Hexyl aminolevulinate, 5-aminolevulinic acid nanoemulsion and methyl aminolevulinate in photodynamic therapy of non-aggressive basal cell carcinomas: A non-sponsored, randomized, prospective and double-blinded trial.

BACKGROUND: In the photodynamic therapy (PDT) of non-aggressive basal cell carcinomas (BCCs), 5-aminolevulinic acid nanoemulsion (BF-200ALA) has shown non-inferior efficacy when compared with methyl aminolevulinate (MAL), a widely used photosensitizer. Hexyl aminolevulinate (HAL) is an interesting alternative photosensitizer. To our knowledge, this is the first study using HAL-PDT in the treatment of BCCs. OBJECTIVES: To compare the histological clearance, tolerability (pain and post-treatment reaction) and cosmetic outcome of MAL, BF-200 ALA and low-concentration HAL in the PDT of non-aggressive BCCs. METHODS: Ninety-eight histologically verified non-aggressive BCCs met the inclusion criteria, and 54 patients with 95 lesions completed the study. The lesions were randomized to receive LED-PDT in two repeated treatments with MAL, BF-200 ALA or HAL. Efficacy was assessed both clinically and confirmed histologically at three months by blinded observers. Furthermore, cosmetic outcome, pain, post-treatment reactions fluorescence and photobleaching were evaluated. RESULTS: According to intention-to-treat analyses, the histologically confirmed lesion clearance was 93.8% (95% confidence interval [CI] = 79.9-98.3) for MAL, 90.9% (95% CI = 76.4-96.9) for BF-200 ALA and 87.9% (95% CI = 72.7-95.2) for HAL, with no differences between the arms (P = 0.84). There were no differences between the arms as regards pain, post-treatment reactions or cosmetic outcome. CONCLUSIONS: Photodynamic therapy with low-concentration HAL and BF-200 ALA has a similar efficacy, tolerability and cosmetic outcome compared to MAL. HAL is an interesting new option in dermatological PDT, since good efficacy is achieved with a low concentration.

Ablative fractional laser-assisted photodynamic therapy for lentigo maligna: a prospective pilot study.

BACKGROUND: Lentigo maligna (LM) is an in situ form of melanoma carrying a risk of progression to invasive lentigo maligna melanoma (LMM). LM poses a clinical challenge, with subclinical extension and high recurrence rates after incomplete surgery. Alternative treatment methods have been investigated with varying results. Photodynamic therapy (PDT) with methylaminolaevulinate (MAL) has already proved promising in this respect. OBJECTIVES: To investigate the efficacy of ablative fractional laser (AFL)-assisted PDT with 5-aminolaevulinic acid nanoemulsion (BF-200 ALA) for treating LM. METHODS: In this non-sponsored prospective pilot study, ten histologically verified LMs were treated with AFL-assisted PDT three times at 2-week intervals using a light dose of 90 J/cm2 per treatment session. Local anaesthesia with ropivacaine was used. Four weeks after the last PDT treatment the lesions were treated surgically with a wide excision and sent for histopathological examination. The primary outcome was complete histopathological clearance of the LM from the surgical specimen. Patient-reported pain during illumination and the severity of the skin reaction after the PDT treatments were monitored as secondary outcomes. RESULTS: The complete histopathological clearance rate was 7 out of 10 LMs (70%). The pain during illumination was tolerable, with the mean pain scores for the PDT sessions on a visual assessment scale ranging from 2.9 to 3.8. Some severe skin reactions occurred during the treatment period, however. CONCLUSIONS: Ablative fractional laser-assisted PDT showed moderate efficacy in terms of histological clearance. It could constitute an alternative treatment for LM but due to the side effects it should only be considered in inoperable cases.

5-aminolaevulinic acid nanoemulsion is more effective than methyl-5-aminolaevulinate in daylight photodynamic therapy for actinic keratosis: a nonsponsored randomized double-blind multicentre trial.

BACKGROUND: Daylight photodynamic therapy (DL-PDT) with methyl-5-aminolaevulinate (MAL) is an effective treatment for mild and moderate actinic keratosis (AK). OBJECTIVES: To assess the clinical efficacy, tolerability and cost-effectiveness of 5-aminolaevulinic acid nanoemulsion (BF-200 ALA) compared with MAL in DL-PDT for grade I-II AKs. METHODS: This nonsponsored, prospective randomized double-blind multicentre trial included 69 patients with 767 grade I-II AKs located symmetrically on the face or scalp. A single DL-PDT was given in a randomized split-face design. The primary outcome was clearance of the AKs at 12 months as assessed by a blinded observer. The secondary outcomes were pain, treatment reactions, cosmetic outcome and the cost-effectiveness of the therapy. RESULTS: In the per-patient (half-face) analysis, clearance was better for the BF-200 ALA sides than for those treated with MAL (P = 0·008). In total, BF-200 ALA cleared 299/375 AKs (79·7%) and MAL 288/392 (73·5%) (P = 0·041). The treatment was practically painless with both photosensitizers, the mean pain visual analogue scale being 1·51 for BF-200 ALA and 1·35 for MAL (P = 0·061). Twenty-six patients had a stronger skin reaction on the BF-200 ALA side, seven on the MAL side and 23 displayed no difference (P = 0·001). The cosmetic outcome was excellent or good in > 90% of cases with both photosensitizers (P = 1·000). The cost-effectiveness plane showed that the costs of DL-PDT were similar for both photosensitizers, but the effectiveness was slightly higher for BF-200 ALA. CONCLUSIONS: Our results indicate that BF-200 ALA is more effective than MAL in DL-PDT for grade I-II AKs. BF-200 ALA provides slightly better value for money than MAL.

Hyperspectral imaging system in the delineation of Ill-defined basal cell carcinomas: a pilot study.

BACKGROUND: Basal cell carcinoma (BCC) is the most common skin cancer in the Caucasian population. Eighty per cent of BCCs are located on the head and neck area. Clinically ill-defined BCCs often represent histologically aggressive subtypes, and they can have subtle subclinical extensions leading to recurrence and the need for re-excisions. OBJECTIVES: The aim of this pilot study was to test the feasibility of a hyperspectral imaging system (HIS) in vivo in delineating the preoperatively lateral margins of ill-defined BCCs on the head and neck area. METHODS: Ill-defined BCCs were assessed clinically with a dermatoscope, photographed and imaged with HIS. This was followed by surgical procedures where the BCCs were excised at the clinical border and the marginal strip separately. HIS, with a 12-cm2 field of view and fast data processing, records a hyperspectral graph for every pixel in the imaged area, thus creating a data cube. With automated computational modelling, the spectral data are converted into localization maps showing the tumour borders. Interpretation of these maps was compared to the histologically verified tumour borders. RESULTS: Sixteen BCCs were included. Of these cases, 10 of 16 were the aggressive subtype of BCC and 6 of 16 were nodular, superficial or a mixed type. HIS delineated the lesions more accurately in 12 of 16 of the BCCs compared to the clinical evaluation (4 of 16 wider and 8 of 16 smaller by HIS). In 2 of 16 cases, the HIS-delineated lesion was wider without histopathological confirmation. In 2 of 16 cases, HIS did not detect the histopathologically confirmed subclinical extension. CONCLUSIONS: HIS has the potential to be an easy and fast aid in the preoperative delineation of ill-defined BCCs, but further adjustment and larger studies are warranted for an optimal outcome.

Daylight photodynamic therapy for actinic keratoses: a randomized double-blinded nonsponsored prospective study comparing 5-aminolaevulinic acid nanoemulsion (BF-200) with methyl-5-aminolaevulinate.

BACKGROUND: Daylight-mediated photodynamic therapy (DL-PDT) using methyl-5-aminolaevulinate (MAL) is effective for thin, grade I, actinic keratoses (AK). There are no published studies of other photosensitizers used in DL-PDT. OBJECTIVES: To compare the efficacy and adverse effects of 5-aminolaevulinic acid nanoemulsion (BF-200 ALA) with MAL in DL-PDT of grade I-III AKs. METHODS: In 13 patients, 177 AKs were randomized symmetrically for a split-face prospective observer-blinded study and received either BF-200 ALA or MAL DL-PDT. Grade I AKs were treated once and grade II-III AKs twice with a 0·25-mm layer of photosensitizer precursors. Pain was assessed during and after the daylight exposure. Efficacy at 3 months was assessed clinically and histologically. RESULTS: BF-200 ALA cleared 71/84 (84·5%) and MAL 69/93 (74·2%) of the AKs (P = 0·099), all grades responding equally, but with new AKs appearing during follow-up (n = 4, BF-200 ALA; n = 8, MAL). In per patient half-face analysis BF-200 ALA showed significantly higher clearance rates for grade I AKs than did MAL (P = 0·027), but for thicker grades, clearance was equal (P = 0·564). BF-200 ALA and MAL treatments resulted in 61·5% and 38·5% complete histological clearance (P = 0·375), respectively. p53 expression decreased by 54·4% and 33·7%, respectively (P = 0·552). Both treatments were nearly painless with similar adverse reactions and no difference in patient preference. CONCLUSIONS: BF-200 ALA showed a trend towards improved efficacy results compared with MAL. Thicker lesions in both groups responded when treated repeatedly. Importantly, a thin 0·25-mm layer of the photosensitizer precursors was sufficient, which may lead to lower expense.

Long-term renal function following bone marrow transplantation.

Renal function, evaluated as glomerular filtration rate (GFR) and effective renal plasma flow (ERPF), was investigated in 187 pediatric patients who underwent allogeneic (n=169) or autologous bone marrow transplantation (BMT). Allogeneic BMT patients were divided into three groups: hematological malignancies, aplastic anemia and non-malignant diseases, whereas autologous patients constituted a fourth group. A total of 64% received total body irradiation (TBI) as conditioning therapy, and 50 healthy children served as controls. GFR and ERPF were normal before transplantation. After 1 year, both GFR and ERPF were significantly reduced. GFR had recovered slightly after 3 years and remained stable thereafter. Recovery in ERPF was not apparent. Renal impairment was found in 41% of patients at 1 year, in 31% at 3 years and in 11% 7 years after BMT. Patients with hematological malignancies had lower GFRs than patients with non-malignant diseases at all time points. The most important risk factor as regards chronic renal impairment was TBI. Type of donor, cyclophosphamide (CY), or acute graft-versus-host disease (GVHD) did not seem to contribute to the development of chronic renal impairment. We suggest that tests of renal function should be included in long-term followup after BMT.

Clinicopathological characteristics and cell cycle proteins as potential prognostic factors in myoepithelial carcinoma of salivary glands.

Myoepithelial carcinoma (MCA) is a rare malignancy of salivary glands that was included in the WHO Classification of Head and Neck Tumors in 1991. MCA has shown a broad spectrum of clinical outcomes, but attempts to identify prognostic markers for this malignancy have not resulted in significant progress. Conventional histopathological characteristics such as tumour grade, nuclear atypia, mitotic index and cell proliferation have failed to predict the outcome of MCA. In this study, we reviewed the histopathology of 19 cases of MCA focusing on nuclear atypia, mitotic count, tumour necrosis, nerve and vascular invasion and occurrence of a pre-existing pleomorphic adenoma in connection to the MCA. Histopathological characteristics and clinical information were correlated with the immunohistochemical expression of cell cycle proteins including c-Myc, p21, Cdk4 and Cyclin D3. The proportion of tumour cells immunoreactive for these markers and their intensity of staining were correlated with clinical information using logistic regression, Kaplan-Meier and Cox regression. Using logistic regression analysis, cytoplasmic c-Myc expression was associated with the occurrence of metastases (P = 0.019), but limitations of semi-quantitation of immunostaining and the limited number of cases preclude definitive conclusions. Our data show that the occurrence of tumour necrosis predicts poor disease-free survival in MCA (P = 0.035).

Sex steroid, gonadotropin, cortisol, and prolactin levels in healthy, massively obese women: correlation with abdominal fat cell size and effect of weight reduction.

To examine hormonal status in obese, gynecologically normal women we studied 25 regularly menstruating, massively obese (mean weight, 120 kg) women participating in a weight reduction program and 25 age-matched normal weight (mean weight, 60 kg) women. Serum 17 beta-estradiol (E2), estrone (E1), androstenedione (A), dehydroepiandrosterone sulfate, testosterone, LH, FSH, PRL, and cortisol concentrations were measured during the follicular phase of the menstrual cycle. Waist to hip ratio and abdominal fat cell size were measured at the beginning of the study. The serum levels of E2 (P less than 0.04) as well as those of A, SHBG, and LH (P less than 0.002) were lower in the obese group. Consequently, the testosterone to SHBG ratio and the E1 to A ratio were higher and the LH to FSH ratio was lower in this group. Waist to hip ratio did not correlate with the levels of circulating hormones or SHBG, but an inverse correlation was found between abdominal fat cell size and A as well as the LH to FSH ratio in the nonhirsute women of the obese group. Subsequent to moderate weight reduction (13.2 kg), serum A and E1 levels (P less than 0.01) increased, and serum cortisol levels decreased (P less than 0.001). Thus, massive obesity is associated with abnormalities in hormonal balance in gynecologically symptomless women, there being an association between E1, E2, A, LH, cortisol, and relative weight and/or abdominal fat cell size.

Effect of high dose progestin on serum lipids.

The effect of high dose medroxyprogesterone (MPA) on serum lipids was studied in 31 postmenopausal patients with endometrial cancer. After 3 months of MPA treatment, total cholesterol decreased by 18% (P less than 0.001), LDL cholesterol by 16% (P less than 0.01) and HDL cholesterol by 38% (P less than 0.001) from the respective pretreatment values; correspondingly, the ratio of HDL to total cholesterol decreased (P less than 0.001). Similar changes were found as early as 2 weeks after start of treatment. In the 15 controls receiving no progestin treatment, full dose intracavitary radiotherapy and gynecological surgery had no effect on these serum lipids.

Growth of human aortic smooth muscle cells cultured with human serum is retarded when serum lipids are lowered by medroxyprogesterone.

Human aortic smooth muscle cells were cultured in the presence of sera from 7 normolipidemic women before and after treatment with high-dose medroxyprogesterone acetate, which caused 16% and 25% decreases in serum cholesterol and HDL-cholesterol concentrations, respectively. As assessed by cell counting and by DNA determination the growth of the cells was retarded significantly in the presence of sera taken after the treatment. At the same time, there were no marked changes in the incorporation rate of [3H]proline into collagen or [3H]glucosamine into hyaluronic acid by the cells. The results indicate that: (1) the mitogenicity of human serum can be altered by drug treatment of serum donors, (2) simultaneously with a lowering of serum lipids in man in vivo, a decreased mitogenicity of sera occurs in vitro.

Endometrioid carcinoma of the ovary. A clinicopathologic, histochemical, and electron microscopic study.

A material consisting of 23 endometrioid ovarian carcinomas, including 2 rare endometrioid tumors with argyrophil cells, was analyzed clinically and with the use of various histochemical staining methods. Electron microscopy was performed in 3 cases. Apical neutral mucin mixed with sulfate and carboxyl groups was typical for the cells at the light microscopic level, and a prominent Golgi complex with many small secretory vesicles was commonly seen at the ultrastructural level. The nuclei had concentric nuclear bodies and nucleoli with mesh-basket appearance. There was a positive correlation between the grade of differentiation and clinical stage. The corrected 5-year survival rate was 80% in stage I, 50% in stage II, 17% in stage III, and 0% in stage IV; the overall 5-year survival rate was 46%. Signs of increased endometrial estrogen activity were found in 6 of the 12 postmenopausal patients. In the whole series, 6 endometrial carcinomas were found simultaneously with the ovarian carcinoma.

Response of ovarian cancer to combined cytotoxic agents in the subrenal capsule assay: Part I.

The subrenal capsule assay in normal immunocompetent mice was used to test the responsiveness of ovarian cancer to combination chemotherapy. Of the assays, 42 were of untreated tumors and 19 of previously treated tumors. Fifty-nine (97%) of the assays were evaluable. The previously treated tumors were less sensitive than the untreated ones. Of the treated tumors 44% were sensitive, 33% intermediately sensitive, and 22% resistant versus 56, 44, and 0%, respectively, of the untreated tumors (P less than .01). Repeat assays for the tumors of seven patients were performed successfully after five to eight courses of therapy with the combination of doxorubicin, cyclophosphamide, and cisplatin. The responsiveness to this combination had weakened significantly (P less than .01); the response of only one tumor remained unchanged. The rates of resistance to the drug combinations doxorubicin-cyclophosphamide-cisplatin, doxorubicin-cyclophosphamide-tegafur, and cyclophosphamide-vincristine were 11, 10, and 21%, respectively; there was, however, considerable interindividual variation in tumor responses to these combinations. Of other combinations, hexamethylmelamine combined with 4-epidoxorubicin, aclarubicin, or chlorambucil and cisplatin had effect, whereas the combinations of cisplatin and etoposide and of tegafur and methotrexate or mitomycin were quite ineffective, as measured by the assay. The reliability of the subrenal capsule assay in normal immunocompetent mice is discussed, and it is concluded that the assay can be used to assess the response of ovarian cancer to chemotherapy, including multidrug therapy, without routine histologic control.

Proliferating glia and other heterotopic tissues in the uterus: fetal homografts?

The authors describe clinically and histologically the cases of 5 patients with glial tissue in the uterus and discuss the explanation for this rare phenomenon. The glial tissue was generally manifested as an endocervical polyp, and in one case as a large polypoid tumor on the ectocervix. Histologically, apart from glial tissue, one patient had islands of cartilage, bone, and keratinizing squamous epithelium both in the cervix and in the endomyometrial layers. Only a few investigators have found cartilage and bone in addition to glial tissue, and the authors know of no other case in which epidermal tissue has been found. The authors believe that the theory postulating the fetal origin for these foreign tissues in the uterus is the most plausible one. The specific immunologic as well as cytologic and cytogenetic factors remain to be defined.

Clinical outcome in endometrial cancer.

Patients with endometrial carcinoma (N = 1113) were treated by conventional therapy, using surgery and radiotherapy, complemented by daily administration of 100 mg oral medroxyprogesterone acetate (MPA) for a 2-year period. Only 7.3% of the malignancies were at an advanced clinical stage (III or IV), whereas 75.9 and 16.8% of the carcinomas were detected at clinical stages I and II, respectively. The 5-year survival rate was 71.0% overall, and 77.8%, 61.0, 29.0, and 5.3 for clinical stages I, II, III, and IV, respectively. Patients with anaplastic carcinoma (grade 3) at all clinical stages had significantly lower survival rates than had patients with well-differentiated (grade 1) and moderately differentiated (grade 2) adenocarcinomas. Death of grade 1, grade 2 and grade 3 endometrial carcinoma during the first 2 years occurred in 4.7, 6.8, and 18.2% of cases, respectively, in stage II, indicating that adjuvant MPA cannot totally prevent the progression of endometrial malignancy. The incidence of anaplastic endometrial carcinoma increased with the spread of the disease. It often appeared in patients with low body weight or a second invasive malignancy, but seldom occurred in young patients or patients with diabetes, uterine myoma, or a history of previous estrogen use. The worsened prognosis associated with old age, low body weight, and presence of a second invasive malignancy thus seems at lest partly due to the increased incidence of anaplastic carcinoma, which, on the other hand, did not contribute to the decreased 5-year survival rate of patients with diabetes or severe hypertension.

Mesonephroid carcinoma of the ovary. A clinicopathologic, histochemical, and electron microscopic study.

Eighteen patients with mesonephroid ovarian carcinoma were investigated. Typical findings for the mesonephroid tumors were abundant extracellular an some intracellular neutral mucin mixed with sulfate and carboxyl groups, and large amounts of glycogen, especially in clear cells. The latter observation is considered to be an important aid in distinguishing them from other epithelial ovarian carcinomas. Some cells contained intracellular cysts that were covered with stubby microvilli similar to those found on the lumenal surfaces of the larger cysts in the tumors. Simultaneous estrogenic endometrial activity in the post-menopausal patients was frequently observed. The significance of this observation is discussed.

Iron deficiency in women using modern copper intrauterine devices.

To evaluate the risk of iron deficiency and anemia connected with the use of modern copper intrauterine devices, serum ferritin, transferrin, iron, hemoglobin and hematocrit levels, red cell counts, and morphology, as well as red cell indexes were determined in 40 women and in 19 controls. Follow-up was for one year. Mean hemoglobin, hematocrit, serum iron, and serum ferritin levels decreased and serum transferrin levels increased significantly in the study population. About 20% of intrauterine device users but none of the controls showed signs of iron deficiency, and 10% had clinical anemia at 12 months of use. No differences were found between the three different copper intrauterine devices tested (Nova T, Multiload and Fincoid). Because the risk of anemia did not correlate with subjective evaluation of the amount of bleeding, it is recommended that hemoglobin levels should be determined for all intrauterine device users before its insertion and at six and 12 months of use. In those with decreased hemoglobin levels, serum ferritin should be measured and iron replacement instituted or the device removed.

Management of low birth weight breech delivery: should cesarean section be routine?

A total of 434 low birth weight deliveries between 1967 and 1976 were studied retrospectively. Of these, 217 were breech deliveries, and the other 217 constituted a control series of vertex deliveries. In the breech deliveries the perinatal mortality was 1.8 times that of the cephalic cases, and the neonatal mortality was 2.9 times greater. During the last 5 years of the study, the cesarean section rate increased for the group of infants weighing between 1500 and 2499 g; this policy did not improve the prognosis in breech presentations. Malformations and respiratory distress syndrome were more frequent in breech presentations. Conditions associated with the corrected perinatal mortality (cerebral hemorrhage, fetal asphyxia, prolapsed cord) were also more common in breech presentations, but especially in the group of infants weighing less than 1500 g. This weight group, for which the cesarean section rate did not rise, emerged in the study as a special area of concern. Conclusions and recommendations for management are presented.

A new triphenylethylene compound, Fc-1157a. II. Antitumor effects.

The antitumor effects of a new antiestrogen, Fc-1157a have been studied in vitro and in vivo. In vitro the effect of Fc-1157a was comparable to that of tamoxifen. The effect was dose-dependent, and at concentrations higher than 10(-6) mol/1 Fc-1157a induced real cell death of the MCF-7 cells. In DMBA-induced mammary cancer in rats Fc-1157a decreased the number of new tumors and inhibited the growth of existing tumors, these effects being statistically highly significant. The ratio of growing tumors to stable and regressing tumors was significantly decreased. Although these effects were slightly stronger with Fc-1157a than with tamoxifen, the difference between these two compounds was not statistically significant. Murine uterine sarcoma, an estrogen receptor-negative tumor, was resistant to tamoxifen, but was statistically significantly inhibited by high doses (100 and 200 mg/kg-1 day-1 for 5 days) of Fc-1157a. The antitumor effects of Fc-1157a are due mainly to the antiestrogenic activity. At high concentrations in vitro and at high doses in vivo Fc-1157a exerts antitumor effects some of which are different from those of tamoxifen and are directed even against estrogen receptor-negative tumors. The exact mechanism of the observed cytolytic effect at high doses is unknown.