Development of a core outcome set for cutaneous squamous cell carcinoma trials: identification of core domains and outcomes.

BACKGROUND: The lack of uniformity in the outcomes reported in clinical studies of the treatment of cutaneous squamous cell carcinoma (cSCC) complicates efforts to compare treatment effectiveness across trials. OBJECTIVES: To develop a core outcome set (COS), a minimum set of agreed-upon outcomes to be measured in all clinical trials of a given disease or outcome, for the treatment of cSCC. METHODS: One hundred and nine outcomes were identified via a systematic literature review and interviews with 28 stakeholders. After consolidation of this long list, 55 candidate outcomes were rated by 19 physician and 10 patient stakeholders, in two rounds of Delphi exercises. Outcomes scored 'critically important' (score of 7, 8 or 9) by ≥ 70% of patients and ≥ 70% of physicians were provisionally included. At the consensus meeting, after discussion and voting of 44 international experts and patients, the provisional list was reduced to a final core set, for which consensus was achieved among all meeting participants. RESULTS: A core set of seven outcomes was finalized at the consensus meeting: (i) serious or persistent adverse events, (ii) patient-reported quality of life, (iii) complete response, (iv) partial response, (v) recurrence-free survival, (vi) progression-free survival and (vii) disease-specific survival. CONCLUSIONS: In order to increase the comparability of results across trials and to reduce selective reporting bias, cSCC researchers should consider reporting these core outcomes. Further work needs to be performed to identify the measures that should be reported for each of these outcomes.

Activation of human squamous cell carcinoma ornithine decarboxylase activity by guanosine triphosphate.

Previous studies have demonstrated the presence in mouse epidermal tumors of a structurally and functionally altered ornithine decarboxylase (ODC). In this report, the enzymatic properties of ODC from normal human skin and squamous cell carcinomas are examined. Some tumors contained a more heat stable ODC than the enzyme found in normal skin. GTP stimulated enzyme activity in four of seven tumor extracts tested but had no effect on normal skin ODC. Kinetic analyses indicated that GTP either lowered the apparent Km of tumor ODC for L-ornithine, increased the Vmax, or had both effects, depending on the tumor examined. Gel filtration chromatography of crude tumor extracts indicated the existence of multiple molecular weight forms of ODC, some of which can be activated by GTP and some of which are unaffected by GTP. Some tumors contain both a GTP-activatable and -nonactivatable form of the enzyme. Immunolocalization studies demonstrated the presence within squamous cell carcinomas of cells with a constitutively high level of immunoreactive ODC, a situation never observed in normal skin tissue. These results suggest that some human squamous cell carcinomas contain a functionally altered ODC that may be aberrantly regulated.

Urokinase plasminogen activator is immunocytochemically detectable in squamous cell but not basal cell carcinomas.

The presence of plasminogen activators (PA) in a variety of solid tumors appears to correlate, in a number of instances, with enhanced invasive or metastatic capabilities. In the present study, we have immunocytochemically examined basal cell (BCC) and squamous cell carcinomas (SCC) comprising a spectrum of histologic subtypes for the presence of urokinase-type (uPA) and tissue-type (tPA) PA. Neither uPA nor tPA was noted in any BCC, whether of the nodular, infiltrative, morpheaform, or basosquamous variety. uPA but not tPA was seen in 12 of 16 SCC examined; the tumors lacking uPA were all histologically well differentiated. No relationship between uPA expression and depth of invasion was noted, and uPA was not preferentially expressed at tumor borders. We conclude that uPA presence in SCC may relate to the degree of differentiation.

Mouse skin is particularly susceptible to tumor initiation during early anagen of the hair cycle: possible involvement of hair follicle stem cells.

Stem cells are believed to be a necessary target of chemical carcinogens. Based on autoradiographic, ultrastructural, and biologic criteria, we have recently proposed that hair follicle stem cells reside not in the bulb, but in the upper outer root sheath in an area called the bulge. Proliferating cells have been shown to be more susceptible to tumor initiation, and we have recently demonstrated that cells in the bulge undergo transient proliferation during early anagen. Therefore, we theorized that mouse skin should be particularly susceptible to carcinogen application during early anagen phase. In this paper, we show that early anagen Swiss and Sencar mouse skin is indeed particularly susceptible to one- and two-stage chemical carcinogenesis, resulting in tumor yields one to five times those obtained with telogen-timed carcinogen application. Our findings implicate a possible involvement of the bulge cells as precursors to some of the skin cancers, and support the concept that these are stem cells. These observations also raise important questions about the cellular origins and biologic behavior of chemically induced murine skin tumors.

Computer simulation of the metabolism of guinea pig brain slices, and how they differ from the intact brain.

A computer model of the metabolism of glutamate, glutamine, gamma-aminobutyrate and the Krebs cycle in guinea pig cortex slices has been constructed in terms of 98 reactions among 38 unlabeled species. Fitting the data from slices required the addition of a third small compartment to previous 2-compartment models based on whole brain experiments. This third compartment corresponds to the tissue damaged during the slicing process, and dominates the metabolism of 14C-labeled substrates at early times. The times required for equilibration between this additional compartment and the bulk of the slice are no longer than expected. Interpretation of short-term slice experiments may be subject to appreciable error owing to the presence of this additional compartment.

Blood pressure as a parameter in dermatologic surgery.

Elevated blood pressure is a major cause of perioperative bleeding and postoperative hematoma. Seventy-five patients scheduled for dermatologic surgical procedures were prospectively asked if they were aware of any personal history of hypertension. If patient response alone is relied on as a preoperative screen for hypertension, over half of the individuals affected with this disease will be missed. Epinephrine-containing local anesthetics were found not to increase blood pressure in doses commonly employed by dermatologists; in fact, they lowered blood pressure in hypertensive individuals.

Aging of the skin: implications for cutaneous surgery.

There are precious few benefits, save perhaps experience and wisdom, that those of advanced age may claim over those who continue to dwell in their youth. One somewhat paradoxical advantage, however, is the ability of older patients to apparently heal better than younger patients after cutaneous surgery. In older patients, the incision lines are less red, the scarring is less hypertrophic, and "normalization" of appearance occurs more rapidly. And yet, the "wrapping" does not necessarily reflect the contents of the "box." Unfavorable age-dependent alterations in the physical properties of the skin and the wound-healing cascade may affect the viability and structural integrity of the postoperative result. Surgery on the aged population must therefore couple the optimism for a pleasing aesthetic result with the caution reflecting a cutaneous substrate altered by the perturbations of time. This somewhat shaky balance, although not altogether understood, is worthy of study by the physician approaching the patient of advanced age.

Risk factors for local recurrence of primary cutaneous squamous cell carcinomas. Treatment by microscopically controlled excision.

Four hundred fourteen primary cutaneous squamous cell carcinomas were treated by microscopically controlled excision. A five-year mortality-table adjusted cure rate of 93.3% was achieved. The following six parameters were analyzed for correlation with the local recurrence rate: sex, age, lesion diameter, history of previous therapy, anatomic site, and number of stages of Mohs' surgery required for treatment. Only the number of stages correlated significantly with the recurrence rate. However, subpopulations at high risk for recurrent disease could be identified. These consisted of male patients younger than 60 years of age, male patients requiring five or more stages of Mohs' surgery, and patients of either sex with carcinoma of the lower extremity. Modifications of microscopically controlled excision may be warranted in selected patients.

Delayed reconstruction following Mohs' chemosurgery for skin cancers of the head and neck.

The case records of 52 patients with 55 cutaneous neoplasms treated by Mohs' chemosurgery and subsequently reconstructed by plastic surgeons were reviewed to determine if delay between resection and reconstruction adversely affected the outcome of reconstruction. Reconstruction was performed from 5 to 61 days after Mohs' chemosurgery for 45 basal cell carcinomas and 10 other cutaneous neoplasms. There were no complications during the interval between resection and reconstruction. Following reconstruction, minor wound complications occurred in 6% of patients; there were no major complications. Microscopic examination of the re-excised wound revealed residual disease in 2 of 45 cases of basal cell carcinoma and 0 of 10 other cutaneous malignancies. Both patients with residual basal cell carcinomas (i.e., false-negative margins after Mohs' surgery) had presented to the Mohs' surgeon with recurrent tumors. During a follow-up period of 3 months to 3 years after complete resection, recurrent tumor developed in 2 of 45 cases of basal cell carcinoma and 3 of 8 cases of squamous cell carcinoma. Delayed reconstruction, usually 5 to 20 days after Mohs' chemosurgery, can be performed without significant morbidity. Re-excision of the Mohs' chemosurgical wound for pathologic examination can detect residual disease and may be especially indicated for large recurrent wounds.

Basal-cell carcinoma of the eyebrow region.

Five women (21 to 43 years of age), each with a basal-cell carcinoma involving the eyebrow region, are presented. The implications of the clinical situation in terms of therapy and reconstruction are discussed.

Tissue movement--a macrobiomechanical approach.

The surgical movement of skin involves both a respect for the biological integrity of the involved tissues and an understanding of its mechanical properties. The interaction of tissue biology and mechanics on the level of the organism therefore represents a macrobiomechanical approach to tissue movement. An understanding of anatomy and tissue movement dynamics is key in the performance of successful cutaneous surgery.

False-negative tumor-free margins following Mohs surgery.

The inability to identify a neoplasm upon examination of an initial Mohs histologic section is not uncommon. Although often the neoplasm has been enclosed within the layer or extirpated by a prior biopsy, there are instances when the negative marginal reading is incorrect. This report describes circumstances when the initial Mohs layer failed to show positive tumor margins in the face of residual in situ neoplasm.

Histologic and temperature alterations induced by skin refrigerants.

The histologic alterations induced by spray refrigerants independent of and in combination with dermabrasion were studied with the use of the domestic pig as a model. Tissue injury was found to be a function of spray duration and freeze intensity. Both preabrasion freezing and postabrasion refreezing could produce damage additive to that of mechanical planing. Skin surface and intradermal temperature variations during refrigeration were recorded. The possible implications of these findings as they pertain to clinical dermabrasion are discussed.

The dynamics of dog-ear formation and correction.

Dog-ears are tissue redundancies secondary to length inequalities, rotation or contour changes. An understanding of the mechanics of dog-ear formation provides a logical foundation for approaching treatment.