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大阪医科大学皮膚科において平成7年4月から平成18年12月の約12年間に経験した転移性皮膚癌37例 (男性21例, 女性16例) を集計した。同期間内に当科外来を受診した新患総数に対する転移性癌の頻度は0.08%であった。受診時の平均年齢は64.7歳, 原発巣として肺癌 (9例) , 乳癌 (7例) , 胃癌 (5例) が多くこれらで全体の57%をしめていた。皮膚への転移部位では胸腹部に最も多くみられ, 臨床型では小結節が多発する例が84%と大多数をしめ, 病理組織像は79%が腺癌であった。原発巣が発見されたのちに皮膚転移が出現した例は27例で, 出現するまでの平均期間は20ヵ月であった。また, 皮膚転移が出現したあとに全身検索にて原発巣が発見された症例が10例みられた。

A new human malignant melanoma cell line, designated DEOC-1, was established from the heel lesion of a 59-year-old man. This cell line has grown well for 84 months. The monolayer, cultured cells are polygonal in shape, appear to be spindle-shaped cells or multipolar cells, and have a tendency to pile up without contact inhibition. The cells are aneuploid, and the modal chromosomal number is in the hyper-triploid range. The cells were transplanted into the subcutis of SCID mice and produced tumors resembling the original tumor. The DEOC-1 cells (1 x 10(6)/5 mL) produced 5-S-cysteinyldopa (5-S-CD). The cells were not sensitive in vitro to any anticancer drug currently used for the treatment of malignant melanoma. Increases in both the protein and the transcriptional levels (mRNA) of multidrug resistance-related genes (multidrug resistance gene 1, multidrug resistance-associated protein 1 and lung resistance-related protein) were observed in DEOC-1 cells. The DEOC-1 cells are well characterized and are a very useful material for basic research of malignant melanoma.

光線力学療法 (photodynamic therapy; PDT) は皮膚科領域において表在性皮膚悪性腫瘍に対する治療例が数多く報告され, すでにその有用性は確立されている。しかし, 光源として頻用されているエキシマダイレーザー (浜松ホトニクス) は高価かつ広いスペースが必要とされるため本邦では現在20数ヵ所に導入されているのみである。今回我々は表在性皮膚悪性腫瘍に対し, 比較的安価で移動も容易である直線偏光近赤外線治療器スーパーライザーTM (東京医研) を用いた5-aminolevulinic acid (ALA) 外用PDTを試みた。日光角化症患者6例, ボーエン病患者4例において, ほぼ全例に満足すべき効果を得た。ALA外用PDTは高齢者にも少ない肉体的負担で施行できる表在性皮膚悪性腫瘍に対する有効な治療法の一つであり, スーパーライザーTMを光源とすることで一般のクリニックでも試みても良い方法となる可能性が示唆された。

62歳, 女性。右腋窩に5年前より徐々に増大する3.5×2.5cmの腫瘤を認め生検の結果, 汗腺癌と診断した。免疫組織学所見にてS-100, CEA, CK7, EMA, GCDFP-15, HMFGに陽性を認め, 病理組織学所見にて断頭分泌を認めたためアポクリン腺癌と診断した。術後, シスプラチンと5-フルオロウラシルを用いたlow-dose FP療法, 放射線療法を施行した。

Bowen病は1912年, Bowenが表皮内限局型有棘細胞増殖を示す例を前癌病変として発表したことに端を発するが, 本体は表皮内有棘細胞癌である。成長速度は緩徐で稀に自然消退を示すことがある。予後は悪くないが時に浸潤転移を来す。今回我々は30年来の病変に自然消退傾向を認めたBowen病の1例を経験したので, 若干の考察を加えて報告する。

Background: The etiology of the nonlesional dry and barrier-disrupted skin of patients with atopic dermatitis (AD) is still unclear. Objective: To determine whether disrupted barrier function in the nonlesional skin is associated with inflammatory or postinflammatory events, which are relevant to the severity of AD or local dry skin properties, respectively. Methods: We evaluated the barrier function and the water content of nonlesional forearm skin and compared these with the severity of AD and the intensity of dryness/scaling/itchiness at the same skin sites. Results: The transepidermal water loss (TEWL) significantly increased in proportion to the severity of AD with a markedly high correlation coefficient (r = 0.834, p < 0.0001, n = 106), while the capacitance decreased in proportion to the severity of AD with a relatively lower correlation coefficient (r = –0.720, p < 0.0001, n = 106) compared with TEWL. Relationship between TEWL and capacitance values in association with the AD severity revealed that the two parameters are well distributed, corresponding to the severity of AD, and that the elevated TEWL more adequately reflects the difference between healthy control and the mild group of AD compared with the reduced capacitance. Comparison with dry skin properties revealed that while the capacitance values were highly correlated with dryness (r = –0.752, p < 0.0001, n = 106) and with scaling (r = –0.697, p < 0.0001, n = 106), the TEWL was also related to dryness (r = 0.788, p < 0.0001, n = 106) with a higher correlation coefficient compared with capacitance and to scaling (r = 0.697, p < 0.0001, n = 106). Conclusion: Our results indicate that the barrier disruption in the nonlesional skin is well suited to reflect the severity of AD as well as the dry skin properties, providing a useful insight into understandings of diagnosis and clinical improvement during therapy.

Background: Atopic dermatitis (AD) can be considered a barrier disease in which antigens and irritants that can easily penetrate clinically normal, nonlesional skin due to its defective barrier function trigger and worsen the dermatitis. Thus, replenishing the barrier function in clinically normal, nonlesional skin of patients with AD seems to be a key for preventing the refractory nature of the dermatitis. Objective: To determine whether the disrupted barrier function of AD nonlesional skin can be repaired by topical application of a synthetic ceramide known to induce barrier recovery and to subsequently evaluate the relationship between enhanced barrier function and improved dry skin conditions. Methods: We applied topically a synthetic ceramide (CER) or hirudoid (HIRU)-containing cream to the nonlesional skin of AD patients for 4 weeks and evaluated their efficacy by measuring transepidermal water loss (TEWL) and capacitance values as well as clinical scoring for scaling/dryness/itchiness. Results: Treatment for 4 weeks with the CER cream significantly reduced dryness/scaling/itchiness which was accompanied by significant decreases in TEWL and increases in capacitance values at 2 and 4 weeks. In contrast, treatment for 4 weeks with the HIRU cream elicited a similar but lesser reduction in dryness/scaling/itchiness which was accompanied by significant but lesser decreases and increases in TEWL and capacitance values, respectively, at 2 and 4 weeks. Comparison of TEWL and capacitance values during the 4 weeks of treatment with CER or HIRU creams revealed that while the two parameters of CER cream-treated skin were generally similar to healthy control skin, those of the HIRU cream-treated skin remained similar to mild or moderate AD skin. Conclusion: It is likely that the recovery of barrier function reflects the improvement in clinically evaluated dry skin conditions of the nonlesional skin to a greater extent than that in water deficiency, which suggests that the barrier-replenishing effect is a more important factor for treatment of AD nonlesional skin than is the improvement of water deficiency.

Background: Psoriasis vulgaris is a chronic inflammatory disorder characterized by epidermal hyperproliferation. Transforming growth factor β (TGFβs) have a major antiproliferative action in epidermis. Objective: We evaluated the distribution and levels of expression of TGFβ isoforms and their receptors in psoriatic versus normal skin with the goal of discovering potential alterations in TGFβ signal transduction associated with psoriasis. Methods: Expression of TGFβ isoforms and their receptors was analyzed in normal and psoriatic skin using immunohistochemistry and reverse transcriptase-polymerase chain reaction (RT-PCR) techniques. Furthermore, DNA synthesis was measured in normal keratinocytes transfected with a dominant-negative TGFβ receptor II (TβRII) vector that eliminated most of the cytoplasmic TβRII domain. Results: Marked elevations in DNA synthesis, as assessed by BrdU incorporation and proliferating cell nuclear antigen (PCNA) immunoreactivity, were confirmed in psoriatic epithelial cells. Using immunohistochemistry and RT-PCR analysis, expression of TGFβ2 and 3 was diminished in the psoriatic epidermis as compared with those observed in normal skin. With respect to TGFβ receptors, expression of TβRI and II was markedly decreased in the psoriatic epidermis. In addition, levels of Smad2 mRNA were also decreased in psoriatic skin. Transfection of normal keratinocytes with the dominant-negative TβRII vector significantly elevated DNA synthesis as compared with keratincoytes transfected with control vector (under condition of TGFβ addition), suggesting that the dominant-negative TβRII mutant inhibits the antiproliferative effects of TGFβ. Conclusion: The present investigation strongly suggest that the TGFβ signaling pathway is downregulated in psoriatic skin and this situation leads to abnormal cell proliferation due to a functional decrease in growth regulation.

The patient was an 18-year-old male. On the left thigh, he had a purplish blue, smooth, and rubbery mass (8×8×4cm) . The lesion was composed of four lobules, and compression produced a bloody discharge. Hematoxylin and eosin staining of a biopsy specimen showed the uniform proliferation of small round tumor cells that had nuclei atypia with loosely arranged chromatin. Scattered mitotic figures were also seen, but there was no rosette formation. Periodic acid-Schiff staining revealed strongly positive granules in the cytoplasm, which were digested by diastase. On immunohistochemical staining, the tumor cells were positive for p30/p32MIC2 and vimentin, but negative for epithelial, neural, and myogenic markers. Cytogenetic studies revealed reciprocal translocation t (10; 11; 22) (p11. 2; q12; q24), and reverse transcriptase polymerase chain reaction demonstrated expression of the chimera gene EWS-FLI 1. General examination revealed no other tumor suggesting Ewing's sarcoma; these results indicated a diagnosis of primary extraosseus Ewing's sarcoma of the skin. [Skin Cancer (Japan) 2003; 18: 320-324]

A 65-year-old woman attended our hospital with indurated subcutaneous nodule on the bilateral axillary regions, right arm, left chest, and left abdominal wall that grew to the size of about 1cm. Skin biopsy of the lesions showed infiltration of abnormal lymphocytes into the subcutaneous tissue. Immunohistochemically, tumor cells were positive for CD8, CD45RO, CD68, but negative for CD20, CD30, CD56. From the above findings, a diagnosis of subcutaneous panniculitis-like T-cell lymphoma was made. [Skin Cancer (Japan) 2003; 18: 270-273]

It has been known that there are individual differences in terms of effectiveness of anticancer agents for advanced skin cancers even in cases when patients had the same type of cancer. The chemosensitivity test for advanced stomach cancers has been covered by insurance since 2000 in Japan and it is now widely used in anticancer chemotherapy to determine the maximum effect with minimum side effects.It would be possible to generalize the tests in skin cancers because of their superficial location on the skin and the facility of their repeated excision. A three-dimensional cellular growth assay using a collagen gel matrix with an MTT assay, one of the chemosensitivity tests, has been applied to four cases of advanced skin cancers (malignant clear cell adenoma, malignant eccrine poroma, squamous cell carcinoma and malignant melanoma) and to two cases of lymphoma from 1999 to 2000. The anticancer agents tested are 5-Fu, adriamycin, cisplatin, bleomycin, actinomycin D, dacarbazine, etoposide and vincristine. Furthermore, the appearance of multidrug resistance (MDR) agents, which include p-glycoprotein, MDR-related protein, lung resistance protein, glutathion-s-transferase π and topoisomerase, was studied immunohistochemically in six cases.A chemosensitivity test is useful to determine regimens of chemotherapy. Each case showed sensitivity to some anticancer agents and some MDR agents. There is, however, no considerable relationship between drug resistance and MDR agents. [Skin Cancer (Japan) 2002; 17: 83-88]

Polymorphisms of the cyclin-dependent kinase inhibitor gene p21 have recently been reported to be associated with several human cancers. To determine whether the polymorphisms are also associated with human skin cancers, we investigated the p21 polymorphisms in 165 healthy Japanese and 113 Japanese with malignant skin tumors: 30 squamous cell carcinoma, 20 malignant melanoma, 33 basal cell carcinoma, and 30 Bowen's disease. The p21 polymorphisms were characterized by single base substitutions in the following two sites: the last nucleotide of codon 31 of exon 2 and the site 20 nucleotides downstream from the 3′ end of exon 3. The two polymorphic sites were reported to be firmly linked to each other. We have shown that the two sites were firmly linked to each other also in Japanese and that no associations of the polymorphisms with the skin cancers in Japanese were detected by statistical analysis. Although the p21 polymorphisms were found not to be involved with skin carcinogenesis, ethnic differences of the allele frequency distribution must be taken into account in studying the role of the p21 polymorphism in carcinogenesis.

The incidence of epithelioid sarcoma among patients with malignant soft tissue tumors is small, but the rates of recurrence and metastasis of this type of sarcoma are high. To date, effective chemotherapy for advanced epithelioid sarcoma has not been established and, furthermore, epithelioid sarcoma is known to exhibit multidrug resistance (MDR). The chemosensitivities to anticancer agents of two cell lines established from epithelioid sarcoma were examined in this study. The results showed that the ES-OMC-MN and SFT-8606 cell lines were resistant to vincristine (IC 50 1190 nM and 872 nM, respectively) and Adriamycin (IC 50 921 nM and 650 nM, respectively), but sensitive to actinomycin D (IC 50 < 10 nM). P-glycoprotein (p-Gp) and MDR-associated protein (MRP) were not expressed in these cell lines, but a high expression level of lung resistance protein (LRP) was observed. The original tumor tissues from which the two cell lines were established were also found to be LRP-positive but not to express p-Gp or MRP. Their chemosensitivities to Adriamycin were not significantly altered in the presence of 2.5 μg/ml anti-LRP antibody (LRP-56), but the IC 50 of vincristine was much less (IC 50 128 nM and 27 nM, respectively) than that for an untreated cell line. It is thus suggested that the vincristine resistance in the two cell lines is LRP-mediated. Since cyclosporin A, known to be a modifier of p-Gp, also induced reversal of vincristine resistance in the ES-OMC-MN and SFT-8606 cell lines (IC 50 6.2 nM and 17 nM, respectively), it is suggested that cyclosporin A acts as a modifier of MDR mediated by LRP.

We determined the relationship between p53 expression and p53 gene mutations in squamous cell carcinoma occurring in scars and unrelated to UV light irradiation. We analyzed biopsy specimens obtained from three patients with squamous cell carcinoma. A monoclonal antibody against p53 (DO-7) was used for the immunohistochemical analysis. p53 gene mutations were detected by the polymerase chain reaction and single-strand conformation polymorphism analysis and direct DNA sequencing. p53 overexpression was observed in atypical squamous cells of one case. Those of two other cases, however, showed negative immunoreactivity to p53. Exon 6 of the p53 gene in all three cases and exon 7 in one case showed electrophoretic mobility shifts in polymerase chain reaction and single-strand conformation polymorphism analysis. DNA sequencing analysis showed a missense mutation and a silent mutation in exon 6 of the case with p53 overexpression, a three-base deletion in exon 6 of one case with no p53 overexpression, and a three-base deletion in exon 6 and a missense mutation in exon 7 of another such case. Although immunohistochemical overexpression of p53 has been thought to result from p53 gene mutations, our results suggest that negative immunoreactivity to p53 also can result from p53 gene mutations, for example, short gene deletions.

We reported a case of mucoepithelioid carcinoma arising from a minor salivary gland in the lower lip. A 44-year-old woman presented at local medical doctor, because of a mass in the lower lip. Histopathological diagnosis of a mucoepithelioid carcinoma was made on examination of a biopsy specimen. Then, she was presented to our clinic. There was a white submucosal tumor measuring 15mm in diameter, in the lower lip. The tumor was excised with a 5mm safety margin. A microscopic examination of the tumor revealed mucous, epidermoid and intermediate cells. The most common location is the parotid gland in the major salivary glands and the palate in the minor salivary glands. She is followed by taking 5-FU internally now.

The diagnosis of soft tissue tumors is difficult for several reasons.Many soft tissue tumors have overlapping histologic appearances, may change during the course of the disease.Liposarcoma is one of the most common soft tissue sarcoma. It is classified by the histological findings. Myxoid liposarcoma, the most common type of it, is difficult to distinguish from other myxoid tumors, especially myxoid malignant fibrous histiocytoma. Lipid stain and immunohistochemical examination are helpful for the diagnosis.We report a case of a 36-year old male with a tumor on his left leg.Histologically, we found round cells, signet-like cells, vacuolated cells and myxoid material. There were a few mitotic figures.Special stain (lipid stain, S-100 protein, vimentin, PAS, alucian blue, silver stain) and electron microscopic examination help us to diagnosis of the tumor.

A novel epithelioid sarcoma (ES) cell line, designated as ES-OMC-MN, was established from a 44-year-old woman with recurrence and metastasis of ES. The cells were spindle-shaped or polygonal and were positive for cytokeratin and vimentin on immunohistochemical staining. Electron microscopy revealed desmosome-like structures between the cells. These characteristics were also noted in the original tumor. Southern blot analysis of HindIII digests showed an additional 8.0 kb band and an 8.8 kb band in DNA from the cultured cells and the original tumor as well as the peripheral blood cells of the patient, while only an 8.8 kb band was observed in control human placental DNA. There were no point mutations of N-ras codons 12, 13, and 61, suggesting that the abnormality of N-ras was not due to mutation but to polymorphism. Interleukin-6 (IL-6) was secreted into the culture medium at high levels. Recombinant IL-6 augmented the proliferation of these cells, while cell growth was inhibited by incubation with an anti-IL-6 antibody. The cells also expressed surface IL-6 receptors, indicating that IL-6 acted on this cell line in an autocrine manner. IL-6 and IL-6 receptors were also found in the original tumor. These results demonstrate that ES-OMC-MN cells retained all the morphological and biochemical characteristics of the original tumor and suggest that an autocrine effect of IL-6 may be involved in the development of ES.

Liposarcoma in the face region is extremely rare. We reported a case of recurrent liposarcoma of the right cheek of a 54-year-old man. He received first tumor excision in another hospital in May, 1994. In the histologic examination, the tumor mass consisit of lipoblast, uniformly shaped, small round microvacuolated cells containing atypical hyperchromatic vesicular nuclei were present from lower dermis to subctaneous tissue. The histopathologic classification was round cell type. Partially, transitions toward the myxoid type and screlosing type were present. One year later, local recurrence occured, but there was no metastasis. Second wide local excision was performed in June, 1995. Few changes occured in the histological findings of the second excision and it revealed round cell type.

Calponin (h1 isoform) was characterized as a smooth muscle specific, actin-, tropomyosin-, calmodulin-binding protein and described as a factor which inhibits contraction. H2-calponin, encoded by a different gene from h1-calponin, was identified from the smooth muscles of mouse and pig. However, non-muscle calponin analogues have recently been reported in rat and pig brains. Here we show the presence of calponin expressed in human skin tissue and in cultured human keratinocytes using polyclonal antibodies to bovine aortic smooth muscle calponin. Western blot analysis demonstrated that calponin with a molecular weight around 36000 existed in extracts of keratinocytes. Immunofluorescence microscopy displayed the localization of calponin in the cytoplasm of the basal cells in situ, and along the cell-to-cell borders in cultured human keratinocytes maintained in standard calcium medium. Furthermore, according to RT-PCR analysis using human h1- and h2-calponin-specific primers, calponin expressed by cultured human keratinocytes was identified as the h2 isoform. We demonstrated the presence of h2-calponin in human keratinocytes, and it might play a role in the structural organization of actin cytoskeleton at the cytoplasmic region of cell-to-cell junctions of keratinocytes.

At age 25 a Japanese woman noticed an elastic-hard nodule 2 cm in diameter on the anterior side of her right leg. The nodule had developed an ulcer in its center. Simple resection was performed several times. However, the lesion recurred repeatedly. The patient underwent amputation of the right leg at the age of 34, because the diagnosis of epithelioid sarcoma was established histologically. No recurrence was observed for 9 years. Recently, the patient noticed multiple painful, ulcerative nodules about 1 cm in diameter on her scalp, trunk, and extremities. She refused extensive resection for a religious reason and died of massive hematemesis. Autopsy revealed metastatic epithelioid sarcoma in the skin, lungs, kidneys, pancreas, transverse colon, thyroid, and sternum. Chromosomal analysis of the tumor revealed various aberrations and an N-ras oncogene mutation.

A 43-year-old-woman developed an elastic, hard node (2cm in diameter) on the anterior side of the right leg. The lesion was left untreated, until an ulcer had formed in its center. Simple resection was performed several times. However, the lesion recurred repeatedly. Based on a histopathological diagnosis of epithelioid sarcoma, the woman underwent amputation of the right leg 9 years ago. For 9 years after surgery, no recurrence was observed. The patient recently developed multiple painful ulcerative nodes (about 1cm in diameter) on the head, trunk and extremities. Because the patient refused extensive resection for religious reasons, local OK-432 therapy and high-dose cepharanthin therapy have been performed. Node formation is still continuing. Chromosomal analysis of removed tissue revealed various aberrations and N-ras oncogene rearrangement was detected.

Late recurrence, defined as that occurring 10 or more years after diagnosis, is an unusual event in cutaneous malignant melanoma (MM). A 59-year-old woman presented with a black nodule measuring 10 mm x 9 mm on the sole of her right foot. She was diagnosed with MM and the tumor was totally excised with 5 cm of the normal surrounding skin. Eleven years after the operation, five in-transit metastases were found in her right limb. They were all excised and beta-interferon (IFN-beta) was injected into the skin around the postoperative scars. However, numerous new in-transit skin metastases have been emerging every year in her right limb. Fifty-four in-transit skin metastases have so far been found. Recently, there have been few in-transit metastases. All in-transit metastatic lesions were excised and local IFN-beta injections were conducted continuously. There is no evidence of metastases to the internal organs or lymph nodes. This report describes this case with a brief review of the published work concerning the rare late recurrences of MM.

At the spinal level, nociceptin/orphanin FQ (Noc/OFQ) produces pronociceptive and allodynic effects at low doses (picogram range), while causing antinociceptive effects at high doses (microgram range). The discrepancy of pain modulation by Noc/OFQ at low and high doses raised a question whether Noc/OFQ exerted actions through the same Noc/OFQ receptor. In the present study, we examined the involvement of the Noc/OFQ receptor in pain responses with the novel nonpeptide antagonist N-(4-amino-2-methylquinolin-6-yl)-2-(4-ethylphenoxymethyl) benzamide monohydrochloride (JTC-801). Allodynia and hyperalgesia evoked by intrathecal administration of Noc/OFQ (50 pg/mouse) were dose dependently blocked by simultaneous administration of JTC-801 with IC(50) values of 32.2 and 363 pg, respectively. JTC-801 did not induce allodynia by itself. Subcutaneous injection of formalin into a hindpaw evoked biphasic pain behaviors such as flinching and biting in mice. Noc/OFQ at 10 pg increased the second-phase pain behaviors evoked by 1% formalin, whereas it strongly inhibited both the first-phase and second-phase pain evoked by 2% formalin at 1 microg. Although the pronociceptive effect by 10 pg of Noc/OFQ was dose dependently blocked by JTC-801 with an IC(50) value of 4.58 pg, the antinociceptive effects by 1 microg of Noc/OFQ were not antagonized by JTC-801. Furthermore, both phases of 2% formalin-induced pain behaviors were relieved by JTC-801. These results demonstrate that pronociceptive responses induced by a low dose of Noc/OFQ may be mediated through the Noc/OFQ receptor in the spinal cord and that JTC-801 can be a useful antagonist to examine the involvement of endogenous Noc/OFQ and mediation of the Noc/OFQ receptor under physiological and pathophysiological conditions including pain.

Specific cutaneous lesions appearing during acute monocytic leukemia (AMoL) are more frequent than those associated with other types of leukemia. However, skin involvement preceding the presence of leukemic cells in the peripheral blood is quite rare. In this paper, we describe a case where a 25-year-old male had multiple infiltrative erythemas and nodules on his arms. Histologically, the nodules were formed by masses of tumor cells in the dermis. Peripheral-blood tests revealed no abnormalities, but bone marrow aspiration from the sternum led to a diagnosis of AMoL. The diagnosis of specific cutaneous lesions of AMoL was confirmed by the results of cytochemical studies of bone marrow smears, and cutaneous nodules of cutaneous biopsy specimens led to early diagnosis. Complete remission was achieved with combination chemotherapy and peripheral blood stem cell transplantation.

Microautoradiography at 3, 6 and 15 min after intravenous injection of 125I-EGF was used to investigate the distribution of epidermal growth factor (EGF) binding sites in the pancreas of normal male mice. The autoradiographs were observed by confocal laser microscopy, which allows the quantification of silver grains. The results demonstrated that both endocrine and exocrine pancreatic cells exhibited substantial specific binding of 125I-EGF. The highest level of EGF binding was found in the duct cells of the exocrine pancreas followed by the acinar cells. The cells of the islets of Langerhans also showed substantial specific binding of 125I-EGF though the binding level was lower than that of the exocrine pancreas. In the control experiments, mice were injected with 125I-EGF and various amounts of unlabeled EGF.