Mesh Versus Patch Repair for Epigastric and Umbilical Hernia (MORPHEUS Trial); One-Year Results of a Randomized Controlled Trial.

DESIGN: This trial is a randomized controlled, patient-blinded, multicentre, superiority trial. METHODS: All patients ≥18 years with a single, symptomatic and primary umbilical or epigastric hernia (<2 fingers) qualified for participation in the study. Flat polypropylene mesh repair was compared to patch repair (PROCEED® Ventral Patch) (PVP). The objective of this trial was to identify a superior method for umbilical and epigastric hernia repair in terms of complication rates. RESULTS: A total of 352 patients were randomized in this trial; 348 patients received the intervention (n = 177 PVP vs. n = 171 mesh). No peri-operative complications occurred. PVP placement was significantly faster compared to mesh placement (30 min, SD 11 vs. 35 min, SD 11) and was scored as an easier procedure. At 1-month follow-up, 76 patients suffered any kind of complication. There was no significant difference in the proportion of complications (24.9% for PVP and 18.7% for mesh, p = 0.195). A significant difference was seen in re-operation rate within 1 month, significantly less early re-operations in the mesh group (0.0 vs. 2.8%, p = 0.027). After 1-year follow-up, no significant differences are seen in recurrence rates (n = 13, 7.8% PVP vs. n = 5, 3.3% mesh, p = 0.08). CONCLUSIONS: Both mesh and PVP had a comparable amount of reported complications. There was a significantly higher incidence of early re-operations due to early complications in the PVP group. No differences were seen in infection rates and the need for antibiotic treatment. No significant difference was seen in the recurrence rates. REGISTRATION: This trial was registered in the Dutch Trail Registry (NTR) NTR2514NL33995.060.10. [12].

Quality of life after Nissen fundoplication in patients with gastroesophageal reflux disease: Comparison between long- and short-term follow-up.

INTRODUCTION:: Nissen fundoplication is the golden standard for surgical treatment of gastroesophageal reflux disease (GERD). Numerous studies report excellent short-term results. However, data regarding long-term quality of life are lacking. The aim of this study is to investigate the long-term quality of life after Nissen fundoplication in patients with GERD and to compare this with the short-term results. PATIENTS AND METHODS: We retrospectively analysed all patients who underwent laparoscopic Nissen fundoplication for GERD between January 2004 and January 2016. All patients received a validated GERD-Health-Related Quality of Life questionnaire by mail to assess post-operative quality of life. Maximum quality of life is represented by a score of 75. Secondary outcome measures were complications and recurrence rate. RESULTS:: One hundred and seventy-five (77.1%) of the 227 operated patients returned the questionnaire. The median follow-up was 3.7 (0.1-10.3) years. Mean age was 51.6 (range 15-85) and 72 patients were male. We report an excellent quality of life with a median total score of 70 (range 2-75). Re-operation rate was 13.6% (23/169); the re-operation was due to recurrent reflux in 12 patients and due to persistent dysphagia in 11 patients. 91.3% of the re-operations were performed within the first 5 years after surgery. Mortality rate was zero. CONCLUSION:: We report a large series of single-centre, single-surgeon laparoscopic Nissen fundoplication. Despite the re-operation rate of 13.6%, we found excellent long-term symptomatic outcome. There was no difference between short- and long-term results.

A collective review of biological versus synthetic mesh-reinforced cruroplasty during laparoscopic Nissen fundoplication.

BACKGROUND: Laparoscopic cruroplasty and fundoplication have become the gold standard in the treatment of hiatal hernia and gastro-oesophageal reflux disease (GERD). The use of a mesh-reinforcement of the cruroplasty has been proven effective; although, there is a lack of evidence considering which type of mesh is superior. The aim of this study was to compare recurrence rates after mesh reinforced cruroplasty using biological versus synthetic meshes. METHODS: We performed a systematic review of all clinical trials published between January 2004 and September 2015 describing the application of a mesh in the hiatal hernia repair during Nissen fundoplication for both GERD and hiatal hernia. The primary outcome was the recurrence rate, and secondary outcomes were complication rate, mortality and symptomatic outcome. RESULTS: We included 16 studies and extracted data regarding 1089 mesh operated patients of whom 385 received a biological mesh and 704 a synthetic mesh. The mean follow-up was 53.4 months. The recurrence rate in the synthetic mesh group was 6.8% compared to 16.1% in the biological mesh group (P < 0.05). The complication rate was 5.1% and 4.6% (P = 0.694), respectively, and there were 12 mesh-related complications. No mesh-related mortality was reported. CONCLUSION: Mesh reinforcement of hiatal hernia repair seems safe in the short-term follow-up. The available literature suggests no clear advantage of biological over synthetic meshes. Regarding cost-efficiency and short-term results, the use of synthetic nonabsorbable meshes might be advocated.

Randomized clinical trial of extended versus single-dose perioperative antibiotic prophylaxis for acute calculous cholecystitis.

BACKGROUND: Many patients who have surgery for acute cholecystitis receive postoperative antibiotic prophylaxis, with the intent to reduce infectious complications. There is, however, no evidence that extending antibiotics beyond a single perioperative dose is advantageous. This study aimed to determine the effect of extended antibiotic prophylaxis on infectious complications in patients with mild acute cholecystitis undergoing cholecystectomy. METHODS: For this randomized controlled non-inferiority trial, adult patients with mild acute calculous cholecystitis undergoing cholecystectomy at six major teaching hospitals in the Netherlands, between April 2012 and September 2014, were assessed for eligibility. Patients were randomized to either a single preoperative dose of cefazolin (2000 mg), or antibiotic prophylaxis for 3 days after surgery (intravenous cefuroxime 750 mg plus metronidazole 500 mg, three times daily), in addition to the single dose. The primary endpoint was rate of infectious complications within 30 days after operation. RESULTS: In the intention-to-treat analysis, three of 77 patients (4 per cent) in the extended antibiotic group and three of 73 (4 per cent) in the standard prophylaxis group developed postoperative infectious complications (absolute difference 0·2 (95 per cent c.i. -8·2 to 8·9) per cent). Based on a margin of 5 per cent, non-inferiority of standard prophylaxis compared with extended prophylaxis was not proven. Median length of hospital stay was 3 days in the extended antibiotic group and 1 day in the standard prophylaxis group. CONCLUSION: Standard single-dose antibiotic prophylaxis did not lead to an increase in postoperative infectious complications in patients with mild acute cholecystitis undergoing cholecystectomy. Registration number: NTR3089 (www.trialregister.nl).

Subjective outcome after laparoscopic hiatal hernia repair for intrathoracic stomach.

PURPOSE: For decades, an intrathoracic stomach (ITS) has been a definite indication for surgery due to the perceived risk of an acute volvulus with perforation, gangrene, or hemorrhage. At the present time, elective laparoscopic repair is the first choice for treatment of ITS. There is a lack of evidence in the long-term quality of life after a hiatal hernia repair for an intrathoracic stomach. METHODS: A retrospective analysis was performed on all patients undergoing a hiatal hernia repair for an intrathoracic stomach between January 2004 and January 2015. Additionally, to a hiatal closure, the patients received an antireflux procedure. Outcome measures included patient characteristics, operative details, complications, and postoperative morbidity and mortality. All patients were sent a quality of life questionnaire to assess long-term quality of life and patient satisfaction. A higher quality of life score represents a better quality of life. RESULTS: Eighty-six patients underwent laparoscopic repair for ITS, from which, one patient died during surgery. Eighty-five patients were contacted and 81 completed the questionnaire, resulting in a response rate of 95.3 %. At a median follow-up of 2.7 years (range 0.1-9.6), the mean quality of life score was 13.5 (standard deviation 2.8). The mean overall satisfaction was 8.4. There were four recurrences: three in the first 12 days after surgery and one in 2.4 years. CONCLUSIONS: Very good results in patient satisfaction and symptom reduction were achieved after a median follow-up of 2.7 years in this laparoscopic repair of the intrathoracic stomach single center experience study. The symptomatic recurrence rate was very low.

A common cell-type specific surface antigen in cultured human glial cells and fibroblasts: loss in malignant cells.

Fibroblast surface antigen (SFA) is a high molecular weight protein antigen, first shown on the surface of cultured fibroblasts in fibrillar structures. It is shed to the extracellular medium and also present in the circulation (serum and plasma). Fibroblasts transformed by tumor viruses produce SFA but do not retain it on cell surface. In this report we show that SFA is also present in cultured nonestablished astroglial cells. The glial and fibroblast SFAs are immunologically indistinguishable. Glial cells (three different nonestablished lines) contain more SFA per milligram cellular protein than fibroblasts. SFA was located on cell surface in fibrillar striae that frequently extended out from the cell body. Fluorescence was also found intracellularly in the cytoplasm. Malignant gliomas (astrocytomas) established to grow in culture from human tumor material produced SFA into the growth medium but had very little (lines U-105 MG and U-343 MG) or no detectable (lines U-118 MG, U-251 MG, and U-343 MG-a) cell surface SFA. In cultures of the glioma cells many cells, in particular those that appeared to be in the telophase stage, stained strongly positive for intracellular cytoplasmic SFA. These data demonstrate that similar to fibroblasts transformed experimentally by oncogenic viruses, cells grown from naturally occurring human tumors (glioblastomas) produce SFA but lose ability to retain it on cell surface.

The region ion sensitive field effect transistor, a novel bioelectronic nanosensor.

A novel type of bioelectronic region ion sensitive field effect transistor (RISFET) nanosensor was constructed and demonstrated on two different sensor chips that could measure glucose with good linearity in the range of 0-0.6mM and 0-0.3mM with a limit of detection of 0.1 and 0.04 mM, respectively. The sensor is based on the principle of focusing charged reaction products with an electrical field in a region between the sensing electrodes. For glucose measurements, negatively charged gluconate ions were gathered between the sensing electrodes. The signal current response was measured using a low-noise pico ammeter (pA). Two different sizes of the RISFET sensor chips were constructed using conventional electron beam lithography. The measurements are done in partial volumes mainly restricted by the working distance between the sensing electrodes (790 and 2500 nm, respectively) and the influence of electrical fields that are concentrating the ions. The sensitivity was 28 pA/mM (2500 nm) and 830 pA/mM (790 nm), respectively. That is an increase in field strength by five times between the sensing electrodes increased the sensitivity by 30 times. The volumes expressed in this way are in low or sub femtoliter range. Preliminary studies revealed that with suitable modification and control of parameters such as the electric control signals and the chip electrode dimensions this sensor could also be used as a nanobiosensor by applying single enzyme molecule trapping. Hypotheses are given for impedance factors of the RISFET conducting channel.

Detection of preinvasive cancer of the cervix and the subsequent reduction in invasive cancer.

BACKGROUND: Cytologic screening and follow-up can reduce the incidence of cervical cancer by detection and removal of precursor lesions. It is unknown, however, whether differences in histopathologic criteria for these precursor lesions affect the benefit of screening. These criteria may be difficult to study, but they are likely to be reflected in reported incidence of in situ cancer in small areas of Sweden. PURPOSE: Our purpose was to test the hypothesis that the benefit of screening can be predicted by histopathologic criteria as reflected in the reported incidence of cancer in situ. METHODS: Incidence data were from the Swedish National Cancer Registry. Regression models showing the relationship between in situ and invasive cancer were formulated and estimated. Each county (total, 24) was a unit of measurement, and adjustment was made for the incidence of invasive cancer before screening. RESULTS: During population-based screening in Sweden, the incidence of cancer in situ varied about fourfold among the 24 counties, which indicates that the criteria used to diagnose cancer in situ differed markedly. No statistically significant (P < .05) associations were found between the incidence of cancer in situ in 1965, 1970, or 1975 and the reduction in invasive cancer 5, 10, or 15 years later. According to the best-fitting model, detection of 100 extra cases of cancer in situ per 100,000 women per year in 1975 resulted in a reduction of 1.0 (95% confidence interval [CI] = -1.6-3.7) cases of invasive cancer 10 years later. The corresponding best model estimate implied a reduction of 4.6 cases (95% CI = 1.5-7.7) in a model restricted to cancer in situ in patients aged 20-50 years (when organized screening took place), invasive cancer in patients aged 30-60 years, and cancer in situ measured in 1970. CONCLUSIONS: The absent, or at most weak, association between detection of cancer in situ and subsequent reduction in invasive cancer indicates that relaxed histopathologic criteria for cancer in situ may result in extensive, unnecessary treatment of lesions that would regress spontaneously. IMPLICATION: Further studies are urgently needed to enable identification of neoplasms likely to progress to invasive, fatal disease.

Increasing survival trend after cancer diagnosis in Sweden: 1960-1984.

We analyzed the survival trend after cancer was diagnosed by complete follow-up through 1986 of 591,456 (99.4%) of all those patients in whom a first malignant disease was diagnosed in Sweden from 1960 to 1984. From 1960-1964 to 1980-1984, the 5-year relative survival increased from 34.2% to 47.1% in males and from 48.7% to 56.9% in females. The mean loss of expected life among cancer patients decreased from 9.6 to 7.0 years. During the first 5 years after diagnosis, the cancer-specific hazard rate decreased by 34% in males and 30% in females. Thus several analytical approaches revealed a substantial increase in cancer patient survival since 1960.

Clones of normal keratinocytes and a variety of simultaneously present epidermal neoplastic lesions contain a multitude of p53 gene mutations in a xeroderma pigmentosum patient.

A patient with xeroderma pigmentosum group C was extensively examined for mutations in the p53 gene in normal skin exposed to varying degrees of sunlight and in excisional biopsies of basal cell cancer, squamous cell cancer, and squamous cell dysplasia. Seventy-three samples were analyzed by microdissection of small cell clusters, followed by PCR and direct DNA sequencing. In skin taken from areas that most likely had never been exposed to the sun, no mutations were found. However, in skin exposed to the sun, we observed a multitude of mutations in the p53 gene. UV light-induced mutations were found in all types of lesions, as well as in clusters of morphologically normal epidermal cells. Twenty-nine distinct mutations were found in exons 5-8, all missense or nonsense, of which 27 (93%) were UV-specific C --> T or CC --> TT transitions at dipyrimidine sites of the nontranscribed strand. Two types of normal skin areas containing p53 mutations were observed: areas that stain strongly with p53 antibody (p53 patches) and those that do not stain. Because no silent or intron mutations were found in these cell clusters, the alterations in the p53 gene of morphologically normal cells are likely to have resulted in a selective growth advantage. The poor correlation between mutations and morphological phenotypes demonstrates that p53 mutations alone do not determine the phenotypes observed.

A prospective study showing long-term infection with human papillomavirus 16 before the development of cervical carcinoma in situ.

Human papillomavirus 16 (HPV16) is a predominant cause of cervical neoplasia. However, no population-based study with long-term follow-up has clarified the temporal relationship between HPV16 infection and occurrence of carcinoma in situ, or the importance of recurrent or persistent infection. This nested case-control study was carried out in a population-based cohort of women participating in cytological screening whose initial smear, taken in 1969-1995, was normal. During up to 26 years of follow-up, carcinoma in situ was diagnosed in 484 eligible women. Archival smears from these women were compared with smears from 619 individually matched controls. After DNA extraction, a highly sensitive PCR system was used to detect HPV16. Among case women, the prevalence of HPV16 positivity was 56% at the time of diagnosis. The relative risk of cervical carcinoma in situ increased from 3.6 (95% confidence interval, 1.2-11.0) 13 years before diagnosis to 11.1 (95% confidence interval, 5.5-22.2) 1 year before diagnosis. Having a positive smear at entry to the cohort increased risk >5-fold, whereas having persistent infection with HPV in two subsequent smears increased risk 30-fold. We estimated that among HPV16-positive women, the median incubation period from infection to carcinoma in situ was 7-12 years. We conclude that evidence of persistent and/or recurrent infection is associated with a drastically higher risk of cervical carcinoma in situ than occasional infection with HPV16.

An umbilical surprise: a collective review on umbilical pilonidal sinus : An uncommon alternative diagnosis in common umbilical symptoms.

PURPOSE: Umbilical pilonidal sinus (UPS) has an atypical clinical presentation and is therefore not well recognized. The aim of this case series and review of the literature, is to provide more insight in the underlying pathology and a guidance for the treatment of this condition. METHODS: Three recent clinical cases are described that made us perform a multi-database research was to reveal relevant literature. RESULTS: Three relevant clinical cases from our clinic are described. Thirth three studies, describing 463 patients were included. Most studies were case reports or series; few were case series or cohort studies. UPS develops by loose hairs getting caught in the umbilical pit and subsequently penetrate the umbilical cicatrix by friction. In this way an inflammatory response is triggered, resulting in oedema that further narrows the umbilical orifice, hence forming a sinus. Several risk factors are identified. There is no particular consensus on the treatment of this disease. Although older literature advocates immediate umbilical excision without exception, recent studies provide evidence that supports multiple courses of conservative treatment. Several cases were described in which surgery consisted of excision of the sinus and hair tufts in contrast to excision of the entire umbilicus. CONCLUSIONS: Umbilical pilonidal disease has an atypical presentation and might mimic conditions such as incarcerated hernia, Anterior Cutaneous Nerve Entrapment Syndrome or urachal cyst. Risk factors that can bring physicians closer to a reliable diagnosis are identified. An example of a treatment algorithm is provided, suggesting surgery should only be considered when conservative treatment fails.

Molecular pathology in basal cell cancer with p53 as a genetic marker.

Human basal cell cancer (BCC) has unique growth characteristics with virtual inability to metastasize. We investigated clonality and genetic progression using p53 mutations as marker. Sampling was done through microdissection of frozen immunohistochemically stained 16 microm slices of tumors. From 11 BCC tumors 78 samples were analysed. Direct DNA sequencing of exons 5-8 was performed, haplotypes were determined after cloning of p53 exons and loss of heterozygosity (LOH) ascertained by microsatellite analysis. All tumors had p53 mutations and in a majority both p53 alleles were affected, commonly through missense mutations. Microdissection of small parts (50-100 cells) of individual tumors showed BCC to be composed of a dominant cell clone and prone to genetic progression with appearance of subclones with a second and even third p53 mutation. Samples from normal immunohistochemically negative epidermis always showed wild type sequence, except for a case of previously unknown germline p53 mutation. Our analysis also included p53 immunoreactive patches i.e. morphologically normal epidermis with a compact pattern of p53 immunoreactivity. Mutations within those were never the same as in the adjacent BCC. This detailed study of only one gene thus uncovered a remarkable heterogeneity within a tumor category famous for its benign clinical behavior.

Genetic instability in the 9q22.3 region is a late event in the development of squamous cell carcinoma.

Squamous cell carcinoma (SCC) of the skin represents a group of neoplasms which is associated with exposure to UV light. Recently, we obtained data suggesting that invasive skin cancer and its precursors derive from one original neoplastic clone. Here, the analysis were extended by loss of heterozygosity (LOH) analysis in the chromosome 9q22.3 region. A total of 85 samples, taken from twenty-two sections of sun-exposed sites, corresponding to normal epidermis, morphological normal cells with positive immuno-staining for the p53 protein (p53 patches), dysplasias, cancer in situ (CIS) and squamous cell carcinomas (SCC) of the skin were analysed. Overall, about 70% of p53 patches had mutations in the p53 gene but not LOH in the p53 gene or 9q22.3 region. Approximately 70% of the dysplasias showed p53 mutations of which about 40% had LOH in the p53 region but not in the 9q22.3 region. In contrast, about 65% of SCC and CIS displayed LOH in the 9q22.3 region, as well as frequent (80%) mutations and/or LOH in the p53 gene. These findings strongly suggest that alterations in the p53 gene is an early event in the progression towards SCC, whereas malignant development involves LOH and alterations in at least one (or several) tumor suppressor genes located in chromosome 9q22.3.

Human epidermal cancer and accompanying precursors have identical p53 mutations different from p53 mutations in adjacent areas of clonally expanded non-neoplastic keratinocytes.

Microdissection of biopsies with sequencing of exons 4-8 of the p53 gene permitted precise morphological identification of correlation between mutations and/or loss of heterozygosity, immunoreactivty of p53 and type of squamous neoplasia. Seventy-two specimens from ten lesions of sun-exposed sites including normal epidermis were analysed. Irrespective of p53 immunoreactivity and morphological grade dysplasia, in situ or invasive cancer, in each case, carried the identical mutation indicating that invasive skin cancer and its precursors derive from the same original neoplastic clone. Additionally, morphologically normal epidermis showed some sharply demarcated immunoreactive areas. These never had the same p53 mutation as that of the adjacent tumor, indicating that their mutations were separate events and ruling them out as common precursors of cancer. Non-immunoreactive normal epidermis did not show p53 mutations. Our findings indicate that a large fraction of keratinocytes in sun-exposed human skin carry mutations of p53 and suggest that at least two options exist for such cells (i) innocuous clonal expansion with preserved morphology and normal differentiation or (ii) malignant transformation with the p53 mutation as an early event. Suggestive evidence existed that the p53 mutations were qualitatively different in the two respective groups of lesions.

Improved control of invasive cervical cancer in Sweden over six decades by earlier clinical detection and better treatment.

PURPOSE: Cancer of the cervix uteri can be controlled by cytologic screening for the detection of precursor lesions, but such intervention remains unrealistic in many countries in which this cancer is common. The possibility of reducing mortality by earlier clinical detection, followed by basic therapy, has never been properly assessed. PATIENTS AND METHODS: We compiled records of incident cases of invasive cancer of the cervix diagnosed in a defined area of Sweden from 1930 through 1990. In a cohort of 6,044 women, we analyzed temporal trends in incidence and survival by clinical stage and age at diagnosis. Generalized proportional hazards models were used to study several factors simultaneously and quantify the overall reduction in mortality. RESULTS: For each successive stage at diagnosis, the overall risk of dying increased 2.5-fold (95% confidence interval [CI], 2.4 to 2.7). From 1930, a marked improvement in stage distribution was accompanied by increasing survival rates in stages I and II disease. These changes largely took place before the introduction of screening and external-beam radiation. The 10-year relative survival rate increased from 33% in the 1930s to approximately 55% in the 1950s and thereafter. CONCLUSION: Improvements in public and professional awareness of cervical cancer resulted in diagnoses at earlier clinical stages. The rate of cure in early stages improved when basic local treatment was introduced, but only little of the progress was attributable to the introduction of more advanced treatment technologies. These findings offer considerable hope for a substantial reduction in the mortality of cervical cancer without cytologic screening, even in countries with limited resources.

A consecutive series of 235 epigastric hernias.

BACKGROUND: Epigastric herniation is a common, though not always symptomatic condition. It is likely, that in accordance to the tension-free principles for other hernias, epigastric hernia repair should be mesh based. METHODS: Patients from two large hospitals were investigated retrospectively if they were operated on an epigastric hernia for the past 6 years. Follow-up was completed with a postal questionnaire. RESULTS: A total of 235 patients (50 % male) were operated. Sixty-eight patients were operated with mesh and 167 patients with suture repair. Forty-six patients were loss-to follow-up (19.6 %). In the mesh operated patients the recurrence rate was 10.9 % (n = 6) compared to 14.9 % (n = 20) in the suture repair group. Cox-regression analysis showed an increased risk for recurrence in the suture repair group (odds ratio 1.43; 95 % CI 0.56-3.57; p = 0.44). Operation time for mesh repair (47 min) was significantly longer compared to suture repair (29 min) (p < 0.0001). Thirty-seven patients had previous or other anterior wall hernias. A total of 51 patients smoked and 14 patients had diabetes mellitus. Fourteen patients used steroids and 22 patients suffered from a chronic lung disease. Subgroup analysis showed a significant difference for pain in patients in which re-operation for a recurrence occurred (p = 0.004). CONCLUSIONS: This is one of the largest reported series on solely epigastric hernias. A recurrence occurred more often after sutured repair compared to mesh repair. No differences in chronic pain was seen between mesh and suture repaired patients. Male:female ratio of 1:1, which is different from the 3:1 ratio found in previous older smaller studies, could be more reliable.

Epithelial-stromal interactions in basal cell cancer: the PDGF system.

A proposed progenitor cell for basal cell carcinoma is a stem cell located in the bulge of the hair follicle. Previous investigations have shown that basal cell carcinoma has a specific stroma requirement for its growth. Likewise the development of a normal hair follicle requires the inductive force of a specialized structure with condensed mesenchyme that eventually forms the dermal hair papilla. Investigations in mouse embryos also strongly indicate that induction/growth of skin structures is dependent on platelet-derived growth factor (PDGF) alpha-receptor expression in the mesenchyme. We therefore investigated the expression of PDGF A and B chain and PDGF alpha and beta receptors in basal cell carcinoma and in normal skin by immunohistochemistry and in situ hybridization. alpha and beta receptors were found in the specific stroma components of basal cell carcinoma, dermal hair papilla, and sweat glands, but not in the epithelial structures. The A and B chains, on the other hand, were mainly found in basal cell carcinoma cells, in hair matrix, and in sweat gland epithelium. This "appositional" expression of PDGF/PDGF receptor closely resembles that found in epithelial/mesenchymal structures during normal development. The findings also suggest that PDGF receptor expression is one of the characteristics of the specific stroma that is necessary for basal cell carcinoma growth.

Ultraviolet light induces expression of p53 and p21 in human skin: effect of sunscreen and constitutive p21 expression in skin appendages.

It has been suggested that p53 plays an important role in skin carcinogenesis. The p21 molecule acts as a downstream effector of wild-type p53 by enacting cell cycle arrest. We studied p53 and p21 expression in sun-exposed skin. Healthy volunteers were exposed to ultraviolet irradiation (UVA + UVB) in normal, previously non-sun-exposed skin, and skin biopsies were taken. Immunohistochemically detectable p53 and p21 were quantified, and the pattern of distribution was recorded. p53 was induced in epidermal cells 4 h after irradiation and returned to nearly normal levels after 120 h. Suprabasal cells showed a peak at 4 h, whereas basal cells peaked later, at 48 h. In epidermis, the expression of p21 was induced with a pattern that mirrored that of p53. In addition, p21 was induced in mesenchymal cells of the upper dermis, where there was no p53, suggesting an alternative pathway for p21 induction. Topical sunscreen and pigmentation (skin type 5) nearly eliminated UV-induced expression of p53 and p21. In contrast to the complete absence of p53 in skin never exposed to UV radiation, p21 reactivity was found in sharply demarcated areas of anagen hair follicles and sebaceous glands, as well as in scattered epidermal cells. The prevalence and distribution suggest a physiologic role of p21 in stopping the cell cycle in terminally differentiating skin epithelium. Archival skin material from the vicinity of skin lesions with variable sun exposure were also stained for p53. There was an increased "disperse" reactive staining pattern in skin samples excised in the summer as compared with less sunny seasons. Intensely stained p53 foci were detected as "compact bands" in morphologically normal epidermis, predominantly in sun-exposed areas of the skin, suggesting the existence of clonal proliferation of p53 mutated keratinocytes. These data show that p53 and p21 play a role in the human skin response to UV exposure and that p21 is implicated in the homeostasis of differentiating skin appendages.

Heterogeneity of Genotypic and phenotypic characteristics of fifteen permanent cell lines derived from human gliomas.

Six new permanent cell lines were established from human gliomas and compared to nine other cell lines from human gliomas. All fifteen lines had individually distinct HLA phenotypes and all but two, which were from a black patient, had type B glucose-6-phosphate-de;hydrogenase isoenzymes. Morphologically, the lines could be classified into four patterns descriptively designated as fibroblastic, fascicular, epithelial, or glial. Four of the lines grew progressively and could be serially transplanted when injected into athymic mice; two others grew initially and then regressed. From none to 100% of cells developed elongated tapering processes and showed reduction in nuclear-cytoplasmic ratio in the presence of 1 mM cyclic AMP and theophylline. Levels of 2'-3' cyclic nucleotide 3'-phosphohydrolase activity ranged from nondetectable to 12.78 +/- 1.49 micromoles 2' AMP formed per hr mgm total protein. None of the lines had detectable S-100 protein, but two had readily demonstrable glial fibrillary acidic protein in indirect immunofluorescence. Fibronectin levels in spent culture supernatants ranged from undetectable levels to 21.4 micrograms/ml/10(5) cells. All but one line shared surface antigens with normal human adult or fetal brain, as detected in absorption analyses with nonhuman primate antiserum raised against glioblastoma multiforme tissue or cell line U-251 MG. Although there were many common properties of the lines, each line had a unique profile of the parameters evaluated. This heterogeneity most likely reflects the individuality of the tumors of origin and individual genotypes and capacity for a range of phenotypic expression of cells.