions and preventive health behaviors in those who survive this cancer are relatively unknown. OBJECTIVES: To assess the impact of the disease and its treatment on sun-protective behaviors, general preventive health behaviors, and risk perception in NMSC patients, and to determine factors associated with behavioral change. DESIGN AND SETTING: A prospective study was conducted of 211 consecutive NMSC patients presenting to a dermatologic surgery clinic at a tertiary care university medical center from February 2005 to March 2006. These patients were all adults, were fluent in English, and had NMSC of the head and neck. Of the 211 eligible patients, complete data was obtained for 183 (87%). The most common reasons for dropout were voluntary withdrawal and incompletely answered surveys. INTERVENTION AND OUTCOME MEASURES: Surveys that assessed disease-specific quality of life (QoL), preventive health behaviors, sun-protective behaviors, and risk perception were administered before and after surgical treatment of NMSC. RESULTS: Sun-protective behaviors improved postsurgery even after controlling for seasons (P<0.001). Predictor factors associated with increased sun-protective behavior included poor skin tanning ability, summer season, no employment, less comorbid conditions, and previous NMSC treatment. Baseline QoL was not predictive of behavioral change. As for risk perception, respondents thought they were more likely than someone similar to themselves to develop future NMSCs but thought they had similar risks of developing melanoma or other non-skin cancers (P<0.001). NMSC patients demonstrated disease-specific behavior modifications by selectively improving their sun habits but showed no significant improvement in other preventive health behaviors. This finding is consistent with patients' specific perception of increased risk for future NMSCs, but surprisingly, not for melanoma. Increased patient education of associated cancer risks with NMSC is warranted. CONCLUSIONS: NMSC patients demonstrated disease-specific behavior modifications by selectively improving their sun habits but showed no significant improvement in other preventive health behaviors. This finding is consistent with patients' specific perception of increased risk for future NMSCs, but surprisingly, not for melanoma. Increased patient education of associated cancer risks with NMSC is warranted.

Transplant-associated skin cancer: role of reducing immunosuppression.

This article explores the role of reducing immunosuppression as a therapeutic strategy for the problem of transplant-associated skin cancer. The specific issue of immunosuppression reduction is based on a brief historic review of the epidemiology of skin cancer in transplant patients, followed by a description of the role of immunosuppression as a cause of skin cancer. Finally, the literature pertaining to the hypothesis that reducing immunosuppression in solid organ transplant recipients favorably impacts both the incidence of cutaneous malignancy and outcomes relating to individual aggressive malignancies is presented.

The skin cancer index: clinical responsiveness and predictors of quality of life.

OBJECTIVE: To establish the clinical responsiveness of the Skin Cancer Index (SCI), a new disease-specific quality of life (QOL) instrument, and to assess demographic and clinical factors which impact QOL in patients with nonmelanoma skin cancer (NMSC). STUDY DESIGN: Prospective study of 183 patients with NMSC of the face and neck referred to a tertiary care Mohs surgery clinic. METHODS: The SCI is a 15 item, validated, disease-specific QOL instrument with 3 distinct subscales, Emotion, Social, and Appearance. Higher scores reflect better QOL. The SCI and the Dermatology Life Quality Index (DLQI), a general dermatology instrument, was administered at initial consultation and 4 months after surgical treatment. Multivariate analysis was conducted to assess demographic and clinical factors predictive of QOL for both instruments. RESULTS: The SCI total score and all three subscale scores increased with treatment, demonstrating strong evidence of responsiveness over time (P < .001) in contrast with the DLQI (P = .46). Predictors of poorer QOL for the SCI included female sex and cancers located on the lip. Patients who demonstrated greatest improvement in QOL with treatment included those who were younger (<50 yr) and had lower reported household income. Also, first time NMSC patients and those patients who underwent less extensive reconstructions demonstrated greater improvements in QOL. CONCLUSION: The SCI is a sensitive and responsive QOL instrument for patients with NMSC. Distinct demographic and clinical variables that impact QOL have been demonstrated using this multidimensional, disease-specific instrument.

Validation of a quality-of-life instrument for patients with nonmelanoma skin cancer.

OBJECTIVE: To validate a disease-specific quality-of-life instrument--the Skin Cancer Index--intended to measure quality-of-life issues relevant to patients with nonmelanoma skin cancer. METHODS: Internal reliability, convergent and divergent validity with existing scales, and factor analyses were performed in a cross-sectional study of 211 patients presenting with cervicofacial nonmelanoma skin cancer to a dermatologic surgery clinic. RESULTS: Factor analyses of the Skin Cancer Index confirmed a multidimensional scale with 3 distinct subscales-emotional, social, and appearance. Excellent internal validity of the 3 subscales was demonstrated. Substantial evidence was observed for convergent validity with the Dermatology Life Quality Index, Rosenberg Self-Esteem Scale, Lerman's Cancer Worry Scale, and Medical Outcomes Survey Short-Form 12 domains for vitality, emotion, social function, and mental health. CONCLUSIONS: These findings validate a new disease-specific quality-of-life instrument for patients with cervicofacial nonmelanoma skin cancer. Studies on the responsiveness of the Skin Cancer Index to clinical intervention are currently under way.

Development of the facial skin care index: a health-related outcomes index for skin cancer patients.

BACKGROUND: Existing health-related quality-of-life (HRQOL) tools do not appear to capture patients' specific skin cancer concerns. OBJECTIVE: To describe the conceptual foundation, item generation, reduction process, and reliability testing for the Facial Skin Cancer Index (FSCI), a HRQOL outcomes tool for skin cancer researchers and clinicians. METHODS: Participants in Phases I to III consisted of adult patients (N=134) diagnosed with biopsy-proven nonmelanoma cervicofacial skin cancer. Data were collected via self-report surveys and clinical records. RESULTS: Seventy-one distinct items were generated in Phase I and rated for their importance by an independent sample during Phase II; 36 items representing six theoretical HRQOL domains were retained. Test-retest I results indicated that four subscales showed adequate reliability coefficients (alpha=0.60 to 0.91). Twenty-six items remained for test-retest II. Results indicated excellent internal consistency for emotional, social, appearance, and modified financial/work subscales (range 0.79 to 0.95); test-retest correlation coefficients were consistent across time (range 0.81 to 0.97; lifestyle omitted). CONCLUSION: Pretesting afforded the opportunity to select items that optimally met our a priori conceptual and psychometric criteria for high data quality. Phase IV testing (validity and sensitivity before surgery and 4 months after Mohs micrographic surgery) for the 20-item FSCI is under way.

Creation of a quality of life instrument for nonmelanoma skin cancer patients.

OBJECTIVE: Malignancies of the skin are the most common cancers among humans. The cervicofacial region is most affected by cutaneous malignancies, with approximately 80% of nonmelanoma skin cancers (NMSC) occurring in the head and neck. Treatment of cervicofacial skin cancers also is more likely to result in significant patient morbidity, because of the functional and cosmetic importance of this region. Unlike other malignancies, skin cancer has not been well investigated in terms of patient quality of life (QOL) assessment. Furthermore, no validated disease-specific QOL instrument currently exists for skin cancer. The aim of this study was to construct a new QOL instrument, The Facial Skin Cancer Index (FSCI), that captures the relevant QOL issues for NMSC patients. STUDY DESIGN: Cross-sectional study of patients presenting to a dermatologic surgery clinic with NMSC of the head and neck. METHODS: For stage I, item generation, a sample of 20 patients with cervicofacial NMSC and six health care providers specializing in the care of NMSC patients completed semistructured interviews. For stage II, item reduction, a second sample (n = 52) of NMSC patients rated the items in terms of their importance for QOL among skin cancer patients. Domains of the FSCI were evaluated in terms of data quality, item variability, internal consistency, and range and skewness of scale score on aggregation and floor and ceiling effects. RESULTS: A total of 71 distinct items were generated in stage I. After using the outlined item reduction techniques in stage II, the FSCI was reduced from 71 to 36 items, representing 6 domains. With the exception of Physical Functioning (alpha = 0.63) that suggested adequate reliability, all subscale scores showed excellent reliability coefficients, with Cronbach's alpha ranging from 0.78 (Lifestyle) to 0.87 (Social/Family). CONCLUSIONS: A new disease-specific QOL instrument for patients with NMSC of the head and neck has been created. Validation studies are currently underway. Future directions will include sensitivity analysis to determine whether the FSCI is sensitive to change over time among patients undergoing treatment for NMSC.

Skin cancer and quality of life: assessment with the Dermatology Life Quality Index.

BACKGROUND: Quality of life (QOL) has been identified as an important outcome in cancer research, yet the most common malignancy among humans, nonmelanoma skin cancer (NMSC), has been poorly studied in this regard. OBJECTIVE: To determine whether change occurred in the QOL of NMSC patients after surgery using a general, validated dermatology QOL instrument: the Dermatology Life Quality Index (DLQI). METHODS: A prospective study was conducted on 121 consecutive patients referred to a dermatologic Mohs surgery clinic with NMSC of the head and neck. QOL assessment was performed using the DLQI before (n=121) and after surgical treatment at 4 months (n=101). RESULTS: QOL scores demonstrated little handicap at initial diagnosis. The total DLQI scores showed little change over time, but an item analysis revealed that 2 of the 10 items demonstrated statistically significant change over time, with QOL improving after treatment-decreased painfulness/itchiness/soreness and less necessity to use concealing clothing. CONCLUSIONS: General dermatology QOL instruments demonstrated minimal handicap at initial diagnosis and little change after treatment of NMSC. Although the associations were modest, improvement in some aspects of well-being after treatment of NMSC was demonstrated. A more disease-specific instrument may be necessary to study this disease process further.

Quality of life and sun-protective behavior in patients with skin cancer.

OBJECTIVES: To determine whether change occurred in the general quality of life (QOL) of nonmelanoma skin cancer (NMSC) patients following surgery, to identify variables associated with patients' change in QOL, and to assess the impact of the disease and treatment on sun-protective behaviors and cigarette smoking. DESIGN: Longitudinal prospective study of 121 consecutive patients referred to a dermatologic Mohs surgery clinic with NMSC of the head and neck. INTERVENTIONS: Quality-of-life, smoking habit, and sun-protective behavior assessments were performed before treatment (N=121) and after surgical treatment at 1 (n=105) and 4 (n=101) months. Quality-of-life measures included the Medical Outcomes Study 36-Item Short-Form Health Survey and the Functional Assessment of Cancer Therapy-General. RESULTS: Overall, general QOL measures demonstrated little change over time. Only the mental (Medical Outcomes Study 36-Item Short-Form Health Survey) and emotional (Functional Assessment of Cancer Therapy-General) domains of QOL showed statistically significant change over time. A 2-way interaction showing effects for age and time on emotional well-being was modified by a 3-way interaction that depended on employment status. Emotional well-being scores for younger employed NMSC patients increased over time compared with scores among younger unemployed patients. In addition, many patients adopted greater use of sun-protective behaviors at 4 months following surgery. No change in cigarette smoking status was evidenced. CONCLUSIONS: Use of sun-protective behaviors increases after treatment. General QOL instruments demonstrate little change following treatment of NMSC. Although the associations are modest, improvements in emotional and mental health well-being following treatment of NMSC were demonstrated, especially for those younger than 65 years and employed. A disease-specific instrument may be necessary to further study this disease process.

Quality of life assessment in nonmelanoma cervicofacial skin cancer.

OBJECTIVES/HYPOTHESIS: Health-related quality of life (QOL) assessment of patients with nonmelanoma skin cancer is poorly understood. The objectives of the study were to determine the general QOL of patients with cervicofacial skin cancer and to identify patient, clinical, and preventive behavior variables associated with patients' QOL. STUDY DESIGN: Cross-sectional study of 121 consecutive patients (65 female and 56 male patients) presenting to a dermatological Mohs surgery clinic with nonmelanoma skin cancer of the head and neck. METHODS: Quality of life assessment was performed before counseling or treatment. Measures included the Medical Outcomes Study Short Form 36-item Health Survey (SF-36) and the Functional Assessment of Cancer Therapy-General (FACT-G). RESULTS: Both instruments demonstrated good internal consistency as measured by Cronbach's alpha (SF-36, alpha = 0.45-0.91; FACT-G, alpha = 0.61-0.90). The SF-36 scores were similar to historical norms. Bivariate analysis indicated significant correlation coefficients between QOL and patients' coexisting illnesses and medical risk factors. Sun-protective behaviors were associated with better QOL. The relationship appeared to be minimally influenced by patients' sociodemographic characteristics and disease-related variables (size, location, extent). CONCLUSIONS: Sun-protective behaviors were positively associated with certain QOL subscale scores in the population in the study. General QOL instruments demonstrated minimal impact of nonmelanoma skin cancer on patients at initial diagnosis. However, general measures may not be sensitive to the impact of nonmelanoma skin cancer. The development of a more disease-specific instrument may be necessary to evaluate this disease process.

Diagnosis, workup, and prognosis of cutaneous metastases of unknown primary origin.

BACKGROUND: Metastatic cancer of unknown primary (MCUP) accounts for 5-10% of presenting oncology patients. Premorbid identification of the primary source occurs in only 20-25% of cases. A small fraction of these tumors present in the skin and are thus likely to be encountered by dermatologists and dermatologic surgeons. OBJECTIVE: To present a practical schema for the diagnosis and evaluation of patients with MCUP. METHODS: Case report and literature review. CONCLUSION: The diagnosis of MCUP is associated with a poor prognosis, with median survival rates of less than 1 year. Efforts to identify subgroups of patients with understanding of these subgroups will enable early identification of patients with treatable disease and more favorable prognoses.