Phase I chemoprevention study of difluoromethylornithine in subjects with organ transplants.

Individuals who receive life-saving organ transplants and the required immunosuppression often develop secondary cancers. One of the most common secondary cancers is nonmelanoma skin cancer in sun-exposed areas. Attempts to prevent these cancers have not been successful. Difluoromethylornithine (DFMO), a suicide inhibitor of ornithine decarboxylase (ODC), is a known experimental cancer prevention agent that is being evaluated in a number of human cancer prevention trials. This report describes a Phase I trial in 18 organ transplant recipients, randomized to 1.0 and 0.5 g of DFMO or a placebo, designed to look at short-term toxicities over 28 days as well as the impact of DFMO on two biological parameters, skin polyamines and 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced ODC activity. Blood levels of DFMO were also measured. The results indicate that DFMO was well tolerated over the 28-day period. The TPA-induced ODC activity in 3-mm skin biopsies was significantly lowered by 80 and 67% at the two dose levels. Polyamine levels were not affected significantly except for putrescine at the 0.5-g level. Blood levels of DFMO were about two times higher than expected, based on our prior pharmacokinetic studies. Our studies indicate that DFMO is a reasonable agent that should be tested further in larger Phase 2b trials in this population as a chemopreventive agent. TPA-induced ODC activity appears to be a relevant intermediate biological assay.

Merkel cell carcinoma of the skin and mucosa: report of 12 cutaneous cases with 2 cases arising from the nasal mucosa.

BACKGROUND: Merkel cell carcinoma (MCC) is an uncommon skin tumor that most frequently arises on sun-exposed facial sites. It rarely occurs on mucous membranes of the head region. The primary MCC is usually treated by wide excision followed by radiation to the primary site and regional lymph nodes. Using traditional surgery the local recurrence rate ranges from 20 to 50%. In our clinic, Mohs surgery is used to excise the primary MCC completely, followed by radiation. Here we present our treatment experiences and outcomes. OBJECTIVE: To document our experience of MCC treated by Mohs surgery. We present our series of 12 cases of MCC, 2 cases of which arose from mucosal sites of the nasal cavity. METHODS: We reviewed 12 cases of MCC from the Mohs clinic database. We also reviewed the literature for cutaneous and mucosal MCC. RESULTS: There were 12 cases of MCC: 10 cutaneous and 2 mucous. The site distribution of cutaneous MCC was eight on the head, one on the neck, and one on the groin. Of these, nine were treated by Mohs excision. Two patients developed local recurrence following Mohs treatment. The local recurrence rate was 22% (2 of 9). The sites of mucosal MCC were the nasal septum and nasopharynx. One case had a history of previous radiation and developed an MCC 40 years later. This case also demonstrated epidermotropic spread of Merkel cells to the overlying mucous epithelium. This patient required extensive intranasal and cranial surgery to remove the tumor. Both patients with mucosal MCCs died of their disease. The overall mucocutaneous survival of MCC at 1 year was 80% and at 2 years was 50%. CONCLUSION: In our series, local control of the primary MCC was achieved in 70% of patients (7 of 10) using combined Mohs excision and radiation. Two recurrences had primary tumors larger than 3.5 cm in diameter, while the other case was nonresectable by Mohs surgery. Tumor size appeared to determine the degree of local control. When the postoperative Mohs defect was less than 3.0 cm in diameter, local and regional control appeared to be more favorable. When the primary facial MCC is relatively small, removal by Mohs surgery followed by radiation was effective, therapeutic, and less disfiguring. Mucosal MCC is rare and may occur as a long-term sequelae after radiation therapy to the skin.

Phase I chemoprevention study of piroxicam and alpha-difluoromethylornithine.

A two-step Phase I study of piroxicam (PXM) and a-difluoromethylornithine (DFMO) alone and in combination was initiated to assess toxicity and the impact of these drugs on several biological markers. In step 1, 12 subjects with a history of skin cancers were assigned to receive PXM 10 mg every day (q.d.) or 10 mg every other day (q.o.d.). The dosage of PXM 10 mg q.o.d. was tolerated. No changes were seen in 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced ornithine decarboxylase (ODC) or urinary polyamine levels. Steady-state serum levels of PXM were consistent with the oral dose level. In step 2, 31 subjects with stage 0 or I nonmelanoma skin cancers, stage A or B prostate or colon cancer, or stage I breast cancer or who had a family history of cancer were randomized to receive DFMO 0.5 g/m2, PXM 10 mg q.o.d., or the combination of DFMO and PXM. In addition to the biological markers of TPA-induced ODC activity in skin biopsies and urinary polyamine levels, we measured urinary 11-dehydrothromboxane B2, a specific metabolite of thromboxane A2. Of the 12 subjects on DFMO/PXM, 2 dropped out for non-drug-related reasons. Three developed grade-2 drug-related toxicities. One subject developed dyspnea that resolved and was able to continue on the study for 6 months. One subject who developed diarrhea that resolved after 5 days was also able to restart the drug without a recurrence. A third subject described intermittent episodes of tinnitus starting 4 h after taking PXM that lasted only 5 s and did not progress on treatment. Comparing the 6-month measurements with pretreatment, DFMO/PXM or DFMO significantly reduced TPA-induced ODC levels (Ps, 0.03 and 0.05). Urinary polyamine levels of spermidine decreased slightly with the DFMO/PXM or DFMO alone, whereas putrescine decreased with PXM alone. Levels of 11-dehydrothromboxane B2 were depressed by PXM and PXM/DFMO. The doses of DFMO/PXM determined in step 2 are potential starting dosages for Phase IIa and IIb chemoprevention trials.

Angiosarcoma of the head and neck managed by a combination of multiple biopsies to determine tumor margin and radiation therapy. Report of three cases and review of the literature.

BACKGROUND: Cutaneous angiosarcoma (AS) is a rare, often multicentric vascular tumor of the head and neck region with a rather poor prognosis. The original clinical size of the tumor rarely correlates to the degree of microscopic tissue invasion. Treatment by surgical excision sometimes requires very wide excision. Treatment by radiation or electron beam appears less mutilating but its efficacy is not well documented. OBJECTIVE: To present our experience with a combined surgical delineation of tumor margins followed by radiation treatment. METHODS: We treated three patients with extensive AS of the scalp and face. Prior to radiation, in two cases the tumor margins were determined by grid-pattern punch biopsies. In the third patient, the tumor margins were determined by Mohs mapping system. All three patients then received radiation either by rotational arc electron beam (n = 2) and standard radiation. RESULTS: One patient developed two local recurrences in nonirradiated areas plus a metastatic cervical node, all of which responded to additional electron beam. The patient has no evidence of disease (NED) after 30 months of observation. The other two patients were treated by electron beam and radiation have NED at 5 and 1 years follow-up, respectively. CONCLUSIONS: Local control of AS of the scalp may be achieved by assessment of the tumor margin by peripheral biopsies or Mohs technique followed by electron beam and radiation.

Multiple agminated Spitz nevi: report of two cases and review of the literature.

Spitz nevus is most commonly a benign solitary lesion. Multiple lesions arranged in clusters (agminated) are very rare. Malignant degeneration has not been reported. Although spontaneous involution may occur, the nevi are frequently treated by surgical excision. We describe two preschool girls with multiple agminated Spitz nevi, and review the current world literature on multiple Spitz nevi.

Mohs micrographic surgery for penile tumors.

The advantages of the total microscopic control of excision that is provided by Mohs micrographic surgery often justify consideration of this modality in neoplasms of the penis. The excision in successive layers with complete microscopic scanning of the entire underside of each horizontally cut layer assures eradication of the silent outgrowths that often extend well beyond the clinically visible and palpable borders of the cancer. With elimination of all ramifications, the excisions are abruptly stopped, and removal of a substantial surgical margin of normal tissue is obviated. Other advantages are the absence of need for general anesthesia and the fact that most patients remain ambulatory.

Excision of exposed cartilage for management of Mohs surgery defects of the ear.

Cartilage of the ear is often exposed during Mohs surgical procedures. Fenestration of the cartilage with a skin punch has been recommended to stimulate granulation tissue where the perichondrium has been destroyed. This article describes an alternative method--the excision of a window through the exposed cartilage, fully exposing the perichondrium on the other side of the cartilage. This promotes the rapid healing by second intention or provides a vascular bed for immediate skin grafting. Also, aggressive excision of nonviable cartilage helps prevent chondritis or perichondritis.

Stability of buffered lidocaine and epinephrine used for local anesthesia.

Buffered lidocaine has been recently recommended for local anesthesia, as there is less pain on injection of the buffered solution. Reduced pain on injection of lidocaine and epinephrine buffered to a neutral pH was confirmed in 20 subjects (P less than .01). Concentrations of buffered lidocaine and epinephrine were performed in order to evaluate their stability. Buffered lidocaine dropped to 66.1% of initial concentrations after 4 weeks when stored at 25 degrees C. Buffered epinephrine fell to 1.34% of its initial concentration under similar conditions. Buffered lidocaine and epinephrine maintained 94.54% and 82.04%, respectively, of their initial concentrations after 4 weeks when refrigerated at 0-4 degrees C. Both lidocaine and epinephrine maintained greater than 90% concentration 2 weeks after buffering when stored at 0-4 degrees C. This permits batch buffering of lidocaine with epinephrine and storage for periods up to 2 weeks when properly refrigerated.

Metastatic basal cell carcinoma: report of twelve cases with a review of the literature.

Metastatic basal cell carcinoma was found in 12 patients at the University of Wisconsin Mohs Surgery Clinic during the period 1936 to 1989. All patients were white men. The time of onset of the primary tumor ranged from childhood to 71 years. Eleven patients had previous treatment for basal cell carcinoma; two patients had received x-ray radiation to the face for teenage acne. The locations of the primary basal cell carcinomas were the face (n = 10), back (n = 1), and arm (n = 1). The primary tumors ranged from 3.6 x 3.0 to 20.0 x 7.0 cm. The interval from onset to the first sign of metastases ranged from 7 to 34 years. In all cases, the primary tumor was histologically identical to the metastatic lesion. Perineural extension of the basal cell carcinoma in the primary lesion was found in five cases. Regional lymph nodes were the most frequent site of metastasis. Treatment consisted of a combination of surgery, radiation, and chemotherapy. Only two patients survived more than 5 years after surgical treatment. One patient has survived 25 years and is still alive.

Mohs micrographic surgery fixed-tissue technique for melanoma of the nose.

Mohs micrographic surgery, fixed-tissue technique, for excision of nasal melanoma provides three important benefits: 1) assurance of eradication of the main mass along with its "silent" contiguous outgrowths, 2) safe management of non-contiguous satellites too small to be visible initially, and 3) safe sparing of maximal amounts of surrounding normal tissues. These benefits are achieved because all incisions are through chemically fixed (killed) tissue, eliminating the danger of disseminating the highly transplantable melanoma cells and permitting the excision of successive layers for microscopic scanning of their undersurfaces by the systematic use of frozen sections. The process is continued to the termination of each ramification. There is no need to remove a wide margin of normal tissue as is customary with conventional surgery. Clinically invisible satellites are not moved or disturbed and can be removed safely by the same method if they appear. The reliability of the method is manifested by the 62.5% 5-year cure in a series of 10 consecutive patients, all of whom had no local recurrence after micrographic surgery.

Foam-rubber stents for skin grafts.

A variety of stents are used to immobilize skin grafts and to hold them firmly to the recipient site. Tie-down stents, the most common type, are constructed from bulky, sterile dressing and are overtied with suture material. These stents are often cumbersome to apply. As an alternative, stents made from foam-rubber pads (Reston, 3M Company, St. Paul, MN) were stapled over skin grafts. These stents could be applied quickly, and they maintain continuous, uniform pressure on the immobilized grafts.

Anatomic rubber stamps of the face and body to document procedures in dermatologic surgery: one picture is worth a thousand words.

Representations of the anatomic surface location of cutaneous lesions and the surgical procedures performed on these lesions can be transferred to the medical charts using simple anatomic rubber stamps (ARS) of the body. The technique is exemplified with symbols to represent surgical excision, chemical face peel, dermabrasion, micrographic surgery, and the harvesting of flaps and grafts. ARS are also useful in liposuction surgery, punch grafts for pitted facial scars, hair transplantation, sclerotherapy, laser surgery, and other cosmetic dermatologic procedures. ARS are particularly valuable in micrographic surgery for skin cancer because they help document the depth and breadth of cancer invasion and aid in the follow-up of recurrent skin cancer, especially when defects are reconstructed.

Reusable loop stitches for inspection of grafts.

Reusable loop stitches are a good method of securing the stent in skin grafts. Two suture methods are presented: the free-loop and the loose-loop suture technique. Their main advantage is that they provide a loop of suture that can be repeatedly rethreaded with suture, thereby permitting reexaminations and re-stentings of the graft site without additional anesthesia.

Topical hemostatic agents for dermatologic surgery.

Topical hemostatic agents are very helpful in attaining capillary and small vessel hemostasis in dermatologic surgery. The commonly used topical hemostatic agents, including oxidized cellulose, absorbable gelatin, and thrombin are reviewed, along with newer agents such as microfibrillar collagen, fibrin sealants, and acrylates. Agents best suited for certain situations are recommended.

Stenosis of the external ear canal: prevention using hydroxylated polyvinyl acetal wicks.

Hydroxylated polyvinyl acetal wicks may be very helpful in preventing postsurgical stenosis of the external ear canal. The wick is inserted into the canal, wetted with Polysporin Otic, and changed periodically until scar tissue becomes stabilized. This method is simple, quick, and well tolerated by the patient. Polyvinyl wicks provide a useful adjunct in preventing stenosis of the external ear canal.

Staple and double-staple method of tissue orientation in Mohs micrographic surgery.

Mohs micrographic surgery has been used with a high degree of success to remove neoplasms of the skin. This method relies on thin-layer excision, orienting, mapping, and microscopic examination of tissue specimens, followed by reexcision of outlying extensions of tumor until a tumor-free plane is reached. Accurate and precise orienting and mapping of tissue are critical in order to attain high cure rates. The orienting, mapping, and reexcision of tissue of large or complicated tumors can be more rapidly and accurately accomplished by using metal staples.

Keratoacanthomas treated with Mohs' micrographic surgery (chemosurgery). A review of forty-three cases.

A series of forty-three keratoacanthomas were treated with Mohs' micrographic surgery with the use of the fresh-tissue technic. Of forty-two keratoacanthomas followed from 6 to 24 months, one aggressive keratoacanthoma recurred, yielding an overall recurrence rate of 2.4%. Micrographic surgery is an expedient treatment that allows for complete microscopic examination of the keratoacanthoma, maximum preservation of normal tissue, and a high degree of assurance of cure.